Conditions: Gastrointestinal Stromal Tumors
Keywords: Gastrointestinal Stromal Tumors,GIST,DCC-2618,Ripretinib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
The primary objective of this trial is to evaluate the progress free survival (PFS) of DCC-2618 in patients with advanced gastrointestinal stromal tumors who have progressed with prior anticancer therapies based on independent radiologic review.

Detailed description:
The primary objective of this trial is to evaluate the progress free survival (PFS) of DCC-2618 in patients with advanced gastrointestinal stromal tumors who have progressed with prior anticancer therapies based on independent radiologic review. This study enrolled 39 subjects of 9 sites in China mainland, and all enrolled subjects received DCC-2618 after enrollment as treatment.

The study used EDC to collect patient data and IRT system for patient randomization, using Imaging Endpoints as the central image to evaluate the PFS.

Arms:
arm 1: DCC-2618 drug is 50mg per tablet, 150mg once a day, with 28 days as a treatment cycle.

Interventions: intervention 1: DCC-2618
Intervention descriptions: intervention 1: Oral kinase inhibitor

Protocol document:
Prot_SAP_000.pdf: 
DCC-2618 (Ripretinib)
Zai Lab 
Clinical Trial Protocol Number: 
ZL-2307-002 
Clinical Study Protocol, Version 
2.0/14 September 2020 
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Clinical Study Protocol 
Study Title: 
A Multicenter Phase 2, Single-Arm Open-Label Study of DCC-2618 
to Assess Efficacy, Safety, and Pharmacokinetics in Patients With 
Advanced Gastrointestinal Stromal Tumors Who Have Progressed 
On Prior Anticancer Therapies 
Project No.: 
ZL-2307-002 
Version No. and 
Version Date: 
30 October 2019/Version 1.0 (First Version) 
14 September 2020/Version 2.0 (Revised according to the opinions 
on the investigator meeting) 
Investigational 
Drug: 
DCC-2618(ZL-2307)
Study phase: 
Phase Ⅱ Study 
Sponsor: 
Zai Lab (Shanghai) Co., Ltd. 
Principal 
Investigator: 
Professor SHEN Lin 
Beijing Cancer Hospital 
Privacy statement 
Confidential information of the investigational drugs involved in this protocol belongs to Zai 
Lab. The document is accessible to investigators, research consultants or relevant personnel, 
Institutional Review Board/Independent Ethics Committee only. The contents inside the 
document may not be disclosed to any third party without the written approval of the sponsor 


DCC-2618 (Ripretinib)
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Clinical Trial Protocol Number: 
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Signature page (Sponsor) 
Protocol title: A Multicenter Phase 2, Single-Arm Open-Label Study of DCC-2618 to 
Assess Efficacy, Safety, and Pharmacokinetics in Patients With Advanced 
Gastrointestinal Stromal Tumors Who Have Progressed On Prior Anticancer Therapies 
Clinical Study No.: ZL-2307-002 
Sponsor: Zai Lab (Shanghai) Co., Ltd. 
Hei Yongjiang 
Chief Medical Officer 
(printed) 
Chief Medical Officer 
(signature) 
Date 


DCC-2618 (Ripretinib)
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Clinical Trial Protocol Number: 
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Protocol Synopsis 
Sponsor/company 
name 
Zai Lab (Shanghai) Co., Ltd. 
Study Title 
A Multicenter Phase 2, Single-Arm Open-Label Study of DCC-2618 to Assess 
Efficacy, Safety, and Pharmacokinetics in Patients With Advanced Gastrointestinal 
Stromal Tumors Who Have Progressed On Prior Anticancer Therapies 
Protocol No. 
ZL-2307-002 
Study phase 
Phase 2 
Study site 
Beijing Cancer Hospital, etc. 
Principal 
Investigator 
Professor SHEN Lin 
Planned number of 
subjects: 
About 35 
Study objectives 
Primary objectives: 
To evaluate the progress free survival (PFS) of DCC-2618 in patients with 
advanced gastrointestinal stromal tumors who have progressed with prior anticancer 
therapies based on independent radiologic review. 
Key secondary objectives: 
To evaluate the objective response rate (ORR) of DCC-2618 in patients with 
advanced gastrointestinal stromal tumors who have progressed on prior anticancer 
therapies based on independent radiologic review. 
Secondary objective: 
To evaluate overall survival (OS) in DCC-2618-treated patients with advanced 
gastrointestinal stromal tumors who have progressed on prior anticancer therapies. 
To evaluate the pharmacokinetic (PK) profile of DCC-2618 in patients with 
advanced gastrointestinal stromal tumors who have progressed on prior anticancer 
therapies. 
To evaluate the safety of DCC-2618 in patients with advanced gastrointestinal 
stromal tumors who have progressed on prior anticancer therapies. 
Exploratory objective: 
To evaluate the efficacy of DCC-2618 in the patients when the dosage is increased 
to 150 mg BID. 
Study design 
This study is a multicenter phase 2, single-arm open-label study of DCC-2618 to 
assess efficacy, safety, and pharmacokinetics (PK) in patients with advanced 
gastrointestinal stromal tumors who have progressed on prior anticancer therapies. 
This study targets at the patients with advanced gastrointestinal stromal tumors who 
have progressed on prior anticancer therapies. It is planned to enroll about 35 
subjects in total. Prior anticancer therapies must include imatinib, sunitinib, and one 
or two other drugs, and the number of patients who have previously received 
treatment with ≥ fourth-line drugs should be 40% or less. 


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In this study, progression free survival (PFS) based on independent radiologic 
review is the primary efficacy indicator and RECIST v1.1-GIST Specific Standard 
is used for tumor efficacy assessment. 
After being fully informed, signing the informed consent forms and passing the 
screening, the subjects will receive DCC-2618 (150 mg, QD) continuously until the 
occurrence of an event for treatment termination as specified in the protocol, 28 
days as a treatment cycle, followed by a safety follow-up period until 30 days after 
the termination of study treatment. 
During the study period, the subjects will be subject to visits as scheduled in the 
protocol. On the day of the scheduled visit as per the protocol, the subjects should 
bring the drug to the study site, where they will complete all the pre-dose 
examinations, and take the drug of the day after being suitable to continue the 
administration, in the discretion of the investigator. In the first four cycles 
(inclusive), an radiographic examination will be performed within ±7 days of each 
cycle and tumor efficacy will be assessed according to RECIST v1.1-GIST Specific 
Standard. After that, it should be performed within ±7 days every  two cycles. 
If the subject discontinues treatment for reasons other than progressive disease, 
death, withdrawal of informed consent and lost to follow-up, the subject should 
receive radiographic examination for tumor assessment by independent radiologic 
review (IRR) after treatment withdrawal according to the frequency consistent with 
that during the study until presence of disease progression meeting "RECIST v1.1-
GIST Specific Standard" or until starting of new anti-tumor therapy, whichever is 
the first. 
Based on independent radiologic review, if a subject has a radiologically confirmed 
progression disease (PD), the subject can choose: 
○ 
To continue DCC-2618, at an increased dose of 150 mg BID, until the 
occurrence of an event for treatment termination as specified in the 
protocol; in the case of the efficacy evaluation for such patient, the lesion 
diameter before the increase of dosage (but not screening period) should 
be taken as the baseline value. 
○ 
To continue DCC-2618 at a dose of 150 mg QD, until the occurrence of 
an event for treatment termination as specified in the protocol, if the 
subject can benefit from the treatment with DCC-2618, but cannot 
tolerate the increase of dosage, after being fully assessed by the 
investigator; 
○ 
To terminate the treatment with DCC-2618. 
In the study, intensive blood collection is only necessary for the first 10-15 enrolled 
subjects, and for the rest, they will receive sparse blood collection. 
After PK sampling, the subjects can continue the treatment with DCC-2618, safety 
visits and efficacy evaluation, until the occurrence of an event for treatment 
termination as specified in the protocol. 
Treatment suspension or dosage reduction or treatment withdrawal is allowed at 
any time during the study for subjects with an intolerant toxicity reaction. 
Inclusion Criteria: 
The eligible subjects for this study must meet all of the following inclusion criteria: 


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1. 
Male or female patients ≥18 years of age. 
2. 
Patients with histopathologically-confirmed advanced gastrointestinal stromal 
tumors. 
3. 
Subjects who have progressed on previous treatments with imatinib, sunitinib 
and one or two other drugs or have documented intolerance to any of these 
treatments. Note: A documented intolerance must be after the dosage 
adjustment (including suspension and reduction). 
4. 
ECOG PS of 0-2. 
5. 
Female patients of childbearing potential must have a negative serum beta-
human chorionic gonadotrophin (β-hCG) pregnancy test at screening and 
negative pregnancy test at Cycle 1 Day 1 prior to the first dose of 
investigational drug. 
6. 
Patients of reproductive potential must agree to follow the contraception 
requirements. 
7. 
Patient is capable of understanding and complying with the protocol. Signed 
written informed consent before any study-related procedures were performed. 
8. 
Subject must have at least 1 measurable lesion (non-nodal lesions must be ≥ 
1.0 cm in the long axis or ≥ 2 times the slice thickness) according to the 
RECIST v1.1-GIST Specific Standard. A lesion with definite progression after 
local treatment can also be considered to be measurable. Radiographic 
examination results must be available within 21 days prior to the first dose of 
the investigational drug. 
9. 
Good organ function and bone marrow reserve function, including: 
● 
Neutrophil count ≥ 1,000/µL 
● 
Hemoglobin ≥ 8 g/dL 
● 
Platelet count ≥75,000/µL 
● 
Total bilirubin ≤1.5*the upper limit of normal (ULN) 
● 
AST and ALT ≤3*ULN, and AST and ALT≤5*ULN in the presence of 
hepatic metastases 
● 
Serum creatinine ≤1.5*ULN or creatinine clearance ≥50 mL/min (based 
on Cockcroft-Gault estimation) Formulas for calculation: 
Note: within 2 weeks prior to the above laboratory assessments, patients 
should not receive granulocyte colony-stimulating factor, interleukin-11 or 
infusion of red blood cells or platelets or other blood products. 
● 
Prothrombin time (PT) or international normalized ratio (INR) or partial 
thromboplastin time ≤1.5 × ULN. Patients on a stable, maintenance 
regimen of anticoagulant therapy for at least 30 days prior to 
investigational drug administration may have PT/INR measurements >1.5 
× ULN if, in the opinion of the investigator, the patient is suitable for the 
study. An adequate rationale must be provided to the sponsor prior to 
randomization. 
10. Resolution of all toxicities from prior therapy to ≤Grade 1 (or baseline) within 


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1 week prior to the first dose of investigational drug (excluding alopecia and ≤ 
Grade 3 clinically asymptomatic lipase, amylase, and creatine phosphokinase 
laboratory abnormalities). 
Exclusion Criteria: 
Subject meeting any of the following criteria should not be enrolled in this study: 
1. 
Treatment with anticancer therapy, including investigational therapy, or 
investigational procedures within 14 days or 5 x the half-life (whichever is 
longer) prior to the first dose of investigational drug. For prior biological 
therapies, eg, monoclonal antibodies with a half-life longer than 3 days, the 
interval must be at least 28 days prior to the first dose of investigational drug. 
2. 
Prior treatment with DCC-2618. 
3. 
Previously or currently has an additional malignancy that is progressing or 
required active treatment, which may interfere with the safety or efficacy 
evaluation of DCC-2618. If the patient is receiving the adjuvant therapy that is 
likely to be effective for GIST or should be excluded based on the protocol 
(see Section 5.9.3), the patient should not be included in this study. 
4. 
Patient has known active central nervous system metastases. 
5. 
New York Heart Association class II - IV heart disease, active ischemia or any 
other uncontrolled cardiac condition such as angina pectoris, clinically 
significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or 
congestive heart failure. 
6. 
Arterial thrombotic or embolic events such as cerebrovascular accident 
(including ischemic attacks) or hemoptysis within 6 months before the first 
dose of investigational drug. 
7. 
Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial 
events (eg, pulmonary embolism) within 3 months before the first dose of 
investigational drug. Patients with venous thrombotic events ≥3 months before 
the first dose of investigational drug on conventional anticoagulation therapy 
are eligible. 
8. 
12-lead electrocardiogram (ECG) demonstrating QT interval corrected by 
Fridericia's formula >450 ms in males or >470 ms in females at screening or 
history of long QT interval syndrome. 
9. 
Left ventricular ejection fraction (LVEF) <50% at screening. 
10. Use of strong or moderate inhibitors and/or inducers of cytochrome P450 
(CYP) 3A4, including certain herbal medications (eg, St. John's Wort) and 
consumption of grapefruit or grapefruit juice within 14 days or 5 x the half-life 
(whichever is longer) prior to the first dose of investigational drug. 
11. Use of known substrates or inhibitors of breast cancer resistance protein 
(BCRP) transporters within 14 days or 5 x the half-life (whichever is longer) 
prior to the first dose of investigational drug. 
12. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of 
investigational drug; Following major surgeries, >4 weeks prior to the first 
dose of investigational drug, all surgical wounds must be healed and free of 
infection or dehiscence. 
13. Any other clinically significant comorbidities, such as uncontrolled pulmonary 


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disease, active infection, or any other condition, which in the judgment of the 
investigator, could compromise compliance with the protocol, interfere with 
interpretation of the study results, or predispose the patient to safety risks. 
14. Active viral infections such as human immunodeficiency virus, hepatitis B, 
hepatitis C infection, etc. 
15. Female patients who are pregnant or lactating or who are expected to become 
pregnant during the study treatment period 
16. Known hypersensitivity to any component of the investigational drug. Patients 
with Stevenson Johnson syndrome in previous TKI treatment need to be 
excluded. 
17. Gastrointestinal abnormalities including but not limited to: 
● 
inability to take oral medication 
● 
malabsorption syndrome 
● 
Requiring intravenous nutrition 
18. Any active hemorrhages, excluding hemorrhoids or gum bleeding. 
Investigational 
Drug 
Drug: DCC-2618 
Dosage form: Tablet 
Dosage: 150 mg QD 
Administration route: oral 
Study endpoints 
Primary endpoints: 
Progression‑free survival (PFS): based on independent radiology review using 
“RECIST v1.1-GIST Specific Standard" which includes: 
● 
Lymph nodes cannot be taken as target lesions; enlarged lymph nodes 
will be followed as non-target lesions. 
● 
Bone lesions cannot be taken as target lesions; 
● 
Positron emission tomography (PET) cannot be used in efficacy 
assessment; 
● 
According to "RECIST v1.1-GIST Specific Standard", new tumor 
nodules within the pre-existing tumor lesion that are gradually growing 
must meet the following criteria before being determined as definite 
progression: (a) The lesion diameter should be at least 2 cm and 
confirmed as active GIST lesion (for example, using contrast or other 
criteria for enhanced scanning to rule out the possibility of false 
appearance); Or (b) At least 2 consecutive radiographic examinations 
indicative of enlarged lesion. 
Key secondary efficacy indicator: 
Objective response rate (ORR) as determined by confirmed CR + confirmed PR by 
independent radiologic review 
Secondary efficacy indicator 
● 
Overall survival (OS) 


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● 
Time to best response (TBR) based on independent radiologic review 
● 
PFS based on investigator’s assessment 
● 
Disease control rate (DCR,  CR+PR+SD) on Week 12 based on 
independent radiologic review 
Safety: 
● 
Incidence and severity of treatment emergent adverse event (TEAE), 
adverse event of special interest (AESI) and serious adverse event (SAE) 
during the study (including intensive blood collection); severity will be 
assessed based on NCI-CTCAE V4.03. 
● 
Incidence of adverse events resulting in dose reduction, suspension and 
termination of the investigational drug; 
● 
Changes from baseline in ECOG score, vital signs, ECG, left ventricular 
ejection fraction, dermatological examination and laboratory parameters. 
Pharmacokinetic profile: 
● 
The PK parameters will be calculated according to the plasma 
concentration of DCC-2618 and the metabolite DP-5439, including but 
not limited to Cmax, Tmax, AUC and T½, etc. 
Exploratory indicator: 
PFS2 based on investigator's assessment: the duration from the date of the first dose 
of the investigational drug (150 mg, BID) after the dose is increased to 150 mg to 
the date of first recording tumour progression after increasing the dose or the date 
of death for any reasons, whichever occurs first. 
Statistical Analysis 
● 
Single-arm, open-label study: 
● 
Primary efficacy indicator is the PFS based on independent radiologic 
review: 
● 
Calculation of sample size: 
This phase 2 bridging study is to prove the efficacy of DCC-2618 in Chinese 
patients is consistent with or similar to that in global patients using the primary 
endpoint of progression‑free survival (PFS) on the basis of independent radiologic 
review. Standard definition of bridging study success (consistent or similar): mPFS 
of ripretinib in Chinese patients will be statistically longer than 1 month, that is, the 
lower limit of bilateral 90% confidence interval of the observed mPFS is longer 
than 1 month. Statistical hypothesis: H0: mPFS is 1 month; Ha: mPFS is 2.5 months; 
bilateral significant level is 0.1; assumed enrollment duration is 6 months; follow-
up duration is 2 months; drop-out rate is 15% under at least a 90% test power; 
approximately 35 subjects should be enrolled to satisfy test purposes. 
All statistical analysis will be programed and calculated using SAS9.2 software or 
higher. 
The results of this study mainly adopt statistical description method. The 
measurement data are expressed as the mean, standard difference, median, 
maximum and minimum; Enumeration data and ranked data are expressed as the 
frequency (constituent ratio), rate and confidence interval. 


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During the study (including intensive blood collection period), the TEAEs and drug 
combination, clinical laboratory parameters, vital signs, ECG and UCG will be 
summarized according to the study visits and the analysis will present the 
observations from each visit in the trial and its changes from baseline. 
The PK parameters of DCC-2618 and its metabolite DP-5439 are calculated by 
WinNonlin 7.0 or higher with non-compartment model for patients after a single 
and multiple doses, and descriptive statistics are made for PK parameters obtained 
from the calculation. 
Study duration 
The study will be terminated when the last subject has been enrolled for 2 years or 
after the last visit of the last subject or on the sponsor's decision, whichever is the 
first. 
For patients still taking investigational drug after the clinical trial database has been 
closed, if the investigator thinks that they can get continuous clinical benefit and if 
the sponsor agrees, those patients may continue taking DCC-2618 until presence of 
disease progression, death, or intolerable toxicity, or their demand to discontinue 
treatment. Such patients will only be monitored for all serious adverse events until 
30 days after the last dose of the investigational product or the initiation of new 
anti-tumor therapies (whichever is the first). 
Schedule of visits 
and the content 
thereof 
Please refer to Table 1 
 


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Figure 1 Study Diagram 
 
Note: Based on IRR, continued treatment with an increase to 150 mg BID or with the original dosage should not be provided for a patient after the first PD, unless he 
or she is evaluated by the Investigator as able to tolerate. The diameter of the lesion before the increase of dosage (other than that during the Screening Period) should 
be used as baseline diameter when the effect on the patient after dose up-titration is evaluated. 
 
 
Signing the 
informed 
consent form 
and eligible for 
screening 
Treatment 
with the 
investigation
al drug, PK 
blood 
collection 
DCC-2618 
150mg QD 
Progression 
disease (PD) 
based on 
independent 
radiologic 
review (IRR) 
Events for 
treatment 
termination as 
specified in the 
protocol 
Increase the dose of DCC-2618  
to 150 mg BID 
Continue treatment at  
the original dose 
Treatment withdrawal 
Events for treatment 
termination as 
specified in the 
protocol 
Safety follow-
up and 
survival 
follow-up 


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Table 1: Schedule of Study Visits 
Evaluation/procedure1 
Screening 
period2 
Single-
dose PK 
blood 
sampling 
C1 
C1 
After C2 
Terminati
on of 
study 
treatment 
Follow-up period 
(30 days after the 
last dose) 
OS follow-up3 
Cycle/day 
-28 ~ -8 
-7 ~ -1 
1 
(baseline) 
15 (±1 day) 
1 (±3 day)  
Within 7 
days after 
the last 
dose 
(±5 days)  
Every month  
(± 5 days)  
Site visit 
X 
X 
X 
X 
X 
X 
 
 
Telephone follow-up 
 
 
 
 
 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Past medical history and tumor history 
X 
 
 
 
 
 
 
 
Previous medications/treatment 
operation4 
X 
 
 
 
 
 
 
 
Serum/urine pregnancy test5 
X 
 
X 
 
X 
X 
 
 
Laboratory test 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
X 
X 
X 
 
 
Blood biochemistry 
X 
 
X 
X 
X 
X 
 
 
Blood coagulation function6 
X 
 
X 
X6 
X 
X 
 
 
Urine routine7 
X 
 
 
 
X7 
X 
 
 
Thyroid function test 
 
 
X 
 
 
 
 
 
Physical examination 
X8 
Perform examination according to clinical findings and/or 
subject’s complaints 
 
 
ECOG score9 
X 
 
X 
X 
X 
X 
 
 
Vital signs and body weight10 
X 
 
X 
X 
X 
X 
 
 


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Evaluation/procedure1 
Screening 
period2 
Single-
dose PK 
blood 
sampling 
C1 
C1 
After C2 
Terminati
on of 
study 
treatment 
Follow-up period 
(30 days after the 
last dose) 
OS follow-up3 
Cycle/day 
-28 ~ -8 
-7 ~ -1 
1 
(baseline) 
15 (±1 day) 
1 (±3 day)  
Within 7 
days after 
the last 
dose 
(±5 days)  
Every month  
(± 5 days)  
Site visit 
X 
X 
X 
X 
X 
X 
 
 
Telephone follow-up 
 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
12-lead ECG 11 
X 
 
X 
 
X 
X 
 
 
Echocardiography12 
X 
 
 
 
X12 
X 
 
 
Dermatologic examination13 
X 
 
 
 
X13 
X 
 
 
Ophthalmological examination14 
X 
 
 
 
 
 
 
 
AE evaluations 
From signing an ICF to the end of the safety follow-up 
 
Enquire about concomitant 
medications/treatment operation 
From the first dose to the end of the safety follow-up 
 
DCC-2618 dosing15 
 
 
X 
X 
X 
 
 
 
DCC-2618 dispensing and recovery 
 
 
X 
 
X 
X 
 
 
PK sampling16 
 
X 
X 
X 
X 
 
 
 
Radiographic examination17 
X 
 
 
 
X 
 
 
 
Survival follow-up 
 
 
 
 
 
 
 
X 
1. 
All evaluations must be completed before administration unless specified otherwise. The Investigator may prescribe relevant additional examinations at any time 
as clinically indicated. 
2. 
The Screening Period covers 21 days from Day -28 to Day -8. Radiographic examination must be performed within 21 days before the first dose of drug. 
Radiographic examination performed before signing an ICF can be used in the Screening Period as long as it is performed within 21 before the first dose and the 
examination method and result comply with the protocol. 
3. 
Survival follow-up will be given to all subjects, until withdrawal of ICFs or lost to follow-up or death due to any cause. After the end of the safety follow-up, 


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survival follow-up visits will be made by phone on a monthly basis (±5 days).  
4. 
The collection of previous medications starts 30 days before the signing of ICFs. The history of tumor treatment needs to be collected from the time when the 
tumor is first diagnosed. 
5. 
Serum pregnancy test needs to be performed on women of childbearing age within 7 days before the first dose, which is to be followed by a urine pregnancy test 
on Day 1 of each cycle as well as at the end of the study treatment, for confirmation of a negative result. 
6. 
For patients taking anticoagulants, coagulation tests will be performed according at C1D15 visit. During the study treatment, the blood coagulation function 
must be monitored according to appropriate clinical needs in case of any change in the dosage of anticoagulants. 
7. 
Urinalysis will be performed during the Screening Period, on C2D1, C3D1, C4D1 as well as at the end of the study treatment. 
8. 
A general physical examination is required during the Screening Period: 
9. 
During the study treatment, ECOG score can be rated before or after administration. 
10. Data on vital signs must be collected at least 5 minutes after the patient has a rest (in a sitting or supine position). Additionally, weight data must be collected at 
each visit. 
11. 12-lead ECG must be performed at least 15 minutes after the patient has a rest (in a supine or semi-recumbent position). 
12. Echocardiography only needs to be performed during the Screening Period, C3D1, once in every three cycles (Cycles 6, 9, 12, etc.) and at the end of the study 
treatment. Additional ones may be performed during the study treatment as clinically indicated. If the ECG is performed before signing an ICF, it can be used as 
one performed during the Screening Period provided that the examination is performed within 21 before the first dose and as per the protocol. 
13. Dermatological examinations only need to be performed in the Screening Period, at C3D1, and then once every three cycles (Cycles 6, 9 and 12, etc.) and at the 
end of the study treatment. Additional ones may be performed as clinically indicated. The examinations must cover the whole skin. Special attentions should be 
paid to squamous cell carcinoma of skin, actinic keratosis and keratoacanthoma. If the dermatological examination is performed before signing an ICF, it can be 
used as one performed during the Screening Period provided that the examination is performed within 21 before the first dose and as per the protocol. 
Dermatological examinations may be performed within 7 days before the follow-up visit or after the administration on the date of the follow-up visit. 
14. Ophthalmological examination can be performed during the Screening Period or as clinically indicated only. Ophthalmological examination may not be repeated 
during the Screening Period, provided that it has been performed within 28 days before signing an ICF on the patient who discontinued previous anti-tumor 
therapy, with the examination report available, and that the examination conforms to the requirement of the protocol. 
15. Administration: For patients who take part in intensive blood collection, blood samples need to be collected on D-7 first, which is followed by administration of 
one dose of the drug, and then intensive blood sample collection without taking the investigational drug until D-1. Collect blood sample once first on C1D1, 
which is to be followed by continuous administration with investigational drug from C1D1. The investigational drug should be taken at the same time each day 
as far as possible during the study. On the visit date, subjects need to bring their medication to the study site and not to take the investigational drug until the 
pre-dose assessments are completed. 
16. Refer to Section 6.12 of the text on Intensive and Sparse Blood Collection Time Points. Unscheduled blood collection may be requested by the Sponsor at the 


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time of certain AEs that are possibly related to treatment. 
17. Radiographic examination during the Screening Period should cover the chest, the abdomen and the pelvis (within 21 days before the first dose). Only abdomen 
and pelvis are examined during the study; for patients with pulmonary metastases in the screening period or pulmonary metastases symptoms during the study at 
the investigator's discretion, chest examination should be performed during the study. It is performed once in each of the first four cycles (including Cycle 4), 
and then once in every two cycles (e.g., Cycles 6, 8 and 10). Initial evaluation of CR or PR should be conformed 4 weeks later at least. Enhanced scanning is 
required for the examination. MRI may be applied to subjects allergic to CT enhancer to examine the abdomen and the pelvis, with plain CT scanning for the 
chest. Ensure consistency in examination means during the study. No ultrasonic examination is allowed. If the subject discontinues treatment for reasons other 
than progressive disease, death, withdrawal of informed consent and lost to follow-up, the subject should receive radiographic examination for tumor assessment 
by IRR after treatment withdrawal according to the frequency consistent with that during the study until presence of disease progression meeting "RECIST v1.1-
GIST Specific Standard" or until starting of new anti-tumor therapy, whichever is the first. 
 


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Table of Abbreviations and Definitions of Terms 
Abbreviations 
Chinese Terminology 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Neutrophil count 
APTT 
Activated partial thromboplastin time 
ASM 
Aggressive systemic mastocytosis 
AST 
Aspartate aminotransferase 
ATC 
Chemical drug classification system 
AUC 
Area under the concentration-time curve 
β-hCG 
Human Chorionic Gonadotropin 
BCRP 
Breast cancer resistance protein 
BID 
Twice daily 
BP 
BP 
CI 
Confidence interval 
CL/F 
Apparent plasma clearance 
Cmax 
Maximum concentration 
CPK 
Creatine kinase 
CR 
Complete response 
CSF1R 
Macrophage colony stimulating factor receptor 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EOT 
End of Study Treatment 
ESMO 
European Society for Medical Oncology 
FDA 
Food and Drug Administration 


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Abbreviations 
Chinese Terminology 
GCP 
Good Clinical Practice 
GGT 
Glutamyl transpeptidase 
GIST 
Gastrointestinal stromal tumor 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Independent Radiologic Review 
IWRS 
Interactive web response system 
KIT 
cKIT proto-oncogene 
LVEF 
Left ventricular ejection fraction 
MCL 
Hypertrophy cell leukemia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDR 
Multidrug resistance protein 
MPN 
Myeloproliferative neoplasm 
MRI 
Magnetic Resonance Imaging 
NADPH 
Nicotinamide adenine dinucleotide phosphate 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Disease progression 
PDGFRA 
Platelet-derived growth factor receptor α 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
QD 
Once daily 


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Abbreviations 
Chinese Terminology 
QTc 
Corrected QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase II Dose 
SAE 
Severe adverse events 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SM 
Systemic mastocytosis 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/ 2 
Half-life 
FT3 
Tri-iodothyronine free 
FT4 
Free thyroxine 
TEAE 
Treatment-emergent adverse events 
Tmax 
Time to maximum observed drug concentration 
TSH 
Thyrotropic hormone 
ULN 
Upper limit of normal 
Vd/F 
Apparent volume of distribution at the terminal phase 
VEGFR2 
Vascular endothelial growth factor 2 
 
 


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Table of Contents 
Protocol Synopsis ..................................................................................................................... 3 
Table of Abbreviations and Definitions of Terms ............................................................... 15 
Table of Contents ................................................................................................................... 18 
1 
INTRODUCTION AND RATIONALE ...................................................................... 24 
1.1 
INTRODUCTION.................................................................................................... 24 
1.2 
Intended Indication .................................................................................................. 26 
1.2.1 
Non-clinical Summary .................................................................................. 27 
1.3 
Investigational drug ................................................................................................. 32 
1.3.1 
Clinical summary .......................................................................................... 33 
1.4 
Study rationale ......................................................................................................... 38 
1.4.1 
Rationale for the Study ................................................................................. 38 
1.4.2 
Rationale for Dose, Dosing Regimen, and Treatment Period ................... 39 
2 
Study objectives ............................................................................................................. 44 
2.1 
Primary Objectives .................................................................................................. 44 
2.2 
Secondary objective ................................................................................................. 44 
2.2.1 
Key secondary objective ............................................................................... 44 
2.2.2 
Other secondary objectives ........................................................................... 44 
2.3 
Exploratory objective .............................................................................................. 44 
3 
Study design ................................................................................................................... 44 
3.1 
Overview of Study Design ....................................................................................... 44 
3.2 
Number of subjects .................................................................................................. 46 
3.3 
Study duration .......................................................................................................... 46 
4 
Study Population ........................................................................................................... 46 
4.1 
Inclusion Criteria ..................................................................................................... 46 
4.2 
Exclusion Criteria .................................................................................................... 47 
4.3 
Procedure for handling of subjects who are enrolled incorrectly ....................... 49 
5 
Study Treatment and Management ............................................................................. 49 
5.1 
Description of investigational drug ........................................................................ 49 
5.2 
Investigational Products .......................................................................................... 49 
5.2.1 
Dose escalation ............................................................................................... 50 


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5.3 Dose interruption and modification for investigational drug ................................... 50 
5.3.1 
Dose discontinuation caused by medical procedures ................................. 51 
5.3.2 
Dose interruption and dose reduction due to adverse events .................... 51 
5.4 
Drug Packaging and Labeling ................................................................................ 54 
5.5 
Drug storage ............................................................................................................. 54 
5.6 
Medication compliance ............................................................................................ 54 
5.7 
Responsibilities for Reception, Storage, and Management of  
Investigational Drugs ......................................................................................................... 55 
5.8 
Drug Recovery and Destruction ............................................................................. 55 
5.9 
Prior and Concomitant Medications ...................................................................... 55 
5.9.1 
Previous treatments ....................................................................................... 55 
5.9.2 
Prior Anti-Cancer Therapy .......................................................................... 55 
5.9.3 
Concomitant medication ............................................................................... 55 
5.9.4 
Accompanying treatment .............................................................................. 57 
5.10 Other Notice to Applicants ...................................................................................... 57 
5.11 Channels to access the investigational drug after the end of the trial................. 57 
6 
Visit Schedule and Assessments ................................................................................... 58 
6.1 
Screening ................................................................................................................... 58 
6.2 
Re-screening ............................................................................................................. 58 
6.3 
Study period ............................................................................................................. 58 
6.4 
Follow-up .................................................................................................................. 58 
6.5 
Lost to Follow-up ..................................................................................................... 59 
6.6 
Study evaluation ....................................................................................................... 59 
6.6.1 
Time points assessed ...................................................................................... 59 
6.7 
Informed Consent Form .......................................................................................... 59 
6.8 
Assigned Subject No. ............................................................................................... 59 
6.9 
Demographics and Medical History ....................................................................... 59 
6.10 Efficacy...................................................................................................................... 60 
6.10.1 
Radiographic examination ............................................................................ 60 
6.10.2 
Survival follow-up ......................................................................................... 61 
6.11 Safety ......................................................................................................................... 61 
6.11.1 
Physical examination ..................................................................................... 62 
6.11.2 
ECOG score ................................................................................................... 62 


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6.11.3 
Vital sign and height ...................................................................................... 62 
6.11.4 
Electrocardiogram ......................................................................................... 62 
6.11.5 
Echocardiogram ............................................................................................ 63 
6.11.6 
Dermatologic examination ............................................................................ 63 
6.11.7 
Ophthalmological examination .................................................................... 63 
6.11.8 
Laboratory test .............................................................................................. 63 
6.11.9 
Pregnancy tests .............................................................................................. 64 
6.11.10 
Contraception ................................................................................................ 65 
6.11.11 
AE ................................................................................................................... 65 
6.11.12 
Safety follow-up ............................................................................................. 65 
6.12 Pharmacokinetics ..................................................................................................... 65 
6.12.1 
Blood sampling .............................................................................................. 65 
6.12.2 
Blood samples and data analysis .................................................................. 67 
7 
Recording, grading and reporting of adverse events and serious adverse events ... 67 
7.1 
Definition of adverse events (AEs).......................................................................... 67 
7.2 
Judgment of severity ................................................................................................ 68 
7.3 
Determination of drug relationship ........................................................................ 68 
7.4 
Measures Taken to the IMPs .................................................................................. 69 
7.5 
Outcome of adverse event ....................................................................................... 69 
7.6 
Treatment measures taken for AEs........................................................................ 70 
7.7 
Other considerations for AE ................................................................................... 70 
7.8 
Defination of SAEs ................................................................................................... 71 
7.9 
Adverse Events of Special Interest (AESIs)........................................................... 71 
7.10 Time Limit for Collection of Adverse Events ........................................................ 72 
7.11 Requirements for reporting AE, SAE and AESI .................................................. 72 
7.12 Drug abuse, misuse, overdose and medical errors ................................................ 74 
8 
Subject Withdrawal and Replacement ........................................................................ 74 
8.1 
Subject withdrawal .................................................................................................. 74 
8.2 
Subject replacement................................................................................................. 75 
9 
Statistical Analysis ......................................................................................................... 76 
9.1 
Determination of sample size .................................................................................. 76 
9.2 
Endpoints of study analysis ..................................................................................... 76 


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9.2.1 
Primary endpoints ......................................................................................... 76 
9.2.2 
Secondary endpoints ..................................................................................... 77 
9.2.3 
Exploratory endpoint .................................................................................... 77 
9.3 
Analysis data sets ..................................................................................................... 77 
9.4 
Statistical methods ................................................................................................... 78 
9.4.1 
General methods ............................................................................................ 78 
9.4.2 
Subject disposition ......................................................................................... 78 
9.4.3 
Demographic and baseline characteristics .................................................. 79 
9.4.4 
Degree of exposure ........................................................................................ 79 
9.4.5 
Efficacy analysis ............................................................................................ 79 
9.4.6 
Safety analysis ................................................................................................ 80 
9.4.7 
Pharmacokinetics analysis ............................................................................ 81 
10 
Quality Control and Assurance .................................................................................... 81 
10.1 Monitoring ................................................................................................................ 81 
10.2 Source Data Verification ......................................................................................... 81 
10.3 Audit .......................................................................................................................... 81 
10.4 Protocol compliance ................................................................................................. 82 
11 
DATA MANAGEMENT AND DATA RETENTION ............................................... 82 
11.1 Electronic Case Report Form (eCRF) .................................................................... 82 
11.2 DATA RETENTION ............................................................................................... 83 
12 
Ethics .............................................................................................................................. 83 
12.1 Ethics ......................................................................................................................... 83 
12.2 Informed Consent Form .......................................................................................... 84 
12.3 IRB/IEC .................................................................................................................... 84 
12.4 Patient Privacy ......................................................................................................... 84 
13 
Termination of study ..................................................................................................... 85 
13.1 Criteria for Suspension or Early Termination of the Study ................................ 85 
13.2 Criteria for Premature Termination or Suspension of Study Sites .................... 86 
13.3 Procedures for Early Termination or Suspension of the Study or Study Site ... 86 
14 
Paper publication .......................................................................................................... 86 
15 
References ...................................................................................................................... 87 
16 
Annexes ........................................................................................................................... 90 


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Annex 1 Response Evaluation Criteria in Solid Tumors - GIST Specific Standard 
(RECISTv1.1-GIST Specific Standard) ........................................................................... 90 
Annex 2 Eastern Cooperative Oncology Group (ECOG) Performance Status Score . 91 
 
 
 


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List of Tables 
Table 1: Schedule of Study Visits ......................................................................................... 11 
Table 2 Interaction between DCC-2618, its metabolite DP-5439 and transporters ........ 31 
Table 3 Patients exposed to DCC-2618 in study DCC-2618-01-001 .................................. 35 
Table 4 In vitro inhibitory effect on recombinant KIT and KIT mutants ....................... 40 
Table 5 Typical steady-state exposure of DCC-2618 and DP-5439 predicted by models in 
patients with advanced malignant tumors ............................................................. 41 
Table 6 DCC-2618 Dose Modification Scheme ................................................................... 51 
Table 7 Handling of dermatological toxicity and joint pain/myalgia and principles of 
dose adjustment ........................................................................................................ 52 
Table 8 Handling of hypertension and principles of dose adjustment .............................. 53 
Table 9 Treatment of AEs except for dermatological toxicity and joint pain/myalgia and 
hypertension and principles of dose adjustment ................................................... 53 
Table 10 Clinical laboratory tests ......................................................................................... 64 
Table 11 Pharmacokinetic blood sampling time points...................................................... 66 
 
List of Figures 
Figure 1 Study Diagram ........................................................................................................ 10 
Figure 2 Various secondary KIT mutations in cross-exon 13 - 18 in GIST patients (N = 
27) ............................................................................................................................ 25 
Figure 3 Drug pharmacokinetic model of DCC-2618 and DP-5439 in patients with 
advanced malignant tumors .................................................................................. 41 
 
 
 


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1 
INTRODUCTION AND RATIONALE 
1.1 
INTRODUCTION 
Studies showed that mutations of proto-oncogene cKIT (KIT) and/or platelet-derived growth 
factor receptor α (PDGFRA) exist in various types of cancers, such as gastrointestinal stromal 
tumor (GIST), melanoma subtype, seminoma, and acute myeloid leukemia (AML), and 
myeloproliferative neoplasm (MPN) such as systemic mastocytosis (SM) including 
aggressive SM (ASM) and mast cell leukemia (MCL)[2, 3, 4, 5, 6]. Studies also revealed that 
GIST, melanoma, AML, glioma, and neuroendocrine tumor presented abnormal wild-type 
KIT and/or PDGFRA over-expression[7, 8, 9, 10]. 
GIST is induced by activated mutation in KIT (about 80%) or relevant PDGFRA (about 10%) 
receptor tyrosine kinase[1, 2, 3]. Generally, KIT exons 9 or 11 mutation was found in patients 
with GIST. Primary exon 11 mutation destroys autoinhibitory domains of kinase and primary 
exon 9 mutation increases receptor dimerization. Both mechanisms lead to ligand-
independent receptor activation, making the growth and transformation of cells out of control. 
Multiple KIT target treatments have been approved for the treatment of GIST, but the 
efficacy is limited. 
After receiving target therapy, secondary drug-resistant KIT mutations often occur in 
catalytic domains of kinase and these mutations usually map to interconversion and control 
mechanism of embedded conformations that regulate KIT activity. (Figure 2). Secondary KIT 
mutations usually occur in exons 13 and 14 (approaching adenosine triphosphatase [ATP]-
binding pocket and in conformational switch control pocket), and destroy drug binding 
capacity in space or activate KIT conformation. These mutations can also occur in the 
activation loop (conformational control switch) encoded by exons 17 and 18[11, 12]. Activation 
loop mutation can transform kinase into activation conformation, making it difficult to bind 
to the approved therapeutic drugs[13]. Other diseases harboring primary KIT (or PDGFRA) 
activation loop mutations include SM, AML and PDGFRA-induced GIST[7, 14, 15]. 


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Figure 2 Various secondary KIT mutations in cross-exon 13 - 18 in GIST patients (N = 
27) 
 
Source: Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, et al. Heterogeneity of kinase 
inhibitor resistance mechanisms in GIST, J. Pathol. 2008 Sep;216(1):64-74. 
At present, multiple target therapeutic drugs have been approved for the treatment of 
advanced GIST. The first-line therapeutic drug imatinib is the first FDA-approved KIT 
inhibitor and was approved in 2002 for the treatment of advanced GIST[16]. However, it is 
usually incurable, with a complete response (CR) rate of 5% and objective response rate 
(ORR) of 68%[17]. More than 80% GIST patients can benefit from imatinib monotherapy, but 
it is inevitably to have secondary drug resistance. More than half of the patients would 
experienced disease progression within 2 years[18]. Progression is likely to be related to 
secondary mutation in KIT kinase domains that result in imatinib resistance[12]. Although 
imatinib has a good efficacy in patients with KIT exon 11 mutation and an increased dose to 
800 mg also presented certain efficacy in patients with KIT exon 9 mutation, but for other 
KIT exon mutations or PDGFRA mutations, the efficacy is either weak or none[18, 19]. 
Sunitinib was approved by FDA in 2006 for the treatment of advanced GIST patients who do 
not respond to or can’t tolerate imatinib. Compared with imatinib, sunitinib shows a good 
efficacy in GIST patients with KIT exon 9 mutation and a weak efficacy in GIST patients 
with KIT exon 11 mutation[15, 18]. In addition, sunitinib presented anti-tumor activity to KIT 
exons 13 and 14, but only half of the patients benefited from it, with a median 
progression‑free survival (mPFS) of 5.5 months[18]. Sunitinib was ineffective in patients with 
Switch pocket area 
Exon 13 
Switch area 
Exon 14 
Exon 17 
Exon 18 
ATP-binding pocket 
42.9% 
Kinase activation loop 
57.1% 
Color code of primary mutations 
Exon 11  
Exon 9  
Exon 13 


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KIT exons 17 and 18 mutations and PDGFRA exon 18 mutation. 
Regorafenib was approved by FDA in 2013 for the third-line treatment of adult patients with 
unresectable and/or metastatic GIST after failure of imatinib and sunitinib and could 
significantly prolong patients’ overall survival. Besides being effective in patients with KIT 
exon 11 mutation, regorafenib is the only approved drug targeting KIT exon 17 mutation and 
mPFS in patients with response was nearly 5 months. However, some patients were resistant 
to regorafenib due to secondary KIT mutations[12]. 
Complex heterogenicity of KIT mutations in individual patient is the major reason for drug 
resistance[12]. Therefore, a broad-spectrum kinase inhibitor that can inhibit multiple KIT 
mutations in individual patient has a very high treatment value in relapsed GIST patients. 
What’s more, it is an important treatment objective to confirm whether DCC-2618 can delay 
the occurrence of KIT mutations leading to drug resistance. 
At present, no broad-spectrum inhibitor has been approved for marketing against secondary 
KIT mutations leading to drug resistance. Therefore, it is urgent to develop a kinase inhibitor 
targeting multiple KIT and PDGFRA mutations. 
At present, imatinib, sunitinib and regorafenib have been approved in China for the treatment 
of unresectable and/or metastatic GIST patients. The main data supporting the approval of 
regorafenib in China are from a global, international, multicenter, phase 3, randomized, 
controlled, double blind study where 199 patients were included, including 11 Chinese 
patients. Due to limited sample size, Chinese patients were not analyzed independently. Up to 
now, regorafenib has not been widely used as third line therapy in Chinese GIST patients. 
GIST patients are facing difficulties of out of medication after failure of imatinib and 
sunitinib. Patients have to enter the follow-up period for disease monitoring and passively 
wait for unavoidable disease recurrence. Therefore, it is still an urgent and important clinical 
project to research and develop new target drugs that target GIST drug resistance mechanism, 
prolong disease control, and delay recurrence and to excavate molecular markers of 
significance to prognosis prediction. 
1.2 
Intended Indication 
DCC-2618 is a orally administered KIT/PDGFRA kinase inhibitor, developed by Deciphera, 
used to treat KIT/PDGFRA-driven GIST and other proto-oncogene tyrosine kinase-driven 
malignant tumors. DCC-2618 can not only inhibit KIT and PDGFRA but also inhibit 
macrophage colony stimulating factor receptor (CSF1R, also known as FMS), vascular 
endothelial growth factor receptor 2 (VEGFR2) and endothelial tyrosine kinase receptor TIE2. 
According to literatures, these substances seldom induce tumor progression, but are 
associated with tumor growth. 
Gastrointestinal stromal tumor is a disease seriously threatening human health and is the most 
common mesenchymal cell tumor of the gastrointestinal tract[20], accounting for 1% - 3% of 


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malignant gastrointestinal tumors. The annual incidence in China is 4.3 - 22 out of 1,000,000 
persons[21, 22]. There are about 3000 - 6000 new GIST cases every year in American adults[23, 
24, 25]. GIST often occurs in population who are older than 50 years of age, mostly between 55 
- 65, and there is no significant difference in incidence between males and females[26]. For 
local GIST, surgical resection is the basic treatment approach. For metastatic or unresectable 
GIST, radiotherapy and conventional chemotherapy are basically ineffective[20, 27]. About 50% 
GIST patients would have metastasis at the first diagnosis. Imatinib, sunitinib and regorafenib 
have opened a era of target therapy for GIST, but are difficult to realize complete response[20]. 
Similar to the target therapies for other tumors, most patients would experience drug 
resistance within months to years of treatment[23]. 
1.2.1 
Non-clinical Summary 
Refer to the Investigator's Brochure for detailed information on nonclinical studies. 
1.2.1.1 
Pharmacology 
Recombinant kinase test and cell test were carried out with drug-resistant cell lines of GIST 
patients, cell lines of acute myeloid leukemia (AML) and mastocytosis or cell lines 
transfected with KIT or PDGFRA mutants, so as to conduct in vitro evaluation of DCC-2618. 
The above study revealed that DCC-2618 can comprehensively inhibit clinically significant 
KIT and PDGFRA mutations that can’t be treated with or don’t respond to the current 
therapies. Evaluation results of tumor cell lines provide guidance for further in vivo 
assessment of refractory/drug-resistant tumor xenograft models. 
In vivo pharmacology of DCC-2618 was evaluated in several tumor models: efficacy was 
evaluated in human xenograft model in nude mice; PK/PD study was carried out in tumor-
bearing mice to assess the necessary exposure of DCC-2618 for persistent inhibition of KIT 
mutations. 
In vivo, DCC-2618 presented potent antitumor activity in GIST model carrying KIT mutation. 
Moreover, DCC-2618 can also effectively inhibit KIT phosphorylation in GIST model. 
PK/PD study in human GIST xenograft model in mice indicated that after a single dose of 50 
mg/kg, exposure of DCC-2618 was 2500 ng*hr/mL (including after active metabolite DP-
5439, exposure was 5000 ng*hr/mL); inhibition rate against KIT was 69 - 88% within 8 
hours after administration and about 40% 12 hours after administration. In GIST T1 model, 
after administration at 50 mg/kg twice daily (BID), combining exposure (AUC0-24hr) of DCC-
2618 and metabolite DP-5439 was 10,000 ng*hr/mL and tumor inhibition rate reached 90%. 
Exposure measured in the PK/PD study is used to guide the confirmation of toxic products 
that can reach several times the above exposure for persistent KIT inhibition. 
Hepatocellular metabolite identification study indicated that the main metabolic pathway of 
DCC-2618 is active metabolite named DP-5439 formed by N-demethylation. In preclinical 
studies in animals, significant fraction of DP-5439 was detected in plasma of mice, rats and 


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dogs. Yield of the metabolite was highest in mice. PK parameters showed that in terms of 
AUC0-24hr, DP-5439 exposure in mice was equivalent to DCC-2618 exposure. Total active 
drug exposure of (AUC0-24hr) was calculated based on the combining exposure of DCC-2618 
and metabolite DP-5439. After single-dose oral administration at 50 mg/kg, total active drug 
exposure of in mice was 5000 ng*hr/mL; after administration at 50 mg/kg twice daily (BID), 
combining exposure of DCC-2618 and metabolite DP-5439 (AUC0-24hr) was 10,000 
ng*hr/mL, which has reference value for non-clinical safety study and analysis. Metabolite 
DP-5439 was also detected in a phase 1 ascending dose study. At a clinically effective dose, 
exposure of metabolite was higher than DCC-2618 exposure. 
Efficacy and tolerability observed in these model systems support the clinical development of 
DCC-2618. 
1.2.1.1.1 Safety pharmacology 
Binding of DCC-2618 to human ether-à-go-go related gene (hERG) potassium channel 
components can be ignored. 
DCC-2618 at 15, 60 or 300 mg/kg was administered to rats and it did not have influence on 
any combination items of modified behavior Irwin test combination at all measuring time 
points. When the administration dose was 15 mg/kg, tidal volume of rats decreased by 10%; 
when the dose was 300 mg/kg, it decreased by 17%. Physiologically, the observed tidal 
volume was of no significance because these changes were temporary and not significant. 
A 4-week multiple-dose toxicological study was carried out in dogs, and cardiovascular 
safety was assessed by measuring their electrocardiogram (ECG), blood pressure and 
troponin I levels. The study showed that the investigational drug did not have significant 
impact on blood pressure, heart rate, ECG intervals, and troponin I level. In an independent 
cardiovascular safety study, after investigators gave single dose of DCC-2618 to Beagle, 
diastolic blood pressure and mean arterial pressure of Beagle (2 - 6 hours after administration) 
increased, which was generally related to the expected time to maximum plasma 
concentration (Tmax). At doses of 7, 20 and 75 mg/kg, the diastolic blood pressure was higher 
than that of the control group (higher by 12%, 12% and 17%, respectively), the mean arterial 
pressure was higher than that of the control group (higher by 12, 10 and 14 mmHg at most, 
respectively); there was no change in systolic blood pressure or arterial pressure. 
In the later stage of the study, that is, 9 - 19 hours after administration, heart rate increase was 
observed, and QT interval and PR interval shortened (likely to be second to heart rate 
changes); there was no change in QTc interval. In the whole later stage, heart rate increased. 
At doses of 7, 20 and 75 mg/kg, the maximum difference occurred within 13 - 17 hours after 
administration; heart rate was higher by 45%, 70% and 129% than the control group in the 
same period, respectively. At present, mechanism of these changes is unknown; blood 
pressure and heart rate will be closely monitored in the clinical trial. Although attentions 


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should be paid to change degree of blood pressure and heart rate, this does not mean the 
investigational drug has severe toxicity. 
1.2.1.2 
Pharmacokinetics and absorption, distribution, metabolism and excretion 
In vitro and in vivo studies were carried out in human and other drug development-related 
mammal species to confirm absorption, distribution, metabolism and excretion characteristics 
of DCC-2618 and active metabolite DP-5439. In vivo PK studies (oral administration and 
intravenous injection) were carried out in rodents (mice and rats) and non-rodents (dogs and 
cynomolgus monkeys). 
DCC-2618 presented certain oral bioavailability in different species, which proved its 
development potential as an oral therapeutic drug. 
Exposure (AUC0-24hr) of DCC-2618 in dogs and rats was 1.9 - 2.6 times that of DCC-2618 
and metabolite DP-5439 in the mouse GIST efficacy model. Dogs and rats were given a 
single IV dose, and T1/2 was equivalent in dogs (2.7 hours) and rats (2.0 hours). 
Metabolite identification study indicated that all metabolites found in human were also 
observed in Sprague-Dawley rats and/or Beagle, indicating these specimens had correlation 
with toxicological studies. The main hepatocellular metabolite in all specimens was N-
desmethyl metabolite (DP-5439). The study has confirmed that DP-5439 is a receptor 
tyrosine kinase inhibitor and remains the inhibitory activity to wild-type and KIT and 
PDGFRA mutations similar to drug DCC-2618. In testing of 19 single and double KIT 
mutants conducted in transfected Chinese Hamster Ovary Cells (CHO), DCC-2618 inhibited 
phosphorylation of mutant KIT; median maximum inhibition concentration (IC50) ranged 6 
nM - 221 nM. Similarly, IC50 range of metabolite DP-5439 in inhibiting phosphorylation of 
mutant KIT was 21 nM - 191 nM. 
In in vitro metabolism study, in vitro metabolism of DCC-2618 and active metabolite DP-
5439 by human liver microsome was studied to confirm which human cytochrome P450 
(CYP) is conducive to DCC-2618 metabolism. It is found that metabolism of DCC-2618 was 
dependent upon the existence of reduced nicotinamide adenine dinucleotide phosphate 
(NADPH). By jointly giving specifically direct or metabolism-dependent CYP inhibitors to 
block the metabolism of DCC-2618 in cultured human liver microsome, it was found that 
CYP3A4/5 was the main metabolic enzyme ( ketoconazole, 63% inhibition; troleandomycin, 
79% inhibition) of DCC-2618; CYP2C8 (gemfibrozil-glucuronic acid, 24% inhibition) and 
CYP2D6 (quinidine, 26% inhibition) were regarded as secondary metabolic enzymes. 
However, in recombinant human CYP enzyme products, it was also found that CYP2D6 and 
CYP2C8 were potent metabolic enzymes of DCC-2618. It was found that the metabolism of 
DP-5439 was inhibited by adding direct inhibitor ketoconazole (CYP3A4/5, 72％ inhibition), 
metabolism-dependent inhibitor gemfibrozil-glucuronic acid (CYP2C8, 59％ inhibition), 
esomeprazole (CYP2C19, 31% inhibition), paroxetine (CYP2D6, 42% inhibition), 


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diethyldithiocarbamate (CYP2E1, 50% inhibition) and troleandomycin (CYP3A4/5, 100% 
inhibition) into cultured human liver microsome. When DP-5439 and other direct or 
metabolism-dependent inhibitors were cultured together, inhibition rate was lower than 14%. 
The study indicated that CYP3A4/5 was the main metabolic enzyme of DP-5439, but 
CYP2C8, CYP2E1 and CYP2D6 also played an important role in the metabolism of DP-5439. 
In in vitro metabolism study, DCC-2618 did not significantly inhibit cytochrome P450 (CYP) 
3A4, CYP1A2 or CYP2B6. IC50 of DCC-2618 in inhibiting CYP2C8, CYP2C9, CYP2C19 
and CYP2D6 ranged 0.12 - 1.8 μM. There is little or no evidence that DCC-2618 has time- or 
metabolism-dependent inhibitory effect on any of the evaluated 7 main CYP enzymes. 
Similarly, it was also found that IC50 of metabolite DP-5439 in inhibiting CYP2C8, CYP2C9, 
CYP2C19 and CYP2D6 ranged 0.30 - 2.0 μM. DP-5439 did not directly inhibit CYP3A4, 
CYP1A2 or CYP2B6. However, after incubating together with human liver microsome for 30 
minutes in the presence of NADPH, it was proved that DP-5439 had metabolism-dependent 
(time-dependent and NADPH-dependent) inhibitory effect on CYP3A4/5-mediated 
testosterone 6β-hydroxylation. After preincubating, it was observed that the inhibition rate 
increased by 41% in the presence of 7.0 μMDP-5439. There is little or no evidence that DP-
5439 has metabolism-dependent (time- and NADPH-dependent) inhibitory effect on 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. DCC-2618 and DP-5439 
have potential drug interaction with other drugs metabolized dependent upon CYP2C8, 
CYP2C9, CYP2C19 or CYP2D6. 
In the presence of 10 μM DCC-2618 or 7 μM DP-5439, organic anion transporter (OAT) 
OAT1 and OAT3, organic cation transporter (OCT) OCT1 and OCT2 were mildly or 
moderately inhibited  ≤ 55%. Inhibition rate of DCC-2618 on OATP1B3 was 78% and that of 
DP-5439 on OATP1B1 was 73% (Table 2). 
In vitro vesicular transportation analysis showed that both DCC-2618 and DP-5439 inhibited 
efflux transporter breast cancer resistance protein (BCRP), and IC50 was 0.04 µM and 1.26 
µM, respectively. Although DCC -2618 is not the substrate of BVRP transporter (efflux rate 
[ER] 2.36), metabolite DP-5439 presented significant substrate activity (ER 85.0), indicating 
the possibility of drug-metabolite interaction. DCC-2618 was the substance inducing 
interaction (BCRP IC50 was 0.04 μM) and metabolite DP-5439 may be a substance 
influenced by DDI (BCRP ER 85.0). DCC-2618 may have drug interaction with substrate or 
inhibitor of other BCRP efflux transporters. 
DCC-2618 and DP-5439 had a moderate to weak inhibitory effect on multidrug resistance 
efflux transporter 1 (MDR1), and IC50 was 1.95 µM an d > 7 µM, respectively. Although 
DCC-2618 is a moderate substrate of MDR1 transporter (ER 12.9), metabolite DP-5439 
exhibited significant substrate activity (ER 72.4), indicating that the possibility of drug-
metabolite interaction was low to moderate; DCC-2618 was likely to be the substance 
inducing interaction (MDR1 IC50 1.95 µM), and metabolite DP -5439 may be a substance 


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influenced by DDI (MDR1 ER 72.4). 
Table 2 Interaction between DCC-2618, its metabolite DP-5439 and transporters 
 
Inhibiting transporter 
Transporter substrate 
DCC-2618 
DP-5439 
DCC-2618 
DP-5439 
BCRP 
IC50 0.040 µM  
IC50 1.26 µM  
ER 2.36 
ER 85.0a 
MDR1 
IC50 1.95 µM  
IC50 >7 µm  
ER 12.9 
ER 72.4 
BSEP 
IC50 1.63 µM  
7 µM inhibition rate 
54% 
NT 
ER <2 
OATP1B1 
10 µM inhibition rate 32%  
7 µM inhibition rate 
73% 
NT 
ER <2 
OATP1B3 
10 µM inhibition rate 78%  
7 µM inhibition rate 
43% 
NT 
ER <2 
OCT1 
10 µM inhibition rate 30%  
NT 
NT 
NT 
OCT2 
10 µM inhibition rate 55%  
10 µM inhibition rate 
6% 
NT 
ER<2 
OAT1, 
OAT3, 
10 µM inhibition rate≤15% 
7 µM inhibition 
rate≤13% 
NT 
ER <2 
BCRP = breast cancer resistance protein; BSEP = bile salt export pump; ER = efflux rate; IC50 = median 
maximum inhibition concentration; MDR1 = multidrug resistance protein 1; NT = not tested;  OAT = 
organic anion transporter; OATP = organic anion transporting polypeptide; OCT = organic cation 
transporter 
a. 
In the study of MDCKII cells expressing BCRP transporter, ER of BCRP transporter was 85.0. 
Because MDCKII cells also express other background transporters, study personnel also studied the 
characteristics of BCRP substrate of DP-5439 in vesicles only expressing BCRP transporter. In the 
BCRP vesicle study, DP-5439 did not show substrate activity. However, it was proved in a qualitative 
study in LLC-PK1 cells expressing and controlling human BCRP that DP-5439 was a substrate of 
BCRP and efflux rate was 41.8. 
1.2.1.3 
Toxicology 
In vivo and in vitro toxicological characteristics of DCC-2618 were assessed in bacterial 
mutagenicity analysis in nude mice, Sprague-Dawley rats and Beagle. Under the maximum 
test concentration of 3000 µg/plate (precipitation concentration), regardless of  metabolic 
activation, bacterial mutagenicity was not observed. 
In a critical study in rats, oral doses of DCC-2618 included: 0, 15, 60 and 300 mg/kg/day, and 
there was a 4-week recovery period after administration. There were no drug-related deaths 
or adverse events in this study. Incidence of hair thinning at 300 mg/kg/day was high. Weight 
and food consumption decrease was observed in animals processed with DCC-2618. In the 
recovery period, weight and food consumption reversed and it did not have any impact on the 
overall status of animals. Several minor clinical pathological findings were observed on Day 
29. These changes were not mild, showed no microscopic correlation, presented reversibility 
after the recovery period, and were not regarded to be adverse. DCC-2618-related lung 
weight increase (15 - 33%) was observed in male rats administered at a dose of 300 


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mg/kg/day and female rats administered at a dose ≥15 mg/kg/day. In the recovery period, 
there was no related microscopic change and lung weight increase was partially reversed. 
Microscopic changes were limited to forestomach (nonglandular stomach) of rats 
administered at doses ≥ 60 mg/kg/day (diffuse hyperplasia/hyperkeratoses) and were partially 
reversed in the recovery period. These changes were unrelated to human because human do 
not have the anatomical feature. On the basis of these results, 300 mg/kg/day is the no-
observed-adverse-effect level (NOAEL) after 4 weeks of administration 
 in a critical study of  4-week oral administration at 0, 7, 20 and 75 mg/kg/day in Beagle dogs 
complying with the GLP. There was a 4-week recovery period after administration. Since 
DCC-2618-related adverse events were observed, the drug was withheld in several animals in 
20 and 75 mg/kg/day dose groups at weeks 2 and 3. Due to DCC-2618-related adverse events, 
3 male rats in 75 mg/kg/day dose group were executed on Day 13; 4 rats (2 males and 2 
females) in 20 mg/kg/day group and 3 rats (females) in 75 mg/kg/day dose group were 
executed at Week 4. Adverse events in these animals included foot erythema, erythema in 
ears, mouth, periorbital area and on ventral chest, and head hair thinning. Some dogs also 
manifested dry and flaky skin, otitis, external ear canal erythema, excessive salivation, 
vomiting and shapeless/liquid feces. In dogs of the 7 mg/kg/day dose group, the severity of 
skin changes was mild and was not judged as adverse. In the recovery period, skin damage in 
the 20 and 75 mg/kg/day dose groups partially or completely resolved. Body weight of male 
rats in 20 or 75 mg/kg/day dose groups decreased. Body weight of animals in the 7 
mg/kg/day dose group changed slightly, which was not regarded as adverse. Change in blood 
pressure or ECG intervals was not observed in any DCC-2618 dose groups. In animals of 
dose ≥ 20 mg/kg/day group, mild hematological, clinical biochemical and/or coagulation 
function abnormalities were observed and there was evidence that all changes were reversed 
after the recovery period. In animals handled with DCC-2618, troponin I was not influenced 
by drug. In animals of dose ≥20 mg/kg/day group, such as hyperkeratoses, microscopic 
changes of sparse cytoplasm of liver cells, consistent with glycogen increased,  lymphocytes 
decreased in lymphoid tissues and one case of intraepithelial pustule were observed. The only 
microscopic finding related to the test product in animals in the recovery period was 
minimum cytoplasm sparsity in hepatocytes of some animals in the 75 mg/kg/day group, 
indicating that the abnormality was only partially recovered. 
On the basis of these results, NOAEL in Beagle dogs 4 weeks after administration was 7 
mg/kg/day and the dose was also considered to be the highest non-severely toxic dose. 
1.3 
Investigational drug 
DCC-2618 is a new orally administered KIT kinase and PDGFRA kinase inhibitor developed 
by Deciphera Pharmaceuticals, LLC using its special kinase switch control inhibitor 
technological platform. DCC-2618 can comprehensively and potently inhibit extensive 
primary and secondary KIT and PDGFRA kinase mutants, including primary exons 9 and 11 


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mutations, secondary exons 13 and 14 mutations in KIT ATP-binding/transformation pocket, 
and primary and secondary exons 17 and 18 mutations in activation loop conformation-
control switch region. DCC-2618 can also inhibit primary exon 18 D842V mutations in 
PDGFRA conformation-control switch region and assist in inhibiting exon 12 mutation in 
switch region. DCC-2618, as an enhanced type II kinase inhibitor, penetrates embedded 
KIT/PDGFRA switch pocket by binding to extensively inhibit KIT/PDGFRA mutants. 
1.3.1 
Clinical summary 
As of the data cutoff 10 August 2019 of Investigator’s Brochure Version 5.0, Deciphera had 
finished two clinical studies and four clinical studies are on-going. The completed studies 
include two phase 1 clinical pharmacological studies in healthy subjects. On-going studies 
include a phase 1 study in patients with advanced malignant tumors (DCC-2618-01-001), a 
phase 1 study in patients with hepatic impairment (DCC- 2618-01-004), and two phase 3 
studies in GIST patients (INVICTUS, DCC-2618-03-001; INTRIGUE, DCC-2618-03-002). 
Study DCC-2618-01-001 is a study first conducted in human being and a open-label, 
ascending dose study in patients with advanced malignant tumors with molecular evidence. 
The primary objective of this study is to assess the safety, tolerability, preliminary efficacy, 
PK and PD effect of DCC-2618. The study consists of two parts: (1) Dose escalation phase; 
(2) Extension stage. 
In the dose escalation period, the safety of DCC-2618 administered  orally twice daily (BID) 
based on a 28-day cycle was evaluated according to 3+3 dose escalation rules as 
pharmacologically guided until confirming the maximum tolerated dose or recommended 
expansion dose. Plasma half-life of active metabolite may be very long (30 - 60 hours), 
administration daily is supported. Therefore, dosing regimen of DCC-2618 administered 
orally once daily (QD) is also evaluated. 
In the dose escalation period, 9 dose levels were evaluated: 20 mg BID, 30 mg BID, 50 mg 
BID, 100 mg BID, 150 mg BID, 200 mg BID, 100 mg QD, 150 mg QD and 250 mg QD. In 
the dose escalation period, three cases of dose-limiting toxicity occurred: one patient in 100 
mg BID group and 200 mg BID group respectively experienced asymptomatic grade 3 lipase 
increased; one patient in the 150 mg QD group experienced asymptomatic grade 4 creatine 
phosphokinase (CPK) increased. As specified in the protocol, the above lipase increased and 
creatine phosphokinase (CPK) increased are dose-limiting toxicities. Because patients did not 
have related symptoms, the investigator judged that they were not clinically significant. 
The MTD was not reached during the dose escalation phase. According to data of safety, 
tolerability, PK and efficacy observed in the dose escalation phase, it is suggested that the 
recommended phase 2 dose (RP2D) be 150 mg QD. At present, the 150 mg QD group in the 
dose expansion period is recruiting patients to further evaluate safety, PK, PD and inhibitory 
activity on multiple tumors with gene changes (DCC-2618 target). The expansion study will 


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recruit several groups of patients who have the following diseases: GIST, SM and other 
malignant hematological tumors, malignant glioma, other solid tumors, melanoma, soft tissue 
sarcoma, germ cell neoplasm, penis carcinoma, non-small cell lung cancer (NSCLC), solid 
tumors with renal insufficiency carrying KIT or PDGFRA mutations. 
As of 10 August 2019, 256 patients were enrolled to study DCC-2618-01-001 and received at 
least one dose of ripretinib. Therefore, these patients were included to safety population. 68 
out of 256 patients (26.6%) are still taking part in the study and continue receiving the study 
treatment. Patient recruitment has stopped for the dose escalation stage of the study, whereas 
it is underway for the dose expansion stage. 
Study DCC-2618-01-004 is an on-going, phase 1, open-label study to assess PK, safety and 
tolerability profile of ripretinib in patients with hepatic image defined based on Child Pugh 
classification compared with healthy subjects. The study plans to enroll about 40 subjects (a 
maximum of 24 patients with hepatic damage and a maximum of 16 matching healthy 
subjects). The study is enrolling subjects and clinical data was not available on data cutoff 
(10 August 2019). 
DCC-2618-03-001 (Invictus) is a phase 3, double-blind, placebo-controlled, randomized (at a 
2:1 ratio between the DCC-2618 group and the placebo group), multinational study 
conducted in patients with advanced gastrointestinal stromal tumors (GIST) who have 
received ≥ 3 prior treatments (including designated imatinib, sunitinib and regorafenib). The 
primary objective of this study is to evaluate the efficacy in the DCC-2618 group and the 
placebo group (independent radiology review based progression-free survival [PFS]). As of 
31 May 2019, 114 patients were exposed to ripretinib in study INVICTUS. Eighty-five 
patients receive randomized allocation and treatment with ripretinib at 150 mg QD. Forty-
four patients were randomized to receive placebo therapy (1 patient received randomized 
allocation but didn’t receive treatment; therefore, only 43 patients received placebo therapy). 
Another 29 patients receiving placebo have crossly given ripretinib treatment after disease 
progression based on IRR was determined.  
Study DCC-2618-03-002 (Intrigue) is a phase 3, interventional, randomized, multicenter, 
open-label study aiming to compare the efficacy of DCC-2618 and sunitinib in patients with 
advanced GIST after treatment with imatinib. It is planned that about 358 patients will be 
randomly assigned (1:1) into the test group and control group. About 115 study sites 
worldwide will take part in the study and the primary endpoint is IRR-assessed PFS. 
Recruitment of this study is underway. As of 10 August 2019, 38 patients had been enrolled. 
Specific information of two completed clinical studies can refer to relevant sections of 
Investigator’s Brochure Version 5.0. 
1.3.1.1 
Clinical Safety 
1.3.1.1.1 Study DCC-2618-01-001 


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The study is the first study of DCC-2618 in human subjects. As of August 10, 2018, a total of 
256 patients were exposed to the initially assigned dose of DCC-2618 in study DCC-26180-
1-001 (see Table 3), including 184 GIST patients (81%), 24 patients with brain carcinoma 
(11%), 5 patients with melanoma (2%), 4 SM patients (1.8%) and 10 patients with other solid 
tumors (4%). GIST patients enrolled in DCC-2618-01-001 have received 1 to 7 prior 
treatments. 
Table 3 Patients exposed to DCC-2618 in study DCC-2618-01-001 
 
Assigned dose 
 
Dose 
20 mg 
BID 
n (%) 
30 mg 
BID 
n (%) 
50 mg 
BID 
n (%) 
100 mg 
QD 
n (%) 
150 mg 
QD 
n (%) 
200 mg 
QD 
n (%) 
100 mg 
QD 
n (%) 
150 mg 
QD 
n (%) 
250 mg 
QD 
n (%) 
Total 
N 
Number 
of 
Subjects 
4 (1.6) 
4 (1.6) 11 (4.3) 12 (4.7) 7 (2.7) 
7 (2.7) 
6 (2.3) 
199 
(77.7) 
6 (2.3) 
256 
BID = twice daily; QD = once daily; N = total number of patients. 
Data cutoff date: 10 August 2019 
Regardless of the correlation with the investigational drug and dose level received by the 
reported case, TEAE (all levels) with an incidence ≥ 25% included: lassitude (50.4%), 
alopecia (46.5%), nausea (37.1%), myalgia (34.4%), constipation (32.4%), appetite decreased 
(31.3%), palmar-plantar erythrodysesthesia syndrome (30.9%), diarrhea (28.1%) and lipase 
increased (27.3%). 
As of 10 August 2019, of the 256 patients: 
Ninety-seven (39.2%) experienced at least one SAE during the study and most of which were 
not related to the investigational drug at the investigator’s discretion. According to the 
preferred term, the most common SAEs (≥ 5 cases) included: death (n = 16, 6.3%), 
abdominal pain (n = 15, 5.9%), cancer surgery (n = 9, 3.5%), breathing difficult (n = 8, 3.1%), 
anemia and septicemia (n = 7 for each, 2.7%), GIST and urinary tract infection (n = 5 for 
each, 2.0%). 
Thirty-six (14.1%) patients experienced at least one SAE related to the investigational drug at 
the investigator’s discretion. Thirty-three patients experienced ≥ grade 3 SAE related to the 
investigational drug at the investigator’s discretion, including: one case (0.4%) of grade 5 
myocardial infarction; one case (0.4%) of each of grade 4 blood creatine phosphokinase 
(CPK) increased, hyponatremia, lipase increased and pancreatitis; grade 3 SAEs included two 
cases 0.8% of each of blood bilirubin increased and pancreatitis; one case (0.4%) of each of 
dissection of aorta, deep vein thrombosis, heart failure, myocardiosis, cognitive disorder, 
diarrhea, diastolic dysfunction, ECG abnormality, enterocolitis, flushing, gastrointestinal tract 
bleed, hypertension, hypertriglyceridemia, hypotension, infection, lipase increased, 
myasthenia, non-cardiac chest pain, pain in extremity, plasma cell myeloma, pulmonary 
embolism, pyramidal tract syndrome, Syndrome Stevens-Johnson (SJS), and supraventricular 


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tachycardia (SVT). 
1.3.1.1.2 Study DCC-2618-03-001 
As of 31 May 2019, the most common TEAEs (≥ 25%) in patients who are randomized to 
ripretinib group in the double-blind stage included: alopecia (51.8%; placebo 4.7%), fatigue 
(42.4%; placebo 23.3%), nausea (38.8%; placebo 11.6%), abdominal pain (36.5%; placebo 
30.2%), constipation (34.1%; placebo 18.6%), myalgia (31.8%; placebo 11.6%), diarrhea 
(28.2%; placebo 14.0%) and appetite decreased (27.1%; placebo 20.9%). 
As of 31 May 2019, 26/85 patients (30.6%) and 19/43 patients (44.2%) in the ripretinib group 
and placebo group in the double-blind stage reported at least one case of SAE during 
treatment. Eight patients (9.4%) and three patients (7.0%) experienced at least one case of 
SAE related to the investigational drug. In the double-blind stage, SAEs (n ≥ 2) in the 
ripretinib (150 mg QD) treatment group included: abdominal pain (n = 4, 4.7%), anemia and 
death (n = 3 for each, 3.5%), nausea and vomiting (n = 2 for each, 2.4%). 
As of 31 May 2019, in the double-blind stage or long-term follow-up, a total of 25 patients 
died (12 patients received ripretinib treatment and 13 patients received placebo treatment). 
Most of the deaths were caused by disease progression (11 patients in each of ripretinib group 
and placebo group). Five patients (5.9%) in the ripretinib group and 10 patients (23.3%) in 
the placebo group died during the study treatment or within 30 days after the last dose. 
As of 31 May 2019, 6 patients (7.1%) in the ripretinib group and 1 patient (2.3%) in the 
placebo group reported AESI in the double-blind stage. 
Please refer to the Investigator's Brochure Version 5.0 for more detailed safety information. 
1.3.1.2 
Clinical Pharmacokinetics and Pharmacodynamics 
It was confirmed in non-clinical study that DP-5439 as an active metabolite had a similar 
activity with the original drug DCC-2618. Long half-life of metabolite (30 - 60 hours) 
supports the dosing regimen on a once daily basis. Food influence study showed that DCC-
2618 taken with food did not have influence on absorption. 
The mean T1/2 of DCC-2618 ranged from 8.04 - 11.1 hours and was evaluated only in the 
single dose group. Detected active metabolite DP-5439 was about 50 - 200% of the original 
drug (DCC-2618). Half-life of DP-5439 was not calculated. 
Study personnel compared the rate of accumulation of DCC-2618 and DP-5439 on C1D15 
and C1D1. For QD dosing regimen, in terms of Cmax and AUC0-12, the rate of accumulation of 
DCC-2618 was 0.725 - 1.47 and 0.707 - 1.69, respectively. In terms of Cmax and AUC0-12, the 
rate of accumulation of DP-5439 was 0.968 - 3.46 and 1.32 - 4.88, respectively. 
From 100 mg QD to 250 mg QD, exposure of DCC-2618 and DP-5439 was likely to be 
proportional to the dose. Because pharmacokinetices of the drug changes rapidly and sample 
size for each dose level was small, formal PK linear correlation assessment was not carried 


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out. 
For GIST patients who have received multiple prior treatments, DCC-2618 could rapidly 
eliminate plasma cfDNA with broad-spectrum KIT mutations. Overall, total plasma 
concentration (Cmax) in the 100 mg BID group on C1D15 was very high, more than 5 μM 
(3,000 ng/mL); the observed mean exposure was far more than the target plasma level, 
including exposure level for KIT mutations (V654A and T670I) most insensitive to DCC-
2618. 
At baseline, all GIST patients received next generation plasma free DNA sequencing (cfDNA) 
once every 2 cycles during the study. Mutations were tested and quantified with Guardant 
360 v2.9 or v2.10. Amino acid mutation only in KIT and PDGFRA was regarded as 
resistance-conferring mutations. Free DNA was not detected in all patients. According to the 
preliminary data, 19 unique gene mutations were observed in GIST patients with 11/29 KIT 
mutations. In exons 9. 11, 13, 14, 17 and 18, a total of 43 mutations were detected in KIT 
gene. Of 4 enrolled patients with PDGFRA D842V-mutation (confirmed according to 
previous archived results of patients), PDGFRA D842V-mutation was detected only in the 
sample of one patient. 
1.3.1.3 
Clinical Efficacy 
1.3.1.3.1 Study DCC-2618-01-001 
As of 10 August 2019, study personnel had obtained efficacy data of 178 evaluable patients 
(measured according to Response Evaluation Criteria In Solid Tumours [RECIST] Version 
1.1), including 142 GIST patients who received 150 mg QD dose. Study personnel analyzed 
PFS data according to the number of treatment. Data indicated that the number of patients 
who took DCC-2618 as second-, third-, fourth-line treatment and above was 31, 28, 46 and 
83, respectively; confirmed ORR was 19.4%, 14.3%, 10.9% and 7.2%, respectively; mPFS 
was 46.4 weeks, 36.3 weeks, 24.1 weeks, and 23.9 weeks respectively. 
1.3.1.3.2 Study DCC-2618-03-001 
Only efficacy data (n = 129) in the double-blind stage as of 31 May 2019 are listed. The 
median (95% CI) of PFS in the ripretinib group was 27.6 (20.0, 29.9) weeks and that in the 
placebo group was 4.1 (4.0, 7.3) weeks. Risk of disease progression or death in patients who 
received ripretinib treatment decreased by 85%, showing statistically significant difference 
with the placebo group (HR 0.15; stratified log-rank test P < 0.0001). At week 26, 51.0% of 
patients receiving ripretinib treatment and 3.2% of patients receiving placebo didn’t have 
disease progression (estimated PFS rate). 
Confirmed ORR was 9.4% in the ripretinib group and 0% in the placebo group (P = 0.0504, 
Fisher’s exact test); however, statistical significance was not reached. 
OS results of the placebo group included OS data of patients in the placebo group who 


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received ripretinib treatment crossly after IRR-assessed disease progression. During the final 
analysis, 29 patients (65.9%) in the placebo group were subject to crossover treatment in the 
treatment group and received at least one dose of ripretinib. Of 85 patients in the ripretinib 
group, 26 patients (30.6%) experienced OS events and 59 patients (69.4%) were censored. Of 
44 patients in the placebo group, 26 patients (59.1%) experienced OS events and 18 patients 
(40.9%) were censored. 
The median (95% CI) of OS in the ripretinib group was 65.6 (53.6, 65.6) weeks and that in 
the placebo group was 28.6 (17.9, 50.4) weeks. Compared with those in placebo group, the 
risk of death in patients receiving ripretinib decreased by 64% (HR 0.36; stratified log-rank 
test P = 0.0004). 
1.4 
Study rationale 
1.4.1 
Rationale for the Study 
There is no standard treatment for advanced or unresectable GIST patients after failure of 
imatinib, sunitinib and regorafenib. Secondary KIT mutations causing drug resistance are 
highly heterogeneous. Patients who failed prior treatments may have multiple acquired 
resistance-conferring mutations, and it is difficult to carry out clinical study in the population. 
There are very limited data that support the resuming of drugs which were ineffective in the 
past. A Korean, single-center, randomized, placebo-controlled study (RIGHT trial) showed 
that benefit from resuming imatinib (mPFS = 1.8 months) was less than that from using 
placebo (mPFS = 0.9 month)[28]. However, subgroup analysis in the study showed that 
accompanying symptoms of patients were not relieved[29], and health-related quality of life 
was assessed with EORTC QLQ-C30 questionnaire. RIGHT trial excluded patients who 
obtained limited benefit from initial imatinib treatment (defined as PFS ≤ 6 months). 
Therefore, patients who succeeded in initial imatinib treatment are inclined to be enrolled. 
Resuming imatinib is not the approved standard treatment worldwide. Many doctors choose 
imatinib as second-line treatment according to patients’ medical history. 
DCC-2618 is a pan KIT and PDGFRA inhibitor. In phase 1 study DCC-2618-01-001, all 
patients received adequate prior treatment and were resistant to TKI. DCC-2618 presented an 
encouraging anti-tumor effect (see Section 1.3.2 Clinical Summary for specific data). Phase 1 
study results were consistent with non-clinical study results, indicating that DCC-2618 was 
effective on all tested KIT and PDGFRA mutations. For GIST patients who have received 
adequate prior treatments and are resistant to TKI, DCC-2618 can significantly decrease 
allete frequency with KIT exons 13, 14, 17 and 18 and PDGFRA D842V resistance-
conferring mutations. The above observed clinical efficacy and decreased allele frequency 
support that DCC-2618 can effectively treat GIST patients who failed prior treatments (7 at 
most). 
In view of the above basis, Deciphera carried out a phase 3, double-blind, placebo-controlled, 


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randomized (at a 2:1 ratio between the DCC-2618 group and the placebo group), 
multinational study (Invictus) in patients with advanced gastrointestinal stromal tumors 
(GIST) who have received ≥ 3 prior treatments (including imatinib, sunitinib and regorafenib). 
Deciphera had submitted new drug application (NDA) to FDA in December 2019 based on 
data of studies DCC-2618-01-001 and DCC-2618-03-001 and FDA approval of marketing in 
US was obtained on 15 May 2020 for the treatment of four-line and higher advanced GIST 
patients (see Section 1.3.2 Clinical Summary for specific data). 
This study is a phase 2 bridge study in Chinese population. Considering that GIST 
epidemiology, pathogenesis, and clinical treatment practice are highly similar in Chinese and 
western populations, the study adopted single-arm design. Study population was consistent 
with the population in study Invictus, that is, advanced GIST patients who have received ≥ 3 
prior treatments (including designated imatinib, sunitinib and regorafenib). For patients who 
do not have standard treatment after failure of imatinib, sunitinib and regorafenib, their 
unsatisfied clinical demand was similar and comparable to study Invictus. This study 
evaluated the efficacy and safety of DCC-2618 and observed pharmacokinetic characteristics 
of DCC-2618 in Chinese GIST patients. If data of DCC-2618 in Chinese patients who 
received the same number of treatments were consistent with data obtained by study Invictus, 
and pharmacokinetic characteristics of DCC-2618 were consistent with that in foreign 
patients, it is supported that DCC-2618 can be used in this indication in China. 
1.4.2 
Rationale for Dose, Dosing Regimen, and Treatment Period 
1.4.2.1 
Dose Selection 
This section describes the scientific basis for selecting the dosing regimen of 150 mg QD of 
DCC-2618 for advanced GIST patients in the phase 3 study. Dose selection is based on non-
clinical pharmacology, clinical PK evaluation and PD results in phase 1 study (as of 1 June 
2017). 
1.4.2.1.1 In Vitro Pharmacology 
In vitro pharmacological study proved that DCC-2618 and its metabolite DP-5439 can 
potently inhibit wild-type, carcinogenic KIT mutants, and IC50 was 3 - 20 nM. See Table 5. 
The following table shows the available data of KIT inhibitors including imatinib, sunitinib 
and regorafenib for reference. Imatinib, sunitinib, regorafenib and DCC-2618 generated 
active metabolites. The following doses are mainly based on pharmacological characteristics 
of drug prototype compound. 


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Table 4 In vitro inhibitory effect on recombinant KIT and KIT mutants 
 
wt 
KIT 
KIT 
V654A 
Exon 13 
KIT 
T670I 
Exon 14 
KIT 
D816H 
Exon 17 
KIT 
D816V 
Exon 17 
KIT ΔV559- 
V560/D816V 
Exon 11&17 
IC50 (nM) 
Imatinib 
34 
606 
3500 
>10.000 
>10.000 
>10.000 
Sunitinib 
6 
3 
9 
1800 
2,200 
770 
Regorafenib 
3 
28 
7 
120 
>3,300 
>3,300 
DCC-2618 
3 
11 
8 
3 
8 
9 
DP-5439 
6 
15 
19 
20 
11 
n.d 
IC50 = median maximum inhibition concentration; n.d. = not determined; wt = wild type 
It is reported that unbound fraction (fu) of imatinib and sunitinib was same (5%), but in vitro 
effect of sunitinib (wide-type) was 6 times that of imatinib. For the treatment of GIST, daily 
dose of sunitinib (125 µmol, 50 mg) was 6.5 times lower than that of imatinib (810 µmol, 400 
mg) (based on molar dose ratio). It is reported that fu of regorafenib was 0.5%, 10 times 
lower than that of sunitinib, but in vitro effect was 2 times that of sunitinib. However, for the 
treatment of GIST, daily dose (331 µmol, 160 mg) of regorafenib was only 2.6 times that of 
sunitinib (based on molar dose ratio). This may be cause it has an inhibitory effect on more 
KIT mutants. 
In vitro fu of DCC-2618 to albumin and alpha-1-acid glycoprotein was 0.2% and 0.6-1.4%, 
respectively, closer to that of regorafenib (fu = 0.5%) than that of imatinib or regorafenib (fu 
= 5%). Molecular weight of DCC-2618 (510.4 Dalton) is slightly higher than that of 
regorafenib (482.8 Dalton). Therefore, for the treatment of GIST, estimated daily dose of 
DCC-2618 (294 µmol, 150 mg) was close to that of regorafenib (331 µmol, 16 0 mg). 
However, because inhibitory effect of DCC-2618 was stronger on KIT mutant exons 17 and 
11, its optimal dose may be lower. 
1.4.2.1.2 In Vivo Pharmacology 
In exon 11 mutant KIT GIST T1 cell line xenograft mouse model, within 8 hours after single 
oral dose of DCC-2618 at 50 mg/kg, inhibition rate of KIT signal transduction reached 69 - 
88%; within 12 hours after administration, the inhibition rate remained 40%. After orgal 
administration to the GIST T1 xenograft model, 50 mg/kg DCC-2618 could significantly 
inhibit tumor growth, with an inhibition rate reaching 90%. In imatinib-resistant GIST 
patient-derived xenograft (PDX) model, 100 mg/kg QD or 50 mg/kg BID DCC-2618 could 
completely stop tumor growth. In Kasumi-1 AML xenograft model expressing primary exon 
17 KIT mutation (N822KKIT), DCC-2618 100 mg/kg and 50 mg/kg showed stable efficacy, 
while imatinib 50 mg/kg BID was ineffective. 
According to in vivo pharmacological study, under the steady state, in terms of combining 
24-hour area under the time-concentration curve (AUC0-24hr) of DCC-2618 and DP-5439, it 


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was confirmed that target PK exposure for suppressing tumor growth was 10,000 ng*h/mL. 
1.4.2.1.3 Clinical Pharmacokinetic Evaluation 
Group PK analysis was carried out by collecting data of patients with advanced malignant 
tumors administered BID and QD from the ongoing phase 1 study (study DCC-2618-01-001; 
data cutoff 1 June 2017). Please see Figure 3 for model structure. PK characteristics of DCC-
2618 and DP-5439 were described through two-compartment model. Reservoir means the 
gastrointestinal tract with oral DCC-2618. KA is first-order absorption rate constant of DCC-
2618; K23 is the first-order rate constant of DCC-2618 metabolizing its active metabolite 
DP-5439 through CYP3A4/5. CL and CLM represent DCC-2618 clearance and DP-5439 
clearance through other enzyme pathways, respectively. It is assumed that central and 
peripheral volume of distribution of DP-5349 are similar to those of DCC-2618 to avoid 
over-parametrization. 
Figure 3 Drug pharmacokinetic model of DCC-2618 and DP-5439 in patients with 
advanced malignant tumors 
 
Although there were a few patients in each group, group analysis of combining data of BID 
and QD groups (total number = 44) showed PK of DCC-2618 and DP-5439 in cancer patients 
was dose proportionally. See Table 5 for steady-state PK exposure predicted by the model. 
Table 5 Typical steady-state exposure of DCC-2618 and DP-5439 predicted by models in 
patients with advanced malignant tumors 
Dose interval 
Dose 
Analyte 
Ctrough 
(ng/mL) 
Cmax 
(ng/mL) 
AUC24h 
(ng·h/mL)  
BID 
20 
DCC-2618 
131 
171 
3736 
DP-5439 
207 
225 
5211 
Combination 
338 
396 
8947 
30 
DCC-2618 
197 
257 
5603 
DP-5439 
310 
337 
7816 
Reservoir 
DCC-2618 
peripheral (V4) 
DCC-5439 
peripheral  
(V5 = V4) 
DCC-2618 
central (V2) 
DCC-5439 
central 
(V3=V2) 


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Dose interval 
Dose 
Analyte 
Ctrough 
(ng/mL) 
Cmax 
(ng/mL) 
AUC24h 
(ng·h/mL)  
 
 
联合 
507 
594 
13419 
50 
DCC-2618 
328 
428 
9339 
DP-5439 
517 
561 
13027 
Combination 
845 
989 
22366 
100 
DCC-2618 
655 
857 
18678 
DP-5439 
1034 
1123 
26054 
Combination 
1689 
1980 
44732 
150 
DCC-2618 
983 
1285 
28017 
DP-5439 
1551 
1684 
39081 
Combination 
2534 
2969 
67098 
200 
DCC-2618 
1311 
1714 
37356 
DP-5439 
2068 
2246 
52108 
Combination 
3379 
3960 
89464 
QD 
100 
DCC-2618 
249 
510 
9348 
DP-5439 
457 
609 
13041 
Combination 
706 
1119 
22389 
150 
DCC-2618 
373 
766 
14021 
DP-5439 
685 
914 
19562 
Combination 
1058 
1680 
33583 
Ctrough = concentration at the end of dose interval; Cmax = maximum concentration; AUC24h = 24-hour area 
under the time-concentration curve; BID = twice daily; QD = once daily 
Group PK analysis indicated after administering 30 - 200 mg BID or 100 - 150 mg QD DCC-
2618  to typical cancer patients, combining stable PK exposure (AUC0-24hr) of DCC-2618 and 
DP-5439 was more than 10,000 ng*h/mL efficacy threshold confirmed by xenograft mice 
institution. However, PK of DCC-2618 and DP-5439 observed in patients was highly variant. 
One hundred studies were simulated with group PK model and each study contained 100 
patients; the proportion of subjects reaching 10,000 ng*h/mL efficacy threshold was 
evaluated. Results showed that at a dose of 150 mg QD (estimated by comparing in vitro 
pharmacology), it was estimated that PK exposure of 93.6% of patients maintained over 
10,000 ng*h/mL. When it was simulated with 100 mg QD, it was estimated that 87.9% of 
patients would reach the efficacy threshold. 
1.4.2.1.4 Summary 
It is recommended oral DCC-2618 150 mg QD be taken the optimal dose regimen for the 
treatment of GIST for the following reasons: 
● 
Comparison of in vitro pharmacological properties between DCC-2618 and three 
approved target therapeutic drugs for the treatment of GIST showed that when treating 
GIST patients, effectively daily dose of DCC-2618 was ≤ 160 mg. 


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● 
In vivo pharmacological study in xenograft mouse model indicated that target 
combination PK exposure (AUC0-24hr = 10,000 ng*h/mL) of DCC-2618 and DP-5439 
could inhibit tumor growth. At the dose of oral 150 mg daily, it was estimated that 
exposure of 93.6% of patients maintained over the threshold. 
● 
Both in vitro and in vivo pharmacological data showed that 150 mg QD was an effective 
dose. 
● 
Safety data collected from phase 1 study support that the dose of 150 mg QD is the 
tolerable dose. 
Other considerations are as follows: 
● 
Compared with BID dosing regimen for reaching the effective exposure, administration 
once daily is more convenient and increases patient compliance. Therefore, 150 mg QD 
is better than 150 mg BID. 
● 
In view of significant individual difference in PK, doses lower than 150 mg may result in 
exposure of more patients lower than the effective exposure threshold. 
● 
For most patients (87.9%), it is estimated that a dose of 100 mg QD can reach the 
effective exposure threshold. If individual patient is unable to tolerate 150 mg QD, the 
dose can be reduced to 100 mg QD without influencing the efficacy. 
● 
Further PK-efficacy and PD-safety assessment proved that the optimal dosing regimen of 
DCC-2618 in GIST patients was 150 mg QD. 
1.4.2.2 
Dose escalation after PD 
Dose escalation of other TKIs (imatinib) has become a treatment choice for patients with 
primary and secondary drug resistance to standard dose of imatinib. 
On the basis of group PK model simulation, by using 150 mg QD regimen, it is estimated that 
about 93% of patients reach effective exposure threshold. In view of significant individual 
difference in PK, doses lower than 150 mg may result in exposure of more patients lower 
than the effective exposure threshold. Moreover, efficacy may be further improved 
progressively at higher doses. 
The sponsor recognizes the challenge of dose optimization and well monitored dose increase 
after independent radiology review-based disease progression to prevent that dose increase is 
effective but patients can’t tolerate it. 
Exploratory exposure of dose increase after independent radiology review-based disease 
progression is allowed in individual patient - results comparison, and it can provide important 
information for comprehensive safety and efficacy analysis. 
 
 


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2 
Study objectives 
2.1 
Primary Objectives 
● 
To evaluate the progress free survival (PFS) of DCC-2618 in patients with advanced 
gastrointestinal stromal tumors who have progressed with prior anticancer therapies 
based on independent radiologic review. 
2.2 
Secondary objective 
2.2.1 
Key secondary objective 
● 
To evaluate the objective response rate (ORR) of DCC-2618 in patients with advanced 
gastrointestinal stromal tumors who have progressed on prior anticancer therapies based 
on independent radiologic review. 
2.2.2 
Other secondary objectives 
● 
To evaluate overall survival (OS) in patients with advanced gastrointestinal stromal 
tumors treated with DCC-2618. 
● 
To evaluate the pharmacokinetic (PK) profile of DCC-2618 in patients with advanced 
gastrointestinal stromal tumors who have progressed on prior anticancer therapies. 
● 
To evaluate the safety of DCC-2618 in patients with advanced gastrointestinal stromal 
tumors who have progressed on prior anticancer therapies. 
2.3 
Exploratory objective 
● 
To evaluate the efficacy of DCC-2618 in the patients when the dosage is increased to 150 
mg BID. 
3 
Study design 
As mentioned above, global clinical development project of DCC-2618 has comprehensively 
studied the efficacy, safety and pharmacokinetics of the drug. DCC-2618 presented a good 
efficacy, safety, tolerability and pharmacokinetic characteristics in the patient population 
most of whom were western patients. The study is carried out to further confirm the efficacy, 
safety and pharmacokinetic characteristics of DCC-2618 in Chinese advanced GIST patients 
who failed standard treatment, 
3.1 
Overview of Study Design 
This study is a multicenter phase 2, single-arm open-label study of DCC-2618 to assess 
efficacy, safety, and pharmacokinetics in patients with advanced gastrointestinal stromal 
tumors who have progressed on prior anticancer therapies. 
This study targets at the patients with advanced gastrointestinal stromal tumors who have 
progressed on prior anticancer therapies. It is planned to enroll about 35 subjects in total. 


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Prior anticancer therapies must include imatinib, sunitinib, and one or two other drugs, and 
the number of patients who have previously received treatment with ≥ fourth-line drugs 
should be 40% or less. 
In this study, PFS based on independent radiologic review using RECIST v1.1-GIST Specific 
Standard is used as the primary efficacy measure for tumor efficacy assessment. 
After being fully informed, signing the informed consent forms and passing the screening, the 
subjects will receive DCC-2618 (150 mg, QD) continuously until the occurrence of an event 
for treatment termination as specified in the protocol, 28 days as a treatment cycle, followed 
by a safety follow-up period until 30 days after the termination of study treatment. 
During the study period, the subjects will be subject to visits as scheduled in the protocol. On 
the day of the scheduled visit as per the protocol, the subjects should bring the drug to the 
study site, where they will complete all the pre-dose examinations, and take the drug of the 
day after being suitable to continue the administration, in the discretion of the investigator. In 
the first four cycles (inclusive), an radiographic examination will be performed within ±7 
days of each cycle and tumor efficacy will be assessed according to RECIST v1.1-GIST 
Specific Standard. After that, it should be performed within ±7 days every two c ycles. 
If the subject discontinues treatment for reasons other than progressive disease, death, 
withdrawal of informed consent and loss to follow-up, the subject should receive 
radiographic examination for tumor assessment by independent radiologic review (IRR) after 
treatment withdrawal according to the frequency consistent with that during the study until 
presence of disease progression meeting "RECIST v1.1-GIST Specific Standard" or until 
starting of new anti-tumor therapy. 
Based on independent radiologic review, if a subject has a radiologically confirmed 
progression disease (PD), the subject can choose: 
○ 
To continue DCC-2618, at an increased dose of 150 mg BID, until the occurrence of 
an event for treatment termination as specified in the protocol; in the case of the 
efficacy evaluation for such patient, the lesion diameter before the increase of dosage 
(but not screening period) should be taken as the baseline value. 
○ 
To continue DCC-2618 at a dose of 150 mg QD, until the occurrence of an event for 
treatment termination as specified in the protocol, if the subject can benefit from the 
treatment with DCC-2618, but cannot tolerate the increase of dosage, after being 
fully assessed by the investigator; 
○ 
To terminate the treatment with DCC-2618. 
After subjects are enrolled into the study, PK blood samples will be collected according to the 
time specified in the protocol. 
After PK sampling, the subjects can continue the treatment with DCC-2618, safety visits and 


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efficacy evaluation, until the occurrence of an event for treatment termination as specified in 
the protocol. 
Treatment suspension or dosage reduction or treatment withdrawal is allowed at any time 
during the study for subjects with an intolerant toxicity reaction. 
3.2 
Number of subjects 
The study will enroll about 35 subjects (see section “Statistical Analysis) and carried out at 
about 10 study sites in China. 
3.3 
Study duration 
The study will be terminated when the last subject has been enrolled for 2 years or after the 
last visit of the last subject or on the sponsor's decision, whichever is the first. 
For patients still taking investigational drug after the clinical trial database has been closed, if 
the investigator thinks that they can get continuous clinical benefit and if the sponsor agrees, 
those patients may continue taking DCC-2618 until presence of disease progression, death, or 
intolerable toxicity, or their demand to discontinue treatment. Such patients will only be 
monitored for all serious adverse events until 30 days after the last dose of investigational 
product or the initiation of new anti-tumor therapies (whichever is the first). 
4 
Study Population 
4.1 
Inclusion Criteria 
The eligible subjects for this study must meet all of the following inclusion criteria: 
1. Male or female patients ≥18 years of age. 
2. Patients with histopathologically-confirmed advanced gastrointestinal stromal tumors. 
3. Subjects who have progressed on previous treatments with imatinib, sunitinib and one 
or two other drugs or have documented intolerance to any of these treatments. Note: 
A documented intolerance must be after the dosage adjustment (including suspension 
and reduction). 
4. ECOG PS of 0-2. 
5. Female patients of childbearing potential must have a negative serum beta-human 
chorionic gonadotrophin (β-hCG) pregnancy test at screening and negative pregnancy 
test at Cycle 1 Day 1 prior to the first dose of investigational drug. 
6. Patients of reproductive potential must agree to follow the contraception requirements. 
7. Patient is capable of understanding and complying with the protocol. Signed written 
informed consent before any study-related procedures were performed. 
8. Subject must have at least 1 measurable lesion (non-nodal lesions must be ≥ 1.0 cm in 


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the long axis or ≥ 2 times the slice thickness) according to the RECIST v1.1-GIST 
Specific Standard. A lesion with definite progression after local treatment can also be 
considered to be measurable. Radiographic examination results must be available 
within 21 days prior to the first dose of the investigational drug. 
9. Good organ function and bone marrow reserve function, including: 
● 
Neutrophil count ≥ 1,000/µL 
● 
Hemoglobin ≥ 8 g/dL 
● 
Platelet count ≥75,000/µL 
● 
Total bilirubin ≤1.5*the upper limit of normal (ULN) 
● 
AST and ALT ≤3*ULN, and AST and ALT≤5*ULN in the presence of hepatic 
metastases 
● 
Serum creatinine ≤1.5*ULN or creatinine clearance ≥50 mL/min (based on 
Cockcroft-Gault estimation) Formulas for calculation: 
Note: within 2 weeks prior to the above laboratory assessments, patients should not 
receive granulocyte colony-stimulating factor, interleukin-11 or infusion of red blood 
cells or platelets or other blood products. 
● 
Prothrombin time (PT) or international normalized ratio (INR) or partial 
thromboplastin time ≤1.5 × ULN. Patients on a stable, maintenance regimen of 
anticoagulant therapy for at least 30 days prior to investigational drug 
administration may have PT/INR measurements >1.5 × ULN if, in the opinion of 
the investigator, the patient is suitable for the study. An adequate rationale must 
be provided to the sponsor prior to randomization. 
10. Resolution of all toxicities from prior therapy to ≤Grade 1 (or baseline) within 1 week 
prior to the first dose of investigational drug (excluding alopecia and ≤ Grade 3 
clinically asymptomatic lipase, amylase, and creatine phosphokinase laboratory 
abnormalities). 
4.2 
Exclusion Criteria 
Subject meeting any of the following criteria should not be enrolled in this study: 
1. Treatment 
with 
anticancer 
therapy, 
including 
investigational 
therapy, 
or 
investigational procedures within 14 days or 5 x the half-life (whichever is longer) 
prior to the first dose of investigational drug. For prior biological therapies, eg, 
monoclonal antibodies with a half-life longer than 3 days, the interval must be at least 
28 days prior to the first dose of investigational drug. 
2. Prior treatment with DCC-2618. 


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3. Previously or currently has an additional malignancy that is progressing or required 
active treatment, which may interfere with the safety or efficacy evaluation of DCC-
2618. If the patient is receiving the adjuvant therapy that is likely to be effective for 
GIST or should be excluded based on the protocol (see Section 5.9.3), the patient 
should not be included in this study. 
4. Patient has known active central nervous system metastases. 
5. New York Heart Association class II - IV heart disease, active ischemia or any other 
uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac 
arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure. 
6. Arterial thrombotic or embolic events such as cerebrovascular accident (including 
ischemic attacks) or hemoptysis within 6 months before the first dose of 
investigational drug. 
7. Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg, 
pulmonary embolism) within 3 months before the first dose of investigational drug. 
Patients with venous thrombotic events ≥3 months before the first dose of 
investigational drug on conventional anticoagulation therapy are eligible. 
8. 12-lead electrocardiogram (ECG) demonstrating QT interval corrected by Fridericia's 
formula >450 ms in males or >470 ms in females at screening or history of long QT 
interval syndrome. 
9. Left ventricular ejection fraction (LVEF) <50% at screening. 
10. Use of strong or moderate inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, 
including certain herbal medications (eg, St. John's Wort) and consumption of 
grapefruit or grapefruit juice within 14 days or 5 x the half-life (whichever is longer) 
prior to the first dose of investigational drug. 
11. Use of known substrates or inhibitors of breast cancer resistance protein (BCRP) 
transporters within 14 days or 5 x the half-life (whichever is longer) prior to the first 
dose of investigational drug. 
12. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of 
investigational drug; Following major surgeries, >4 weeks prior to the first dose of 
investigational drug, all surgical wounds must be healed and free of infection or 
dehiscence. 
13. Any other clinically significant comorbidities, such as uncontrolled pulmonary 
disease, active infection, or any other condition, which in the judgment of the 
investigator, could compromise compliance with the protocol, interfere with 
interpretation of the study results, or predispose the patient to safety risks. 
14. Active viral infections such as human immunodeficiency virus, hepatitis B, hepatitis 


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C infection, etc. 
15. Female patients who are pregnant or lactating or who are expected to become 
pregnant during the study treatment period 
16. Known hypersensitivity to any component of the investigational drug. Patients with 
Stevenson Johnson syndrome in previous TKI treatment need to be excluded. 
17. Gastrointestinal abnormalities including but not limited to: 
● 
inability to take oral medication 
● 
malabsorption syndrome 
● 
Requiring intravenous nutrition 
18. Any active hemorrhages, excluding hemorrhoids or gum bleeding. 
4.3 
Procedure for handling of subjects who are enrolled incorrectly 
Patients who do not meet the inclusion criteria should not be enrolled in the study, and no 
exceptions will be allowed to the specification. Subjects found to be ineligible for inclusion 
should not initiate the study treatment and must withdraw from the study. In the event of a 
subject who does not meet the inclusion criteria  but is unintentionally given the 
investigational drug, the investigator should immediately notice the Sponsor. On the 
protocol-specified visit date, the subject should be asked to bring the investigational drug to 
the study site and not to take it until the pre-dose assessments are completed. 
5 
Study Treatment and Management 
Therapeutic drug in the study is DCC-2618. 
5.1 
Description of investigational drug 
Strength of DCC-2618 is 50 mg tablets taken orally. Formulation of active pharmaceutical 
ingredients (API) of tablet is 25% w/w amorphous dispersions and Hypromellose Acetate 
Succinate (grade H [HPMCAS-HG] multimer matrix [33.33%]). Other excipients include 
microcrystalline cellulose (Avicel PH-101) (29.84%), lactose 310 (29.83%), crosslinked 
polyvinylpyrrolidone (5%), fumed silica (CabOSil M5P) (1%) and magnesium stearate (1%). 
5.2 
Investigational Products 
The investigational drug can be distributed only under the supervision of the investigator or 
authorized designated personnel and administered to subjects of the study only. 
The investigator or designated personnel should instruct subjects to take the investigational 
drug according to the protocol; 
● 
The investigational drug should be taken at the same time each day as far as 
possible. 


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● 
You can take it before or after a meal. 
● 
The investigational drug should be taken as a whole, not squashed, chewed or 
dissolved in food or liquid. 
● 
Subjects should record medication date, time and dose from 3 days before PK 
sampling to the date of PK sampling. 
● 
On the visit date specified in the protocol, the subject should bring the drug to the 
study site, complete all pre-dose examinations, and evaluate as appropriate by the 
investigator before taking the drug on the same day. Administration date, time and 
dose should be recorded. 
If the dose is increased to 150 mg BID, the investigator or designated personnel should 
instruct subjects to take the investigational drug according to the protocol. 
● 
Subjects should take the investigational drug twice daily with an interval of at least 6 
hours at the same time every day. 
● 
Other requirements are same as administration at 150 mg QD. 
If subjects forget to take the investigational drug at the predetermined time, subjects who 
receive 150 mg QD administration can take the missed dose within 8 hours and subjects who 
receive 150 mg BID administration can take the missed dose within 4 hours. The missed dose 
of the investigational drug should not be taken more than 8 hours or 4 hours after the 
predetermined time. The investigational drug can be taken at the predetermined time next 
day. On the protocol-specified visit date, subjects were instructed to bring their medication to 
the study site and not to take their study medication until the pre-dose assessments were 
completed. 
If subjects vomit immediately after taking the investigational drug, the dose should not be 
supplemented and prophylactic antemetics can be used before the next dose. 
5.2.1 
Dose escalation 
DCC-2618 will be continued after the subject has radiologically confirmed disease 
progression based on independent imaging review and the dose was escalated to 150 mg 
twice daily (BID) until the protocol-specified event of treatment discontinuation; For the 
assessment of efficacy in this part of patients, the diameter of the lesion before dose 
escalation (not at screening) should be used as the baseline diameter. 
On the basis of independent radiology review, when subjects experience disease progression, 
they should be informed of other optional treatments. 
5.3 
Dose interruption and modification for investigational drug 
Treatment interruptions or dose reductions or treatment termination will be permitted at any 
time during the study for subjects who experienced intolerable toxicity; study treatment may 


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be interrupted for subjects who experience toxicity, but no longer than 28 consecutive days of 
discontinuation. If subjects resume administration, the investigational should arrange 
subsequent visits according to the predetermined visit cycle and it is not influenced by drug 
discontinuation. 
5.3.1 
Dose discontinuation caused by medical procedures 
If subjects need to undergo a surgery during the study, the degree of surgery and wound 
healing speed should be considered. It should be handled according to the following 
principles: 
● 
Planned minimally invasive surgery: discontinue the investigational drug 3 days in 
advance, resume the investigational drug 3 days after the surgery. 
● 
Planned major surgery: discontinue the investigational drug at least 5 days in 
advance; the investigator should discuss with the sponsor to determine when to 
resume the investigational drug after surgery. 
● 
Unplanned major surgery: discontinue the investigational drug immediately; the 
investigator should discuss with the sponsor to determine when to resume the 
investigational drug after surgery. 
5.3.2 
Dose interruption and dose reduction due to adverse events 
Treatment suspension and/or dosage reduction of the investigational drug or treatment 
termination will be allowed at any time during the study for subjects with an intolerant 
toxicity reaction of any levels. If the drug is resumed after dose suspension, calculation of 
visit cycle should be based on the predetermined arrangement and not influenced by dose 
suspension. See Table 6 for dose adjustment regimen. 
If subjects can’t tolerate 50 mg QD or experience disease progression based on independent 
radiology review after dose reduction, the study treatment should be terminated and subjects 
should enter the safety follow-up period and start survival follow-up. 
All dose interruptions, reductions (including missed doses), downtitration, or uptitration, and 
reasons must be recorded on the eCRF form. 
Table 6 DCC-2618 Dose Modification Scheme 
 
Initial dose 
First reduction 
Second reduction 
Initial Patient 
150mg QD 
100mgQD 
50mg QD 
Patients whose 
dosage are increased 
to 150 mg BID after 
disease progression 
150mg BID 
100mgBID 
150mg QD 
If the adverse event resolves to grade 1 or baseline level and the drug is resumed, the subject 
will be allowed to resume the drug at the dose when the adverse event occurred. If the dose 


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for the subject has been reduced to the first reduced dose and the adverse event resolves to 
grade 1 or baseline level, the subject will be allowed to resume the drug at the initial dose. If 
the subject has experienced two consecutive reductions and the adverse event resolves to 
grade 1 or baseline level, the subject will be only allowed to resume the drug at the first 
reduced dose for at least one cycle (28 days) continuously and then use the drug at the initial 
dose. 
If the adverse event does not resolve to grade 1 or baseline level within 28 days, the study 
treatment should be discontinued, unless the investigator evaluates that the adverse event is 
not clinically significant. After discussing with the sponsor, there may be an opportunity to 
resume the drug at a dose reduced by one level. 
Table 7 Handling of dermatological toxicity and joint pain/myalgia and principles of 
dose adjustment 
Severity of AE 
Handling of AE and dose adjustment principles 
Grade 1 
Provide symptomatic and supportive treatment, and continue the drug at the original 
dose. 
Grade 2 
Provide symptomatic and supportive treatment, and continue the drug at the original 
dose. 
If the AE is not improved within 7 days, the treatment should be withheld: 
● 
If the AE resolves to grade 1 or baseline level within 7 days, the drug can be 
resumed at the original dose; 
● 
If the AE resolves to grade 1 or baseline level within 7 days, the drug can be 
resumed at a lower dose level; 
If the AE occurs for the second time, regardless of the time of resolving to grade 1 
or baseline level, the drug can be resumed at a lower dose level. 
After reducing the dose, if AE remains grade 1 or baseline level for at least 2 
consecutive cycles (56 days), the dose can be increased by one level. 
Grade 3 
Symptomatic and supportive treatment 
 
Withhold the invstigational drug for at least 7 days or until the AE resolves to grade 
1 or baseline level (28 days at most). 
● 
Resume medication at a lower dose level. 
After reducing the dose, if AE remains grade 1 or baseline level for at least 2 
consecutive cycles (56 days), the dose can be increased by one level. 
Grade 4 
Discontinuation of study treatment. After the investigator evaluates and discusses 
with the sponsor, for non-life-threatening adverse events, medication can be 
continued. 
Any Grade 
Stevens-Johnson syndrome 
If patients have Stevens-Johnson syndrome (SJS), the investigational drug must be 
discontinued permanently. Patients should be sent to hospital immediately to 
receive clinical assessment and supportive treatment according to institutional 
guidance. Because there is risk of recurrence of SJS, the investigational drug should 
not be administered again. 
 


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Table 8 Handling of hypertension and principles of dose adjustment 
Severity of AE 
Handling of AE and dose adjustment principles* 
Grade 1 (systolic BP 120-139 mmHg, 
diastolic BP 80-89 mmHg) 
Start blood pressure monitoring;  
The original dose was continued. 
Grade 2 (systolic blood pressure 140 - 
159 mmHg, diastolic blood pressure 
90 - 99 mmHg or elevation > 20 
mmHg (diastolic blood pressure), 
with accompanying symptoms or 
elevation of previous normal blood 
pressure to 140 / 90 mmHg) 
Adopt antihypertensive therapy to make diastolic blood pressure 
≤ 90 mmHg or systolic blood pressure 140 ≤ mmHg. 
● 
If previous blood pressure is in the normal range, 
monotherapy can be adopted; 
● 
If the subject has previously adopted antihypertensive 
therapy, the dose should be increased; 
The original dose was continued. 
If the blood pressure elevates by > 20 mmHg (diastolic blood 
pressure) and there are accompanying symptoms, the treatment 
should be withheld until symptom resolution or diastolic blood 
pressure ≤ 90 mmHg; 
Medication can be resumed at the original dose. 
Grade 3 (systolic blood pressure ≥ 
160 mmHg, diastolic blood pressure ≥ 
100 mmHg) or one additional drug 
required or more aggressive treatment 
required 
Adopt antihypertensive therapy to make diastolic blood pressure 
≤ 90 mmHg or systolic blood pressure 140 ≤ mmHg. 
● 
Initiation of antihypertensive therapy and/or 
● 
Increase the intensity of antihypertensive treatment and/or 
● 
Add additional antihypertensive therapy 
 
If there are accompanying symptoms, the treatment should be 
withheld until diastolic blood pressure ≤ 90 mmHg and/or systolic 
blood pressure ≤ 140 mmHg and symptom resolution; 
Medication can be resumed at the original dose. 
If the blood pressure is inadequately controlled after adding one 
drug or enhancing antihypertensive therapy, the dose should be 
reduced by one level; 
If grade 3 hypertension occurs again, regardless of whether the 
dose has been reduced or antihypertensive therapy has been 
adopted, the dose should be reduced by one level again. 
Grade IV (life threatening) 
Handle according to treatment principles of local hospital;  
Discontinue the treatment with the investigational drug. 
* 
If the blood pressure can be stably controlled within one cycle, the dose can be increased after 
investigator assessment. 
Table 9 Treatment of AEs except for dermatological toxicity and joint pain/myalgia and 
hypertension and principles of dose adjustment 
Severity of AE 
Handling of AE and dose adjustment principles 
Grade 2 weight loss 
or other grade 3 or 4 
AEs 
Withhold treatment until the AE resolves to grade 1 or baseline level; 
● 
Reduce by one dose level; 
● 
If the subject can tolerate the reduced dose level and the same AE does not 
occur for at least 3 consecutive cycles, the former dose level can be 
restarted; 


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Severity of AE 
Handling of AE and dose adjustment principles 
Asymptomatic grade 
3 or 4 laboratory 
abnormality 
(including CPK and 
lipase) for ≤ 10 days 
Monitor clinical symptoms closely and continue medication at the original dose; 
If related clinical symptoms are accompanied, treatment with the investigational 
drug should be withheld. 
If the investigator considers after evaluation that medication should be restarted 
for the patient’s benefit, it is necessary to discuss with the sponsor to decide 
whether to restart medication. 
Asymptomatic grade 
3 or 4 laboratory 
abnormality 
(including CPK and 
lipase) for > 10 days 
Monitor clinical symptoms closely; for grade 4 AEs, the treatment should be 
withheld until the AE resolves to grade 3; 
● 
For asymptomatic CPK and lipase increased, the treatment does not need to 
be withheld; 
Once the AE resolves to grade 3, the drug can be resumed at the original dose or a 
lower dose level as per the decision of the investigator and the sponsor. 
Clinically significant 
grade 3 or 4 
laboratory 
abnormality 
(including CPK and 
lipase) for > 10 days 
If related clinical symptoms are accompanied, treatment with the investigational 
drug should be withheld. 
If the investigator considers after evaluation that medication should be restarted 
for the patient’s benefit, it is necessary to discuss with the sponsor to decide 
whether to restart medication. 
 
5.4 
Drug Packaging and Labeling 
DCC-2618 provided by the sponsor is tablets, 50 mg/tablet, and will be packaged in high 
density polyethylene bottles sealed with child-resistant closures, 30 tablets/bottle. 
Drug label will be prepared according to regulations. 
5.5 
Drug storage 
DCC-2618 must be stored at 5 - 25 ℃ (41 - 77 °F). Seal up, protected from light and 
moisture (such as places close to shower of the bathroom). The allowed storage temperature 
range is  2 - 27 ℃ (35.6 - 80.6°F).  
Study sites should store the drugs at safe places with temperature monitoring and can obtain 
the drugs after obtaining authorization. 
5.6 
Medication compliance 
In order to ensure subjects’ compliance, the investigator or designated personnel should 
supervise all administrations at the site. At each visit, the investigator or designated personnel 
should review subject compliance and remind subjects of medication requirements. 
If subject compliance is poor and not improved after education and training, the treatment 
should be discontinued. 


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5.7 
Responsibilities for Reception, Storage, and Management of Investigational 
Drugs 
It is the responsibility of the investigator to manage the investigational products and 
equipment on its study site that are provided by the sponsor. The investigational products and 
supplies must be recorded accurately in accordance with the protocol and national laws and 
regulations, supplied as required by the study at any time and maintained, stored, dispensed, 
used and disposed according to the regulations. The investigator should designate a person to 
receive, store, dispense and return all investigational drugs during the study, and to record the 
dispensing accurately. Drug dispensing management form should include subjects’ 
identification number, quantity of the drugs and drug bottles dispensed and returned. The 
return of the drug from the subject to the study site should be marked as "returned" to 
separate from the drug not yet dispensed. 
All dispensing and management records should be accessible to the Sponsor for review. 
Study monitors will verify according to drug dispensing management form and stored drugs. 
Designated drug managers will dispense the investigational drugs according to the study 
protocol and drug management manual and cooperate with monitors’ audit. 
5.8 
Drug Recovery and Destruction 
Subjects should be instructed to return all used and partially used drug bottles. The 
investigator or the designated personnel should correctly record all dispensed and returned 
investigational drugs, including date, quantity and patients who used the drug. Unused 
investigational drugs should be uniformly returned after the end of study to the sponsor for 
uniform destruction. 
5.9 
Prior and Concomitant Medications 
5.9.1 
Previous treatments 
Previous treatments (including drug therapy and non-drug therapy and surgery) should be 
recorded from 30 days prior to signing the informed consent form and recorded in the 
original medical record and eCRF. 
5.9.2 
Prior Anti-Cancer Therapy 
Any prior anti-tumor therapies should be recorded in the original medical record and eCRF. 
5.9.3 
Concomitant medication 
All concomitant medications during the study, including vitamin supplementation, non-
prescription medication and herbal medicines (generic name of drug, administration purpose, 
administration dose and time, etc.) must be recorded in the original medical record and the 
eCRF in detail from the date of the first dose to 30 days after the last dose. 


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5.9.3.1 
Drugs Allowed to be Used 
Subjects can use drugs for improving symptoms (e.g., analgesics, laxative and antiemetics). 
Drugs (e.g., antacid) for increasing pH value of gastric juice are allowed to be used , as long 
as they are not used within 2 hours before and after taking the investigational drug. 
5.9.3.2 
Drugs to be avoided or used with caution 
The following drugs should not be used or used with caution: 
● 
Potent or moderate inhibitors or inducers of CYP2D6, CYP2C8 or CYP2E1. For 
related drugs, please refer to the website of the Indiana University, School of 
Medicinehttp://medicine.iupui.edu/clinpharm/ddis/main-table/ 
● 
Known substrates or inhibitors of P-glycoprotein 1 (permeability glycoprotein, also 
known as multidrug resistance protein 1 or MDR1). Refer to the website of FDA for 
related 
inhibitors: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc 
es/DrugInteractionsLabeling/ucm093664.htm#table5-2 
and 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc 
es/DrugInteractionsLabeling/ucm093664.htm#table5-1 for MDR1. 
● 
Known substrates of OATP1B1 and OATP1B3. Refer to FDA website for related 
drugs: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc 
es/DrugInteractionsLabeling/ucm093664.htm#table5-1 
● 
Drugs metabolized through CYP2C8, CYP2C9, CYP2C19 or CYP2D6. For related 
drugs, please refer to the website of the Indiana University, School of Medicine: 
http://medicine.iupui.edu/clinpharm/ddis/main- table/ 
For example: 
○ 
Warfarin can be used under close monitoring since the investigational drug has 
an inhibitory effect on CYP2C9. 
○ 
Clopidogrel should be avoided. The activity of clopidogrel should be dependent 
upon CYP2C19. The efficacy of clopidogrel may be reduced if combined with 
the investigational drug. 
Considering that taking the investigational drug and the above drugs simultaneously may 
have potential drug interaction, any of the above drugs should be taken under close 
monitoring. 
5.9.3.3 
Prohibited Drugs 
Some drugs and foods are prohibited from the start of the screening period to the end of 


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safety follow-up in this study. The following drugs should be prohibited: 
● 
Potent or moderate inhibitors or inducers of CYP3A4, including some herbal 
medicines (e.g., St. John's wort), should be discontinued 14 days or 5 x half-life 
prior to the first dose of the investigational drug (whichever is longer). For related 
drugs, please refer to the website of the Indiana University, School of Medicine: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
● 
Grapefruit or grapefruit juice should be discontinued 14 days prior to the first dose 
of the investigational drug. 
● 
Known substrates or inhibitors of BCRP transporter should be discontinued 14 days 
or 5 x half-life prior to the first dose of the investigational drug (whichever is 
longer). 
For 
related 
drugs, 
please 
refer 
to 
FDA 
website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource 
s/DrugInteractionsLabeling/ucm093664.htm 
● 
Anti-tumor therapy, including investigational treatment, should be discontinued 14 
days or 5 x half-life prior to the first dose of the investigational drug (whichever is 
longer). For prior biological therapies, eg, monoclonal antibodies with a half-life 
longer than 3 days, the interval must be at least 28 days prior to the first dose of 
investigational drug. 
5.9.4 
Accompanying treatment 
All treatment operations must be recorded in the original medical record and the eCRF in 
detail from the date of the first dose to 30 days after the last dose. 
Surgical resection or palliative radiotherapy during the study (including the intensive blood 
collection period) should not be conducted before communication with the Sponsor. If the 
investigator or the sponsor considers this meets subjects’ best benefit, surgical resection or 
palliative radiotherapy can be performed. However, in PFS analysis, subjects should be 
deleted. 
5.10 
Other Notice to Applicants 
To relieve potential risks of photostimulation/phototoxicity, patients should be instructed to 
avoid strong sunlight, fluorescent lamp and other ultraviolet radiation sources during the 
study. It is suggested all patients adopt protective skin care measures, including: sunscreen 
cream with a sun protection factor ≥ 30, hypoallergenic moisturizing cream or ointment 
suitable for dry skin, cleaning and caring the skin with soaps and detergents not containing 
perfume. 
5.11 
Channels to access the investigational drug after the end of the trial 
The study endpoints and discontinuation criteria are based on disease progression by 
independent imaging review, so there is no plan to provide investigational drug or other study 


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intervention to patients after the end of the study or after any patient has withdrawn 
prematurely. The Sponsor will evaluate the possibility to continue providing DCC-2618 to 
study patients after the primary study endpoint and safety data collected in the study are 
evaluated. 
6 
Visit Schedule and Assessments 
Visit schedule of the study is shown in Table 1. All times should be recorded in a 24-hour 
format (e.g., 23:20 other than 11:20 PM). 
6.1 
Screening 
Before starting any study-related procedures, the informed consent form signed by the 
patients must be obtained. 
The screening period was limited to 21 days. 
For the screening test, if the patient is routinely examined during the diagnosis and treatment 
of GIST and completed within the corresponding time limit required by the protocol (such as 
21-day screening window,7 days before the first dose of investigational drug, etc.), and the 
test requirements of the protocol are met, The results of these tests may be used as screening 
assessments if earlier than the informed consent is signed. 
6.2 
Re-screening 
Subjects can receive re-screening after obtaining the approval of the sponsor. If patients have 
received re-screening, except for ophthalmological examination, other assessments in the 
screening period should be performed again. If radiographic examination and dermatologic 
examination are performed 21 days prior to the first dose of the investigational drug, the 
examinations are not need to be performed again. Patients can be re-screened once only. If 
patients enter re-screening, the screening window will be calculated after the start of the re-
screening. 
6.3 
Study period 
After confirming patients meet the inclusion criteria, the drug will be administered once on 
Day -7. Intensive blood collection will be carried out after that. Hospitalization is suggested 
during intensive blood collection. Continuous administration starts on C1D1 and subjects 
enter the study treatment period. See Table 1 for visits in the study period. All study visits 
should be carried out in the window. 
All subjects who withdraw treatment should carry out visit at study site within 7 days after 
the last dose. 
6.4 
Follow-up 
All subjects will receive safety follow-up 30 days (± 5 days) after the last dose and ask 
subjects through telephone adverse events after the last dose and drug therapies including 


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anti-tumor therapy and other treatments. 
Survival follow-up should be carried out once monthly after that to ask subjects through 
telephone survival status and anti-tumor therapy condition. 
6.5 
Lost to Follow-up 
If the following two conditions are met, it will be considered subjects are lost to follow-up: 
● 
The subject has missed two consecutive visits and can’t be contacted through 
telephone after the second missed visit (contacting through telephone for 3 times 
within 2 weeks). 
● 
After the subject can’t be contacted through telephone for 3 times, a registered mail 
is sent to the subject, but the subject does not reply within 2 weeks. 
6.6 
Study evaluation 
This section will describe special assessments during the study in detail. See Table 1 for 
conventional assessments. 
At any time during the study, if clinically indicated, unscheduled safety and efficacy 
assessment can be carried out. 
6.6.1 
Time points assessed 
Examinations will be carried out according to time points described in Table 1. 
6.7 
Informed Consent Form 
All patients should sign a written informed consent form before carrying out any procedures. 
The informed consent form approved by the sponsor, institutional review board 
(IRB)/independent ethics committee (IEC) should be used. The investigator should record 
informed consent process, including date of signing the informed consent form. 
6.8 
Assigned Subject No. 
Each patients will be assigned a subject number after signing the informed consent form. If 
the patient receives re-screening, the original subject number will be used. 
6.9 
Demographics and Medical History 
Demographic data must be collected during the screening period. 
Tumor history and prior treatments (including reasons for treatment discontinuation): 
● 
Known GIST histological diagnostic results. 
● 
KIT/ PDGFRA gene mutation status. 
● 
All prior anti-neoplastic therapies, including 
● 
Surgery: including surgery date, site and method (e.g., only tumor tissue samples are 


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collected or R0, R1 and R2) 
● 
Systemic therapy: including treatment date, drug (including dose and dosing 
regimen), treatment purpose (e.g., adjuvant therapy or treatment for metastases), best 
response, date of progressive disease or other reasons and date for treatment 
discontinuation. 
● 
Radiation therapy: including site, total dose, date and treatment efficacy. 
● 
Other treatments: such as radiofrequency ablation, including site, date and treatment 
efficacy. 
Other medical history: any clinically significant diseases prior to signing the informed 
consent form should be collected during the screening period to evaluate whether patients 
have diseases listed in the inclusion and exclusion criteria. Medial history should include 
review of all organ and system, prior medical and surgical history and allergic history. 
Diseases that still exist when signing the informed consent form will be regarded as 
concomitant diseases and the starting date should be recorded. 
6.10 
Efficacy 
6.10.1 Radiographic examination 
All subjects will receive radiographic examination of the chest, abdomen and pelvis. See 
Table 1 for arrangement of time points. 
Radiographic examination during the Screening Period should cover the chest, the abdomen 
and the pelvis (within 21 days before the first dose). Only abdomen and pelvis are examined 
during the study; for patients with pulmonary metastases in the screening period or 
pulmonary metastases symptoms during the study at the investigator's discretion, chest 
examination should be performed during the study. It is performed once in each of the first 
four cycles (including Cycle 4), and then once in every two cycles (e.g., Cycles 6, 8 and 10). 
Radiographic examination must be performed within 21 days before the first dose of drug. 
Radiographic examination performed before signing an ICF can be used in the Screening 
Period as long as it is performed within 21 before the first dose and the examination method 
and result comply with the protocol. Radiographic examination can be performed within ± 7 
days of the scheduled visit . On the basis of independent radiology review, patients assessed 
as CR or PR in the first assessment should undergo confirmation at least 4 weeks later. 
Enhanced scan should be performed. If subjects are allergic to CT enhancer, MRI can be 
performed for abdominal and pelvic examinations and CT for chest examinations as long as 
examination methods are consistent during the study. Ultrasound examination cannot be 
performed. 
If the subject discontinues treatment for reasons other than progressive disease, death, 
withdrawal of informed consent and lost to follow-up, the subject should receive radiographic 


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examination for tumor assessment by IRR after treatment withdrawal according to the 
frequency consistent with that during the study until presence of disease progression meeting 
"RECIST v1.1-GIST Specific Standard" or until starting of new anti-tumor therapy, 
whichever is the first. 
Copies of all radiographic scans should be obtained and, according to the regulations, sent to 
the independent imaging supplier designated by the sponsor. The independent imaging 
supplier will assess imaging quality and be responsible for independent radiology review. 
Independent imaging supplier must ensure independent radiology reviewers are blinded to 
investigator's assessment and other information. Before any independent radiology review, 
this procedure and all other radiographic images procedures will be recorded in the specified 
review rules of protocol between the sponsor and the independent imaging supplier. 
Independent radiology reviewers and investigators will assess tumor response based on 
RECISTv1.1-GIST Specific Standard. Response confirmed by investigators will be recorded 
in the eCRF. Data from independent radiology review will be used for primary endpoint 
analysis. 
Confirmation of absence of progressive disease: if independent radiology reviewers 
confirm there is no progressive disease, the patient will continue to receive treatment with the 
investigational drug, unless there are medical needs requiring discontinuation of the 
investigational drug (that is, rapid progression or clinical worsening). If investigators confirm 
progressive disease according to clinical worsening, scan should be performed and reviewed 
by independent radiology reviewers to confirm whether the patient has progression. Basis of 
confirming progressive disease as per clinical worsening should be recorded in patients' 
source documents and eCRF. 
Confirmation of progressive disease: subjects who have radiologically confirmed 
progressive disease on the basis of independent radiology review can continue DCC-2618 
treatment at a dose increased to 150 mg, BID; subjects who can benefit from DCC-2618 
treatment but cannot tolerate the increased dose will continue DCC-2618 treatment, 150 mg 
QD; or discontinue DCC-2618 treatment. If subjects use the drug at the original dose, dose 
escalation will not be performed in the future. 
6.10.2 Survival follow-up 
All subjects should receive survival follow-up until withdrawal of consent inform, lost to 
follow-up or death for any reasons. After the safety follow-up, the investigator should call the 
subject to follow-up the survival status and anti-tumor therapy once monthly (± 5 days).  
6.11 
Safety 
Safety was assessed based on changes from baseline in physical examination, ECOG score, 
vital signs, ECG, left ventricular ejection fraction, dermatological examination and laboratory 


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parameters, and reported adverse events. 
6.11.1 Physical examination 
Comprehensive physical examination should be carried out in the screening period, including 
head/neck/thyroid gland, eye/ear/nose/throat, respiratory system, cardiovascular system, 
lymph node, abdomen, skin, muscle and musculoskeletal and nervous system. Breast, 
anorectum and reproductive organ examination will be carried out only if clinically indicated. 
Targeted examinations can be carried out during the study (including the intensive blood 
collection period) according to clinical symptoms and subjects’ chief complaints. 
After the screening period, any clinically significant abnormal physical examinations must be 
recorded as AEs. 
6.11.2 ECOG score 
ECOG scoring will be carried out according to Table 1 before or after administration. 
6.11.3 Vital sign and height 
The time points of vital signs, including blood pressure, heart rate, respiration and body 
temperature, will be as specified in Table 1. Patients were to rest in a seated or recumbent 
position for at least 5 minutes before starting the examination. 
Height is measured at the screening visit only. 
6.11.4 Electrocardiogram 
12-lead ECG examination will be performed according to Table 1-2 Schedule or at the time 
when any cardiac-related adverse event occurs during the study. 
ECG examination should follow the following regulations: 
● 
12-lead ECG must be performed at least 15 minutes after the patient has a rest (in a 
supine or semi-recumbent position). 
● 
ECG examination should be carried out before administration. 
All ECG assessment items include: 
● 
Heart rate 
● 
PR interval 
● 
QT interval: QTcB (Bazett’s corrected QT interval [QTcB = QT/(60/heart rate)0.50] 
and QTcF(QTcF = QT (60/heart rate)1/3) 
● 
QRS wave group 
● 
RR interval 


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6.11.5 Echocardiogram 
All echocardiograms will be performed at time points outlined in Table 1 Schedule of Study 
Visits and may be used as a screening examination as long as the patient's echocardiogram is 
within 21 days prior to the first dose and is in compliance with protocol requirements. Left 
ventricular ejection fraction should be recorded in the original medical record and the eCRF. 
6.11.6 Dermatologic examination 
Dermatologic examination should be carried out according to the study visit schedule in 
Table 1 or if clinically indicated. The examinations must cover the whole skin. Special 
attentions should be paid to squamous cell carcinoma of skin, actinic keratosis and 
keratoacanthoma. If the dermatological examination is performed before signing an ICF, it 
can be used as one performed during the Screening Period provided that the examination is 
performed within 21 before the first dose and as per the protocol. Any new or changed skin 
damages from baseline during the study (including the intensive blood collection period) 
should be recorded in the original record and the eCRF. Once it is suspected as squamous cell 
carcinoma of skin or keratoacanthoma, biopsy skin should be carried out at study site and it 
should be diagnosed by qualified pathologist. 
6.11.7 Ophthalmological examination 
Ophthalmological examination should be carried out according to the study visit schedule in 
Table 1. If clinically indicated, consultation by qualified ophthalmologist should be carried 
out. 
Examination includes anterior structures (including cornea, anterior chamber, iris and lens) 
and posterior structures (including optic nerve, yellow spot, retinal blood vessels, peripheral 
retina and vitreous body); intraocular pressure and vision should be evaluated. 
Ophthalmological examination may not be repeated during the Screening Period, provided 
that it has been performed within 28 days before signing an ICF on the patient who 
discontinued previous anti-tumor therapy, with the examination report available, and that the 
examination conforms to the requirement of the protocol. 
6.11.8 Laboratory test 
All laboratory test time points will be performed according to the schedule of study visits in 
Table 1, and the test may be added according to the clinical judgment of the investigator. 
All findings must be documented in the original medical record and recorded in the eCRF. 
Abnormal laboratory test results, if considered to be clinically significant by the investigator, 
should be recorded as AEs. 
Grade of laboratory test results should be judged in accordance with NCI-CTCAE V4.03. 
The laboratory test items are shown in Table 10: 


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Table 10 Clinical laboratory tests 
Serum biochemistry 
Hematology and Coagulation 
Urine routine 
Glucose 
Blood urea nitrogen or urea 
Creatinine 
Haemoglobin 
● 
Mean corpuscular hemoglobin 
● 
Mean corpuscular hemoglobin 
concentration 
 
 
 
Na 
● 
Mean corpuscular hemoglobin 
volume 
Protein 
K 
Hematokrit 
Occult blood 
Ca 
PLT 
Specific gravity 
Mg 
WBC 
Ketone bodies 
P 
Reticulocyte 
Glucose 
Bilirubin 
total 
and 
Bilirubin 
direct 
Alkaline phosphatase 
Aspartate aminotransferase 
Differential and absolute white 
blood cell count: 
● 
Neutrophils 
● 
Basophil (BASO) 
 
Alanine aminotransferase 
Lactic dehydrogenase 
Creatine phosphokinase 
● 
Eosinophils 
● 
Lymphocyte 
● 
Monocytes 
 
Total protein 
Blood coagulation function test 
Albumin 
Activated partial thromboplastin 
time1 
Globulin 
Prothrombin time 
Triglyceride 
International normalized ratio 
Lipase 
 
Amylase 
 
Thyroid function test 
Thyrotropic hormone 
Tri-iodothyronine free 
Free thyroxine 
 
 
1 
For patients taking anticoagulants, coagulation tests will be performed according to Table 1. During 
the study, the blood coagulation function must be monitored according to appropriate clinical needs in 
case of any change in the dosage of anticoagulants. 
6.11.9 Pregnancy tests 
Serum pregnancy test needs to be performed on women of childbearing age within 7 days 
before the first dose, which is to be followed by a urine pregnancy test on Day 1 of each cycle 
as well as at the end of the study treatment, for confirmation of a negative result. 
Female subjects without reproductive potential don’t need to receive pregnancy test, defined 
as postmenopausal patients (amenorrhoea ≥ 12 months, follicle stimulating hormone ≥ 40 
mIU/ mL) or patients with complete ovariectomy or amputation of uterus. 


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6.11.10 Contraception 
Influence of DCC-2618 on sperm, conception, pregnancy and breastfeeding is unknown. 
Subjects with reproductive potential should agree to adopt effective contraceptive methods. 
Male subjects and female subjects of childbearing potential should use adequate 
contraception during the study and for 6 months after discontinuation. 
6.11.11 AE 
All AEs should be evaluated, recorded and reported in accordance with ICH-GCP. Definition 
of AE, collection period, standard and procedure of recording, judgment and reporting of 
grade will be described in detail in Chapter 7. 
6.11.12 Safety follow-up 
All patients will receive safety follow-up to collect information of AEs and drug therapies 
including anti-tumor therapy and other treatment operations until 30 days (± 5 days) after the 
last dose. 
6.12 
Pharmacokinetics 
6.12.1 Blood sampling 
In the study, intensive blood collection will be carried out in the first 10 - 15 enrolled subjects 
to measure blood concentration of DCC-2618 and its metabolite DP-5439. 
Hospitalization  is suggested for patients subject to intensive blood collection. Blood samples 
need to be collected on D-7 first, which is followed by administration with the drug once, and 
then intensive blood sample collection without taking the investigational drug until D-1. 
Collect blood sample once first for C1D1, which is to be followed by continuous 
administration with investigational drug from C1D1. The PK blood sampling schedule is 
presented in Table 11. 
 


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Table 11 Pharmacokinetic blood sampling time points 
Study 
period 
Time points of PK intensive blood collection (hour) 
Pre-
dose 
(-1h) 
0.5±2  
min 
1±3  
min 
2±5  
min 
4±10  
min 
6±10  
min 
8±20  
min 
12±20  
min 
24±1h  
48±1h  
72±1h  
96±2h  
120±2h  
144±2h  
168±2h  
D-7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C1D15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
D1 
(C2-C4) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Except for subjects subject to intensive blood collection, other subjects don’t need to receive 
intensive blood collection, but sparse blood collection should be carried out. The specific 
sampling time points are 6 hours ± 10 minutes after administration on C1D1, within 60 
minutes before administration and 6 hours ± 10 minutes after administration on C2D1; three 
PK samples will be collected from each subject at each sparse time point. Actual 
administration time and actual blood collection time should be accurately recorded. 
Unscheduled blood samples may be requested by the Sponsor at the time of certain treatment-
related AEs. 
Bioanalysis laboratory will measure plasma sample concentration with LC-MS/MS. 
If the dose was withheld due to adverse events in the first cycle and the subject is unable to 
receive steady-state intensive PK sampling at the predetermined visit, the investigator should 
discuss with study doctor of Zai Lab to determine whether the subject needs steady-state PK 
sampling in subsequent therapy. If necessary, steady-state PK sampling can be carried out at 
any time. 
After PK sampling, the subjects can continue the treatment with DCC-2618, safety visits and 
efficacy evaluation, until the occurrence of an event for treatment termination as specified in 
the protocol. 
Sample collection, labeling, processing, storage and transportation should be carried out in 
accordance with laboratory manual. 
6.12.2 Blood samples and data analysis 
After obtaining blood concentration of DCC-2618 and metabolite DP-5439 after single dose 
and multiple doses, the following PK parameters will be calculated with non-compartment 
model, including but not limited to Cmax, Tmax, AUC and T1/2, etc. If necessary, group PK 
analysis of pharmacokinetic data will be carried out with industrial standard software on the 
basis of other clinical study data. Group PK report will be drafted independently and not 
regarded as the appendix of this study report. 
7 
Recording, grading and reporting of adverse events and serious adverse 
events 
7.1 
Definition of adverse events (AEs) 
An adverse event is any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. Example of AEs include, but not limited to adverse signs (including 
abnormal findings in laboratory test) and symptoms, conditions that have a temporal 
relationship with use of investigational drug, regardless of causal relationship to the 
investigational product. AEs include new events or previous diseases with deteriorated 


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severity or frequency after signing the informed consent form. Adverse events include serious 
adverse events (SAEs) and non-serious adverse events. 
Planned hospitalization or surgery for underlying disease and potential disease progression 
before screening should not be reported as an AE, unless the disease deteriorates accidentally 
during the study (e.g., surgery performed in advance). 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as an AE. However, if diseases causing the implementation of these procedures 
meet regulations of AE in this protocol, they should be reported as an AE; in addition, if 
implementation of these procedures cause adverse influence to patients, they should be 
reported as an AE. 
The severity must be judged immediately after the occurrence of an AE to confirm whether it 
is a SAE. 
7.2 
Judgment of severity 
The investigator should confirm and record the severity of all AEs. 
Severity of AEs should be evaluated from grade 1 to 5 on the basis of Common Terminology 
Criteria for Adverse Events (CTCAE). 
For adverse events without designated CTCAE grade, criteria recommended by CTCAE may 
be referred to. 
Grade I (mild) 
Temporary symptom, treatment not indicated, subject’s daily activities not 
influenced. Asymptomatic or mild symptoms; clinical or diagnostic observations 
only; 
Grade II (moderate) 
Mild discomfort in subject, daily activities slightly influenced, minimal, local or 
noninvasive intervention indicated; 
Grade III (severe) 
Intolerant symptoms, daily activities significantly influenced, drug therapy or 
other interventions indicated 
Grade 4 (Life 
Threatening) 
Life-threatening; urgent intervention indicated 
5 (Death) 
Results in death 
7.3 
Determination of drug relationship 
The investigator should evaluate the causality between adverse event and the investigational 
drug according to the following table: 
Related 
Definitely 
related 
Adverse event is related to administration of the investigational drug, there is 
rational possibility between the occurrence of the event and the 
investigational drug, and other reasons except for the investigational drug 
have been excluded; and/or the event reoccurs when the investigational drug 
is resumed 
Probably 
related 
Adverse event is related to administration of the investigational drug, there is 
rational mechanism between the occurrence of the event and the 
investigational drug, and the event cannot be rationally explained by 


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patients’ clinical conditions, or there is not other obvious cause 
Possibly 
related 
Adverse event is related to administration of the investigational drug and 
there is rational mechanism between the occurrence of the event and the 
investigational drug; however the event may be induced by other causes, 
such as patients’ clinical conditions and features of underlying diseases. 
Unrelated 
Possibly 
unrelated 
Adverse event is possibly not related to the investigational drug but possibly 
related to other factors. It is more rational to explain from other aspects (such 
as concomitant medications, concomitant diseases), or the causal relationship 
would be impossible in terms of temporal relation. 
Unrelated 
The adverse event is related to other cause than the investigational drug (this 
cause should be recorded in the original medical record of the patient) 
7.4 
Measures Taken to the IMPs 
The investigator must clarify measures to the investigational drug due to AE. Measures taken 
to the investigational drug are shown in the following table: 
Category 
Definition 
Unchanged dosage 
AE doesn’t lead to dose adjustment 
Dose reduction 
AE leads to dose reduction 
Treatment 
discontinuation 
AE leads to dose interruption 
Permanent 
discontinuation 
of 
drug 
AE results in permanent discontinuation of drug 
Not applicable 
Select “not applicable” in case of any of the following conditions: 
● 
AE occurs before the administration of the investigational drug; 
● 
The subject died suddenly during treatment, so it is unable to take measures to 
investigational drug for this event; 
● 
The investigational drug has been discontinued before the occurrence of the 
AE; 
● 
The subject didn’t take the drug when the AE occurs and the occurrence of the 
AE will not influence subsequent medication plan. 
7.5 
Outcome of adverse event 
The investigator must follow all AEs until the final outcome. Outcome of AE can be recorded 
according to the following table: 
Category 
Definition 
Recovered 
AE recovered, without sequela 
Recovered, with 
sequela 
AE recovered, with sequela 
Select “not recovering/not resolving/persistent” for irreversible congenital 
anomaly. 
For other irreversible diseases, select “recovered, with sequela”. 
Recovering/resolving 
AE resolving and recovering 
Not 
recovering/not 
resolving/persistent 
AE not recovering, persistent 


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Category 
Definition 
Death 
Outcome of AE is death. Only when the death is possibly related to AE, can 
“Death” be used 
Unknown 
Outcome of AE is unknown, such as subject lost to follow-up 
The investigator is required to continue to follow up any adverse event that has not recovered 
at the last visit of the study until the event is recovered or stable or resolved to baseline level 
or stable state of chronic diseases or it is unable to obtain more information (e.g., refusing to 
be followed up or lost to follow-up). Subsequent follow-up visits may not be entered into the 
eCRF, but the sponsor considers that there is a right to request further information from the 
investigator if necessary. 
7.6 
Treatment measures taken for AEs 
The investigator should ensure appropriate medical care for any AEs. In addition, the 
investigator should record whether treatment measures have been taken for AE. If treatment 
measures have been given, such as other drugs, hospitalization, surgery or physiotherapy, 
“yes” should be recorded; if the above treatment is not given, “no” should be recorded. 
7.7 
Other considerations for AE 
Evaluation of clinical significance 
Laboratory test, ECG, physical examination and vital signs will be evaluated during the study 
and clinically significant abnormalities should be recorded as AEs. If possible, disease 
diagnosis should be first used as the name of adverse events (e.g., urinary tract infection and 
anemia). If the diagnosis is unable to be confirmed, abnormal test findings will be reported as 
AE (e.g., bacterial in urine or haemoglobin decreased). If the diagnosis is confirmed later, the 
diagnosis should be additionally recorded as an adverse event. If subjects meet one or several 
of the following conditions, abnormal study assessment will be regarded as clinically 
significant: 
● 
Persistent deterioration from baseline, accompanied with corresponding symptoms 
or signs. 
● 
Further diagnostic tests or drug/surgical therapies required. 
● 
Leading to change in dose of the investigational drug, such as drug discontinuation 
or treatment termination. 
The above criteria are not applicable to retesting to ensure whether test value is abnormal. 
Whether the study assessment is clinically significant should be judged by the investigator. 
Grade 4 laboratory test indicator may be not a SAE, unless the patient’s clinical status shows 
it is a life-threatening AE. 
Symptoms of the studied disease should not be taken as AEs as long as these symptoms are 
progressive or expected progressive disease, including obvious deterioration, unless 


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deterioration is not caused by progressive disease and is part of the efficacy data the study 
will collect. 
7.8 
Defination of SAEs 
An SAE is a serious adverse event that occurs during the course of a clinical trial and may 
include: 
● 
Events leading to death; 
● 
A life-threatening event (defined as an event in which the subject was at risk of death 
at the time of the event, not an event that hypothetically might have caused death if it 
were more severe); 
● 
Events requiring hospitalization or prolongation of hospitalization; 
● 
An event that results in permanent or significant disability/ incapacity/ impairment of 
work; 
● 
Results in congenital abnormality or birth defect; 
● 
Other important medical events, defined as an event that may not lead to death, be 
life-threatening, lead to hospitalization, but may jeopardize the subject or may 
require medical intervention to prevent one of above listed outcomes (e.g., allergic 
bronchospasm, aggressive treatment at emergency or home required, cachexia or 
convulsion, or drug dependence or drug abuse). 
The following were not to be reported as SAEs: 
● Any outcome, including death, due to progression of the patient's primary tumor 
disease as assessed by the investigator. 
● Hospitalization or prolonged hospitalization due to economic issue or for purpose of 
reimbursement only. 
● Elective surgery scheduled prior to the start of study treatment. 
● Prescription or study-related examinations can be carried out only during 
hospitalization for hospital management reasons 
7.9 
Adverse Events of Special Interest (AESIs) 
The following adverse events occurring after starting of the investigational drugs require 
special interest: 
● Squamous cell carcinoma of skin 
● Actinic keratosis 
● Keratoacanthoma 
Patients with squamous cell carcinoma of skin, actinic keratosis and/or keratoacanthoma 


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should be managed according to dermatologist and local guidance. 
For the above adverse events of special interest, it is required to fill in the "AESIs Report 
Form" within 24 hours upon the investigator's awareness, and report to the sponsor via email: 
saereporting@zailaboratory.com. If the event meets the criteria for an SAE, it is required 
to fill in the “Clinical Study SAEs Report Form” and it will be reported directly to the 
sponsor according to the SAE reporting process. 
7.10 
Time Limit for Collection of Adverse Events 
Collection and recording of adverse events (including SAE and AESI) will be carried out 
throughout the study, from the date of signing the informed consent form (ICF) to 30 days 
after the last dose of the investigational drug; if the patient starts new anti-tumor therapy, the 
deadline for collection of AEs will be the date of starting new anti-tumor therapy; any SAEs 
or AESIs occurring after the time limit for collection of AEs should be reported immediately 
if suspected to be possibly related to the investigational drug. 
7.11 
Requirements for reporting AE, SAE and AESI 
Whether AE occurs should be monitored seriously in each subject. Information of AEs can be 
obtained by non-induced questions to subjects (e.g., how do you feel?) , signs and symptoms 
of clinical examination, observation of subjects and chief complaints of subjects. Information 
of AEs obtained by the above methods should be recorded in the original medical record and 
the eCRF. 
If possible, disease diagnosis should be first used as the name of adverse events. If a unifying 
diagnosis is not available, then associated symptoms and signs are to be captured. Once the 
diagnosis is confirmed with the follow up information, the symptoms and sign should be 
replaced with diagnosis accordingly. 
Any SAE occurring during the reporting period, whether or not related to the investigational 
drug, should follow the SAE reporting procedures of the relevant regulatory authorities or the 
Independent Ethics Committee. 
The investigator should: 
(1) If necessary, take appropriate medical measures immediately to ensure the safety of 
patients; 
(2) Record SAEs in the AE Form, SAE Form and source documents of eCRF. 
(3) The investigator should immediately fill in the “Clinical Study SAEs Report Form”, 
sign the name and date, and report it to the sponsor within 24 hours upon awareness 
of the event (public email mailbox of Drug Safety Department in Zai Lab: 
saereporting@zailaboratory.com). 
(4) The course of the event was to be followed up and documented until recovery or 


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return to baseline values or until a clinically stable status was reached or the 
investigator agreed with the sponsor that no further follow-up was necessary. For the 
purpose of study analysis, events that are not recovered during the study report 
period should be recorded as persistent. 
DCC-2618 may be continued until disease progression, death, or intolerable toxicity, or 
patient's request to discontinue treatment, in the opinion of the investigator, for patients who 
remain on investigational drug after the clinical trial database has been closed, if clinical 
benefit is sustained, Such patients will only be monitored for all serious adverse events until 
30 days after the last dose of investigational product. The investigator should still collect 
information of drug management and accountability until all patients have finished the 
treatment. 
● 
Treatment of Death Cases 
All deaths occurring during the study, including within 30 days after the last dose of 
investigational drug, during the safety follow-up period of the last dose of investigational 
drug will be reported by the investigator as follows: 
○ 
If death is caused by disease progression, the investigator should notify the 
Sponsor's monitor of the event in the next site monitoring visit and record it in 
relevant section of eCRF, but it will not be reported as a SAE. 
○ 
If it is not determined whether the death is caused by disease progression, the AE 
should be reported as a SAE, informed to the monitor and reported to the relevant 
parties within 24 hours; the SAE report should evaluate whether the disease 
progression jointly contributed to the death of the subject and indicate the main 
cause of death and other related factors, as appropriate. 
○ 
Death cases with unknown causes must be reported within a specified time-line in 
accordance with the SAE, and the cause of death should be clarified with every 
effort. Autopsy may be conductive to assessment on the cause of death. If an autopsy 
is performed, the Sponsor should be notified of the autopsy report. 
● 
Reporting and follow-up of AESI 
AESI occurring in the reporting period should be reported to the sponsor within 24 hours of 
awareness. Follow-up on AESI will be pursued until they are recovered/resolved to the 
baseline level or clinically stable or the investigator and the sponsor consistently consider 
follow-up is not required. For the purpose of study analysis, events that are not recovered 
during the study report period should be recorded as persistent. 
● 
Suspected unexpected serious adverse reaction (SUSAR) 
If SUSAR related to the investigational drug occurs, the sponsor should expeditedly report to 
relevant regulatory authorities and all investigators and clinical trial institutions and ethics 


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committee taking part in the clinical trial. After receiving the relevant safety information of 
the clinical trial provided by the sponsor, the investigator should sign and read it in time, and 
consider whether to make corresponding adjustments to the treatment of the subject. If 
necessary, the investigator should communicate with the subject as soon as possible, and 
should report to the ethics committee SUSAR provided by the sponsor. 
● 
Pregnancy 
Effective contraception is required for both male and female subjects of childbearing 
potential during the trial and for 6 days after discontinuation of investigational drug. If a 
subject is found to be pregnant following initiation of study treat, the investigational drug will 
be permanently discontinued and the subject will be withdrawn from the trial. If a partner of a 
male subject becomes pregnant during the study or within 6 months after the last dose of 
investigational drug, the investigator should be informed immediately. The investigator must 
fill in the “Clinical Study Pregnancy Exposure Reporting Form” and expeditedly report to the 
sponsor 
via 
email 
upon 
24 
hours 
of 
becoming 
aware 
of 
pregnancy 
(saereporting@zailaboratory.com). At the same time, the pregnancy also must be recorded 
on eCRF. All pregnancies must be followed to conclusion to determine their outcome. If the 
outcome of the pregnancy meets SAE criteria (e.g., spontaneous abortion/miscarriage or 
therapeutic abortion with any detected congenital anomaly, stillbirth, neonatal death, or birth 
defect), it will be reported as SAE. The investigator should send the completed “SAE 
Reporting Form” to the Sponsor via email within 24 hours of becoming aware of the event. 
All pregnancies during the trial or within 180 days after discontinuation should be handled in 
accordance to the procedure described above. If necessary, the follow-up period will be 
prolonged to newborn. 
7.12 
Drug abuse, misuse, overdose and medical errors 
Events related to drug abuse, misuse, overdose and medical errors should be reported to the 
sponsor. 
AEs and SAEs related to drug abuse, misuse, overdose and medical errors should be recorded 
and reported according to corresponding requirements. 
Note: Unintentional missing drug does not belong to medical error that must be reported. 
8 
Subject Withdrawal and Replacement 
8.1 
Subject withdrawal 
Subjects can withdraw from the study or discontinue study treatment at any time. As long as 
clinical condition of subjects support, the investigator can discontinue subjects’ treatment at 
any time. Reasons for subjects’ treatment discontinuation or withdrawal from study may 
include the following types: 
● 
Adverse Event 


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● 
Death 
● 
Lost to Follow-up 
● 
Poor compliance 
● 
Investigator's decision 
● 
Pregnancy 
● 
After the first progressive disease based on independent radiology review, subjects 
who are unsuitable for dose escalation or continuing treatment at the original dose as 
per the investigator’s assessment should discontinue the treatment. 
● 
Progressive disease occurs again based on the investigator’s assessment after 
increasing the dose to 150 mg BID. 
● 
Protocol deviation 
● 
Site Closure by Sponsor 
● 
Termination of the study by the sponsor 
● 
Subject's requests to withdraw 
● 
The investigator considers the subject must discontinue the treatment for the 
subject’s benefit. 
If the subject discontinues treatment for reasons other than progressive disease, death, 
withdrawal of informed consent and lost to follow-up, the subject should receive radiographic 
examination for tumor assessment by independent radiologic review (IRR) after treatment 
withdrawal according to the frequency consistent with that during the study until presence of 
disease progression meeting "RECIST v1.1-GIST Specific Standard" or until starting of new 
anti-tumor therapy, whichever is the first. 
If the subject voluntarily withdraws from the study, the investigator should contact the 
subject and ask the subject the reasons for treatment discontinuation and request the subject 
to return to study site to finish end of treatment visit (EOT) and safety follow-up and 
afterwards receive survival follow-up. 
Subjects who discontinue treatment for other reasons must receive end of treatment (EOT) 
visit and safety follow-up and afterwards receive survival follow-up. 
Patients should be asked to return all unused investigational drugs as far as possible. 
In any case, the patient's final condition, particularly safety information, should be fully 
documented as far as possible. 
8.2 
Subject replacement 
The study does not allow subject substitution. 


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9 
Statistical Analysis 
Please refer to Statistical Analysis Plan (SAP) for details of statistical analysis. Statistical 
Analysis Plan will be finalized before database locking. All changes in previously defined 
analytical procedures will be described in the final clinical study report (CSR). 
Data cutoff of the study is 6 cycles after the last subject has been enrolled to the study or the 
time when at least 21 cases of IRR-based PFS have occurred in all enrolled patients, 
whichever occurs first, and the data will be locked for analysis. 
9.1 
Determination of sample size 
This phase 2 bridging study is to prove the efficacy of DCC-2618 in Chinese patients is 
consistent with or similar to that in global patients using the primary endpoint of 
progression‑free survival (PFS) on the basis of independent radiologic review. 
Standard definition of bridging study success (consistent or similar): mPFS of ripretinib in 
Chinese patients will be statistically longer than 1 month, that is, the lower limit of bilateral 
90% confidence interval of the observed mPFS is longer than 1 month. Statistical hypothesis: 
H0: mPFS is 1 month; Ha: mPFS is 2.5 months; bilateral significant level is 0.1; assumed 
enrollment duration is 6 months; follow-up duration is 2 months; drop-out rate is 15% under 
at least a 90% test power; approximately 35 subjects should be enrolled to meet the test 
purposes. 
9.2 
Endpoints of study analysis 
9.2.1 
Primary endpoints 
9.2.1.1 
Efficacy 
● 
Progression‑free survival (PFS) based on independent radiologic review: assess PFS 
according to "RECIST v1.1-GIST Specific Standard" which include: 
● 
Lymph nodes cannot be taken as target lesions; enlarged lymph nodes will be 
followed as non-target lesions. 
● 
Bone lesions cannot be taken as target lesions; 
● 
Positron emission tomography (PET) cannot be used in efficacy assessment; 
● 
According to "RECIST v1.1-GIST Specific Standard", new tumor nodules within 
the pre-existing tumor lesion that are gradually growing must meet the following 
criteria before being determined as definite progression: (a) The lesion diameter 
should be at least 2 cm and confirmed as active GIST lesion (for example, using 
contrast or other criteria for enhanced scanning to rule out the possibility of false 
appearance); Or (b) At least 2 consecutive radiographic examinations indicative of 
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9.2.2 
Secondary endpoints 
9.2.2.1 
Key secondary endpoints 
9.2.2.1.1 
Efficacy 
● 
ORR based on independent radiology review: objective response rate, confirmed CR + 
confirmed PR. 
9.2.2.2 
Other secondary endpoints 
9.2.2.2.1 
Efficacy 
● 
Overall survival (OS) 
● 
TBR based on independent radiology review 
● 
PFS based on investigator’s assessment 
● 
Disease control rate (DCR,  CR+PR+SD) on Week 12 based on independent radiologic 
review 
9.2.2.2.2 
Safety 
● 
Incidence and severity of treatment emergent adverse event (TEAE), adverse event of 
special interest (AESI) and serious adverse event (SAE) during the study (including 
intensive blood collection); severity will be assessed based on NCI-CTCAE V4.03. 
● 
Incidence of adverse events resulting in dose adjustment, suspension and termination of 
the investigational drug; 
● 
Changes from baseline in ECOG score, vital signs, ECG, left ventricular ejection 
fraction, dermatological examination and laboratory parameters. 
9.2.2.2.3 
Pharmacokinetics 
● 
After obtaining blood concentration of DCC-2618 and metabolite DP-5439 after single 
dose and multiple doses, the following PK parameters will be calculated with non-
compartment model, including but not limited to Cmax, Tmax, AUC and T1/2, etc. 
9.2.3 
Exploratory endpoint 
9.2.3.1 
Efficacy 
● 
PFS2 based on investigator’s assessment: it is defined as the period from the first dose of 
investigational drug (150 mg, BID) to the first documented tumor progression or death 
from any cause (whichever is the first) after the dosage is increased to 150 mg (BID). 
9.3 
Analysis data sets 
1) Intent-to-treat (ITT) - Subjects having signed the Informed Consent Form and been 
included in the trial. 


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2) Full analysis set (FAS): All patients who use at least one dose of the investigational 
drug. 
3) Safety set (SS): All patients receiving at least one dose of the investigational drug. In 
the study, the definition of SS is consistent with FAS. SS is the main population for 
safety indicator analysis. 
4) Efficacy analysis set (EAS): all subjects who enter the treatment period and have 
received at least one dose of the investigational drug, that is, all the patients who 
have started to receive continuous treatment with the investigational drug since 
C1D1. 
5) PK analysis set: all subjects who received at least one dose of the investigational 
drug and have at least one blood concentration data of DCC-2618 or DP-5439 after 
administration. 
6) Per protocol population (PP): subjects in FAS population who do not have expected 
protocol violations influencing efficacy and/or safety assessment (e.g., the enrolled 
patient does not comply with critical qualification criteria). Definition of per 
protocol population will be confirmed before database locking. The PP-based 
analysis will support the FAS-based analysis. 
9.4 
Statistical methods 
9.4.1 
General methods 
Data collected in the study will be presented using summary tabulations and patients data 
tabulations. Continuous variables will be summarized with descriptive statistics (number of 
patients, mean, median, standard deviation, minimum and maximum). Categorical variables 
will be summarized with frequency and ratio. Time-event data will be summarized with the 
25th, 50th (median) and 75th percentile and relevant bilateral 90% confidence interval using 
Kaplan-Meier (KM). 
Unless otherwise specified, baseline measurement values should be the latest values prior to 
the first dose of the investigational drug. If not assessed, the last assessment before the visit 
will be used. 
Medical Dictionary for Regulatory Activities (MedDRA) will be used to code medical 
history, adverse event and concurrent diseases. Prior and concomitant medications will be 
coded according to the Drug Dictionary of World Health Organization (WHODrug). 
9.4.2 
Subject disposition 
All subjects who enter this study (that is, signing informed consent forms) will be 
summarized. In addition, number of subjects of each analysis data set and number of subjects 
deleted from each data analysis set (FAS, safety and PP, if applicable) will be summarized. 
Number and percentage of subjects who finish the study and number and percentage of 


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subjects who withdraw from the study and reasons for drug withdrawal will be summarized. 
9.4.3 
Demographic and baseline characteristics 
Descriptive statistic methods will be used to summarize demographics, baseline features, 
medical history, and concomitant medications before dosing of the investigational drug and 
during the study in the FAS population. 
9.4.4 
Degree of exposure 
Total subjects who receive treatment with the investigational drug will be summarized with 
number and percentage. Moreover, continuous descriptive statistics will be used to present 
number of cycles of treatment subjects receive. These analyses will be performed in efficacy 
analysis population. 
9.4.5 
Efficacy analysis 
9.4.5.1 
Primary endpoints: 
PFS analysis based on independent radiology review 
PFS based on independent radiologic review is defined as the time from the first dose of 
investigational drug (C1D1) to the first documentation of disease progression based on 
independent radiologic review or death due to any cause (whichever occurs first). Subjects 
who have previously received surgery for target lesion or non-target lesion, those who have 
previously received other anti-tumor treatments, and those whose progression or death date is 
not recorded for any reasons will be censored on the day of the last assessment. 
EAS will be used as the main analysis set, with PP as the supporting analysis set. Sensitivity 
analysis of progression-free survival will be performed, which will be further described in 
SAP. 
9.4.5.2 
Key secondary endpoints 
Critical secondary endpoint is ORR which is defined as the percentage of patients whose 
efficacy is confirmed as CR or PR based on independent radiologic review after the first dose 
of the investigational drug (C1D1). This analysis will be carried out in the EAS population as 
the main analysis and in the PP population as supportive analysis. Confirmation of CR or PR 
should be carried out at least 4 weeks after patients are first assessed as CR or PR. 
9.4.5.3 
Other secondary endpoints 
9.4.5.3.1 
OS 
OS is defined as the time from the first dose of investigational drug (C1D1) to all-cause 
death. Surviving patients or those lost to follow-up will be censored on the day of the last 
assessment. This analysis will be carried out in the EAS population. 


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9.4.5.3.2 
TBR based on independent radiology review 
TBR based on independent radiologic review is defined as the time from the first dose of the 
investigational drug (C1D1) to the confirmed best response (CR or PR) (calculated based on 
the unit of week), 
TBR analysis will be carried out in the population reaching response with descriptive 
statistical methods. 
9.4.5.3.3 
PFS assessment by investigators 
PFS assessed by investigators is defined as the duration from the first dose of investigational 
drug (C1D1) to the first documentation of disease progression by the investigator or all-cause 
death (whichever occurs first). 
9.4.5.3.4 
DCR 
Disease control rate at week 12 will be calculated and summarized with number and 
percentage. Disease control will be defined as complete response or partial responses or 
stable disease. This analysis will be carried out according to time point. 
9.4.5.4 
Exploratory endpoint 
PFS2 based on investigator’s assessment: it is defined as the period from the first dose of 
investigational drug (150 mg, BID) to the first documented tumor progression or death from 
any cause (whichever is the first) after the dosage is increased to 150 mg (BID). Subjects who 
have previously received surgery for target lesion or non-target lesion, those who have 
previously received other anti-tumor treatments, and those whose progression or death date is 
not recorded for any reasons will be censored on the day of the last assessment. For patients 
who are not assessed after dose increase, the date of the first dose of the investigational drug 
(150 mg, BID) will be taken as the censoring date. 
9.4.6 
Safety analysis 
9.4.6.1 
AE 
The number and percentage of patients in the safety population experiencing AEs will be 
summarized with system organ class and preferred term. 
Only TEAEs will be included in tabulations and TEAE is defined as any AEs newly 
occurring after the date of the first dose of the investigational drug until 30 days after the last 
dose of the investigational drug or those with a higher CTCAE grade. 
Toxicity grade of adverse events will be classified with NCI-CTCAE V4.03. If a patient has 
the same SOC or preferred term for several times, only the severest event will be summarized 
as this SOC and preferred term in tabulation. Adverse events ≥ grade 3 will be summarized. 
Assessment and calculation will not be performed if there is no grade of toxicity. 


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SAEs and the AEs and AESIs that lead to dose suspension, reduction or discontinuation will 
be analyzed. 
9.4.6.2 
ECOG score, vital signs, echocardiogram and laboratory indicators 
Overall summary of ECOG score, vital signs, echocardiogram and laboratory indicators will 
be performed with continuous descriptive statistical method according to time point. In 
addition, changes in continuous variables from baseline will be summarized. Categorical 
variables will be summarized with number and percentage. 
9.4.6.3 
Dermatologic assessment 
Dermatologic assessment will be summarized with number and percentage. 
9.4.7 
Pharmacokinetics analysis 
Descriptive statistics of PK parameters will be carried out. 
10 Quality Control and Assurance 
10.1 
Monitoring 
The Sponsor will designate a CRA for on-site monitoring. The CRAs should operate in 
compliance with the company’s standard operation procedure (SOP). They should perform 
regular visits from the start to the end of study. 
The CRA will have access to relevant original data of the clinical study, and review eCRF 
according to SOP to confirm information completeness, accuracy and consistency with 
original data. 
Source data, eCRFs, copies of laboratory data, and medical test results must be readily 
available to the clinical monitor, IRB/ IEC, and regulatory authorities. The monitor should 
review all eCRF and informed consent forms. 
10.2 
Source Data Verification 
The investigator must appropriately handle all data obtained during the clinical study to 
ensure rights and privacy of patients participating in the clinical study. The investigator must 
permit the monitor/auditor/inspector to consult and review required clinical study data to 
verify accuracy of original data and learn about study progress. If the original records cannot 
be verified, the investigator should agree to assist to further validation of data with them. 
10.3 
Audit 
The quality of all drugs and materials used in the clinical study must be controlled. The 
sponsor, personnel authorized by the sponsor or related medical management institutions 
have the right to audit the clinical study in order to ensure the authenticity of the clinical 
study data and abide by the provisions of the clinical study protocol. Patients participating in 
the clinical study will be informed of the audit, but the privacy and data of patients will be 


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strictly protected. 
10.4 
Protocol compliance 
The investigator should conduct the study in compliance with the study protocol and obtain 
the approval of IRB/IEC and corresponding regulatory authorities. 
The protocol should not be changed without the approval of the sponsor. The changes should 
involve the sponsor and the investigator. Any amendment to the protocol must be recorded in 
detail, and the amendment should be signed, signed and dated by the investigator and the 
sponsor at least. The amendment should be submitted to the Ethics Committee for review and 
approval before implementation of the amendment. The sponsor should ensure all changes be 
submitted to regulatory authorities according to management regulations. 
In case of other accidents needing to deviating from the protocol, monitor should consult with 
relevant personnel of the sponsor (and IRB, IEC, if necessary) to confirm an appropriate 
action plan. 
The investigator should record information of all protocol deviations in the original data. For 
major protocol deviations, the investigator should notify the sponsor, IRB and IEC. Major 
protocol deviations include but are not limited to behaviors involving fraud or misconduct, 
increasing risks to patients’ health or interpretations confusing study assessment. 
11 DATA MANAGEMENT AND DATA RETENTION 
11.1 
Electronic Case Report Form (eCRF) 
The sponsor will provide the eCRF and training for study sites. 
The CRO working on behalf of Zailab is responsible for data management, so as to ensure the 
authenticity, integrity, privacy and traceability of the clinical study data. Data management 
by CRO authorized by the sponsor. 
Data of each patients should be entered into the eCRF. The investigator should be responsible 
for the accuracy, authenticity as well as timely collection and reporting of all clinical, safety 
and laboratory data entered into the eCRF and any other data collection forms. 
The investigator or personnel authorized by the investigator should enter the information into 
the eCRF as soon as possible after collecting the information. Medium 
Upon completion of the original data entry by the investigator or authorized personnel, any 
changes made to the eCRF will be automatically recorded in the system and the audit trail 
will show the user's identification information and the date and time of any corrections. The 
eCRF should be signed by qualified study personnel in an electronic form to prove data in the 
eCRF (including any changes in the eCRF) are correct. 
A complete eCRF is exclusive property of the sponsor and should not be supplied to third 
parties in any forms without written permission of the sponsor, except for the authorized 


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personnel of the sponsor or relevant regulatory authority. 
11.2 
DATA RETENTION 
To make regulatory authorities or the sponsor can carry out assessment and/or review, study 
personnel agrees to retain the identity (including adequate information of records, e.g., eCRF 
and hospital record) of all participating patients, all original signed informed consent forms, 
eCRF, SAE forms, tracing documents, detailed records of treatment management and 
relevant correspondence (e.g., letters, minutes and telephone report). The investigator should 
retain records according to ICH, local regulations or regulations in clinical study protocol, 
whichever is longer. 
If study site can’t continue keeping study records in the required period for any reasons (e,g, 
movement), the sponsor should be notified in advanced. Study records should be transferred 
to the acceptable personnel designated by the sponsor, e.g., other institutions. The 
investigator should obtain written permission of the sponsor before dealing with any records, 
even if the retention requirements have been met. 
12 Ethics 
12.1 
Ethics 
This clinical study shall be implemented and reported in accordance with the Declaration of 
Helsinki, Chinese Good Clinical Practice and regulations. 
The investigator should ensure the study is completely in compliance with regulations on 
protecting human subjects specified in 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, 
21CFR Part 312, 21 CFR Part 314 and ICH GCP E6. 
Before initiating a trial, the investigator should obtain approval from the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, informed consent form 
and any other written information to be provided to subjects. 
Before initiation of the clinical trial, approval must be obtained from the Ethics Committee. 
The approval issued by the Ethics Committee shall be made available to the investigator in 
written form. The investigator is obligated to provide the sponsor of a copy of the approval. 
The Ethics Committee approval should clearly list all the committee members involved in the 
review with their respective responsibilities. 
During the clinical study, any of issues related to the patient safety of the clinical study, such 
as changes in the clinical study protocol or patient informed consent form as well as serious 
adverse events in the clinical study, must be reported to the Ethics Committee in a timely 
manner. The completion or premature termination of the clinical study must also be reported 
to the Ethics Committee. 


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12.2 
Informed Consent Form 
All parties should ensure to protect patients’ personal data and not disclose patients’ name in 
any forms, reports, publications or any other public data, unless otherwise required by laws. 
The sponsor should keep high-standard confidentiality and protection of patients’ individual 
data during data transmission. 
Informed consent form should be in compliance with ICH GCP, requirements of regulations 
and laws. 
Informed consent forms used in this study and any changes during the study should be 
approved before use by the IRB/IEC and the sponsor. 
The investigator has the responsibility to explain to each patient the purpose, methods, 
benefits and potential risks of this clinical study. Signed informed consent must be obtained 
before conducting any study-specific procedures. Informed consent should be expressed in 
written form. The informed consent must be dated and signed by the patient him/herself. For 
those patients who could not sign the informed consent form by themselves for any reasons, 
their parents, legal guardians, or protectors should sign the informed consent form. The 
original signed informed consent form and the process of obtaining informed consent should 
be preserved and documented in the electronic case report form and relevant trial source 
documents by the investigator. 
By signing the informed consent form, the patient must also agree to allow the sponsor, the 
drug approval authorities, and the auditor and (or) the monitor to check and verify the 
obtained source data and materials related to clinical study, and all parties mentioned above 
must comply with confidentiality statement. 
12.3 
IRB/IEC 
The investigator has the responsibility to ensure IRB/IEC approves the study protocol, 
protocol amendment, informed consent form and other related documents (e.g., recruitment 
advertisement, if applicable) in advance. All correspondences with IRB/IEC should be kept in 
study site’s file. 
Amendment can be initiated before obtaining the approval of IRB/IEC only when changes 
should be made to eliminate obvious direct harm to patients. In such case, the investigator 
should notify the IRB/IEC and the sponsor in wirtten immediately after implementation. 
12.4 
Patient Privacy 
The Investigator must ensure that the confidentiality of the information about the Sponsor 
and the investigational drug provided or disclosed by the Sponsor for the clinical study, and 
such information can only be used upon authorization by the Sponsor. 
The commitment is independent, effective and sustained until the permission of the Sponsor. 


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The Investigator also commits to keep confidentiality to a third party for any confidential 
information provided or disclosed by the Sponsor and the investigational products. Any 
intention to use such information must be approved by the Sponsor and agreed upon. 
Investigators are obligated to protect the privacy of patients participating in clinical study. In 
all the documents submitted to the sponsor, the identity of any patient in the clinical study 
will be coded by the clinical trial identification number, while the patient’s name, admission 
number should not show up. The investigator must appropriately keep name and address of 
clinical trial patients, as well as enrollment table corresponding to clinical study patient 
number. These enrollment tables will be strictly kept confidential and stored by the 
investigator. 
The sponsor and personnel designated by the sponsor confirm and maintain the principles of 
patients’ privacy right. Source data of patients can be linked to the sponsor’s clinical study 
database or document only through the unique identification number throughout the study. If 
permitted by all applicable laws and regulations, limited patient properties (e.g., gender, age 
or date of birth) can be used to validate patients and the accuracy of unique identification 
number of patients. 
To comply with ICH GCP and validate whether the protocol is followed, the sponsor will ask 
the investigator to allow its monitor or designated personnel, representative of any regulatory 
authority (e.g., FDA), auditor designated by the sponsor and corresponding IRB and IEC to 
review patients’ original medical record (source data or document), including but not limited 
to any genetic/genome data, laboratory test reports, ECG reports, admission and discharge 
summary before patients are enrolled to the study, hospitalization and autopsy report during 
patients’ participation in the study. Access to original medical record of patients needs special 
authorization of patients as part of informed consent process. 
Some personal identity information (that is, name of patient, address and other information 
not collected in the patient’s eCRF) should be deleted from copies of any patient-sourced 
documents supplied to the sponsor. 
13 Termination of study 
If the sponsor has learned about information of quality, efficacy and safety of the 
investigational drug and other important information that may influence correct conduct of 
the clinical study, the sponsor may discontinue the clinical study and send a written notice to 
the investigator and notify study discontinuation and reasons for discontinuation. 
If the investigator plans to discontinue participation in the study, the sponsor must be 
informed immediately and the reason for discontinuation must be informed. 
13.1 
Criteria for Suspension or Early Termination of the Study 
Criteria for suspension or early termination of the study include: 


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1. New information of safety or efficacy of the investigational drug is obtained and 
indicates changes in known risks/benefits of the compound, making patients participating 
in the study do not have acceptable risks/benefits any more. 
2. Seriously violate GCP and influence the realization of the primary objective or threaten 
patients’ safety. 
3. The sponsor can suspend or prematurely terminate the study for reasons unrelated to the 
study. 
13.2 
Criteria for Premature Termination or Suspension of Study Sites 
If it is found that the study site (including the investigator) seriously violates GCP, the 
protocol, contract/agreement or is unable to ensure normal conduct of the study, the study site 
may prematurely terminate or suspend the study. 
13.3 
Procedures for Early Termination or Suspension of the Study or Study Site 
If the sponsor chooses to terminate or suspend the study or participation of study site, the 
sponsor will provide specific procedure for premature termination or suspension. Study sites 
for which the procedure is applicable should abide by the procedure. 
14 Paper publication 
Zai Lab (Shanghai) Co., Ltd., as the sponsor, has exclusive rights to this study. The 
manuscript and publication will reflect the cooperation among investigators and 
investigator’s institution and Zai Lab. Authors will be identified before drafting of the 
manuscript. Many study institutions and investigators are participating in this study, unless 
prior consent has been obtained from Zai Lab, individual participating institution or 
investigator shall not publish any data related to the clinical study. Zai Lab has the final right 
to determine how the manuscript and its relevant publication will be disclosed. 
 
 


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16 Annexes 
Annex 1 Response Evaluation Criteria in Solid Tumors - GIST Specific Standard 
(RECISTv1.1-GIST Specific Standard) 
"RECIST v1.1-GIST Specific Standard" include: 
● 
Lymph nodes cannot be taken as target lesions; enlarged lymph nodes will be 
followed as non-target lesions. 
● 
Bone lesions cannot be taken as target lesions; 
● 
Positron emission tomography (PET) cannot be used in efficacy assessment; 
● 
According to "RECIST v1.1-GIST Specific Standard", new tumor nodules within 
the pre-existing tumor lesion that are gradually growing must meet the following 
criteria before being determined as definite progression: (a) The lesion diameter 
should be at least 2 cm and confirmed as active GIST lesion (for example, using 
contrast or other criteria for enhanced scanning to rule out the possibility of false 
appearance); Or (b) At least 2 consecutive radiographic examinations indicative of 
enlarged lesion. 
Source: Demetri GD, Jeffers M, Reichardt P, Kang Y-K, Blay J-Y, Rutkowski P, et al. 
Mutational analysis of plasma DNA from patients (pts) in the phase III GRID study of 
regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI) refractory GIST: 
Correlating genotype with clinical outcomes. J Clin Oncol 31, 2013 (suppl; abstr 10503). 
 
 


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Annex 2 Eastern Cooperative Oncology Group (ECOG) Performance Status Score 
Description of physical status 
Score 
Completely normal, being able to perform work before illness without restriction 
0 
Not able to carry out heavy physical work, but be able to walk around and carry 
out light physical work such as light housework or office work 
1 
Can move around, capable of self-care, but unable to carry out any work-related 
activities, confined to bed for less than 50% of the day 
2 
Self-care can only be achieved to a limited extent, with more than 50% of the 
daytime spent in bed rest or chair sitting 
3 
Complete loss of activity of daily living, unable to achieve selfcare, confined to 
bed or wheelchair 
4 
Death 
5