Clinical trial NCT04633122
Conditions: Gastrointestinal Stromal Tumor(GIST)
Keywords: Gastrointestinal Stromal Tumors,GIST,DCC-2618,Ripretinib
Sponsor: Zai Lab (Shanghai) Co., Ltd.
Start date: 2020-11-25; Completion date: 2022-07-20
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
the primary objective of this study is to assess the efficacy (progression-free survival,PFS) of DCC-2618 (ripretinib, ZL-2307) and sunitinib in patients with advanced gastrointestinal stromal tumors after treatment with imatinib. This study will enroll approximately 98 subjects in around 18 sites in China mainland, and all subjects will be receiving DCC-2618 or Sunitinib in equal chance as treatment.

Detailed description:

Arms: arm 1: 50mg/tablet,150 mg QD continuous administration, 6 weeks (42 days) for a cycle. arm 2: 12.5mg/capsule, 50 mg QD, in 6 weeks (42 days) with 4 weeks continuous dosing followed by 2 weeks break.
Interventions: intervention 1: Ripretinib intervention 2: Sunitinib
Intervention descriptions: intervention 1: Oral kinase inhibitor intervention 2: second-line therapy in GIST patients who have progressed after imatinib treatment or are intolerant to imatinib

Protocol documents:
Prot_SAP_000.pdf: 
DCC-2618 (Ripretinib, ZL-2307)
Zai Lab 
Clinical Study Protocol No.: ZL-2307-003 
February 25, 2021/Version 2.0 
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Clinical Study Protocol 
Study Title: 
A phase 2, randomized, multicenter, open-label study of DCC-2618 
(ripretinib, 
ZL-2307) 
vs 
sunitinib in patients 
with 
advanced 
gastrointestinal stromal tumors after treatment with imatinib  
Project No.: 
ZL-2307-003 
Version No. and 
Version Date: 
February 25, 2021/Version 2.0 
Study Drug: 
DCC-2618 (Ripretinib, ZL-2307)
Study phase: 
Phase 2 Study
Sponsor: 
Zai Lab (Shanghai) Co., Ltd.
Principal Investigator: Professor SHEN Lin 
Beijing Cancer Hospital 
Statement of Confidentiality 
Confidential information of the study drug 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, ZL-2307)
Zai Lab 
Clinical Study Protocol No.: ZL-2307-003 
February 25, 2021/Version 2.0 
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Signature page (Sponsor) 
Protocol title: A phase 2, randomized, multicenter, open-label study of DCC-2618 (ripretinib, 
ZL-2307) vs sunitinib in patients with advanced gastrointestinal stromal tumors after treatment 
with imatinib 
Clinical Study Number: ZL-2307-003 
The clinical study protocol has been approved by the sponsor. 
Signature: 
Date: 
Juan Dong 
MedicalDirector  
Zai Lab (Shanghai) Co., Ltd. 


DCC-2618 (Ripretinib, ZL-2307)
Zai Lab 
Clinical trial protocol number: ZL-2307-003 
February 25, 2021/Version 2.0 
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Protocol Synopsis 
Name of 
Sponsor/Company 
Zai Lab (Shanghai) Co., Ltd. 
Study Title 
A phase 2, randomized, multicenter, open-label study of DCC-2618 
(ripretinib, ZL-2307) vs sunitinib in patients with advanced gastrointestinal 
stromal tumors after treatment with imatinib 
Protocol Number 
ZL-2307-003 
Study Phase 
Phase 2 
Study Site 
Beijing Cancer Hospital etc 
Investigator 
Professor SHEN Lin 
Number of Subjects 
Planning to be 
Enrolled: 
About 98 
Study Objectives 
Primary objective: 
• To assess the efficacy (progression-free survival [PFS], by
independent radiologic review) of DCC-2618 (ripretinib, ZL-2307)
and sunitinib in patients with advanced gastrointestinal stromal
tumors after treatment with imatinib
Secondary objective: 
• To assess objective response rate (ORR) by independent radiologic
review using RECIST v1.1-GIST-specific criteria
• To assess disease control rate (DCR) by independent radiologic review
• To assess PFS  based on Investigator assessment
• To assess overall survival (OS)
• To compare the safety profile of DCC-2618 (ripretinib, ZL-2307) to
the safety profile of sunitinib
• To assess pharmacokinetic characteristics of DCC-2618 (ripretinib,
ZL-2307)
Exploratory objective: 
• To evaluate potential biomarkers in blood or tumor tissue which
might predict response to DCC-2618 (ripretinib, ZL-2307)
○To understand potential drug resistance mechanism to DCC-2618
(ripretinib, ZL-2307) in GIST.
○To characterize KIT and PDGFRA mutations at baseline and
DCC-2618 (ripretinib, ZL-2307)-driven longitudinal mutant allele
frequency changes in plasma.
Note: Blood samples and tumor tissues for exploratory purpose
will be collected after obtaining the approval of China 
Human Genetic Resources Administration Office. 
Study Design 
This is a randomized, open-label, multicenter phase 2 clinical study to compare 
the efficacy and safety of DCC-2618 (ripretinib, ZL-2307) to sunitinib in GIST 
patients who progressed on or were intolerant to first-line anticancer treatment 
with imatinib. 


DCC-2618 (Ripretinib, ZL-2307)
Zai Lab 
Clinical trial protocol number: ZL-2307-003 
February 25, 2021/Version 2.0 
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Approximately 98 patients will be randomized in a 1:1 ratio to DCC-2618 
(ripretinib, ZL-2307) 150 mg QD by continuous administration or sunitinib 50 
mg QD, 4 weeks on, 2 weeks off. Up to 10% of randomized patients may have 
KIT/PDGFRA WT GIST (wild-type KIT and wild-type PDGFRA regardless of 
the mutational status of any other gene). 
Randomization will be stratified by: 
•
KIT exon 11 mutation; KIT exon 9 mutation; other (KIT/PDGFRA WT
or other KIT [lacking exon 9 or 11]/PDGFRA mutation);
The primary endpoint of the study will be evaluated using the modified Response 
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1-GIST-specific based 
on independent radiologic review. 
Upon disease progression by RECIST v1.1-GIST-specific based on independent 
radiologic review, patients will discontinue their assigned treatment. 
Patients will be contacted by telephone 30 (±5) days after the last dose of the 
study drug for safety follow-up. 
After the end of the safety follow-up, survival follow-up visits will be made by 
phone every 2 month (±10 days). 
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.
Histological diagnosis of advanced GIST and capability of providing tumor
tissue sample (the interval between tumor tissue collection and signing of
informed consent form should be less than 3 years). Otherwise, biopsy is
required.
3.
Provide molecular test report with KIT/PDGFRA mutation status prior to
randomization. Mutation status must be identified by tissue-based PCR or
sequencing analysis. If molecular test report is not available or insufficient,
biopsy of an archived tumor tissue sample or fresh tumor tissue is required
for mutation status confirmation by the central laboratory prior to
randomization.
4.
Patients must have progressed on imatinib or have documented intolerance
to imatinib. Subjects must have discontinued imatinib treatment 10 days
prior to the first dose of the study drug. All prior imatinib treatments will be
considered as first-line (such as imatinib adjuvant therapy and imatinib dose
increase).
5.
ECOG PS of 0-2.
6.
Female patients of childbearing potential must have a negative serum beta-
human chorionic gonadotropin (β-hCG) pregnancy test at screening.
7.
Patients of reproductive potential must agree to follow the contraception
requirements.
8.
At least 1 measurable lesion according to the "RECIST v1.1-GIST-specific
Criteria" (non-nodal lesions must be ≥1.0 cm in the long axis or ≥ double
the slide thickness in the long axis) ; obtaining radiographic image results
within 28 days prior to the first dose of study drug.


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Clinical trial protocol number: ZL-2307-003 
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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
•
Creatinine clearance ≥ 50 mL/min (based on Cockcroft-Gault
estimation Formulas for calculation)
Note: Patients should receive no corrective treatment with granular colony 
stimulating factor or interleukin-11, infusion of red blood cells or platelets 
or other blood products within 2 weeks prior to detecting haematology. 
•
Prothrombin time (PT), 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 study 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 study drug (excluding alopecia and ≤
Grade 3 clinically asymptomatic lipase, amylase, and creatine
phosphokinase laboratory abnormalities).
11. Patient is capable of understanding and complying with the protocol.
Subjects should sign the written informed consent before any study-related
procedures were performed.
Exclusion criteria: 
Subject meeting any of the following criteria should not be enrolled in this 
study: 
1.
Treatment with any other line of therapy in addition to imatinib for advanced 
GIST. Imatinib-containing combination therapy in the first-line treatment
should not be enrolled.
2.
Patients with a prior or concurrent malignancy whose natural history or
treatment have the potential to interfere with the safety or efficacy
assessment of this clinical trial are not eligible. For example, patients who
received adjuvant treatment for cancer and used drugs which have potential
activity to GIST or are prohibited by study protocol are not eligible.
3.
Patient has known active central nervous system metastases.
4.
New York Heart Association class II - IV heart disease, myocardial infarct,
active ischemia or any other uncontrolled cardiac condition within the first
6 months of the first dose of study drug such as angina pectoris, clinically
significant cardiac arrhythmia requiring therapy, uncontrolled hypertension
or congestive heart failure.
5.
Left ventricular ejection fraction (LVEF) < 50%.
6.
Arterial thrombotic or embolic events such as cerebrovascular accident
(including ischemic attacks) or hemoptysis within 6 months before the first
dose of study drug.
7.
Venous thrombotic events (e.g. deep vein thrombosis) or pulmonary arterial


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events (e.g. pulmonary embolism) within 1 month before the first dose of 
study drug. Patients on stable anticoagulation therapy for at least one month 
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. Use of strong or moderate inhibitors and/or inducers of cytochrome P450 
(CYP) 3A4 within 14 days or 5 x the half-life (whichever is longer) prior 
to the first dose of study drug, including certain herbal medications (eg, St. 
John's Wort) and consumption of grapefruit or grapefruit juice within 14 
days prior to the first dose of study drug. For CYP3A4 enzyme 
inhibition/induction-related drugs, please refer to the website of the Indiana 
University, School of Medicine 
(http://medicine.iupui.edu/clinpharm/ddis/main- table/). 
10. 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 study drug. For information of inhibitors and 
substrates, please refer to Food and Drug Administration (FDA) website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentRe
sources/DrugInteractionsLabeling/ucm093664.htm. 
11. Major surgeries (e.g. abdominal laparotomy) within 4 weeks of the first dose 
of study drug; all major surgical wounds must be healed and free of infection 
or dehiscence before the first dose of study drug. 
12. 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. 
13. Known human immunodeficiency virus or hepatitis C infection only if the 
patient is taking medications that are excluded per protocol, hepatitis B virus 
(HBV) DNA > 2000 IU/ml or > 104 copies/ml. 
14. Female patients who are pregnant or lactating or who plan to become 
pregnant during the study treatment period. 
15. Known hypersensitivity to any component of the study drug. Patients with 
Stevenson Johnson syndrome in previous TKI treatment need to be 
excluded. 
16. Gastrointestinal abnormalities including but not limited to: 
• 
inability to take oral medication 
• 
malabsorption syndrome 
• 
Requiring intravenous nutrition 
17. Any active hemorrhages, excluding hemorrhoids or gum bleeding. 
Study drug 
Drug of the test group: DCC-2618 (Ripretinib, ZL-2307) 
Dosage Form: Tablet 
Dosage: 150 mg QD continuous administration, 6 weeks (42 days) for a cycle. 
Administration route: oral 
Drug of the control group: Sunitinib 
Dosage form: capsule 


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Dosage: 50 mg QD, in 6 weeks (42 days) with 4 weeks continuous dosing 
followed by 2 weeks break. Dose modifications are allowed per approved 
package insert. 
Administration route: oral 
Study Endpoints 
Primary endpoints: 
Progression‑free survival (PFS):Independent radiologic review will assess 
PFS according to “RECIST v1.1-GIST-specific Criteria” which include: 
•
No lymph nodes chosen as target lesions; enlarged lymph nodes will be
followed as non-target lesions.
•
No bone lesions chosen as target lesions;
•
Positron emission tomography (PET) not acceptable for radiological
evaluation;
•
A progressively growing new tumor nodule within a pre-existing tumor
mass must meet the following criteria to be considered as unequivocal
evidence of progression according to the modification of RECIST
Version 1.1: (a) the lesion is at least 2 cm in size and definitively a new
active GIST lesion (e.g. enhancing with contrast or other criteria to rule
out artefact); or (b) the lesion has to be
expanding on at least 2 sequential imaging studies.
Secondary endpoints: 
Efficacy Endpoints 
•
ORR (confirmed CR + confirmed PR) based on independent radiologic
review
•
Disease control rate (DCR) at months 6, 9 and 12, assessed by
independent radiologic review
•
PFS assessed by the investigator according to “RECIST v1.1-GIST-
specific Criteria”
•
Overall survival (OS)
Safety: 
•
Incidence of treatment emergent adverse event (TEAE), adverse event
of special interest (AESI) and serious adverse event (SAE); severity of
adverse event will be assessed (based on NCI CTCAE 5.0);
•
Incidence of adverse events resulting in dose adjustment of the study
drug or termination of the study;
•
Changes in each parameter like ECOG score, vital signs,
electrocardiogram, left ventricular ejection fraction, dermatologic
examination and laboratory indicators from baseline.
Pharmacokinetic profiles: 
•
Descriptive statistics and summary of drug concentration at relevant
time points will be carried out according to plasma concentration of
DCC-2618 (ripretinib, ZL-2307) after administration. If necessary,
pharmacokinetic data of this study will be included into population PK
analysis with industrial standard software. Population PK report will be
drafted independently and not taken as the appendix of the study report.
Exploratory endpoint: 
•
KIT/PDGFRA mutation of tumor tissues at baseline and specific time


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points (e.g., resection of metastasis or progressive disease during the 
study). 
•
KIT/PDGFRA mutations and mutant allele frequency at baseline and
the treatment effect of DCC-2618 (ripretinib, ZL-2307) on
KIT/PDGFRA mutant allele frequency (MAF).
Statistical analysis 
Estimation of Sample Size: 
 This study will bridge foreign clinical trial (study INTRIGUE) 
to prove the efficacy of the investigational drug DCC-2618 (ripretinib, ZL-2307) 
is consistent in foreign population and Chinese population. In the study, no 
statistical test hypothesis is specified in advance. Statistical significance test for 
efficacy endpoint and multiplicity correction for multiple analysis populations 
will not be performed. 
Approximately 98 subjects will be enrolled into the study and 
randomized to a test group and a control group in a 1:1 ratio. The sample size 
eatimation will be based on the same study hypothesis as foreign, that is, median 
progression‑free survival (mPFS) is 9 months in the test group and 6 months in 
the control group. Hazard ratio (HR) of the test group to the control group is 
0.667. If the study keeps ≥50% of the overall effect size of study INTRIGUE, 
that is, point estimate of HR should be ≤ 0.833, it will be considered that results 
of this study are consistent with those of study INTRIGUE. If 58 PFS events 
occur, the conclusion of consistency will be drawn with a probability of 80%. 
Assuming the subjects annual drop-out rate of the total study population is 5%, 
approximately 98 subjects (49 for the test group and the control group, 
respectively) are enrolled within 7 months and followed up for 7 months, and 58 
PFS events will occur. Primary analysis based on ITT will be performed when 
58 PFS events occur and it is estimated that the data cutoff of the analysis will 
be 7 months after completing enrollment. 
In population with KIT exon 11 mutation, it was assumed in 
the foreign study that mPFS of the test group was 9 months and mPFS of the 
control group was 5 months, and HR of the test group to the control group was 
0.556. If the study keeps ≥50% of the overall effect size of study INTRIGUE 
in population with KIT exon 11 mutation, that is, point estimate of HR should 
be ≤ 0.778, it will be considered that results based on KIT exon 11 mutation 
population in this study are consistent with those in study INTRIGUE. If 26 PFS 
events occur in population with KIT exon 11 mutation, the conclusion of 
consistence with study INTRIGUE can be drawn with a probability of 80%. 
Note: If a patient has exon 11 mutation along with 1) exon 9 
and/or PDGFRA mutation, the patient will be considered with exon 11 mutation 
at randomization. Mutation type of the patient will be defined according to a 
mutation with a higher MAF if the patient has mutation allele frequency (MAF) 
data; 2) other KIT exon mutation, the patient will be considered with exon 11 
mutation at randomization. 
Study duration 
Patients will receive treatment until progressive disease confirmed by the 
independent radiologic review based on “RECIST v1.1-GIST-specific Criteria”, 
intolerable toxicity or withdrawal of consent. 
Patients will discontinue the study drug treatment if patients have progressive 
disease based on assessment of the independent radiologic review using 


DCC-2618 (Ripretinib, ZL-2307)
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“RECIST v1.1-GIST-specific Criteria”. 
The longest medication duration of patients is 2 years. For patients with evidence 
of clinical benefit from the drug and tolerance to the drug and following the study 
procedure, the treatment duration will be prolonged by reaching an agreement 
between the sponsor and the investigator. 
The study will be terminated when the last patient has progressive disease or 20 
months after finishing enrollment or when the sponsor determines to terminate 
the study, whichever occurs first. 
Schedule of visits 
and the content 
thereof 
Please refer to Table 1 


DCC-2618 (Ripretinib, ZL-2307) 
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Clinical trial protocol number: ZL-2307-003 
 
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Figure 1:  
Schematic diagram of the study 
 
 
 
Screening and 
Random 
assignment 
Sunitinib 
50 mg QD 
4W on/2W off 
Patients are histologically diagnosed with GIST and must have
progressed during receiving imatinib treatment or intolerance. 
OS 
N = 49 
A treatment cycle consists of 
consecutive 42 days of dosing 
N = 49 
4W on/2W off, 42 days for a 
treatment cycle. 
PFS 
Safety 
follow-up 
Patients will receive treatment until progressive 
disease based on “RECIST v1.1-GIST-specific 
Criteria”, intolerable adverse events or withdrawal 
of consent. If progressive disease is confirmed by 
the independent radiologic review using “RECIST 
v1.1-GIST-specific Criteria”, patients who receive 
DCC-2618 or sunitinib will discontinue treatment 
with the  study drug. 
DCC 2618 
150 mg 
QD 


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Table 1: 
Schedule of Assessments 
Evaluation/Procedure1 
Screening
2
Cycle 1 
Cycle 2 
≥ Cycle 3 
EOT visit 
(Within 7 
days after 
the last dose) 
Safety follow-
up 
Overall 
survival 
follow-up3 
(Every 2 
month ± 10 
days) 
Cycle Day 
-28 to -1
1 
(Baseline) 
15 
(± 1 day) 
29 
(± 1 day) 
1 
(± 3 day) 
29 
(± 3 day) 
1 
(± 3 day) 
Within 30 
days after the 
last dose 
(± 5 day) 
Come to the Study Site 
X 
X 
X 
X 
X 
X 
X 
X 
Tel 
X 
X 
Informed consent 
X 
Inclusion/Exclusion criteria 
X 
Previous medical history and 
tumor history 
X 
Previous 
medications/treatment4 
X 
Pregnancy test5 
X 
X* 
X 
X 
X 
Hepatitis B/C tests6 
X 
X 
X 
HIV antibody test 
X 
Clinical laboratory tests 
Blood routine 
X 
X* 
X 
X 
X 
X 
X 
X 
Blood biochemistry 
X 
X* 
X 
X 
X 
X 
X 
X 
Blood coagulation function7 
X 
X* 
X 
X 
X 
X 
X 
X 
Urine routine8 
X 
X* 
X 
X 
X 
TSH, FT3 and FT49 
X 
X* 
X 
X 
Physical examination 
X 
Examination will be arranged based on clinical findings and/or patients’ chief complaints 
ECOG PS10 
X 
X* 
X 
X 
X 
X 
X 
X 
Vital signs and weight11 
X 
X* 
X 
X 
X 
X 
X 
X 
Height 
X 
12-lead ECG12
X 
X* 
X 
X 
X 
Echocardiography/13 
X 
X 
X 
Dermatologic examination14 
X 
X 
X 


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Evaluation/Procedure1 
Screening
2
Cycle 1 
Cycle 2 
≥ Cycle 3 
EOT visit 
(Within 7 
days after 
the last dose) 
Safety follow-
up 
Overall 
survival 
follow-up3 
(Every 2 
month ± 10 
days) 
Cycle Day 
-28 to -1
1 
(Baseline) 
15 
(± 1 day) 
29 
(± 1 day) 
1 
(± 3 day) 
29 
(± 3 day) 
1 
(± 3 day) 
Within 30 
days after the 
last dose 
(± 5 day) 
AEs reporting 
Continuing from signing an ICF to the safety follow-up 
Concomitant 
medicines/other 
treatment 
From the first dose of the study drug to safety follow-up 
Administration of study drug15 
X 
X 
X 
X 
X 
X 
Distribution and reconciliation 
of the study drug 
X 
X 
X 
PK sampling16 
X 
X 
X 
X 
Molecular test report, marking 
KIT/PDGFRA 
mutation 
status17 
X 
Archived tumor tissue 
sample/tumor biopsy 18 
X 
Optional tumor biopsy 19 
X 
Imageological examination20 
X 
X 
X 
PD sampling (plasma) 21 
X 
X 
Random assignment22 
X 
Evaluate AE, collect 
information of concomitant 
medications/other treatments, 
collect information of new 
anti-tumor therapies 
X 
Collect new information of 
anti-tumor therapy and OS data 
X 
CT = computerised tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; MRI = magnetic resonance 
imaging; PD = pharmacodynamic; PK = pharmacokinetic; PS = performance status 
*: Examination with * doesn’t need to be repeated on C1D1 if examination at screening is performed within 7 days prior to the first dose of the study drug. 


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1. 
Unless otherwise specified, all assessments must be carried out prior to administration and in the predetermined window of visit. Cycle is not influenced by 
suspension or delay of treatment with the study drug. Additional unscheduled safety or efficacy assessment can be carried out at any time with clinical 
indications to confirm the correlation between the specific findings and the study drug and/or duration of event. At unscheduled visits, if necessary, distribution 
and/or recovery of the study drug can be carried out. 
2. 
Screening must be done within 28 days before the first dose of the study drug. 
3. 
All patients will be followed up until withdrawal of consent or death for any reason. After safety follow-up visit, patients will be contacted once every 2 
months (± 10 days) to collect new information of anti-tumor therapy and OS data. 
4. 
Any medications or other therapies taken within 30 days prior to signing the informed consent form and prior to the first dose of the study drug. 
5. 
A serum pregnancy test will be performed, at screening, for females of child-bearing potential. If serum pregnancy test at screening is performed within 7 days 
prior to the first dose of the study drug, urine pregnancy test is not required on C1D1. Urine pregnancy test will be carried out at visit of Day 1 of every 
subsequent cycle and EOT visit. 
6. 
Hepatitis B and C examination: five indicators of hepatitis B and anti-HCV antibody examination will be performed at the screening period. If results of five 
indicators of hepatitis A are abnormal, HBV DNA quantitative test should be performed; if anti-HCV antibody positive, HCV RNA quantitative test should be 
performed. For patients with abnormal baseline HBV DNA, HBV DNA quantitative test should be performed once every 2 weeks during the trial and at the end 
of study. For patients with normal baseline HBV DNA, the test is not required during the trial. 
7. 
For patients who take anticoagulant, the test should be performed on C1D15. If the dose of anticoagulant changes during the study, monitoring of 
coagulation function should be increased if clinically suitable. 
8. 
Routine urine test will be performed at screening, on C1D1, C2D1, C3D1, C4D1, at EOT visit and when clinically necessary. 
9. 
Serum TSH, FT3 and FT4 tests will be performed at screening, C1D1, Day 1 of every odd cycle (that is, Cycles 3, 5 and 7, etc.) and at EOT visit. 
10. 
ECOG PS can be assessed before and after administration. 
11. 
Measurements on vital signs must be collected at least 5 minutes after the patient has a rest (in a sitting or supine position). 
12. 
All 12-lead ECG will be carried out at least 15 minutes after the patient has a rest. 
13. 
Echocardiogram will be performed at screening, on C3D1 and Day 1 of every subsequent 3 cycles (that is, Cycles 6, 9 and 12, etc.) and at EOT visit or when 
clinically indicated. Echocardiogram as standard care before informed consent can be used for screening assessment as long as the echocardiogram is 
performed within 28 days prior to the first dose of the study drug. 


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14. 
For all patients, skin lesions will be assessed by a consultant dermatologist within 28 days (baseline) prior to C1D1, especially squamous cell carcinoma 
of skin, actinic keratosis and keratoacanthoma. After that, patients will receive assessment on C3D1, and Day 1 of every subsequent 3 cycles (that is, 
Cycles 6, 9 and 12, etc.), at EOT visit and when clinically necessary. Dermatologic examination meeting standard of the study protocol performed prior 
to informed consent can be used for screening evaluation as long as the examination is performed within 28 days prior to the first dose of the study drug. 
Dermatological examinations during the treatment period may be performed within at most 7 days before the corresponding follow-up visit or after the 
administration on the date of the follow-up visit. Please refer to Section 6.11.6 for further information. 
15. 
On the date of study visit after finishing pre-dose evaluation, patients will be told to take the study drug at study site. Please refer to Section 5.3 for detailed 
information of dose and administration. 
16. 
Only patients who use DCC-2618 (ripretinib, ZL-2307) will receive PK sampling at the following time points: before administration and 6 hours after 
administration on C1D1, before administration, 2 and 6 hours after administration on C1D15, and before administration on C2D1 and C3D1. All pre-dose 
samples must be collected within 60 minutes prior to administration and all post-dose samples must be collected within the specified time point ± 30 minutes. 
If the sponsor requires, unscheduled PK samples can be collected when new, suspicious, and treatment-related adverse events occur. 
17. 
Molecular test report with KIT/PDGFRA mutation status must be provided. Mutation status must be identified by tissue-based PCR or sequencing analysis. 
Molecular test report with KIT/PDGFRA mutation status must be provided to the investigator before randomization so that the investigator can confirm 
randomization stratification factor. If molecular test report is not available or insufficient, biopsy of an archival tumor tissue sample or fresh tumor tissue is 
required for mutation status confirmation by the central laboratory prior to randomization. 
18. 
In terms of collected archived tumor tissue samples, the central laboratory will analyze tumor tissues to identify molecular mutation of KIT or PDGFRA. 
Formalin-fixed paraffin-embedded tissue blocks (preferred) or unstained FFPE slices are required. If the archived tumor samples are unusable or 
inapplicable, new fresh tumor samples must be collected. 
19. 
Tumor tissue samples can be collected at EOT visit from all patients (optional) and/or from patients who are receiving medical procedures, including 
resection of metastasis in the study, or from patients who have progressed (if the patient agrees). These samples will be used for further molecular test of 
cancer during receving the study drug. 
20. 
Radiographic images must be done within 28 days before the first dose of the study drug. Radiographic examination prior to informed consent can be used 
for screening evaluation as long as the examination is performed within 28 days prior to the first dose of the study drug. Pelvic, abdominal and chest enhanced 
CT scan will be carried out at screening. During the study, pelvic and abdominal enhanced CT scan will be carried out on Day 1 of Cycles 2 - 7 and Day 1 of 
subsequent every odd cycle (such as Cycles 9, 11 and 13). If patients have lung metastases or symptoms of lung metastases at screening and during the study, 
chest CT enhanced scan should be performed (at the investigator’s discretion). Radiographic images can be performed within the corresponding study visit ± 


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7 days. After C7D1, based on the investigator’s assessment, any initially indicated partial or complete response should be confirmed ≥ 4 weeks after the start 
of response. MRI scans of the abdomen/pelvis and CT scan without contrast of the chest can be used for patients who are allergic to radiographic contrast 
media or at the Investigator's discretion based on the best interest of the patient after discussion with the Sponsor. For each patient, the same evaluation 
technology should be adopted during the whole study, and the evaluation technology could not be changed unless the investigator’s consideration of safety 
risk. Ultrasound scan should not replace CT scan. 
Validation of progressive disease: if the independent radiologic review considers there is no progressive disease based on “RECIST v1.1-GIST-specific 
Criteria”, the patient will continue receiving the study drug, unless the study drug should be discontinued for medical need (that is, fast progression or clinical 
worsening). If investigators confirm progression according to clinical worsening, radiographic images should be performed and reviewed by independent 
radiologic institutions to confirm whether the patient has progression. The basis of confirming progression according to clinical worsening must be recorded 
in source data and electronic case report form of patients. If the investigator confirms progressive disease according to “RECIST v1.1-GIST-specific Criteria”, 
the investigator should wait for confirmation by the independent radiologic review and then terminate the patient’s treatment. If the investigator doesn’t hope 
to confirm by the independent radiologic review or hopes to terminate the patient’s treatment according to progressive disease based on “RECIST v1.1-GIST-
specific Criteria” before obtaining results of the independent radiologic review, it is necessary to discuss with the sponsor. Radiographic examination of 
patients of various treatment groups should be performed according to the predetermined time and cycle will not be influenced by suspension or delay of 
treatment with the study drug. If the patient discontinues treatment for reasons other than progressive disease, death, withdrawal of consent and lost to follow-
up, the patient should receive radiographic examination for tumor assessment according to the specified time interval after treatment withdrawal until 
progressive disease based on “RECIST v1.1-GIST-specific Criteria” or initiation of new anti-tumor therapy. 
21. 
Blood samples of patients who use DCC-2618 (ripretinib, ZL-2307) and sunitinib will be collected within 60 minutes prior to administration on C1D1 
(baseline), and when the independent radiologic review confirms progressive disease according to “RECIST v1.1-GIST-specific Criteria” or at EOT visit. 
22. 
Randomization can be carried out on Day -1. Patients who will be randomized on C1D1 can be randomized on the former Friday. 
.


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LIST OF ABBREVIATIONS 
List of Abbreviations 
Definition 
AE 
AEs 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukaemia 
ANC 
Absolute neutrophil count 
ASM 
Aggressive systemic mastocytosis 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
AUC 
Area under the time-concentration curve 
AUC0-24 
24-Hour area under the time-concentration curve 
β-hCG 
β-human chorionic gonadotropin 
BCRP 
Breast cancer resistance protein 
BID 
Twice daily 
BP 
Blood pressure 
BSEP 
Bile salt export pump 
cfDNA 
Cell-free DNA 
Cmax 
Observed maximum concentration 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CT 
Computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOT 
End of treatment 
ER 
Excretion rate 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed, paraffin-embedded 
FSH 
Follicle stimulating hormone 
FT3 
Tri-iodothyronine free 
FT4 
Thyroxine free 
fu 
Free fraction 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GIST 
Gastrointestinal stromal tumor 
GLP 
Good Laboratory Practice 


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List of Abbreviations 
Definition 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independence Ethics Committee 
IC50 
Half maximal inhibitory concentration 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Independent Radiologic Review 
ITT 
Intent-to-treat 
IV 
Intravenous 
KM 
Kaplan-Meier 
LHRH 
Luteinizing Hormone-Releasing Hormon 
LVEF 
Left ventricular ejection fraction 
MAF 
Mutation allele frequency 
MDR1 
Multidrug Resistance Protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPFS 
Median progression-free survival 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
NADPH 
Nicotinamide adenine dinucleotide phosphate 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
OAT 
Organic anoin transporter 
OCT 
Organic cation transporter 
ORR 
Object Response Rate 
OS 
Overall survival 
PD 
Pharmacodynamics 
PET 
Positron Emission Tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Partial response 
PS 
Performance Status 
PT 
Pro-thrombin Time 
PTT 
Partial thromboplastin time 
QD 
Once daily 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected by Bazett’s formula 


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List of Abbreviations 
Definition 
QTcF 
QT interval corrected byFridericia’s formula 
RECIST 
Response Evaluation Criteria In Solid Tumours 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCC 
(Skin) Squamous Cell Carcinoma 
SD 
Stable Disease 
SJS 
Stevens-Johnson syndrome 
SM 
Systemic Mastocytosis 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
Tmax 
Observed maximum concentration 
TSH 
Thyroid Stimulating Hormone 
T1/2 
Half-life 
ULN 
Upper limit of normal 
WT 
Wild type 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .......................................................................................................... 3 
1.
INTRODUCTIONAND BASIC PRINCIPLES ............................................................. 24 
1.1. 
Introduction......................................................................................................... 24 
1.2. 
Clinical Indications ............................................................................................. 27 
1.3. 
DCC-2618 (Ripretinib, ZL-2307) ....................................................................... 27
1.3.1. 
Nonclinical Experience ........................................................................ 28 
1.3.2. 
Clinical Experience .............................................................................. 34 
1.4. 
Sunitinib Overview ............................................................................................. 42 
1.5. 
Basic principles ................................................................................................... 43 
1.5.1. 
Study Principle ..................................................................................... 43 
1.5.2. 
Rationale for Dose, Regimen and Treatment Duration ........................ 44 
2.
STUDY OBJECTIVES ................................................................................................... 49 
2.1. 
Primary objective ................................................................................................ 49 
2.2. 
Secondary objective ............................................................................................ 49 
2.3. 
Exploratory objectives ........................................................................................ 49 
3.
STUDY DESIGN............................................................................................................ 50 
3.1. 
Overview of Study Design.................................................................................. 50 
3.2. 
Number of patients ............................................................................................. 50 
3.3. 
Study duration ..................................................................................................... 50 
4.
STUDY POPULATION ................................................................................................. 51 
4.1. 
Inclusion criteria ................................................................................................. 51 
4.2. 
Exclusion criteria ................................................................................................ 52 
5.
ADMINISTRATION AND MANAGEMENT OF STUDY DRUGS ........................... 54 
5.1. 
Sunitinib .............................................................................................................. 54 
5.1.1. 
Sunitinib Description ............................................................................ 54 
5.2. 
DCC-2618 (Ripretinib, ZL-2307) ....................................................................... 54
5.2.1. 
Description of DCC-2618 (ripretinib, ZL-2307) .................................. 54 
5.3. 
Dosage and route of administration of study drugs ............................................ 54 
5.4. 
Dose interruption and adjustment of study drugs ............................................... 55 
5.4.1. 
Interruption of the study drug due to planned medical procedure ........ 55 
5.4.2. 
Dose interruption and adjustment of DCC-2618 (ripretinib, ZL-
2307) caused by adverse events ........................................................... 56 
5.5. 
Packaging and Labeling ...................................................................................... 60 
5.6. 
Storage Condition of Study drug ........................................................................ 60 
5.7. 
Study drug Compliance ...................................................................................... 60 
5.8. 
Counting of Study drug ...................................................................................... 60 
5.9. 
Disposal, Return or Keep of the Unused Study drugs ........................................ 61 
5.10. 
Method for Assigning Subjects into Treatment Groups ..................................... 62 
5.11. 
Blinding and Unblinding .................................................................................... 62 
5.12. 
Past and Concomitant Treatment ........................................................................ 62 
5.12.1. Previous medications/treatment............................................................ 62 
5.12.2. Prior Anti-Tumor Therapy ................................................................... 62 
5.12.3. Concomitant medication ....................................................................... 62 


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5.12.4. Concomitant medical procedures ......................................................... 64 
5.13. 
Other Precautions................................................................................................ 64 
6. 
STUDY EVALUATION ................................................................................................ 64 
6.1. 
Screening ............................................................................................................ 64 
6.2. 
Re-screening ....................................................................................................... 64 
6.3. 
Treatment period ................................................................................................. 65 
6.4. 
Follow-up ............................................................................................................ 65 
6.5. 
Lost to Follow-up ............................................................................................... 65 
6.6. 
Study Evaluation ................................................................................................. 65 
6.7. 
Inform Consent Process ...................................................................................... 65 
6.8. 
Distribution of Patient Number .......................................................................... 66 
6.9. 
Demographics and Medical History ................................................................... 66 
6.10. 
Effectiveness ....................................................................................................... 67 
6.10.1. Imageological examination .................................................................. 67 
6.10.2. Overall survival follow-up by telephone .............................................. 68 
6.11. 
Safety .................................................................................................................. 68 
6.11.1. Physical examination ............................................................................ 68 
6.11.2. ECOG performance status .................................................................... 68 
6.11.3. Vital sign, weight and height ................................................................ 68 
6.11.4. Electrocardiogram ................................................................................ 69 
6.11.5. Echocardiogram .................................................................................... 69 
6.11.6. Dermatologic examination ................................................................... 69 
6.11.7. Hepatitis B, Hepatitis C and HIV Antibody Testing ............................ 70 
6.11.8. Clinical laboratory tests ........................................................................ 70 
6.11.9. Pregnancy test ....................................................................................... 71 
6.11.10. Contraception and contraceptive measures .......................................... 71 
6.11.11. AEs 
72 
6.11.12. Safety follow-up ................................................................................... 72 
6.12. 
Pharmacokinetics ................................................................................................ 72 
6.12.1. Sampling 72 
6.12.2. Sample evaluation ................................................................................ 72 
6.13. 
Biomarkers and pharmacodynamics ................................................................... 72 
6.13.1. Sample collection ................................................................................. 72 
6.13.2. Sample evaluation ................................................................................ 73 
7. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT DOCUMENTATION, 
SEVERITY GRADING, AND REPORTING ............................................................... 73 
7.1. 
Adverse Events (AEs)......................................................................................... 73 
7.2. 
Severity Assessment ........................................................................................... 74 
7.3. 
Causality assessment .......................................................................................... 74 
7.4. 
Study Drug Action Taken ................................................................................... 75 
7.5. 
Adverse Event Outcome ..................................................................................... 75 
7.6. 
Treatment measures on AEs ............................................................................... 75 
7.7. 
Additional Considerations on  Adverse Events .................................................. 76 
7.7.1. 
Clinical Significance ............................................................................ 76 


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7.8. 
Definition of Serious Adverse Event(SAE) ........................................................ 76 
7.9. 
Adverse Events of Special Interest (AESIs) ....................................................... 77 
7.10. 
Adverse Events Reporting Period ....................................................................... 77 
7.11. 
Adverse Event, Serious Adverse Event, and Adverse Event of Special 
Interest Reporting Requirements ........................................................................ 78 
7.12. 
Drug abuse, misuse, overdose and medication errors......................................... 80 
8. 
PATIENT WITHDRAWAL AND REPLACEMENT ................................................... 80 
8.1. 
End of treatment ................................................................................................. 80 
8.2. 
End of Study ....................................................................................................... 81 
8.3. 
Patient withdrawal and replacement ................................................................... 81 
9. 
STATISTICAL  CONSIDERATION ............................................................................. 81 
9.1. 
Determination of sample size ............................................................................. 81 
9.2. 
Study Endpoints .................................................................................................. 82 
9.2.1. 
Primary endpoints ................................................................................. 82 
9.2.2. 
Secondary endpoints ............................................................................. 82 
9.2.3. 
Exploratory endpoint ............................ Error! Bookmark not defined. 
9.3. 
Analysis Population ............................................................................................ 83 
9.4. 
Processing procedures of missing data, unused data and false data ................... 84 
9.5. 
Statistical Method ............................................................................................... 85 
9.5.1. 
General methods ................................................................................... 85 
9.5.2. 
Patients disposition ............................... Error! Bookmark not defined. 
9.5.3. 
Demographic data and baselinecharacteristics ..................................... 86 
9.5.4. 
Extent of exposure ................................................................................ 86 
9.5.5. 
Efficacy analysis ................................................................................... 86 
9.5.6. 
Safety Analysis ..................................................................................... 87 
9.5.7. 
Pharmacokinetic analysis ..................................................................... 88 
9.5.8. 
Biomarkers and pharmacodynamics analysis ....................................... 88 
9.5.9. 
Procedures to report deviations from the original statistical plan ........ 89 
10. 
QUALITY CONTROL AND ASSURANCE ................................................................ 89 
10.1. 
Monitoring visit at each study site ...................................................................... 89 
10.2. 
Compliance of the study protocol ....................................................................... 89 
11. 
DATA HANDLING AND RECORD STORAGE ......................................................... 90 
11.1. 
Electronic case report form ................................................................................. 90 
11.2. 
Recording storage ............................................................................................... 90 
12. 
ETHICS........................................................................................................................... 90 
12.1. 
Ethical implementationof the study .................................................................... 90 
12.2. 
Subject information and informed consent ......................................................... 91 
12.3. 
IRB/IEC .............................................................................................................. 91 
12.4. 
Keeping confidentiality for patient ..................................................................... 91 
12.5. 
Report of safety issues or conditions seriously violating the study protocol or 
Good Clinical Practice of ICH ............................................................................ 92 
13. 
TERMINATION OF STUDY ........................................................................................ 92 
13.1. 
Criteria for suspension or premature termination of the study ........................... 93 
13.2. 
Criteria for premature termination or suspension of study sites ......................... 93 


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13.3. 
Procedures for early termination or suspension of the study or participation 
of study site ......................................................................................................... 93 
14. 
PUBLICATION OF RESEARCH RESULTS................................................................ 93 
15. 
REFERENCES ............................................................................................................... 94 
16. 
APPENDIX ..................................................................................................................... 97 
16.1. 
“RECIST v1.1-GIST-specific Criteria” response Evaluation Criteria In Solid 
Tumours .............................................................................................................. 97 
 
 


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List of In-text Tables 
Table 1:  
Schedule of Assessments .................................................................................... 11 
Table 2:  
Interaction between DCC-2618 (Ripretinib, ZL-2307) and transporters of its 
metabolite DP-5439 .......................................................................................... 32 
Table 3:  
TEAE with an incidence ≥ 10% at a dose of 150 mg QD (n = 142) .................. 37 
Table 4:  
Typical steady-state drug toxicokinetics exposure in patients with advanced 
malignant tumor predicted by models of DCC-2618 (ripretinib, ZL-23070 
and DP-5439 ..................................................................................................... 47 
Table 5:  
Dose reduction steps of DCC-2618 (ripretinib, ZL-2307).................................. 56 
Table 6:  
Principle of dose adjustment of DCC-2618 (ripretinib, ZL-2307) due to skin 
toxicity and joint pain/myalgia ......................................................................... 56 
Table 7:  
Principle of dose adjustment of DCC-2618 (ripretinib, ZL-2307) due to 
hypertension ...................................................................................................... 58 
Table 8:  
DCC-2618 Dose Modifications for Left Ventricular Systolic Dysfunction ....... 59 
Table 9          DCC-2618 Dose Modifications for Isolated Bilirubin Increased ...................... 59 
Table 10:   Principle of dose reduction of DCC-2618 (ripretinib, ZL-2307) due to 
treatment-related adverse events not mentioned above .................................... 59 
Table 11:  
Safety laboratory tests ......................................................................................... 70 
Table 12:  
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) Version 5.0 Severity Grading Scale ......................................... 74 
Table 13:  
Relationship to Study Drug Criteria ................................................................... 74 
Table 14:  
Classification for Study Drug Action Taken with Regard to an Adverse Event
........................................................................................................................... 75 
Table 15:  
Classification of adverse event outcome............................................................. 75 
Table 16:  
Calculation of some or missing date ................................................................... 84 
 
List of In-text Figures 
Figure 1:  
Schematic diagram of the study ........................................................................ 10 
Figure 2:  
Various secondary KIT mutations in cross-exon 13 - 18 in GIST patients ...... 26 
Figure 3:  
KIT mutation in baseline ctDNA of 131 GIST patients listed according to 
treatment line (n = 95) ...................................................................................... 39 
Figure 4:  
Swimlane diagram of duration of response in GIST patients who received 
the designated starting dose of 150 mg QD in the escalation and extension 
period (intent-to-treat population) summarized according to treatment line .... 41 
Figure 5:   
Kaplan-Meier diagram of PFS of GIST patients who received a starting dose 
of 150 mg QD in the escalation and extension period summarized according 
to treatment line (intent-to-treat population)..................................................... 42 
Figure 6:  
Inhibition of DCC-2618 (ripretinib, ZL-2307) to PDGFRA and KIT 
mutation ............................................................................................................ 45 
Figure 7:  
Drug pharmacokinetic model of DCC-2618 and DP-5439 in patients with 
advanced malignant tumors .............................................................................. 47 
 
 


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1. 
Introductionand Basic principles 
1.1. 
Introduction 
Studies revealed that activating mutation of KIT or PDGFRA of receptor tyrosine kinase exists 
in many cancers such as gastrointestinal stromal tumor (GIST), melanoma subtype,  seminoma 
of testis and acute myeloid leukemia (AML) as well as myeloproliferative neoplasm such as 
systemic mastocytosis (SM) including aggressive systemic mastocytosis (ASM) and mast cell 
leukemia[1,2,3, 4,5]. Studies also revealed that GIST, melanoma, AML, glioma and 
neuroendocrine tumor presented abnormal wild-type KIT and/or PDGFRA over-
expression[6,7,8,9]. 
Most GIST is induced by activated mutation in KIT (about 80%) or relevant PDGFRA (about 
10%) receptor tyrosine kinase[11,300]. In GIST patients, exon 9 or 11 mutations are the most 
common in KIT mutation. 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 treatment, secondary drug-resistant KIT mutation generally occurs in the 
catalytic domain of kinase and these mutations are usually reflected in embedded 
conformational switch control mechanism that regulates KIT activity ( 
 


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Figure 2) Secondary KIT mutations usually occur in exons 13 and 14 (approaching adenosine 
triphosphatase [ATP]-binding 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[10,11]. Activation loop mutation can transform 
kinase into activation conformation, making it difficult to bind to the approved therapeutic 
drugs[12]. Other diseases harboring primary KIT (or PDGFRA) activation loop mutations 
include SM, AML and PDGFRA-induced GIST[6,13,14]. 
 
 


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Figure 2:  
Various secondary KIT mutations in cross-exon 13 - 18 in GIST patients 
 
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. 
Imatinib is the first KIT inhibitor and was approved in 2002 for the treatment of advanced 
GIST [15]. Imatinib generally cannot cure unresectable and/or metastatic diseases and its 
complete response rate (CR) was about 5% and objective response rate (ORR) was 68% [16]. 
Over 80% of GIST patients obtained clinical benefit from imatinib monotherapy. However, 
imatinib resistance was basically unavoidable for patients and over half of patients had 
progressive disease within 2 years[17]. The main cause for progression was secondary KIT 
kinase mutation, inducing resistance to imatinib [11]. Although imatinib can effectively inhibit 
exon 11 mutation in KIT and dose increase to 800 mg was effective to exon 9 mutation, 
imatinib doesn’t or almost doesn’t have inhibitory effect on KIT and PDGFRA mutation, 
especially on mutations of conformation dynamic mediating switch activation [17, 18]. 
In 2006, sunitinib was approved as second-line therapy in GIST patients who have progressed 
after imatinib treatment or are intolerant to imatinib. Sunitinib has a stronger inhibitory effect 
on exon 9 mutation than imatinib and a weaker inhibitory effect on exon 11 mutation [14, 17]. In 
addition, sunitinib presented anti-tumor activity to KIT exons 13 and 14 mutations, but only 
half of the patients benefited from it, with a median progression‑free survival (PFS) of 5.5 
months[17]. Sunitinib was ineffective in patients with KIT exons 17/18 mutations and PDGFRA 
exon 18 mutation r in the activation loop. 
Regorafenib was approved as third-line therapy in 2013 in adult patients with metastatic and/or 
unresectable GIST who have progressed after receiving imatinib and sunitinib treatment or are 
not tolerant to imatinib and sunitinib. Besides inhibitory activity to KIT exon 11 mutation, 
regorafenib is the only approved therapy with an inhibitory activity to KIT exon 17 mutation 
subtype. For patients responding to regorafenib, PFS was nearly 5 months. Regorafenib cannot 
effectively treat some patient with KIT mutation. In such case, these patients may have other 
Distribution of secondary KIT mutation 
 (n = 27) 
Switch pocket 
Switch area 
Exon 13 
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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or multiple secondary mutations, leading to resistance to regorafenib [11]. Studies showed that 
for an individual patient, tumor heterogeneity and multiple secondary KIT mutations were 
observed in different regions of a tumor or different metastatic sites [11]. 
Complex heterogeneity of KIT mutation in individual patient is a main cause for drug 
resistance [11]. Kinase inhibitor that can extensively inhibit clinical KIT mutation or multiple 
KIT mutation in individual GIST patients has a high treatment value for refractory GIST 
patients. What’s more, it is an important treatment objective to confirm whether DCC-
2618(Ripretinib, ZL-2307) can delay the occurrence of KIT mutations leading to drug 
resistance. 
At present, no kinase inhibitor that can extensively inhibit secondary drug-resistant mutation 
in GIST patients has been marketed. Therefore, it is urgent to develop kinase inhibitor that can 
effectively inhibit multiple KIT and PDGFRA mutations. 
1.2. 
Clinical Indications 
DCC-2618 (ripretinib, ZL-2307) is a KIT and PDGFRA kinase inhibitor. At present, the drug 
is under development and expected to treat GIST and other advanced malignant tumors induced 
by proto-oncogene tyrosine protein kinase. DCC-2618 can not only inhibit KIT and PDGFRA 
but also inhibit CSF1R (FMS), VEGFR2 and TIE2. According to literatures, these substances 
seldom induce tumor progression, but are associated with tumor growth. 
GIST is the most common type of sarcoma, formed in human mesenchymal cells but is a 
relatively rare cancer subtype [19]. There are approximately 3000 - 6000 new GIST patients 
every year in America [20, 21, 22] and the age of onset is usually 50 - 70 years, with a similar 
prevalence in males and females [23]. Surgery, as the main treatment for local GIST, can realize 
a radical effect, but over half of patients had local and/or distant metastasis [24]. Approximately 
half of patients had metastatic or unresectable GIST, while radiotherapy and traditional 
chemotherapy are ineffective in these patients [19, 24]. In the era of targeted cancer therapy, 
several new effective therapies have been developed for metastatic and recurrent GIST though 
CR is seldom reached [19]. Most patients have resistance to treatment within several months to 
years depending on treatment method [20], which is similar to result observed in targeted therapy 
of other tumors. 
1.3. 
DCC-2618 (Ripretinib, ZL-2307) 
DCC-2618 (Ripretinib, ZL-2307) is a new orally administered KIT kinase and PDGFRA kinase 
inhibitor developed by Deciphera Pharmaceuticals, LLC (thereafter refer to "the Sponsor") 
using its special kinase switch control inhibitor technological platform. DCC-2618 (Ripretinib, 
ZL-2307) can comprehensively and potently inhibit extensive primary and secondary KIT and 
PDGFRA kinase mutants, including primary KIT exons 9 and 11 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 


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(Ripretinib, ZL-2307) 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 (Ripretinib, ZL-2307), as an enhanced type II kinase inhibitor, penetrates embedded 
KIT/PDGFRA switch pocket by binding to extensively inhibit KIT/PDGFRA mutants. 
1.3.1. 
Nonclinical Experience 
Please refer to Investigator’s Brochure (IB) for more details of summary of non-clinical 
experience of DCC-2618 (ripretinib, ZL-2307). 
1.3.1.1. 
Pharmacology 
Recombinant kinase test and cell test were carried out with drug-resistant cell lines of GIST 
patients, AML and mastocytosis or cell lines transfected with KIT or PDGFRA mutants, so as 
to conduct in vitro active evaluation of DCC-2618 (Ripretinib, ZL-2307) and its active 
metabolite DP-5439. The above study revealed that DCC-2618 (Ripretinib, ZL-2307) can 
comprehensively inhibit clinically significant KIT and PDGFRA mutations that can’t be 
treated with or don’t respond to current therapies. Evaluation results of cancer cell lines provide 
guidance for further evaluation of DCC-2618 (ripretinib, ZL-2307) in refractory/drug-resistant 
in vivo xenograft model. 
Multiple cancer model systems were adopted for in vivo pharmacological evaluation of DCC-
2618 (ripretinib, ZL-2307), including efficacy assessment in human tumor xenograft nude 
mouse model and study of pharmacokinetic (PD)/pharmacodynamic (PD) in tumor-bearing 
mice, so as to evaluate exposure of drug required for persistent inhibition of KIT mutation in 
vivo. 
DCC-2618 (ripretinib, ZL-2307) showed a potent in vivo anti-tumor effect in KIT mutation 
GIST model. Moreover, DCC-2618 (Ripretinib, ZL-2307) can also effectively inhibit KIT 
phosphorylation in GIST model. DCC-2618 (ripretinib, ZL-2307) can also inhibit tumor 
growth in HMC1.2 (exon 11 V560D and exon 17 D816V double mutation) mastocytosis 
xenograft model and presented a potent inhibitory effect in H1703 lung cancer xenograft model 
with PDGFRA amplification. 
A PK/PD study in human GIST xenograft model in mice indicated that after a single dose of 
50 mg/kg, exposure (0-24 hour area under the time-concentration curve [AUC0-24hr]) of DCC-
2618 (Ripretinib, ZL-2307) was 2500 ng•h/mL (including after active metabolite DP-5439, 
exposure was 5000 ng•h/mL); inhibition rate against KIT was 69-88% within 8 hours after 
administration and about 40% 12 hours after administration. In a multiple-dose efficacy study, 
when administering at 50 mg/kg twice daily (BID, daily exposure 10,000 ng•h/mL) to GIST 
T1 model, inhibition rate of the drug exposure to tumor growth was 90%. This PK/PD-derived 
exposure is used to guide the identification of toxicological products that can realize several 
times that of the exposure persistently inhibiting KIT in vivo. 
Hepatocellular metabolite identification study indicated that the main metabolic pathway of 


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DCC-2618 (Ripretinib, ZL-2307) is an active metabolite named DP-5439 formed by N-
demethylation. In preclinical studies in animals, effective dose of DP-5439 was detected in 
plasma of mice, rats and dogs. Yield of the metabolite was highest in mice. PK parameters 
showed that in terms of AUC0-24hr, DP-2618 (Ripretinib, ZL-2307) exposure in mice was 
equivalent to DCC-5439 exposure. Total exposure (AUC0-24hr) of active drug in mice was 
calculated by determining the total exposure of DCC-2618 (ripretinib, ZL-2307) and its 
metabolite DP-5439, that is, exposure was 5000 ng•h/mL after a single oral dose of 50 mg or 
10,000 ng•h/mL after administration at 50 mg/kg BID. This value will be taken as reference 
value in non-clinical safety study. A phase 1 ascending dose study also confirmed that 
metabolite DP-5439 will form. At a clinically effective dose, exposure of metabolite was higher 
than original DCC-2618 (Ripretinib, ZL-2307) exposure. 
Efficacy and tolerability observed in these model systems choose the clinical development of 
DCC-2618 (Ripretinib, ZL-2307). 
1.3.1.1.1. 
Safety pharmacology 
Binding of DCC-2618 (Ripretinib, ZL-2307) to human ether-à-go-go related gene potassium 
channel components can be ignored. 
DCC-2618 (Ripretinib, ZL-2307) 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. DCC-2618 (Ripretinib, ZL-2307) at 15, 60 or 300 mg/kg was 
administered to rats. 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 and 13-week repeat-dose toxicological study was carried out in dogs, and 
cardiovascular safety was assessed by measuring their electrocardiogram (ECG), blood 
pressure (BP) and troponin I levels. The study drug did not have significant impact on BP, heart 
rate, ECG intervals and troponin I level. In an independent cardiovascular safety study, after 
the investigator gave a single dose of DCC-2618 (Ripretinib, ZL-2307) to telemetered Beagle 
dogs, both 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 (Time to observed maximum concentration [Tmax]). At doses of 7, 20 and 
75 mg/kg, diastolic blood pressure was higher than that of the control group (higher by 12, 12 
and 17%, respectively). At doses of 7, 20 and 75 mg/kg of DCC-2618 (ripretinib, ZL-2307), 
the mean arterial pressure was higher than that in the control group (higher by 12, 10 and 14 
mmHg, respectively). Systolic blood pressure or arterial pressure didn’t change. 
In the dark 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). 
The corrected QT interval (QTc) didn’t change. In the whole dark stage, heart rate increased. 


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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; BP and heart 
rate will be closely monitored in the clinical study. Although the change pace of BP and heart 
rate is more significant, this does not mean the study drug has severe toxicity. 
1.3.1.2. 
Pharmacokinetics and characteristics of absorption, distribution, 
metabolism and excretion 
In vitro studies were carried out in human and other drug development-related mammal species 
to confirm absorption, distribution, metabolism and excretion characteristics of DCC-2618 
(Ripretinib, ZL-2307) and its active metabolite DP-5439. In vivo PK studies (the 
administration routes are oral and intravenous injection [IV]) were carried out in rodents (mice 
and rats) and non-rodents (dogs and cynomolgus monkeys). When administered orally, 
bioavailability of DCC-2618 (ripretinib, ZL-2307) was highest in all species, proving its 
development potential as an oral drug. 
Total exposure (AUC0-24hr) of DCC-2618 (ripretinib, ZL-2307) in dogs and rats was 1.9 - 2.6 
times target area under the curve (AUC) 10,000 ng•h/mL of DCC-2618 (ripretinib, ZL-2307) 
and metabolite DP-5439 in mice GIST efficacy model. Dogs and rats were given a single IV 
dose, and half-life time (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 metabolite in liver cells of all species was N-
demethylation metabolite (DP-5439). Accordingly, it can be confirmed that DP-5439 could 
inhibit KIT and PDGFRA wild type and mutation and has an equivalent potency to DCC-2618 
(ripretinib, ZL-2307). In testing of 19 single and double KIT mutants conducted in transfected 
Chinese Hamster Ovary Cells, the result showed that DCC-2618 (Ripretinib, ZL-2307) 
inhibited phosphorylation of mutant KIT, with median maximum inhibition concentration 
(IC50) between 6 nM - 221 nM These studies revealed that DP-5439 can also inhibit 
phosphorylation of KIT mutant and its IC50 ranged 21 - 191 nM. 
In vitro metabolism of DCC-2618 (Ripretinib, ZL-2307) and active metabolite DP-5439 by 
human liver microsome was studied to confirm which human cytochrome P450 (CYP) is 
conducive to DCC-2618 (Ripretinib, ZL-2307) metabolism. Studies showed that metabolism 
of DCC-2618 (ripretinib, ZL-2307) should be carried out in the presence of reduced 
nicotinamide adenine dinucleotide phosphate (NADPH). In the cultured human liver 
microsomes, combination of specific direct CYP inhibitor or metabolism-dependent CYP 
inhibitor was used to block metabolism of DCC-2618 (ripretinib, ZL-2307). Results showed 
that CYP3A4/5 was the main metabolic enzyme (ketoconazole inhibition rate 63%; 
troleandomycin inhibition rate 79%) of DCC-2618 (ripretinib, ZL-2307), while CYP2C8 
(glucuronic acid of gemfibrozil inhibition rate 24%) and CYP2D6 (quinidine inhibition rate 


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26%) were secondary metabolic enzymes. However,the study also found that, in recombinant 
human CYP enzyme products, CYP2D6 and CYP2C8 were potent metabolic enzymes of DCC-
2618 (Ripretinib, ZL-2307). Inhibition to DP-5439 was observed in microsome incubated by 
the following inhibitors, which include: direct inhibitor ketoconazole (CYP3A4/5, 72% 
inhibition), metabolism-dependent inhibitor gemfibrozil-glucuronic acid (CYP2C8, 59% 
inhibition), tienilic acid (CYP2C9, 25% inhibition), esomeprazole (CYP2C19, 31% inhibition), 
paroxetine (CYP2D6, 42% inhibition), diethyldithiocarbamate (CYP2E1, 50% inhibition) and 
troleandomycin (CYP3A4/5, 100% inhibition) . When DP-5439 and other direct or 
metabolism-dependent inhibitors were incubated together, the estimate result showed that 
inhibition rate was lower than 14%. The study indicated that metabolite DP-5439 was mainly 
metabolized through CYP3A4/5, but CYP2C8, CYP2E1 and CYP2D6 may also promote 
significant metabolism. In an in vitro metabolism study, DCC-2618 (ripretinib, ZL-2307) 
didn’t obviously inhibit CYP3A4, CYP1A2 or CYP2B6. IC50 of DCC-2618 (Ripretinib, ZL-
2307) in inhibiting CYP2C8, CYP2C9, CYP2C19 and CYP2D6 ranged 0.12 - 1.8 μM. Of the 
assessed 7 main CYP enzymes, inhibitory effect of DCC-2618 (ripretinib, ZL-2307) was 
unrelated or almost unrelated to time or metabolism. 
IC50 of metabolite DCC-5439 in inhibiting CYP2C8, CYP2C9, CYP2C19 and CYP2D6 ranged 
0.30 - 2.0 μM. DP-5439 did not significantly and directly inhibit CYP3A4, CYP1A2 or 
CYP2B6. However, after incubating together with human liver microsome for 30 minutes in 
the presence of NADPH, DP-5439 had metabolism-dependent (time-dependent and NADPH-
dependent) inhibitory effect on CYP3A4/5-mediated testosterone 6β-hydroxylation. After 
preincubate, inhibition rate of DP-5439 increased by 41% at a concentration of 7.0 µM. DP-
5439 has little or none metabolism-dependent (time-dependent and NADPH-dependent) 
inhibitory effect on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. When 
DCC-2618 (ripretinib, ZL-2307) and DP-5439 are combined with other drugs inhibiting 
CYP2C8, CYP2C9, CYP2C19 or CYP2D6, DDI may occur during metabolism, which is 
dependent upon the drug. 
In the presence of 10 μM DCC-2618 (Ripretinib, ZL-2307) or 7 μM DP-5439, organic anion 
transporter (OAT) OAT1 and OAT3, organic cation transporter (OCT) OCT1 and OCT2 were 
mildly or moderately inhibited, with inhibition ≤ 55%. Inhibition rate of DCC-2618 (Ripretinib, 
ZL-2307) 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 (Ripretinib, ZL-2307) 
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 (ripretinib, ZL-2307) is not the 
substrate of BCRP transporter (excretion rate [E] is 2.36), metabolite DP-5439 shows a 
significant substrate activity (ER os 85.0), indicating the drug may interact with metabolite. 
DCC-2618 (ripretinib, ZL-2307) may be the substance (BCRP IC50 is 0.04 µM) inducing drug 
interaction, while metabolite DP-5439 may be a substance (BCRP ER is 85.0) influenced by 
drug interaction. DCC-2618 (Ripretinib, ZL-2307) may also have drug interaction with 


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substrate or inhibitor as other BCRP efflux transporters. 
DCC-2618 (Ripretinib, ZL-2307) and DP-5439 had a moderate to weak inhibitory effect on 
multidrug resistance efflux transporter 1 (MDR1), and IC50 was 1.95 µM and > 7 µM, 
respectively. Although DCC-2618 (Ripretinib, ZL-2307) 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 
(Ripretinib, ZL-2307) was likely to be the substance inducing interaction (MDR1 IC50 1.95 
µM), and metabolite DP-5439 may be a substance (MDR1 ER 72.4) (Table 2). 
Table 2:  
Interaction between DCC-2618 (Ripretinib, ZL-2307) and transporters of 
its metabolite DP-5439 
 
Inhibition on transporter 
Transporter substrate 
DCC-2618 
DP-5439 
DCC-2618 
DP-5439 
BCRP 
IC50 0.040 µM 
IC50 1.26 µM 
ER 2.36 
ER 85.0 
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 
IC50 = median maximum inhibition concentration; ER = excretion rate; NT = not tested; BSEP = bile salt 
export pump 
 
1.3.1.3. 
Toxicology 
Toxicological characteristics of DCC-2618 (Ripretinib, ZL-2307) were assessed in vivo and in 
vitro bacterial mutagenicity analysis in nude mice, Sprague-Dawley rats and Beagle. In an 
assessment per Good Laboratory Practice, at the maximum testing concentration 3000 µg/plate 
(concentration at which precipitation was formed) in a bacterial mutagenicity test, regardless 
of metabolic activation, no clear bacterial mutagenicity was observed. 
In a critical, per-GLP 4-week oral study in rats, DCC-2618 (ripretinib, ZL-2307) was 
administered at 0, 15, 60 and 300 mg/kg.day. After administration, animals in the observation 
period were observed for 4 more weeks. No drug-related death or adverse clinical observation 
result was reported in this study. Incidence of hair thinning at the dose of 300 mg/kg/day was 
higher. In animals treated with DCC-2618 (ripretinib, ZL-2307), weight decrease and food 
consumption decrease were observed. Body weight and food consumption change was reversed 


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in the recovery period and the drug didn’t have any influence on the overall physical status of 
animals. Several mild clinical pathological findings were observed on Day 29. These changes 
were very minor, were not clinically relevant under microscopy and reversible at the end of the 
recovery period. Therefore, these changes were not considered as adverse reactions. DCC-2618 
(ripretinib, ZL-2307)-related lung weight increase (15 - 33%) was observed in male rats in the 
300 mg/kg/day dose group and female rats in dose ≥ 15 mg/kg/day group There was no related 
microscopic change and lung weight increase was partially reversed during the recovery period. 
Micro-changes in non-glandular stomach (diffuse hyperplasia/hyperkeratosis) were observed 
in rats receiving treatment at ≥ 60 mg/kg/day and some of these changes were reversible in the 
recovery period. This kind of change was unrelated to human because human do not have the 
anatomical feature. According to these results, no observed adverse effect level (NOAEL) after 
4-week administration was 300 mg/kg/day. 
In a 13-week per-GLP study, 30, 100 and 300 mg/kg/day DCC-2618 was given to Sprague 
Dawley rats by oral administration. The study revealed that rats had growing incisor teeth 
loss/discolouration (only 300 mg/kg/day group), skin discoloration and skin lesion (dose ≥ 30 
mg/kg/day group), hair loss or thinning, weight and weight gain decrease, and food 
consumption decrease (only female rats in the 300 mg/kg/day group). Clinical observation 
showed that three rats (one from the main study and two from toxicokinetics study) in the 300 
mg/kg/day group had skin lesions and were killed in an unscheduled period for humanity. 
Clinical pathological findings were consistent with inflammation and/or stress response and 
related to skin changes. Liver enzyme activity increased was related to changes in liver portal 
veins. Microscopic findings indicated degradation of incisor teeth and proximal duodenum 
Brunner's gland in female rats in the 300 mg/kg/day group, testis degeneration/atrophy and 
epididymis cell debris increased in male rats in the 300 mg/kg/day group.The above events 
were severe enough to consider them as adverse events. Therefore, NOAEL of DCC-2618 
(ripretinib, ZL-2307) was 100 mg/kg/day. Exposure (observed maximum concentration [Cmax] 
and AUC) of DCC-2618 (ripretinib, ZL-2307) and DP-5439 on Day 1 was about twice as much 
as that on Day 91. In the 13-week administration period, the most obvious skin changes were 
observed in an early stage.  
In a critical, per-GLP 4-week oral study in beagles, doses were 0, 7, 20 and 75 mg/kg/day. 
After administration, animals in the observation period were observed for 4 more weeks. Due 
to adverse clinical observation results related to DCC-2618 (ripretinib, ZL-2307), the drug was 
discontinued in several animals using the drug at 20 and 75 mg/kg/day at weeks 2 and 3. Due 
to adverse clinical observation results related to DCC-2618 (ripretinib, ZL-2307), three male 
dogs in the 75 mg/kg/day group were killed on Day 13 and another 7 dogs in the 20 mg/kg 
dose group (2 males and 2 females) and 75 mg/kg dose group (3 females) were killed at week 
4 in advance. The clinical observation results of these animals included, erythema in foot, ears, 
nose, mouth, periorbital area and on ventral chest, and head hair thinning. Some test animals 
had skin dryness and crack, otitis, external auditory canal erythema, excessive drooling, 


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vomiting and fecal formlessness/liquid feces. In test dogs in the 7 mg/kg/day dose group, skin 
changes were observed, but the severity was mild. Therefore, the changes were not considered 
as adverse reactions. Skin lesion in the 20 and 75 mg/kg/day dose groups partially or 
completely resolved in the recovery period. Weight decrease was observed in male dogs in 20 
and 75 mg/kg/day dose groups. Body weight change of animals in the 7 mg/kg/day group was 
minor and not considered as adverse reaction. In any dose group of DCC-2618 (ripretinib, ZL-
2307), no BP or ECG interval change was observed. In animals of dose ≥ 20 mg/kg/day group, 
mild hematological, clinical biochemical and/or coagulation abnormalities were observed and 
there was evidence that these changes were reversed after the recovery period. In animals 
treated with DCC-2618 (ripretinib, ZL-2307), troponin I level was not influenced by drug 
therapy. When the administration dose ≥20 mg/kg/day, hyperkeratoses, sparse cytoplasm of 
liver cells (consistent with glycogen increased), lymphocytes decreased in lymphoid tissues 
and one case of intraepithelial pustule were observed in microscopy. In some animals in the 75 
mg/kg/day dose group, the only test product-related microscopic finding when killing animals 
in the recovery period was very mild sparse hepatic cytoplasm, indicating it was recovered in 
some animals. 
On the basis of these results, NOAEL was 7 mg/kg/day. The dose was also considered as the 
highest non-severely toxic dose. 
In a 13-week per-GLP study, 2.5, 5 and 10 mg/kg/day DCC-2618 was given to beagles daily 
and it was found that skin damage, hair thinning/loss were observed in all dose groups. When 
the dose ≥ 5 mg/kg/day, skin sensation of warmth was observed. For adverse skin damage in 
the 10 mg/kg/day group, interventional measures such as non-steroidal anti-inflammatory 
drugs (NSAID) and antibiotics were given from week 6 of the administration period to terminal 
autopsy. Clinical pathological findings were consistent with inflammation and/or stress 
response. Microscopic findings of skin hyperplasia/hyperkeratosis were consistent with 
clinically observed skin damages. One female animal in the 10 mg/kg/day group had poor 
domestication and obvious weight decrease prior to the first dose of the test product. 
Nevertheless, it was still believed that DCC-2618 (ripretinib, ZL-2307) induced physical 
decline of the female rat and study of the animal was terminated prematurely. Therefore, 
NOAEL of DCC-2618 (ripretinib, ZL-2307) was 5 mg/kg/day after 13-week administration. 
1.3.2. 
Clinical Experience 
American IND 125279 became effective in 2015 to support clinical development of ripretinib 
in KIT/PDGFRA-driven malignant tumors. 
First-in-human (FIH) study DCC-2618-01-001 is a phase 1, open-label, dose-escalation and 
expansion study conducted in patients with advanced malignant tumors. The primary objective 
of this study is to confirm the maximum tolerated dose (MTD) of DCC-2618 (Ripretinib, ZL-
2307) and to assess its safety, tolerability, preliminary efficacy, PK and PD effect. Data in the 
dose-escalation period in the FIH study support to select 150 mg QD as the recommended 


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phase 2 dose (RP2D). Extension period of the study was initiated in the middle of 2017 and the 
drug was administered at RP2D. As of March 1, 2019, a total of 237 patients were enrolled into 
the dose-escalation and extension period of the study and 181 patients (12 in the dose-
escalation period and 169 in the extension period) took RP2D 150 mg QD as the starting dose. 
In addition, 142 patients were diagnosed with advanced GIST. 
Another ongoing phase 3 registration study (DCC-2618-03-001; INVICTUS) is a randomized, 
double-blinded, placebo-controlled study in advanced GIST patients who have previously 
received imatinib, sunitinib and regorafenib treatment. The study was initiated in January 2018. 
Enrollment (N=129) of this study was finished in November 2018 and the primary endpoint 
was progression‑free survival (PFS). The number of PFS events required for the planned 
analysis of the study was 90 and was reached in May 2019. Deciphera submitted NDA in 
December 2019 to seek complete approval because the study had reached its primary endpoint 
based on final analysis results. On May 15, 2020, the FDA approved ripretinib for adult patients 
with advanced GIST who have received prior treatment with three or more kinase inhibitors, 
including imatinib. In June and July, 2020, ripretinib was also approved for fourth-line GIST 
in Canada and Australia respectively. 
1.3.2.1. 
Clinical Safety 
1.3.2.1.1. 
Overview 
Because study DCC-2618-01-001 is ongoing, only source of some clinical data may not be 
validated or proved. Therefore, there may be changes. The data represent the latest formal cut-
off data of the study. 
As of March 1, 2019, a total of 237 patients received (DCC-2618 (ripretinib, ZL-2307) 
treatment, 181 (12 in the dose-escalation period and 169 in the extension period) of whom took 
RP2D 150 mg QD as the starting dose, and 142 of whom were diagnosed with advanced GIST. 
The following  
 


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Table 3 lists safety data (TEAE with an incidence ≥ 10% in GIST patients in the 150 mg QD 
dose group) of GIST patients (N = 142) receiving 150 mg QD treatment. 
In general, DCC-2618 (ripretinib, ZL-2307) has a good tolerability and treatment-related 
serious adverse event (SAE) and grades 3/4 event was seldom reported. 
Not captured in Table 3, is a Grade 3 (severe) SAE of Stevens-Johnson syndrome 
(SJS)/hypersensitivity reaction. The event was reported as SJS in a 38-year-old Asian female 10 days 
following the initiation of ripretinib in the Phase I (FIH) study. After a positive re-challenge at a 
reduced dose, the study treatment was permanently discontinued due to the event and the event 
resolved on Day 51 of the study. A Grade 3 SJS corresponds to skin sloughing covering <10% of 
body surface area. It was considered related to DCC-2618. If a patient experiences 
SJS/hypersensitivity reaction while being treated with DCC-2618, DCC-2618 must be permanently 
discontinued. 
 


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Table 3:  
TEAE with an incidence ≥ 10% at a dose of 150 mg QD (n = 142)  
Preferred term 
Second-
line 
(N=31) 
n (%) 
Third-line 
(N=28) 
n (%) 
Fourth-
line (N = 
46) 
n (%) 
> Fourth-
line (N = 
37) 
n (%) 
≥ 
Fourth-
line 
(N = 83) 
n (%) 
Total GIST 
patients (N 
= 142) 
n (%) 
Any event 
31 (100.0) 
28 (100.0) 
46 (100.0) 
37 (100.0) 
83 
(100.0) 
142 (100.0) 
Alopecia 
22 (71.0) 
21 (75.0) 
23 (50.0) 
19 (51.4) 
42 (50.6) 
85 (59.9) 
Fatigue 
20 (64.5) 
15 (53.6) 
25 (54.3) 
16 (43.2) 
41 (49.4) 
76 (53.5) 
Myalgia 
15 (48.4) 
16 (57.1) 
20 (43.5) 
16 (43.2) 
36 (43.4) 
67 (47.2) 
Nausea 
14 (45.2) 
15 (53.6) 
16 (34.8) 
18 (48.6) 
34 (41.0) 
63 (44.4) 
Palmar-plantar 
erythrodysesthesia 
syndrome 
17 (54.8) 
12 (42.9) 
17 (37.0) 
14 (37.8) 
31 (37.3) 
60 (42.3) 
Constipation 
12 (38.7) 
9 (32.1) 
18 (39.1) 
17 (45.9) 
35 (42.2) 
56 (39.4) 
Decreased appetite 
11 (35.5) 
9 (32.1) 
15 (32.6) 
11 (29.7) 
26 (31.3) 
46 (32.4) 
Diarrhoea 
11 (35.5) 
11 (39.3) 
10 (21.7) 
9 (24.3) 
19 (22.9) 
41 (28.9) 
Muscle spasms 
11 (35.5) 
11 (39.3) 
14 (30.4) 
4 (10.8) 
18 (21.7) 
40 (28.2) 
Lipase increased 
6 (19.4) 
13 (46.4) 
9 (19.6) 
9 (24.3) 
18 (21.7) 
37 (26.1) 
Weight decreased 
8 (25.8) 
8 (28.6) 
10 (21.7) 
11 (29.7) 
21 (25.3) 
37 (26.1) 
Abdominal pain 
5 (16.1) 
10 (35.7) 
14 (30.4) 
5 (13.5) 
19 (22.9) 
34 (23.9) 
Vomiting 
6 (19.4) 
8 (28.6) 
12 (26.1) 
8 (21.6) 
20 (24.1) 
34 (23.9) 
Arthralgia 
9 (29.0) 
7 (25.0) 
8 (17.4) 
8 (21.6) 
16 (19.3) 
32 (22.5) 
Headache 
9 (29.0) 
9 (32.1) 
9 (19.6) 
5 (13.5) 
14 (16.9) 
32 (22.5) 
Dry skin 
6 (19.4) 
6 (21.4) 
13 (28.3) 
4 (10.8) 
17 (20.5) 
29 (20.4) 
Back distress 
6 (19.4) 
5 (17.9) 
9 (19.6) 
8 (21.6) 
17 (20.5) 
28 (19.7) 
Hypertension 
8 (25.8) 
6 (21.4) 
8 (17.4) 
6 (16.2) 
14 (16.9) 
28 (19.7) 
Dyspnea 
8 (25.8) 
3 (10.7) 
10 (21.7) 
6 (16.2) 
16 (19.3) 
27 (19.0) 
Anemia 
7 (22.6) 
5 (17.9) 
10 (21.7) 
4 (10.8) 
14 (16.9) 
26 (18.3) 
Cough 
3 (9.7) 
8 (28.6) 
8 (17.4) 
5 (13.5) 
13 (15.7) 
24 (16.9) 
Dizziness 
5 (16.1) 
5 (17.9) 
8 (17.4) 
5 (13.5) 
13 (15.7) 
23 (16.2) 
Rash 
5 (16.1) 
8 (28.6) 
7 (15.2) 
3 (8.1) 
10 (12.0) 
23 (16.2) 
Hypokalaemia 
6 (19.4) 
7 (25.0) 
5 (10.9) 
2 (5.4) 
7 (8.4) 
20 (14.1) 
Hypophosphataemia 
7 (22.6) 
3 (10.7) 
5 (10.9) 
5 (13.5) 
10 (12.0) 
20 (14.1) 
Actinic keratosis 
4 (12.9) 
4 (14.3) 
7 (15.2) 
4 (10.8) 
11 (13.3) 
19 (13.4) 
Blood bilirubin 
increased 
5 (16.1) 
4 (14.3) 
5 (10.9) 
4 (10.8) 
9 (10.8) 
18 (12.7) 
Pain in extremity 
4 (12.9) 
6 (21.4) 
3 (6.5) 
5 (13.5) 
8 (9.6) 
18 (12.7) 
Pruritus 
1 (3.2) 
4 (14.3) 
7 (15.2) 
6 (16.2) 
13 (15.7) 
18 (12.7) 
Maculo-papular 
rash 
3 (9.7) 
2 (7.1) 
9 (19.6) 
4 (10.8) 
13 (15.7) 
18 (12.7) 
Seborrheic keratosis 
3 (9.7) 
6 (21.4) 
6 (13.0) 
2 (5.4) 
8 (9.6) 
17 (12.0) 
Insomnia 
2 (6.5) 
5 (17.9) 
3 (6.5) 
6 (16.2) 
9 (10.8) 
16 (11.3) 


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Preferred term 
Second-
line 
(N=31) 
n (%) 
Third-line 
(N=28) 
n (%) 
Fourth-
line (N = 
46) 
n (%) 
> Fourth-
line (N = 
37) 
n (%) 
≥ 
Fourth-
line 
(N = 83) 
n (%) 
Total GIST 
patients (N 
= 142) 
n (%) 
Papilloma skin 
1 (3.2) 
8 (28.6) 
4 (8.7) 
2 (5.4) 
6 (7.2) 
15 (10.6) 
Urinary tract 
infection 
3 (9.7) 
5 (17.9) 
4 (8.7) 
3 (8.1) 
7 (8.4) 
15 (10.6) 
 
1.3.2.1.2. 
Death 
As of August 10, 2019, a total of 256 patients were enrolled into study DCC-2618-01-001, and 
42 of them died. Twenty-four of 42 deaths were related to progressive disease, 4 deaths related 
to GIST, 5 deaths related to AE (2 related to cardiac arrest, each 1 related to myocardial 
infraction, respiration failure and septicemi), and 9 deaths related to unknown reason. 
1.3.2.1.3. 
Adverse events of special interest 
Adverse events of special interest (AESI) include squamous cell carcinoma of skin (SCC), 
actinic keratosis and keratoacanthoma. As of August 10, 2019, a total of 15 cases (5.9%) of 
SCC, 32 cases (12.5%) of actinic keratosis and 7 cases (2.7%) of keratoacanthoma were 
reported. Except for 2 cases (0.8%) of grade 3 SCC, the remaining cases were grade 1 or 2. It 
is unknown whether these events are related to DCC-2618 (ripretinib, ZL-2307), so they are 
classified as adverse events of special interest. In the early stage of phase 1 study DCC-2618-
01-001, patients didn’t receive baseline assessment based on dermatologic examination and 
may have confounding factors resulting in these events. At present, all patients in study of 
DCC-2618 (ripretinib, ZL-2307) received baseline assessment based on dermatologic 
examination and will receive the planned dermatologic examination in the study. 
1.3.2.2. 
Clinical Pharmacokinetics and Pharmacodynamics Markers 
In the non-clinical study, it has been confirmed that DP-5439 is an active metabolite of DCC-
2618 (ripretinib, ZL-2307) and its activity features are similar to DCC-2618. 
Plasma T1/2 of metabolite is longer (30 - 60 hours), indicating QD dosing schedule is feasible. 
Sub-study of food influence revealed that DCC-2618 (ripretinib, ZL-2307) taken with diet 
didn’t have negative influence on absorption. Please refer to Section 1.5.2 for more information 
of basis of current study dose, dosing schedule and treatment duration. 
In GIST paitents who have previously received multiple therapies, DCC-2618 (ripretinib, ZL-
2307) could rapidly eliminate extensive KIT mutation in plasma DNA. In general, on Day 15 
of Cycle 1, total plasma concentration (Cmax) at the start dose of 100 mg BID was very high, 
more than 5 am (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 inhibiting DCC-2618 (Ripretinib, ZL-2307). 


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In the phase 1 study, next-generation plasma cell-free DNA (cfDNA) sequencing was carried 
out in GIST patients at baseline, Week 2, during patients’ participation in the study and at the 
end of study (Figure 3). Mutations were tested and quantified with Guardant 360 v2.9 or v2.10. 
According to preliminary data (cut-off 18 April 2018), circulation tumor DNA (ctDNA) was 
tested in most baseline cfDNA. In 131 GIST patients with KIT mutation, KIT mutation was 
detected in baseline ctDNA test of 95 patients and the mutation range covered exons 9, 11, 13, 
14, 17 and 18 (Figure 3). Of 9 enrolled patients with PDGFRA exon 18 mutation, PDGFRA 
exon 18 mutation was only detected in ctDNA samples of 2 patients (if archived tissues are 
available, it will be confirmed by testing the tissues). 
Figure 3:  
KIT mutation in baseline ctDNA of 131 GIST patients listed according to 
treatment line (n = 95) 
 
Each list represents one GIST patient. Each color bar in each line represents one or multiple mutations detected 
in KIT exons 9, 11, 13, 14, 17 and 18. In patients with KIT exon 9/11 mutations detected in baseline ctDNA, 
secondary mutation occurred in KIT exons 13, 14, 17 and 18 of second- to ≥ fourth-line patients 
 
1.3.2.3. 
Clinical Effectiveness 
Because phase 1 study DCC-2618-01-001 is ongoing, only source of some clinical data may 
not be validated or proved. Therefore, there may be changes. The data represent the latest 
formal cut-off data of the study. 
As of March 1, 2019, of advanced GIST patients receiving 150 mg QD RP2D treatment in the 
phase 1 study, efficacy of 142 patients could be evaluated. ORR of GIST patients receiving 
150 mg QD treatment was further analyzed according to treatment line and ORR of GIST 
patients receiving second-line treatment with DCC-2618 (ripretinib, ZL-2307) was 19.4%. 
Of GIST patients receiving 150 mg QD treatment (n = 142), the median duration of response 
of 5 patients (11 patients were censored) was 80 weeks. Duration of response of GIST patients 
was further summarized according to treatment line. Of patients who received 150 mg QD for 
second-line treatment, the median response duration was 80 weeks. Figure 4 The duration of 
response of GIST patients who received 150 mg QD treatment in the preliminary stage of the 
Second-
line 
Third-
line 
≥ Fourth-line 
Exon 


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escalation and extension period was summarized according to treatment line. 
For GIST patients who received 150 mg QD treatment (n = 142), mPFS was 24.1 weeks. The 
mPFS of patients who received second-line treatment was 41.7 weeks.  
 


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Figure 5 is Kaplan-Meier diagram of PFS of GIST patients who received 150 mg QD treatment 
in the escalation and extension period summarized according to treatment line. 
Figure 4:  
Swimlane diagram of duration of response in GIST patients who received 
the designated starting dose of 150 mg QD in the escalation and extension 
period (intent-to-treat population) summarized according to treatment line 
 
Duration of response is defined as period from the first complete response or partial response to progressive 
disease or death from any cause. 
Data cutoff date: March 1, 2019 
 
 
Treatment continued 
Treatment discontinued 
Duration of response (week) 
Start of response 
Duration of treatment (week) 
Subject number 


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Figure 5:  
Kaplan-Meier diagram of PFS of GIST patients who received a starting 
dose of 150 mg QD in the escalation and extension period summarized 
according to treatment line (intent-to-treat population) 
 
Data cutoff date: March 1, 2019 
1.4. 
Sunitinib Overview 
Sunitinib (Sutent) is a small molecule that can inhibit multiple receptor tyrosine kinase (RTK), 
some of which are related to tumor growth, pathological angiogenesis and metastatic 
progression of cancer. Inhibotory effect of sunitinib to many kinases (> 80 kinases) has been 
evaluated and the substance is confirmed as an inhibitor of platelet-derived growth factor 
receptor (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, 
VEGFR2 and VEGFR3), stem cell factor receptor (KIT), FMS tyrosine kinase-3 (FLT3), 
colony stimulating factor 1 receptor (CSF-1R) and neural glial cell line-derived neurotrophic 
factor receptor (RET). Inhibitory effect of sunitinib on these RTKs has been proved in 
biochemical and cell tests and it has been proved that it inhibited the function in cell 
proliferation assay. In biochemical and cell tests, the main metabolite of sunitinib had similar 
potency to sunitinib. 
In tumor xenograft expressing target RTK, sunitinib can inhibit phosphorylation of many RTKs 
(PDGFRβ, VEGFR2 and KIT) in vivo and it was proved in some cancer test models that the 
drug had an inhibitory effect on tumor growth or tumor regression and/or metastasis. Sunitinib 
had an inhibitory effect on growth of tumor cells expressing maladjusted target RTK (PDGFR, 
RET or KIT) in vitro and could inhibit tumor angiogenesis dependent on PDGFRβ and 
VEGFR2 in vivo. 
Study NCT#00075218 is a two-arm, international, randomized, double-blinded, placebo-
controlled trial and Sutent was used in GIST patients who have progressed during prior 
imatinib mesylate (imatinib) treatment or are intolerant to imatinib. The study aimed to 
Second 
line 
Third 
line 
Forth 
line 
> Forth 
line 
≥ Forth 
line 
mPFS (week) 
Progression-free survival (week) 
Line of therapy 
Survival probability 


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compare time to tumor progression (TTP) between patients who received Sutent treatment + 
best supportive care and those who received placebo + best supportive care. Other objectives 
included PFS, ORR and overall survival (OS). Patients were randomized (2:1) to receive 50 
mg Sutent or oral placebo QD on a 4/2 regimen basis until progressive disease or withdrawal 
of the study for other reasons. Treatment was unblinded during progressive disease. After that, 
patients randomized to the placebo group received open Sutent cross treatment while patients 
randomized to Sutent group could continue the treatment at the investigator’s discretion. In the 
double-blinded treatment period, the median TTP of the Sutent group was 27.3 weeks and that 
of the placebo group was 6.4 weeks. The median PFS of the Sutent group was 24.1 weeks and 
that of the placebo group was 6.0 weeks. 
1.5. 
Basic principles 
1.5.1. 
Study Principle 
GIST is mainly induced by activated mutation in KIT (about 80%) or relevant PDGFRA (about 
10%) receptor tyrosine kinase[11,300]. In GIST patients, exon 9 or 11 mutations are the most 
common in KIT mutation. Imatinib, as a first-line therapy, generally cannot cure unresectable 
and/or metastatic diseases and CR rate was about 5% and ORR was 68% [16]. More than 80% 
GIST patients can benefit clinically from imatinib monotherapy, but could not avoid imatinib 
drug resistance. More than half of the patients experienced disease progression within 2 years 
[17]. The main cause for progression was secondary KIT kinase mutation, inducing resistance 
to imatinib [11]. Although imatinib can effectively inhibit exon 11 mutation in KIT and dose 
increase to 800 mg was effective to exon 9 mutation, imatinib doesn’t or almost doesn’t have 
inhibitory effect on KIT and PDGFRA mutation, especially on mutations of conformation 
dynamic mediating switch activation [17, 18]. 
In 2006, sunitinib was approved in America as second-line therapy in GIST patients who have 
progressed after imatinib treatment or are intolerant to imatinib. Sunitinib has a stronger 
inhibitory effect on exon 9 mutation than imatinib and a weaker inhibitory effect on exon 11 
mutation [14, 17]. In addition, sunitinib has an inhibitory effect on secondary KIT exons 13 and 
14 mutations, but only half of patients benefited from it. The median PFS was only 5.5 months 
[17]. Sunitinib was ineffective in patients with secondary KIT exons 17/18 mutations and 
PDGFRA exon 18 mutation in activation loop. 
DCC-2618 (ripretinib, ZL-2307) is a kinase inhibitor of KIT and PDGFRA and administered 
orally. DCC-2618 (ripretinib, ZL-2307) can comprehensively and potently inhibit extensive 
primary and secondary KIT and PDGFRA kinase mutants, including primary exons 9 and 11 
mutations, secondary exons 13 and 14 mutations in KIT switch pocket, and primary and 
secondary exons 17 and 18 mutations in activation loop conformation-control switch region, 
primary exon 18 D842V mutation in the PDGFRA conformation-control switch region, and 
primary mutation of exon 14 in the PDGFRA switch pocket region. DCC-2618 (ripretinib, ZL-
2307) can also inhibit mutation-free (original) wild type KIT. DCC-2618 (Ripretinib, ZL-


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2307), as an enhanced type II kinase inhibitor, penetrates embedded KIT/PDGFRA switch 
pocket by binding to extensively inhibit the wild type (original) and mutation of KIT/PDGFRA. 
DCC-2618 (ripretinib, ZL-2307) is expected to provide benefits for all patients with primary 
mutations, including patients who didn’t respond to inhibition of imatinib and had extensive 
drug-resistant mutations. When there is no KIT/PDGFRA mutation (WT GIST), it is known 
that activation of KIT protein in GIST is very strong. In imatinib-resistant GIST, KIT 
expression is always high[27, 28]. These findings reveal that KIT plays an important role in 
the pathogenesis of GIST. 
In phase 1 study DCC-2618-01-001, DCC-2618 (ripretinib, ZL-2307) showed a satisfactory 
preliminary clinical activity in advanced GIST patients. In patients receiving a treatment dose 
≥ 100 mg QD, 3-month DCR of second-, third- and ≥ fourth-line patients was 79% (N = 25), 
82% (N = 29) and 64% (N = 91), respectively. ORR of second- and third-line GIST patients 
was 24% and that of ≥ fourth-line patients was 9%. In phase 1 study[29], KIT drug-resistant 
mutation was observed in second-, third- and fourth-line patients, including exons 13, 14, 17 
and 18 or combined mutation, which supported the need of covering extensive mutations in 
imatinib later treatment lines. 
In the ongoing phase 1 study, DCC-2618 (ripretinib, ZL-2307) covered an extensive rane of 
KIT and PDGFRA mutants, involving KIT exons 9, 11, 13, 14, 17 and 18, PDGFRA exons 12, 
14 and 18, wild type KIT and PDGFRA. Meanwhile, drug toxicity was controllable and 
efficacy data were ideal. Therefore, Deciphera initiated a phase 3 study (INTRIGUE) in GIST 
patients who have previously received imatinib treatment to evaluate the efficacy of DCC-2618 
(ripretinib, ZL-2307). This is a two-arm, randomized, open-label, international, multicenter 
study to compare the efficacy of DCC-2618 (ripretinib, ZL-2307) and sunitinib in GIST 
patients who have progressed after prior imatinib treatment or are intolerant to imatinib. 
Zai Lab will carry out phase 2 bridging study of the study. A study design similar to study 
INTRIGUE will be adopted and study population is also consistent with study INTRIGUE, that 
is, patients with advanced GIST who have progressed after prior imatinib treatment or are 
intolerant to imatinib. The GIST epidemiology, pathogenesis and clinical treatment practice in 
Chinese and western medicine are highly similar. If study data of DCC-2618 and INTRIGUE 
are consistent in Chinese GIST patients receiving the same line of treatment, it will support 
that DCC-2618 is used in the indication in China. 
1.5.2. 
Rationale for Dose, Regimen and Treatment Duration 
1.5.2.1. 
Non-clinical pharmacological and clinical pharmacokinetic analysis 
of supporting the best phase 3 dose selection 
This section describes the scientific basis for selecting the dosing regimen of 150 mg QD of 
DCC-2618 (Ripretinib, ZL-2307) for advanced GIST patients in the phase 3 study. Dose 
suggestion is based on non-clinical pharmacology, clinical PK evaluation and PD results of 
ongoing phase 1 study (as of April 18, 2018). 


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1.5.2.1.1. 
In Vitro Pharmacology 
In vitro pharmacological study proved that DCC-2618 (Ripretinib, ZL-2307) and its metabolite 
DP-5439 can potently inhibit wild-type, carcinogenic KIT and PDGFRA mutants, and IC50 was 
3-36 nM (Figure 6). The section provides the available data of KIT inhibitors including 
imatinib, sunitinib, midostaurin, regorafenib and BLU-285 for reference. At relevant ATP cell 
levels (1 nM), DCC-2618 (ripretinib, ZL-2307) extensively inhibits KIT exons 11, 13, 14 and 
17 mutants and PDGFRA exon 18 mutant. Other type II inhibitors don’t have blocking effect 
on exon 17 mutants such as D816V KIT, while type I inhibitors have a weaker inhibitory effect 
on exon 13/14 mutants. 
Figure 6:  
Inhibition of DCC-2618 (ripretinib, ZL-2307) to PDGFRA and KIT 
mutation 
 
Mutation 
Exon 
KIT V654A 
13 
KIT T670I 
14 
KIT D816H 
17 
KIT D816V 
17 
PDGFRA 
D842V 
18 
 
Imatinib, sunitinib, regorafenib and DCC-2618 (Ripretinib, ZL-2307) generated active 
metabolites. The following doses are mainly based on pharmacological characteristics of drug 
prototype compound. Unbound fraction (fu) of imatinib and sunitinib was reported to be the 
same (5%), but in vitro effect of sunitinib was 6 times (WT KIT) that of imatinib. For the 
treatment of GIST, the corresponding 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). Regorafenib can 
inhibit several exon 17 mutants (not indicated by data) and has a stronger activity. Therefore, 
a reduced dose also has a therapeutic effect. 
In vitro fu of DCC-2618 (Ripretinib, ZL-2307) 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 (Ripretinib, ZL-2307) (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 (Ripretinib, ZL-2307) (294 µmol, 150 mg) was close to that 
of regorafenib (331 µmol, 160 mg). However, because inhibitory effect of DCC-2618 
K IT a
V 6 5 4 A
T 6 7 0 I
D 8 1 6 H
D 8 1 6 V
P D G F R A
D 8 4 2 V
K IT a
V 6 5 4 A
T 6 7 0 I
D 8 1 6 H
D 8 1 6 V
P D G F R A
D 8 4 2 V
K IT a
V 6 5 4 A
T 6 7 0 I
D 8 1 6 H
D 8 1 6 V
P D G F R A
D 8 4 2 V
K IT a
V 6 5 4 A
T 6 7 0 I
D 8 1 6 H
D 8 1 6 V
P D G F R A
D 8 4 2 V
K IT a
V 6 5 4 A
T 6 7 0 I
D 8 1 6 H
D 8 1 6 V
P D G F R A
D 8 4 2 V
K IT a
V 6 5 4 A
T 6 7 0 I
D 8 1 6 H
D 8 1 6 V
P D G F R A
D 8 4 2 V
K IT a
V 6 5 4 A
T 6 7 0 I
D 8 1 6 H
D 8 1 6 V
P D G F R A
D 8 4 2 V
0
100
200
300
400
500
1000
2000
3000
4000
K in a s e In h ib itio n  a t 1  m M  A T P
IC 5 0  (n M )
D C C -2618
(T yp e  II)
D P -5439
(T yp e  II)
Im atinib
(T yp e  II)
S unitinib
b
(T yp e  II)
R egorafenib
(T yp e  II)
M idostaurin
(T yp e  I)
B LU -285
(T yp e  I)
Sunitinib b 
(type II) 
DCC -2618 
(type II) 
DP-5439 
(type II) 
Imatinib 
(type II) 
Regorafenib 
(type II) 
Midostaurin 
(Type I) 
BLU-285 
(Type I) 
IC50 (nM) 
KITa 
V654A 
T670I 
D816H 
D816V 
PDGFRA 
D842V 
KITa 
V654A 
T670I 
D816H 
D816V 
PDGFRA 
D842V 
KITa 
V654A 
T670I 
D816H 
D816V 
PDGFRA 
D842V 
KITa 
V654A 
T670I 
D816H 
D816V 
PDGFRA 
D842V 
KITa 
V654A 
T670I 
D816H 
D816V 
PDGFRA 
D842V 
KITa 
V654A 
T670I 
D816H 
D816V 
PDGFRA 
D842V 
KITa 
V654A 
T670I 
D816H 
D816V 
PDGFRA 
D842V 
Kinase inhibition when ATP is 1 mM 


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(Ripretinib, ZL-2307) was stronger on KIT mutant exons 17 and 11, its optimal dose may be 
lower. 
1.5.2.1.2. 
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 (Ripretinib, ZL-2307) 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 
(Ripretinib, ZL-2307) could significantly inhibit tumor growth, with an inhibition rate reaching 
90%. In imatinib-resistant GIST patient-derived xenograft model, 100 mg/kg QD or 50 mg/kg 
BID DCC-2618 (Ripretinib, ZL-2307) could completely stop tumor growth. In Kasumi-1 AML 
xenograft model expressing primary exon 17 KIT mutation (N822K KIT), DCC-2618 
(Ripretinib, ZL-2307) 100 mg/kg and 50 mg/kg showed powerful efficacy, while imatinib 50 
mg/kg BID was ineffective. In HMC1.2 mastocytosis xenograft model carrying exon 11 
V560D and exon 17 D816V double mutation, after oral administration of DCC-2618 
(ripretinib, ZL-2307) at 25 and 100 mg/kg/day, dose-related tumor burden decrease was 
observed. In H1703 lung cancer xenograft model with PDGFRA amplification, when the drug 
was administered at 25 mg/kg/day, tumor growth was almost inhibited. When the drug was 
administered at 100 mg/kg/day, tumor regression was observed. 
According to in vivo pharmacological study, under the steady state, in terms of AUC0-24hr of 
DCC-2618 (Ripretinib, ZL-2307) and DP-5439, it was confirmed that target PK exposure for 
suppressing tumor growth was 10,000 ng·h/mL. 
1.5.2.1.3. 
Clinical Drug Pharmacokinetic Assessment 
Combined BID and QD data were collected from patients with advanced malignant tumors in 
the ongoing phase 1 study of DCC-2618 (ripretinib, ZL-2307) for population PK analysis 
(study protocol DCC-2618-01-001). Please see Figure 7 for model structure. Two-chamber 
model was used to describe PK characteristics of DCC-2618 (ripretinib, ZL-2307) and DP-
5439. Reservoir means GI of oral DCC-2618 (ripretinib, ZL-2307). KA is first-order absorption 
rate constant of DCC-2618 (Ripretinib, ZL-2307); K23 is the first-order rate constant of DCC-
2618 (Ripretinib, ZL-2307) metabolizing its active metabolite DP-5439 through CYP3A4/5. 
CL and CLM represent DCC-2618 (Ripretinib, ZL-2307) 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 (Ripretinib, ZL-2307) to avoid 
over-parametrization. 
 
 


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Figure 7:  
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 n = 44) showed PK of DCC-2618 (Ripretinib, ZL-2307) and DP-
5439 in cancer patients was dose proportionally. See Table 4 for steady-state PK exposure 
predicted by the model. 
Table 4:  
Typical steady-state drug toxicokinetics exposure in patients with 
advanced malignant tumor predicted by models of DCC-2618 (ripretinib, 
ZL-23070 and DP-5439 
Dose 
interval 
Dose 
Analyte 
Ctrough (ng/mL) 
Cmax (ng/mL) 
AUC0-24hr 
(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 
Combination 
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 


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Dose 
interval 
Dose 
Analyte 
Ctrough (ng/mL) 
Cmax (ng/mL) 
AUC0-24hr 
(ng·h/mL) 
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; AUC0-24hr = 0-24 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 (Ripretinib, ZL-2307)  to typical cancer patients, combining stable PK exposure (AUC0-
24hr) of DCC-2618 (Ripretinib, ZL-2307) and DP-5439 was more than 10,000 ng·h/mL efficacy 
threshold confirmed by xenograft mice institution. However, PK of DCC-2618 (ripretinib, ZL-
2307) and DP-5439 varied greatly among patients. 
One hundred studies were simulated with group PK model and each study contained 100 
subjects; 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 re-simulated with 100 mg QD, it was estimated that 87.9% of patients would reach the 
efficacy threshold. 
1.5.2.1.4. 
Conclusion 
It is recommended oral DCC-2618 (Ripretinib, ZL-2307) 150 mg QD be taken as the optimal 
dose regimen for the treatment of GIST for the following reasons: 
• Comparison of in vitro pharmacological properties between DCC-2618 (Ripretinib, ZL-
2307) and three approved target therapeutic drugs for the treatment of GIST showed that 
when treating GIST patients, effectively daily dose of DCC-2618 (Ripretinib, ZL-2307) 
was ≤ 160 mg. 
• In vivo pharmacological study in xenograft mouse model indicated that target combination 
PK exposure (AUC0-24hr = 10,000 ng·h/mL) of DCC-2618 (Ripretinib, ZL-2307) and DP-
5439 could inhibit tumor growth. For 93.6% of patients, it is estimated that PK value can 
be maintained above the threshold by taking 150 mg of the study drug daily. 
• According to in vitro and in vivo pharmacological data, 150 mg QD predication 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: 


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• Compared with the BID regimen by which the target exposure can be realized to meet 
efficacy requirement, daily administration regimen is more convenient and may improve 
treatment compliance. Therefore, 150 mg QD is better than the similar daily dose BID. 
• Because PK varies greatly between individuals, when the administration dose is lower than 
150 mg, the lower the dose, the more the patients with a PK exposure lower than the 
efficacy threshold. On the other hand, a higher administration dose is unlikely to further 
improve the efficacy. 
• For most patients (87.9%), it is estimated that a dose of 100 mg QD can reach the effective 
exposure target. If individual patient is unable to tolerate 150 mg QD, the dose can be 
reduced to 100 mg QD without influencing the efficacy. 
• PK-efficacy and PK-safety evaluation are ongoing to confirm the selection of 150 mg QD 
as the best treatment regimen of DCC-2618 (ripretinib, ZL-2307) for GIST patients. 
2. 
Study Objectives 
2.1. 
Primary objective 
• To assess the efficacy (progression-free survival [PFS], by independent radiologic 
review) of DCC-2618 (ripretinib, ZL-2307) and sunitinib in patients with advanced 
gastrointestinal stromal tumors after treatment with imatinib. 
2.2. 
Secondary objective 
• To assess objective response rate (ORR) by independent radiologic review using 
RECIST v1.1-GIST-specific criteria  
• To assess disease control rate (DCR) by independent radiologic review 
• To assess  PFS based on Investigator assessment 
• To assess overall survival (OS) 
• To compare the safety profile of DCC-2618 (ripretinib, ZL-2307) to the safety profile 
of sunitinib 
• To assess pharmacokinetic characteristics of DCC-2618 (ripretinib, ZL-2307) 
2.3. 
Exploratory objectives 
• To evaluate potential biomarkers in blood or tumor tissue which might predict response 
to DCC-2618 (ripretinib, ZL-2307)  
○ To understand potential drug resistance mechanism to DCC-2618 (ripretinib, ZL-
2307) in GIST. 
○ To characterize KIT and PDGFRA mutations at baseline and DCC-2618 
(ripretinib, ZL-2307)-driven longitudinal mutant allele frequency changes in 
plasma. 


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Note: Blood samples and tumor tissues for exploratory purpose will be collected after obtaining 
the approval of China Human Genetic Resources Administration Office. 
 
3. 
Study Design 
3.1. 
Overview of Study Design 
This is a randomized, open-label, multicenter phase 2 clinical study to compare the efficacy 
and safety of DCC-2618 (ripretinib, ZL-2307) to sunitinib in GIST patients who progressed on 
or were intolerant to first-line anticancer treatment with imatinib. 
Approximately 98 patients will be randomized in a 1:1 ratio to DCC-2618 (ripretinib, ZL-2307) 
150 mg QD by continuous administration or sunitinib 50 mg QD, 4 weeks on, 2 weeks off. Up 
to 10% of randomized patients may have KIT/PDGFRA WT GIST (wild-type KIT and wild-
type PDGFRA regardless of the mutational status of any other gene). 
Randomization will be stratified by: 
• KIT exon 11 mutation; KIT exon 9 mutation; other (KIT/PDGFRA WT or other KIT [lacking 
exon 9 or 11]/PDGFRA mutation); 
The primary endpoint of the study will be evaluated using the modified Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1-GIST-specific based on independent 
radiologic review. 
Upon disease progression by RECIST-GIST-specific based on independent radiologic review, 
patients will discontinue their assigned treatment. 
If the investigator doesn’t hope to confirm by the independent radiologic review or hopes to 
terminate the patient’s treatment according to progressive disease based on “RECIST v1.1-
GIST-specific Criteria” before obtaining results of the independent radiologic review, it is 
necessary to discuss with the sponsor. 
3.2. 
Number of patients 
Approximately 98 patients will be randomized in a 1:1 ratio to receive DCC-2618 (ripretinib, 
ZL-2307) 150 mg QD by continuous administration or sunitinib 50 mg QD, 4 weeks  on, 2 
weeks off. 
3.3. 
Study duration 
Patients will receive treatment until progressive disease confirmed by the independent 
radiologic review based on “RECIST v1.1-GIST-specific Criteria”, intolerable toxicity or 
withdrawal of consent. 
Patients will discontinue the study drug treatment if patients have progressive disease based on 


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assessment of the independent radiologic review using “RECIST v1.1-GIST-specific Criteria”. 
The longest medication duration of patients is 2 years. For patients with evidence of clinical 
benefit from the drug and tolerance to the drug and following the study procedure, the treatment 
duration will be prolonged by reaching an agreement between the sponsor and the investigator. 
The study will be terminated when the last patient has progressive disease or 20 months after 
finishing enrollment or when the sponsor determines to terminate the study, whichever occurs 
first. 
4. 
Study population 
4.1. 
Inclusion criteria 
Eligible patients must meet all the following criteria in order to be included in this clinical trial: 
1. Male or female patients ≥18 years of age. 
2. Histological diagnosis of advanced GIST and capability of providing tumor tissue sample 
(the interval between tumor tissue collection and signing of informed consent form should be 
less than 3 years). Otherwise, biopsy is required. 
3. Provide molecular test report with KIT/PDGFRA mutation status prior to randomization. 
Mutation status must be identified by tissue-based PCR or sequencing analysis. If molecular 
test report is unusable or insufficient, an archived tumor tissue sample or fresh live tissue 
should be tested to confirm mutation status prior to randomization. 
4. Patients must have progressed on imatinib or have documented intolerance to imatinib. 
Subjects must have discontinued imatinib treatment 10 days prior to the first dose of the study 
drug. All prior imatinib treatments will be considered as first-line (such as imatinib adjuvant 
therapy and imatinib dose increase). 
5. ECOG PS of 0-2. 
6. Female patients of childbearing potential must have a negative serum beta-human chorionic 
gonadotropin (β-hCG) pregnancy test at screening. 
7. Subjects of reproductive potential should adopt effective contraceptive measures. 
8. At least 1 measurable lesion according to the “RECIST v1.1-GIST-specific Criteria" (non-
nodal lesions must be ≥1.0 cm in the long axis or ≥ double the slide thickness in the long 
axis); obtaining radiographic image results within 28 days prior to the first dose of study drug.  
9. Good organ function and bone marrow reserve function, including: 
• 
Neutrophil count (ANC) ≥ 1,000/µL 
• 
Hemoglobin ≥ 8 g/dL 
• 
Platelet count ≥ 75,000 /μL 


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• 
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 
• 
Creatinine clearance ≥ 50 mL/min (based on Cockcroft-Gault Formulas for 
calculation) 
Note: Patients should receive no corrective treatment with granular colony 
stimulating factor or interleukin-11, infusion of red blood cells or platelets or other 
blood products within 2 weeks prior to detecting haematology. 
• 
Prothrombin time (PT), 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 study 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 study drug, excluding alopecia and ≤ Grade 3 clinically asymptomatic lipase, 
amylase, and creatine phosphokinase laboratory abnormalities. 
11. Patient is capable of understanding and complying with the protocol. Subjects should sign the 
written informed consent before any study-related procedures were performed. 
4.2. 
Exclusion criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Treatment with any other line of therapy in addition to imatinib for advanced GIST. Imatinib-
containing combination therapy in the first-line treatment should not be enrolled. 
2. Patients with a prior or concurrent malignancy whose natural history or treatment have the 
potential to interfere with the safety or efficacy assessment of this clinical trial are not eligible. 
For example, patients who received adjuvant treatment for cancer and used drugs which have 
potential activity to GIST or are prohibited by study protocol are not eligible. 
3. Patient has known active central nervous system metastases. 
4. New York Heart Association class II - IV heart disease, myocardial infarct, active ischemia 
or any other uncontrolled cardiac condition within the first 6 months of the first dose of study 
drug such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, 
uncontrolled hypertension or congestive heart failure. 
5. Left ventricular ejection fraction (LVEF) < 50%. 
6. Arterial thrombotic or embolic events such as cerebrovascular accident (including ischemic 
attacks) or hemoptysis within the first 6 months of the first dose of study drug. 


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7. Venous thrombotic events (e.g. deep vein thrombosis) or pulmonary arterial events (e.g. 
pulmonary embolism) within 1 month before the first dose of study drug. Patients on stable 
anticoagulation therapy for at least one month are eligible. 
8. 12-lead ECG demonstrating QT interval (QTc) corrected by Fridericia's formula >450 ms in 
males or  > 470 ms in females at screening or history of long QT interval syndrome. 
9. Use of moderate or strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4 within 
14 days or 5 x the half-life (whichever is longer) prior to the first dose of study drug, including 
certain herbal medications (eg, St. John's Wort) and consumption of grapefruit or grapefruit 
juice within 14 days prior to the first dose of study drug. For CYP3A4 enzyme 
inhibition/induction-related drugs, please refer to the website of the Indiana University, 
School of Medicine (http://medicine.iupui.edu/clinpharm/ddis/main- table/). 
10. 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 
study drug. For information of inhibitors and substrates, please refer to Food and Drug 
Administration (FDA) website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInt
eractionsLabeling/ucm093664.htm. 
11. Major surgeries (e.g. Abdominal laparotomy) within 4 weeks of the first dose of study drug; 
all major surgical wounds must be healed and free of infection or dehiscence before the first 
dose of study drug. 
12. 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. 
13. Known human immunodeficiency virus or hepatitis C infection only if the patient is taking 
medications that are excluded per protocol, hepatitis B virus (HBV) DNA > 2000 IU/ml or > 
104 copies/ml. 
14. Female patients who are pregnant or lactating or who plan to become pregnant during the 
study treatment period. 
15. Known hypersensitivity to any component of the study drug. Patients with Stevenson Johnson 
syndrome in previous TKI treatment need to be excluded. 
16. Gastrointestinal abnormalities including but not limited to: 
• 
inability to take oral medication 
• 
malabsorption syndrome  
• 
Requiring intravenous (IV) nutrition 


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17. Any active hemorrhages, excluding hemorrhoids or gum bleeding. 
5. 
Administration and Management of Study drugs  
5.1. 
Sunitinib 
5.1.1. 
Sunitinib Description 
Sunitinib will be provided as scored hard capsules and contain sunitinib malate equivalent to 
12.5 mg of sunitinib. In active ingredients include mannitol, croscarmellose sodium, povidone 
(K-25) and magnesium stearate. 
5.2. 
DCC-2618 (Ripretinib, ZL-2307) 
5.2.1. 
Description of DCC-2618 (ripretinib, ZL-2307) 
DCC-2618 (ripretinib, ZL-2307) is a 50 mg oral tablet. The tablet contain active ingredient. Its 
formulation is amorphous dispersion and cellulose acetate succinate (mass ratio of grade H 
polymer matrix [33.33%] is 25% [w/w]). Other excipients include microcrystalline cellulose 
(Avicel PH-101) (29.84%), lactose 310 (29.83%), crosslinked polyvinylpyrrolidone (5%), 
fumed silica (CabOSil M5P or Syloid 244FP) (1%) and magnesium stearate (1%). 
5.3. 
Dosage and route of administration of study drugs 
The study drug can be distributed only under the supervision of the investigator or authorized 
designated personnel and administered to subjects of the study only. Patients will be 
randomized to receive DCC-2618 (ripretinib, ZL-2307) 150 mg QD by continuous 
administration based on a 42-day cycle, or sunitinib 50 mg QD in 6 weeks (42 days) with 4 
weeks continuous dosing followed by 2 weeks break. According to the approved package 
insert, dose adjustment of sunitinib is allowed. 
The investigator or designated personnel must guide patients to take DCC-2618 (ripretinib, ZL-
2307) according to the following method: 
• It should be taken at the same time each day. 
• Patient should take study srug with or without food. 
• Swallow as a whole. Tablets must not be crushed, chewed or dissolved in liquid or food. 
• Administration date, dose and time of DCC-2618 (ripretinib, ZL-2307) should be 
recorded 3 days before and on the day of PK sampling. 
If the patient forgets to take DCC-2618 (ripretinib, ZL-2307) at the predetermined time, the 
patient can take the predetermined dose within 8 hours upon the predetermined time. If it has 
been over 8 hours from the predetermined time, the missing dose must be ignored and the next 
predetermined dose of drug can be taken to continue the treatment. 
Please refer to the approved package insert for description of administration of sunitinib. 


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On the scheduled study visit date, patients will be informed of taking the study drug at study 
site according to Table 1 (Schedule of Assessments). Administration of the study drug must be 
carried out at study site after finishing pre-dose assessment. Administration date, dose and time 
of the study drug must be recorded in source documents of patients. 
If subjects vomit immediately after taking the study drug, the dose should not be 
“supplemented” and prophylactic antemetics can be used before the next dose. 
Please refer to Section 7.12 and the approved package insert of sunitinib for information of 
overdose. 
5.4. 
Dose interruption and adjustment of study drugs  
Dose interruption and adjustment of sunitinib will be carried out according to guidelines in the 
approved package insert. 
If AE occurs, the investigator can determine interrupt administration of DCC-2618 (ripretinib, 
ZL-2307) or adjust its dose (that is, dos reduction). If dose adjustment is required for other 
reasons, it is necessary to discuss with the sponsor and make a decision. Interruption duration 
should not be more than 28 consecutive days. 
For sunitinib and DCC-2618 (ripretinib, ZL-2307), department visit and assessment should be 
continued during dose interruption according to Table 1 (Schedule of Assessments). If 
administration is resumed after dose interruption, the investigator must continue administration 
according to the source visit schedule from C1D1 (that is, calculate the number of days of cycle 
continuously and not discontinue calculation due to dose interruption). If dose interruption is 
more than 28 days, treatment with the study drug will be terminated in this patient. If the 
regimen used by the patient is 4-week administration followed by 2-week withdrawal, the 28-
day time limit also includes the 2-week withdrawal. 
5.4.1. 
Interruption of the study drug due to planned medical procedure 
According to the approved package insert, sunitinib should be interrupted if major surgical 
procedure is required. 
For DCC-2618 (ripretinib, ZL-2307), surgery performed in patients during the study, surgical 
range and postoperative healing speed should be considered. It applies to the following 
guidelines: 
• Scheduled minimally invasive surgery: 3 days before and after the surgery, DCC-2618 
(ripretinib, ZL-2307) must be discontinued for 3 days. 
• Scheduled major surgery: 5 days before and after the surgery, DCC-2618 (ripretinib, ZL-
2307) must be discontinued for 5 days. 
• Unscheduled/emergent surgery: DCC-2618 (ripretinib, ZL-2307) must be discontinued 
immediately and resumed according to requirements of the above minimally invasive 
and/or major surgery. 


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5.4.2. 
Dose interruption and adjustment of DCC-2618 (ripretinib, ZL-2307) 
caused by adverse events 
If AE occurs, the investigator can determine to discontinue DCC-2618 (ripretinib, ZL-2307) or 
reduce its dose at any time according to guidelines in Table 6, Table 7 Table 8, Table 9 and 
Table 10. It is necessary to discuss dose reduction with the sponsor in advance as far as 
possible. If DCC-2618 (ripretinib, ZL-2307) is resumed after interruption, the patient should 
use the drug according to the former administration schedule. 
If any patient needs to use the drug at a dose lower than 50 mg QD, or if dose for the patient 
has been reduced and progressive disease is confirmed by independent radiologic reviewers, 
the patient must discontinue the study drug and receive end of treatment (EOT) visit and safety 
follow-up visit. In addition, OS of the patient must be followed up. 
Table 5:  
Dose reduction steps of DCC-2618 (ripretinib, ZL-2307) 
Initial dose of DCC-2618  
The 1st dose reduction 
The 2nd dose reduction 
150 mg QD 
100 mg QD 
50 mg QD 
If AE is recovered to grade 1 or baseline level, the dose should be increased for the patient. It 
is necessary to increase the dose for the patient to the dose level at AE occurrence. If dose level 
is reduced to the first dose reduction level and AE is recovered to grade 1 or baseline level, the 
patient can resume the drug according to the starting dose level. If the patient reduces the dose 
twice continuously and AE is recovered to grade 1 or baseline level after the second dose 
reduction, the drug should be administered at the first dose reduction level which should be 
maintained for at least 1 cycle continuously before increasing the dose to the starting dose level.  
If an AE leads to dose adjustment and is not recovered to grade 1 or baseline level within 1 
cycle (42 days), DCC-2618 (ripretinib, ZL-2307) must be discontinued, unless the investigator 
considers the event is not clinically significant. In such case, feasibility of resuming the drug 
at a dose reduction level should be judged after consulting the sponsor. 
Table 6:  
Principle of dose adjustment of DCC-2618 (ripretinib, ZL-2307) due to skin 
toxicity (except Alopecia) and joint pain/myalgia 
Toxicity 
Grade* 
Dose Adjustment Principle 
Grade 1 
Adopt supportive treatment of study institution and continue DCC-2618 at the current 
dose 
Grade 2 
Adopt supportive treatment of study institution and continue DCC-2618 at the current 
dose 
• 
If the event is not improved within 7 days, DCC-2618 will be discontinued 
• 
If the event is recovered to grade 1 or baseline level within 7 days, DCC-2618 will 
be resumed at the same dose level 
• 
If the event is recovered to grade 1 or baseline level after 7 days, DCC-2618 will 
be resumed at a reduced dose level 
• 
If the event recurs, DCC-2618 will be resumed at a reduced dose after the event is 


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Toxicity 
Grade* 
Dose Adjustment Principle 
recovered to grade 1 or baseline level, regardless of the time to recovery 
• 
If the event maintains grade 1 or baseline level for at least 1 administration cycle 
(42 days) after dose reduction, it can be considered to increase the dose of DCC-
2618 by a dose level 
Grade 3 
Adopt supportive treatment of the study institution 
• 
Withhold DCC-2618 for at least 7 days or until the event resolves to grade 1 or 
baseline level (28 days at most). 
Resume DCC-2618 at a reduced dose 
• 
If the event maintains grade 1 or baseline level for at least 1 administration cycle 
(42 days) after dose reduction, it can be considered to increase the dose of DCC-
2618 by a dose level 
Grade 4 
Discontinuing DCC -2618. 
Grade: any 
Stevens-Johnson syndrome: 
If patients have developed Stevens-Johnson syndrome (SJS)/hypersensitivity reaction 
during treatment period, the DCC-2618 must be discontinued permanently. Patients 
should be transferred to hospital immediately to receive clinical assessment and 
supportive care/treatment accordingly. DCC-2618 should not be resumed due to risks 
of SJS/hypersensitivity reaction recurrence. It is not suggested to use other similar 
drugs (TKI for GIST) to avoid SJS recurrence because similar reaction occurred during 
regorafenib treatment in a patient who was diagnosed with SJS during DCC-2618 
treatment. 
* The severity of AEs outside the CTCAE is confirmed according to Table 12. 
 
 


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Table 7:  
Principle of dose adjustment of DCC-2618 (ripretinib, ZL-2307) due to 
hypertension 
Toxicity Grade 
Dose Adjustment Principle 
Grade 1 
Prehypertension 
(systolic 
blood 
pressure 120-139 mmHg or diastolic 
blood pressure 80-89 mmHg) 
Monitor BP continuously  
Continue DCC-2618 administration at the current dose level 
Grade 2 
Systolic blood pressure 140 - 159 
mmHg or diastolic blood pressure 90 
- 99 mmHg or elevation > 20 mmHg 
(diastolic 
blood 
pressure) 
with 
accompanying symptoms or blood 
pressure > 140/90 mmHg (previous 
normal blood pressure) 
Adopt antihypertensive therapy to make diastolic blood 
pressure ≤ 90 mmHg or systolic blood pressure ≤ 140 mmHg 
Continue DCC-2618 administration at the current dose level 
If a 20 mmHg symptomatic blood pressure increased occurs 
(diastolic blood pressure), DCC-2618 should be discontinued 
until symptom resolved and diastolic blood pressure ≤ 90 
mmHg 
DCC-2618 is resumed at the same dose level 
Grade 3 
Systolic blood pressure ≥ 160 mmHg 
or diastolic blood pressure ≥ 100 
mmHg or more than one hypotensor 
or more intensive treatment required 
Adopt antihypertensive therapy to make diastolic blood 
pressure ≤ 90 mmHg or systolic blood pressure ≤140 mmHg 
• 
Starting hypotensor treatment 
and/or 
• 
Increase the dose of current hypotensor 
and/or 
• 
Add other hypotensor 
If symptomatic, DCC-2618 should be discontinued until 
diastolic blood pressure ≤ 90 mmHg and/or systolic blood 
pressure ≤ 140 mmHg and symptom resolved 
DCC-2618 is resumed at the same dose level 
If BP is uncontrollable after adding new drug or more intensive 
treatment, DCC-2618 will be reduced by a dose level 
If grade 3 hypertension occurs after dose reduction of DCC-
2618 and antihypertension therapy, DCC-2618 will be reduced 
by a dose level again 
Grade 4 
Life-threatening (such as malignant 
hypertension, 
transient 
or 
permanent 
nerve 
damage 
or 
hypertensive crisis) 
Adopt antihypertension therapy according to guidelines for the 
treatment of hypertension 
Discontinuing DCC -2618. 
BP = Blood pressure 
*If BP is controllable within at least 28 days, the investigator may increase the dose of DCC-2618 again 
according to conditions. 
 
 


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Table 8:  
DCC-2618 Dose Modifications for Left Ventricular Systolic Dysfunction 
Toxicity Grade 
Management Guideline 
Any Grade 3 or 4 
Permanently discontinue DCC-2618 
 
Table 9          DCC-2618 Dose Modifications for Isolated Bilirubin Increased 
Toxicity Grade 
Management Guideline 
Grade 2 
Interrupt DCC-2618 until toxicity resolves to Grade 1 or baseline 
(maximum 28 days); resume DCC-2618 at 100 mg. 
Grade 3 or 4 
Interrupt DCC-2618 until toxicity resolves to Grade 1 or baseline 
(maximum 28 days); otherwise permanently discontinue DCC-2618. 
If the event returns to Grade 1 or baseline, resume DCC-2618 at 100 
mg. 
If the reduced dose is tolerated without recurrence of the event for at 
least 28 days, consider re-escalating DCC-2618. 
If Grade 3 or higher toxicity recurs, discontinue DCC-2618 
permanently. 
 
Table 10:       Principle of dose reduction of DCC-2618 (ripretinib, ZL-2307) due to 
treatment-related adverse events not mentioned above 
Toxicity Grade 
Dose Adjustment Principle1 
Any grade 3 or 4 events 
Discontinue DCC-2618 until the event is relieved to grade 1 or 
baseline level. After the event is relieved to grade 1 or baseline 
level, DCC-2618 should be administered at a lower dose level. If 
the patient tolerates the reduced dose and the event doesn’t occur 
within at least 28 days, DCC-2618 can be increased to the former 
dose level again. 
Asymptomatic/not clinically 
significant grades 3 or 4 laboratory 
abnormality (including CPK and 
lipase) lasting ≤ 10 days 
Monitor clinical symptoms closely and continue administration 
of DCC-2618 at the current dose level. Carry out laboratory test 
within 10 days. 
Asymptomatic/not clinically 
significant grades 3 or 4 laboratory 
indicator abnormal (including 
CPK and lipase) lasting > 10 days 
Monitor clinical symptoms closely;  
if it is a grade 4 event, discontinue DCC-2618 until the event is 
recovered to grade 3; after the event is recovered to grade 3, 
resume DCC-2618 at the current dose level or reduce to a lower 
dose level by he investigator according to conditions after 
discussing with the sponsor. 
For asymptomatic grades 3 or 4 lipase or CPK increase, dose 
interruption is not required; 
Clinically significant grade 3 or 4 Discontinuing DCC-2618 dosing. If the investigator considers 


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laboratory abnormality (including 
CPK and lipase) 
that resuming DCC-2618 meets the patient’s best interest, it is 
necessary to discuss with the sponsor to confirm whether to 
resume the drug. 
CPK = Creatine phosphokinase 
1  Dose adjustment principle of laboratory abnormality is based on laboratory test results of study 
institution. 
 
5.5. 
Packaging and Labeling 
DCC-2618 (ripretinib, ZL-2307) will be provided by the sponsor. The drug will be prepared to 
oral tablets containing 50 mg of the study drug and packaged in high density polyethylene 
(HDPE) bottles with child-resistant closures.  
Sutent® (sunitinib malate) 12.5 mg oral capsules will be supplied in the original package in 
HDPE medicine bottles and repasted with labels by the sponsor. 
5.6. 
Storage Condition of Study drug 
DCC-2618 (ripretinib, ZL-2307) bottles must be sealed up and stored at 5°C - 25°C (41°F-
77°F). Protect from high humidity and intensive sunshine (such as places close to shower 
cubicle in the bathroom). A deviation of 2°C-27°C (35.6°F-80.6°F) is allowed. 
Please refer to the package insert for information of storage and disposal of sunitinib. 
The study drug must be stored in a safety place with restricted access and temperature 
monitored at study site. 
5.7. 
Study drug Compliance 
To ensure compliance of the study drug, the investigator or designated personnel must monitor 
all administrations of the study drug by study site. At each visit, personnel of study site must 
review patients’ compliance to the study drug and remind patients to take the study drug as 
required. Compliance should be assessed by continuously counting the study drug. 
If the patient still doesn’t comply with administration of the study drug after education, the 
investigator must contact and discuss with the sponsor to make the patient withdraw from the 
study. 
5.8. 
Counting of Study drug 
The investigator is responsible for counting the study drug at study site. The investigator must 
ensure administration of the study drug only in compliance with the study protocol. If 
conditions allow, the investigator can assign the responsibility of counting the study drug to 
pharmacist or other appropriate personnel. Record of drug counting must be kept by clinical 
study site and the followings should be described in record: date of the study drug sent to study 
site, inventory of the study drug at study site, amount of the study drug distributed to each 
patient, amount of the study drug returned by each patient, amount of the study drug returned 


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to the sponsor and amount of the study drug destructed at study site Counting record should 
include date, amount, bottle number and patient number. Study monitor should continuously 
review drug accountability at study site during visit. The sponsor should be informed of any 
distribution mistake or deviation immediately. 
Patients must be told to return all bottles of unused, partially used and used study drugs to study 
site at each visit. Throughout the study, study monitor must verify record and inventory of the 
study drug. 
5.9. 
Disposal, Return or Keep of the Unused Study drugs 
Patients must be told to return all bottles of used, partially used and unused study drugs. 
Personnel of study site or pharmacy personnel (if applicable) must keep all materials returned 
by patients until they are returned to the sponsor or destructed by study site. If the study drug 
is destructed at study site, the investigator or designated personnel must ensure to destruct these 
materials according to applicable environmental protection law and regulations, institutional 
policies and any special instructions provided by the sponsor. Destruction must be recorded in 
detail. 


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5.10. 
Method for Assigning Subjects into Treatment Groups 
Patients will be randomized at 1:1 to DCC-2618 (ripretinib, ZL-2307) 150 mg group or 
sunitinib 50 mg group. Patients with KIT/PDGFRA WT GIST (KIT and PDGFRA wild-type, 
regardless of status of any other gene mutations) accounted for at most 10% of all enrolled 
patients. Stratification factors of randomization include: 
• KIT exon 11 mutation; KIT exon 9 mutation; other (KIT/PDGFRA WT or other KIT 
[lacking exon 9 or 11]/PDGFRA mutation);  
5.11. 
Blinding and Unblinding 
This is an open-label study and doesn’t involve blinding and unblinding. 
5.12. 
Past and Concomitant Treatment 
5.12.1. 
Previous medications/treatment 
Any information of all medications (including vitamin supplementation, over the counter 
medications and oral herbal preparations) or non-drug treatments used within 30 days prior to 
signing the informed consent form and prior to the first dose of the study drug should be 
recorded in source documents and electronic Case Report Form (eCRF) of patients. 
5.12.2. 
Prior Anti-Tumor Therapy 
Any prior anti-tumor drugs and non-drug treatments should be recorded in source documents 
and eCRF of patients. 
5.12.3. 
Concomitant medication 
Any medications (including vitamin supplementation, over the counter medications and oral 
herbal preparations) or non-drug treatments used in the period from the first dose of the study 
drug to 30 days (including 30 days) after the last dose of the invstigational drug should be 
recorded in source documents and eCRF of patients. 
 
5.12.3.1. 
Drugs Allowed to be Used 
Patients can use drugs that can relieve symptoms (such as analgesics, laxatives and antiemetics) 
as long as they are not prohibited by the study protocol. 
The drug restrictions are not applicable to sunitinib. Please refer to the approved package insert 
for information of sunitinib. 
5.12.3.2. 
Prohibited Drugs and Substances 
Prohibited drugs and some food are not allowed from the screening period to safety follow-up 
visit. Except for the study drug, anti-tumor therapies that have an inhibitory effect or potential 
inhibitory effect on GIST are prohibited during the study. 


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All patients should abide by the following criteria of prohibited drugs before randomization. 
• Receive imatinib treatment within 10 days prior to the first dose of the study drug or any 
other anti-tumor drugs or therapies for advanced GIST. 
• 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, whichever is longer) 
prior to the first dose of the study drug. 
For guidance of CYP3A4 enzyme inhibitor, 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 prohibited within at least 14 days prior to the first 
dose of the study drug. 
• Known BCRP transporter substrate or inhibitor: discontinue within at least 14 days or 5 
half-lives (whichever is longer) prior to the first dose of the study drug. 
For information of BCRP inhibitors and substrates, please refer to Food and Drug 
Administration (FDA) website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm. 
After randomization and during the study, patients randomized to the sunitinib group will 
follow requirements for prohibited drugs specified in the approved package insert. 
The following are prohibited after randomization and during the study for patients randomized 
to DCC-2618: 
• Strong and moderate inducers of CYP3A, including certain herbal medications (e.g. St. 
John’s Wort) 
5.12.3.3. 
Please refer to the Indiana University Department of Medicine 
website (http://medicine.iupui.edu/clinpharm/ddis/main-table/) for 
guidance on medications that induce CYP3A4 enzymes.Drugs to be 
avoided or used with caution 
Patients who use DCC-2618 (ripretinib, ZL-2307) should avoid the following drugs or use the 
following drugs with caution after discussing with the sponsor (provide updated information 
to study site during the study): 
• Strong or moderate inhibitors of CYP3A including grapefruit juice. 
• Known substrates or inhibitors of BCRP transporters and P-glycoprotein 1 (permeability 
glycoprotein, also known as MDR1). Please refer to the FDA’s website for inhibitors 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htmMedications dependent on CYP2C8 for their 
metabolism. Please refer to the Indiana University Department of Medicine website 


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(http://medicine.iupui.edu/clinpharm/ddis/main-table/) for guidance on these medicines. 
o  
For patients who use any of the above drugs, any potential drug interaction with DCC-2618 
(ripretinib, ZL-2307) should be closely monitored. 
Please refer to the approved package insert for drug interaction of sunitinib. 
5.12.4. 
Concomitant medical procedures 
All medical procedures carried out from the first dose of the study drug to 30 days (including 
30 days) after the last dose of the study drug should be recorded in source documents and eCRF 
of patients. 
Surgical resection or palliative radiotherapy during the study treatment should be discussed 
with the sponsor before implementation. For patients who obtain PR, resection of residual 
lesions is allowed if patients have finished 12-month treatment. If the investigator considers 
the treatment meets the patient's best interests, after discussing with the sponsor, surgical 
resection or palliative radiotherapy can be carried out. 
5.13. 
Other Precautions 
To relieve potential risks of photostimulation/phototoxicity, patients should be instructed to 
take DCC-2618 (Ripretinib, ZL-2307), avoid strong sunlight, fluorescent lamp and other 
ultraviolet radiation sources during the study. For all patients who use DCC-2618 (ripretinib, 
ZL-2307), preventive skin care suggestions include use of  SPF ≥ 30 sunscreen cream, anti-
allergy moisturizer or ointment relieving dry skin, and mild skin care products containing 
tasteless soap and detergent. 
Please refer to the approved package insert for warnings and precautions of sunitinib. 
6. 
Study Evaluation 
6.1. 
Screening 
Screening must be carried out within 28 days prior to the first dose of the study drug to confirm 
that the patient meets inclusion criteria of the study. Radiographic examinations and 
dermatologic examinations can be carried out within 28 days prior to the first dose of the study 
drug. See Table 1 (Schedule of Assessments) for items to be assessed. 
6.2. 
Re-screening 
Patients can be re-screened only after obtaining the approval of the sponsor. If patients are re-
screened, all screening evaluation items except tumor tissue specimens (if applicable) should 
be repeated. If radiographic evaluation, echocardiogram and dermatologic examination are 
carried out within 28 days prior to the first dose of the study drug, the examinations don’t need 
to repeat. Patients can be re-screened once only. If patients are re-screened, screening time 
window will be timed after initiating the first re-screening evaluation item. 


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6.3. 
Treatment period 
After confirming that patients meet all criteria, patients will be randomized to the study. The 
first dose of the study drug must be administered in department on C1D1. See Table 1 
(Schedule of Assessments) for study visit schedule during treatment. Patients will be taken as 
outpatients during treatment. All visits should be carried out in the regulated window. 
Patients who discontinue treatment with the study drug must return to the department for EOT 
visit within 7 days after the last dose of the study drug. If the interval between the last visit 
before discontinuing treatment with the invstigational drug and EOT visit is over 14 days 
(excluding 14 days), comprehensive evaluation of items should be carried out according to 
Table 1 (Schedule of Assessments) at EOT visit. If the interval between the last visit before 
discontinuing treatment with the invstigational drug and EOT visit is not more than 14 days 
(including 14 days), only items that are not evaluated at the last visit need to be assessed at 
EOT visit. 
6.4. 
Follow-up 
Patients will be contacted by telephone 30 (±5) days after the last dose of the study drug for 
safety follow-up to evaluate AE, collect information of concomitant medications/other 
treatments and collect new information of anti-tumor therapy. 
After that, patients will be contacted by telephone for OS follow-up to collect new information 
of anti-tumor therapy and OS data. 
6.5. 
Lost to Follow-up 
Patients will be considered lost to follow-up in the following conditions: patients cannot be 
contacted by telephone three times within 2 weeks after the first failure of contact and telephone 
contact records should be made. 
6.6. 
Study Evaluation 
Table 1 Summarizes schedule of assessments of each visit. 
Unless otherwise specified, all assessments must be carried out prior to administration and in 
the predetermined window of visit. 
Additional unscheduled safety or efficacy assessment can be carried out at any time with 
clinical indications to confirm the correlation between the specific findings and the study drug 
and/or duration of the event.  
6.7. 
Inform Consent Process 
Each patient must sign and date the specific ICF before any specific procedure of the study. 
ICF will follow all applicable regulations of patient protection. The ICF approved by the 
sponsor, institutional review board (IRB) of the study site/independent ethics committee (IEC) 
must be used. The investigator or designated personnel must record consent process, including 


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recording the date of signing the informed consent form in source documents of patients. 
6.8. 
Distribution of Patient Number 
After obtaining informed consent, a unique patient identification number (patient number) will 
be assigned to each patient. Please refer to the study reference manual for details of assigning 
patient number. If the patient receives re-screening, a new patient number will be used. 
6.9. 
Demographics and Medical History 
Demographic information must be collected during screening. 
Cancer history and prior treatment history (including reasons for treatment discontinuation) 
should be obtained during screening. Cancer history includes: 
• Known GIST histological diagnostic 
• Tumor mutation status: molecular test report of patients should be collected during 
screening and necessary archived and/or fresh tumor tissue samples should be collected. If 
the molecular test report provided by patients is available, randomization stratification can 
be carried out according to the molecular test report and it is not required to test archived 
tumor tissue samples or fresh live tissues before randomization. If patients cannot provide 
molecular test report or the report is unusable or insufficient, an archived tumor tissue 
sample or fresh live tissue should be tested to confirm KIT or PDGFRA mutation status 
prior to randomization. The central laboratory will analyze tumor tissues to identify 
mutation of KIT or PDGFRA. 
• All prior anti-cancer therapy regimens, including: 
o Surgery (including tumor tissue samples): including date of resection surgery, site and 
range of resection (such as, resection of tumor tissue samples, R0, R1, or R2 only) 
o Prior imatinib treatment: including treatment starting date, dose and dosing schedule, 
treatment reason (such as adjuvant therapy of metastatic disease), best response, 
progressive disease date, date and reasons of treatment discontinuation. 
o Radiation therapy: including treatment site, total dose, treatment date and response 
o Other treatment procedures, such as radiofrequency ablation (if applicable) 
Molecular test report with KIT/PDGFRA mutation status should be provided to the investigator 
before randomization. If molecular test report is unusable or insufficient, an archived tumor 
tissue sample or fresh live tissue should be tested to confirm mutation status prior to 
randomization. 
The investigator must obtain medical history of each patient during screening, including any 
obvious adverse conditions and diseases during and before obtaining informed consent. It is 
necessary to evaluate whether patients have any unqualified medical conditions specified in 
the inclusion and exclusion criteria based on medical history assessment. Medical history 


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should include complete review of system, past medical history, surgery history and any allergy 
history. Ongoing signs of disease should be considered as comorbidities: if possible, starting 
date of these comorbidities should be recorded. 
6.10. 
Effectiveness 
6.10.1. 
Imageological examination 
Enhanced pelvic, abdominal and chest CT scan of all patients will be carried out according to 
Table 1 (Schedule of Assessments) for tumor efficacy assessment. Radiographic examination 
prior to informed consent can be used for screening evaluation as long as the examination is 
performed within 28 days prior to the first dose of the study drug and meets requirements of 
the study. 
Imageological examination can be performed within the corresponding study visit ± 7 days 
during the study. After C7D1, based on the investigator’s assessment, any initially indicated 
PR or CR should be confirmed ≥ 4 weeks after start of response. MRI scans of the 
abdomen/pelvis and CT scan without contrast of the chest can be used for patients who are 
allergic to radiographic contrast media or at the Investigator's discretion based on the best 
interest of the patient after discussion with the Sponsor.For each patient, the same evaluation 
technology should be adopted during the whole study, and the evaluation technology could not 
be changed unless the investigator’s consideration of safety risk. Ultrasound scan should not 
replace CT scan. 
Copies of all imageological examinations must be obtained and sent to the independent imaging 
supplier designated by the sponsor. The independent imaging supplier will assess imaging 
quality and be responsible for institutional independent radioloicy review. 
Independent imaging supplier must ensure institutional independent radiologic reviewers are 
blinded to investigator's assessment. 
Independent radiologic reviewers and the investigator will evaluate tumor response using 
“RECIST v1.1-GIST-specific Criteria” (see Section Error! Reference source not found.). 
Response confirmed by investigators will be recorded in the eCRF. Assessment data obtained 
by the independent radiologic review (IRR) will be used for analysis of the primary endpoint. 
Confirmation of progressive disease: If the independent radiologic reviewer confirms 
progressive disease using “RECIST v1.1-GIST-specific Criteria”, the patient must discontinue 
the invstigational drug and receive EOT visit, safety follow-up, and OS follow-up. 
Confirmation of absence of progressive disease: if institutional independent radiologic 
reviewers confirm there is no progressive disease, the patient will continue to receive the study 
drug, unless there are medical needs requiring discontinuation of the study drug (that is, rapid 
progression or clinical worsening). If investigators confirm progression according to clinical 
worsening, imageological examination should be performed and reviewed by institutional 
independent radiologic reviewers to confirm whether the patient has progression. Basis for 


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confirming progression based on clinical worsening should be recorded in source documents 
and eCRF of patients. If the investigator confirms progressive disease according to “RECIST 
v1.1-GIST-specific Criteria”, the investigator should wait for assessment and confirmation by 
the independent radiologic review and then terminate the patient’s treatment. If the investigator 
doesn’t hope to confirm by the independent radiologic review or hopes to terminate the 
patient’s treatment according to progressive disease based on “RECIST v1.1-GIST-specific 
Criteria” before obtaining results of the independent radiologic review, it is necessary to 
discuss with the sponsor. 
Radiographic examination of patients of various treatment groups should be performed 
according to the predetermined time and cycle will not be influenced by suspension or delay 
of treatment with the study drug. If the patient discontinues treatment for reasons other than 
progressive disease, death, withdrawal of consent and lost to follow-up, the patient should 
receive radiographic examination for tumor assessment according to the specified time interval 
after treatment withdrawal until progressive disease based on “RECIST v1.1-GIST -specific 
Criteria” or initiation of new anti-tumor therapy. 
6.10.2. 
Overall survival follow-up by telephone 
All patients will be followed up until withdrawal of consent or death for any reason. After 
safety follow-up visit, patients will be contacted once every 2 months (± 10 days) to collect 
new information of anti-tumor therapy and OS data. 
6.11. 
Safety 
Safety evaluation will be based on changes in physical examination, ECOG PS and vital signs 
from baseline, ECG, LVEF based on echocardiogram, dermatologic examination, clinical 
laboratory test and AE reports. 
6.11.1. 
Physical examination 
A comprehensive physical examination will be done during screening. Comprehensive 
physical examination includes review of the following system: head/neck/thyroid gland, 
eye/ear/nose/throat, respiratory, cardiovascular, lymph node, abdomen, skin, muscle and 
musculoskeletal and nervous system. If medically indicated, breast, anorectum and genitals 
will be examined. All other visits and examinations will be arranged according to clinical 
findings and/or patients’ chief complaints. After screening, any clinically significant 
abnormalities in physical examination should be reported as AE. 
6.11.2. 
ECOG performance status 
ECOG PS will be evaluated according to Table 1 (Schedule of Assessments)[25]. ECOG PS 
can be assessed before OR after administration. 
6.11.3. 
Vital sign, weight and height 
Vital signs, height and weight will be measured according to Table 1 (Schedule of 


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Assessments). Vital sign assessment involves sitting blood pressure, pulse, respiratory rate and 
body temperature. These parameters will be assessed after 5 minutes of rest (sitting or supine 
position). 
6.11.4. 
Electrocardiogram 
12-lead ECG will be carried out according to Table 1 (Schedule of Assessments). 
All ECG examination must follow the following regulations: 
• All standard digital electrocardiogram must be carried out at least 15 minutes after the 
patient has a rest. 
• ECG examination must be carried out before administration of study drug. 
Heart rate and the following ECG intervals will be entered into the database: 
• PR interval 
• QT, QTcB and Fridericia-corrected QT interval (QTcF) (QTcF = QT/(60/heart rate)1/3) 
• QRS duration 
6.11.5. 
Echocardiogram 
Echocardiography will be performed according to Table 1 (Schedule of Assessments). 
Echocardiogram before informed consent can be used for screening assessment as long as the 
echocardiogram is performed within 28 days prior to the first dose of the study drug. LVEF 
should be recorded in source documents and eCRF of patients. 
6.11.6. 
Dermatologic examination 
All patients will receive evaluation of skin damages by dermatologist according to Table 1 
(Schedule of Assessments) and clinical indications, especially squamous cell carcinoma of 
skin, actinic keratosis and keratoacanthoma. Examination site should include the whole skin. 
Dermatologic examination meeting standard of the study protocol performed prior to informed 
consent can be used for screening evaluation as long as the examination is performed within 
28 days prior to the first dose of the study drug. Any new or changed skin damages during 
treatment must be recorded in source documents and eCRF of patients. If patients are suspected 
with squamous cell carcinoma of skin or keratoacanthoma, diagnosis should be confirmed by 
a certificated pathologist through biopsy skin at study site. Please refer to Section 7.9 for more 
information of diagnosis and treatment of squamous cell carcinoma of skin, actinic keratosis 
and keratoacanthoma (regarded as AESI). 


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6.11.7. 
Hepatitis B, Hepatitis C and HIV Antibody Testing 
Hepatitis B and C examination in the screening period: HBsAg, anti-HBs, HBeAg, anti-HBe 
and anti-HBc and anti-HCV antibody examination will be performed first. If results of five 
indicators of hepatitis A are abnormal, HBV DNA quantitative test should be performed; if 
anti-HCV antibody positive, HCV RNA quantitative test should be performed. For patients 
with abnormal baseline HBV DNA, HBV DNA quantitative test should be performed once 
every 2 weeks during the trial and at the end of study. 
HIV antibody test should be carried out in the screening period. 
6.11.8. 
Clinical laboratory tests 
Blood and urine samples will be collected and analyzed according to Table 1 (Schedule of 
Assessments). All blood samples must be collected when the patient is in a sitting or supine 
position. If laboratory test abnormality is clinically significant, it should be reported as AE 
(Section 7.7.1). All laboratory test results must be graded according to toxicity definition in 
Common Terminology for Adverse Events of National Cancer Institute (NCI CTCAE), v5.0. 
Items of safety laboratory tests refer to Table 1111. 
Table 11:  
Safety laboratory tests 
Blood biochemistry 
Blood routine 
Routine urine test 
Blood glucose 
Blood urea nitrogen/urea 
Creatinine 
Sodium 
Potassium 
Calcium 
Magnesium 
Phosphonium  
Bilirubin total and Bilirubin direct 
Alkaline phosphatase 
Glutamic-oxaloacetic transferase  
Alanine transaminase 
Lactate dehydrogenase 
Total protein 
Albumin 
Creatine phosphokinase 
Globulin 
Triglyceride 
Lipase 
Haemoglobin 
Platelet 
White blood cells 
Reticulocyte 
Classification (absolute count): 
• Neutrophil 
• Lymphocyte  
• Monocyte 
Coagulation tests1 
Activated partial thromboplastin time  
Pro-thrombin Time 
International Normalized Ratio 
Protein urine  
Urine occult blood 
Specific gravity  
Urine ketone body  
Urine Glucose  
Thyroid test 
Thyroid stimulating hormone (TSH) 
Free triiodothyronine (FT3) 


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Blood biochemistry 
Blood routine 
Routine urine test 
Free thyroxine (FT4) 
1. For patients who take anticoagulant, test will be carried out according to Table 1 (Schedule of 
Assessments). If the dose of anticoagulant changes during the study, monitoring of coagulation 
function should be increased if clinically suitable. 
 
6.11.9. 
Pregnancy test 
To exclude pregnancy in women of childbearing potential, serum β-hCG test will be carried 
out at screening. As shown in Table 1 (Schedule of Assessments), urine pregnancy test will be 
completed at all other visits. Pregnancy test is not required in female patients without fertility. 
These patients refer to postmenopausal (amenorrhea ≥ 12 months and follicle stimulating 
hormone [FSH] ≥ 40 mIU/mL) women or women with proof document of total hysterectomy 
or total ovariectomy. 
6.11.10. 
Contraception and contraceptive measures 
6.11.10.1. 
Contraception 
Influence of DCC-2618 (Ripretinib, ZL-2307) on sperm, conception, pregnancy and 
breastfeeding is unknown. Patients who receive DCC-2618 (ripretinib, ZL-2307) in the study 
should agree to take contraceptive measures. Effective contraceptive measures should be taken 
from at least 14 days before the first dose of DCC-2618 (ripretinib, ZL-2307) until 104 days 
after the last dose of DCC-2618 (ripretinib, ZL-2307). 
Patients who use sunitinib in the study should agree to take effective contraceptive measures 
according to the approved package insert. 
Female patients and female partners of male patients who use DCC-2618 (ripretinib, ZL-2307) 
should not plan to become pregnant during the study until 104 days after the last dose of DCC-
2618 (ripretinib, ZL-2307) or the last dose of sunitinib. 
If it is uncertain that whether female or male with fertility will reliably follow requirements for 
contraception, the patient should not be included into the study. 
6.11.10.2. 
Pregnancy 
Patients who receive DCC-2618 (ripretinib, ZL-2307) must inform the investigator of any 
pregnancy during the study treatment and within 104 days after the last dose of DCC-2618 
(ripretinib, ZL-2307). Patients who use sunitinib must inform the investigator of any pregnancy 
during the study treatment. 
If female patient becomes pregnant during the study, treatment with the study drug should be 
discontinued immediately forever. If female partner of male patient becomes pregnant during 
the study, the patient must inform the investigator immediately. Male patients must promise to 
take acceptable contraceptive measures during the study until 104 days after the last dose of 


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CC-2618 (ripretinib, ZL-2307) or the last dose of sunitinib (to ensure fetus is not in contact 
with the study drug). The investigator must inform the sponsor within 1 work days after the 
study site is aware of pregnancy of patients (or partners). 
If the patients is receiving DCC-2618 (ripretinib, ZL-2307) treatment, the patient or female 
partner of male patient must be followed up until end of pregnancy. If informed consent is 
obtained, infants must be followed up until 1 year after birth. Pregnancy itself is not an AE. 
6.11.11. 
AEs 
All AEs will be evaluated, recorded and reported according to Good Clinical Practice (GCP) 
of the International Conference on Harmonization (ICH). Chapter Error! Reference source 
not found. summarizes the definition, collection period, evaluation criteria, recording, grading 
and reporting procedure of AEs. 
6.11.12. 
Safety follow-up 
AE follow-up should be carried out in all patients  30 (±5) days after the last dose of the study 
drug to collect information of concomitant medications/other treatments and collect new 
information of anti-tumor therapy. 
6.12. 
Pharmacokinetics 
6.12.1. 
Sampling 
At visits listed in Table 1 (Schedule of Assessments), blood samples will be collected from 
patients who use DCC-2618 (ripretinib, ZL-2307) to determine the concentration of DCC-2618 
(ripretinib, ZL-2307) and its metabolite DP-5439. Pre-dose blood samples must be collected 
within 60 minutes prior to administration and post-dose blood samples must be collected within 
the specified time point ± 30 minutes. If the sponsor requires, unscheduled PK samples can be 
collected when new, suspicious, and treatment-related AEs occur. 
Detailed information of sample collection, processing, storage and shipment will be provided 
in an independent specific laboratory manual of the study protocol. 
6.12.2. 
Sample evaluation 
Descriptive statistics and summary of drug concentration at relevant time points will be carried 
out according to plasma concentration of DCC-2618 (ripretinib, ZL-2307). If necessary, 
pharmacokinetic data of this study will be included into population PK analysis with industrial 
standard software. Population PK report will be drafted independently and not taken as the 
appendix of the study report. 
6.13. 
Biomarkers and pharmacodynamics 
6.13.1. 
Sample collection 
Tumor tissues and blood samples will be collected according to Table 1 (Schedule of 
Assessments). Laboratory manual will be provided to describe detailed information of sample 


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collection, processing, storage and shipment. 
6.13.2. 
Sample evaluation 
6.13.2.1. 
Tumor tissue samples 
Necessary archived and/or fresh tumor tissue samples will be collected at screening. If archived 
tumor tissues cannot be used or are insufficient for mutation analysis, fresh tumor tissue 
samples should be collected. The central laboratory will analyze tumor tissues to identify 
molecular mutation of KIT or PDGFRA. 
All patients (optional): Tumor tissue samples can be collected at EOT visit and/or from patients 
who are receiving medical procedures, including resection of metastasis in the study, or from 
patients who have progressed (if the patient agrees). These samples will be used for further 
molecular test of cancer during receiving the study drug. 
6.13.2.2. 
Blood sample 
Blood samples will be collected from patients who receive DCC-2618 (ripretinib, ZL-2307) 
and sunitinib treatment according to Table 1 (Schedule of Assessments) and analyzed by the 
central laboratory to evaluate mutation status of KIT or PDGFRA as well as longitudinal 
frequency change of its ctDNA. 
7.
ADVERSE 
EVENT 
AND 
SERIOUS 
ADVERSE 
EVENT
DOCUMENTATION, SEVERITY GRADING, AND REPORTING
7.1. 
Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical 
product during the study, which does not necessarily have a causal relationship with the study drug. 
An AE can be any unfavorable and unintended sign (e.g. including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the study drug, whether or not it is 
considered to be study drug related. This includes any newly occurring event or previous condition 
that has increased in severity or frequency after the ICF is signed. Adverse events include serious 
adverse events (SAEs) and non-serious adverse events. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was screened in the study and progression of underlying disease are not to be considered 
AEs unless the condition deteriorated in an unexpected manner during the study (e.g. surgery was 
performed earlier than planned).  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, must not be 
reported as AEs. However, the medical condition for which the procedure was performed must be 
reported if it meets the definition of an AE.  
Each AE must be assessed immediately to determine if it meets the definition of serious 
(Section 7.8). If an SAE occurs, expedited reporting must follow local and international 
regulations, as appropriate. 


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7.2. 
Severity Assessment 
The Investigator must determine and record the severity of all serious and non-serious AEs. The 
NCI-CTCAE, Version 5.0, must be used for grading the severity of AEs (cancer therapy 
evaluation program website: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0/). 
The severity of an AE that does not appear in the CTCAE scale must be determined according to 
Table 122. 
Table 122:  
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Version 5.0 Severity Grading Scale 
Grade 1 (mild) 
Asymptomatic or only mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; 
Grade 2 (moderate) 
Minimum, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
Grade 3 (severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4 (life threatening) 
Life-threatening results; urgent intervention indicated. 
Grade 5 (death) 
Death related to AE. 
7.3. 
Causality assessment 
The Investigator’s assessment of relationship of the AE, if any to the study drug must be provided 
for all AEs. An Investigator’s causality assessment is the determination of whether there is 
reasonable possibility that the study drug caused or contributed to an AE.  
Relationship to study drug administration must be determined by the Investigator according to the 
following criteria in Table 13.  
Table 133:  
Relationship to Study Drug Criteria 
The investigator must evaluate and provide the causal relationship between adverse event and 
the study drug. The following table 11 can be used as reference for caualtiy assessment. 
Related 
There is an association between the event and the administration of study drug, a 
plausible mechanism for the event to be related to the study drug and causes other than 
the study drug has been ruled out, and/or the event re-appeared on re-exposure to the 
study drug.  
Possibly Related 
There is an association between the event and the administration of the study drug and 
there is a plausible mechanism for the event to be related to study drug, but there may 
also be alternative etiology, such as characteristics of the patient's clinical status or 
underlying disease.  
Unlikely Related 
The event is unlikely to be related to the study drug and likely to be related to factors 
other than the study drug.  
Not Related 
The event is related to an etiology other than the study drug (the alternative etiology must 
be documented in the study patient’s medical record).  
For the purpose of safety analysis, all adverse events that are classified to be possibly related 


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to the study drug will be regarded as treatment-related events. 
7.4. 
Study Drug Action Taken 
The investigator must clarify measures to the study drug due to AE. Measures taken must be 
classified according to categories shown in Table 144. 
Table 144:  
Classification for Study Drug Action Taken with Regard to an Adverse Event 
Classification  
Definition  
Dose Not Changed  
Study drug dose not changed in response to an AE.  
Dose Reduced  
Study drug dose reduced in response to an AE.  
Drug Interrupted  
Study drug administration interrupted in response to an AE.  
Drug Withdrawn  
Study drug administration permanently discontinued in response to an AE.  
Not Applicable  
Action taken regarding study drug administration does not apply.  
"Not applicable" must be used in circumstances such as when the study drug had been 
completed before the AE began and no opportunity to decide whether to continue, 
interrupt, or withdraw study drug is possible.  
 
7.5. 
Adverse Event Outcome 
An AE must be followed until the Investigator has determined and provided the final outcome. The 
outcome must be classified according to the categories shown in Table 15.  
Table 155:  
Classification of adverse event outcome 
Classification  
Definition  
Recovered/Resolved  
Resolution of an AE with no residual signs or symptoms.  
Recovered/Resolved with 
Sequelae  
Resolution of an AE with residual signs or symptoms.  
Recovering/Resolving  
Improvement of an AE  
Not 
Recovered/Not 
Resolved (Continuing)  
Either incomplete improvement or no improvement of an AE, such that it remains 
ongoing.  
Fatal  
Outcome of an AE is death. "Fatal" must be used when death is at least possibly 
related to the AE.  
Unknown  
Outcome of an AE is not known (e.g., a patient lost to follow-up).  
Classification  
Definition  
The investigator should continue to follow up any adverse event that has not recovered at the 
last visit of the study until there is no clinical indications and the patient start new anti-tumor 
theropy, whichever occurs first; and 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. 
7.6. 
Treatment measures on AEs 
The Investigator must ensure adequate medical care is provided to patients for any AEs. In addition, 
the Investigator must describe whether any treatment was given for the AE. "Yes" is used if any 
treatment was given in response to an AE and may include treatments such as other medications, 


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hospitalization, surgery, or physical therapy. "No" indicates the absence of any kind of treatment 
for an AE.  
7.7. 
Additional Considerations on  Adverse Events 
7.7.1. 
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). Once the diagnosis is confirmed with 
the follow up information, the symptoms and sign should be replaced with diagnosis 
accordingly. 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 study drug, such as drug discontinuation or 
treatment termination. 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above 
criteria, does not necessarily meet clinically significant criteria. The determination of whether 
the study assessment results are clinically significant must be made by the Investigator.  
A laboratory abnormality judged to be Grade 4, in itself, may not constitute an SAE unless 
the clinical status of the patient indicates a life-threatening AE.  
Symptoms of the disease under study must not be recorded as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease, including significant 
worsening unless the deterioration was unexpected, and are part of the efficacy data to be collected 
in the study. 
 
7.8. 
Definition of Serious Adverse Event(SAE) 
An AE is considered serious if it meets any of the following:  
• Results in death (regardless of cause, that occurs during participation in the study or 
occurs after participation in the study and is suspected of being a delayed toxicity due 
to administration of the study drug)  
• Is life threatening (an event/reaction in which the patient was at risk of death at the 
time of the event/reaction; it does not refer to an event/reaction which hypothetically 
might have caused death if it were more severe)  


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• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity  
• Results in congenital anomaly/birth defect  
• Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes (i.e. allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency 
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) 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to study 
drug, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor 
is required. Such AEs may require further investigation to characterize and understand them. 
AESIs may be added or removed during a study by a protocol amendment.  
The following AEs are considered AESIs:  
• Squamous cell carcinoma of skin 
• Actinic keratosis 
• Keratoacanthoma 
7.10. 
Adverse Events Reporting Period 
The AE (including SAEs and AESIs) reporting period begins from the time that the patient provides 
informed consent through and including 30 days after the last dose of the study drug, or until a new 
anti-tumor therapy is initated, which occurs first. For any SAEs or AESIs occurring after this 
reporting period, it will be reported only when a causal relationship between the SAEs or AESIs 
and study product is suspected by the study drug. 


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7.11. 
Adverse Event, Serious Adverse Event, and Adverse Event of Special 
Interest Reporting Requirements 
Each patient must be carefully monitored for the development of any AEs. This information must 
be obtained in the form of non-leading questions (e.g. “How are you feeling?”) and from signs and 
symptoms detected during each examination, observations of study personnel, and spontaneous 
reports from patients. All AEs (serious and non-serious) spontaneously reported by the patient 
and/or in response to an open question from study personnel or revealed by observation, physical 
examination or other diagnostic procedures must be recorded. 
When possible, signs and symptoms indicating a common underlying pathology must be noted as 
1 comprehensive event. Accompanying signs or symptoms (e.g. abnormal laboratory values) must 
not be reported as additional AEs. If a diagnosis is unknown, one or more symptoms may be 
reported as separate AEs. If an underlying diagnosis is subsequently determined for the reported 
symptom(s), then the reported symptom(s) term(s) must be revised to be “attributed” or “due” to 
the diagnosis.  
All SAEs and AESIs that occur within the reporting period, regardless of causality, must be 
reported by the Investigator as applicable to competent authoridy, Ethics Committe or sponsor 
pharmacovigilance team within 24 hours from the point in time when the Investigator becomes 
aware of the SAE or AESI. For reporting purpose, the following procedures must be followed. 
The investigator should send completed, signed and dated SAE Report Form to (within 24 
hours of awareness):  the public email mailbox of Drug Safety Department in Zai Lab: 
saereporting@zailaboratory.com. 
(1)  The course of the event was to be followed up and documented until recovery or 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. 
When in the opinion of the investigator when clinical benefit is sustained even after the 
clinical trial is closed, treatment with DCC-2618 (Ripretinib, ZL-2307) will be continued 
until disease progression, death, intolerable toxicity or patient's desire to withdrawal. For 
those patients, only SAEs will be collected 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. 
 
Processing of Death Cases 
All deaths occurring during the study, including within 30 days after the last dose of study 
drug, during the safety follow-up period of the last dose of study drug will be reported by 
the investigator as follows: 


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○ 
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 cannot be 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 or is the main cause of death, 
as appropriate. 
○ 
Death with unknown causes must be reported as SAE. The cause of death should be 
clarified with every effort in follow-up activities. Autopsy is crutial 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. 
• Serious Unexpected Adverse Reactions (SUSARs) 
If drug-related serious unexpected adverse reactions (SUSARs) occur, the sponsor or the 
authorized personnel designated by the sponsor will ensure expedited reporting to 
appropriate regulatory authorities or other investigators taking part in this study. In 
addition, the sponsor or the authorized personnel designated by the sponsor will be 
responsible for reporting SUSARs to the ethics committee. 
• Pregnancy 
Effective contraception is required for both male and female subjects of childbearing 
potential who are treated with DCC-2618 (Ripretinib, ZL-2307) during the trial and for 
104 days after discontinuation of study drug. If a subject is found to be pregnant 
following initiation of study treat, the study 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 104 days after the last dose of study drug, the 
investigator should be informed immediately. The pregnancy must be recorded on 
“Pregnancy Reporting Form” and reported by the investigator to the Sponsor via email 
within 24 hours of becoming aware of the event. 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., 


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spontaneous miscarriage or therapeutic miscarriage [any congenital anomaly detected 
in the miscarriage fetus], stillbirth, neonatal death, or birth defect and any congenital 
anomaly), 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 medication errors 
The adverse events or at risk scenairos including drug abuse, misuse, overdose and medical 
errors should be reported to the sponsor. 
Abuse of a medicinal product: Persistent or sporadic, intentional excessive use of medicinal 
products, which is accompanied by harmful physical or psychological effects [DIR 
2001/83/EC Art 1(16)]. 
Misuse: Intentional and inappropriate use of a medicinal product not in accordance with the 
prescribed or authorized dose, route of administration, and/or the indication(s) or not within 
the legal status of its supply. 
Overdose: Administration of a quantity of study drug given per administration or per day, 
which is above the assigned dose. 
Medication Error: An error made in prescribing, dispensing, administration, and/or use of the 
study drug. Medication errors are reportable to the Sponsor as defined below. 
•The dispensing, administration and/or use of the unassigned study drug. 
•The administration and/or use of an expired study drug. 
Note: Cases of patients missing doses of the study drug are not considered reportable as 
medication errors.  
AEs or SAEs associated with drug abuse, misuse, overdose, or medication error must be 
reported as appropriate (add appropriate section for reporting of AE) 
 
Note: Unintentional missing drug does not belong to medical error that must be reported. 
8. 
Patient withdrawal and replacement 
8.1. 
End of treatment 
Patients may withdraw from treatment with the study drug for any reasons at any time without 
providing any reasons and will not have any punishment or damages. If clinically required, the 
investigator may terminate treatment with the study drug for the patient at any time. The main 
reason for termination or discontinuation of the study drug should be confirmed according to 
the following classification: 
• Clinical progression 
• Disease progression confirmed by institutional independent radiologic review 


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• AE 
• The patients request withdrawal from the treatment  
• Death 
• Lost to Follow-up 
• Investigator's decision 
• Pregnancy 
• Termination of the study by the sponsor 
If the patient requests to withdraw from treatment, the investigator should try to contact the 
patient to confirm reasons for withdrawal and ask the patient to return to study site to receive 
EOT visit and safety follow-up. If the patient withdraws from the study for any reasons other 
than “requesting withdrawal”, EOT visit, safety follow-up visit and OS follow-up visit should 
be carried out. Patients should return all used, partially used and unused study drugs and bottles. 
8.2. 
End of Study 
The main reason for termination or withdrawal form the study should be confirmed according 
to the following classification: 
• Death 
• Lost to Follow-up 
• Termination of the study by the sponsor 
• Patients will withdraw from the study  
8.3. 
Patient withdrawal and replacement 
Patients will be not substituted in the study. 
 
9. 
Statistical  Consideration 
9.1. 
Determination of sample size 
This study will bridge foreign clinical trial (study INTRIGUE) to prove the efficacy of the 
investigational drug DCC-2618 (ripretinib, ZL-2307) is consistent in foreign population and 
Chinese population. In the study, no statistical test hypothesis is specified in advance. 
Statistical significance test for efficacy endpoint and multiplicity correction for multiple 
analysis populations will not be performed. 
Approximately 98 subjects will be enrolled into the study and randomized to a test group and 
a control group in a 1:1 ratio. The sample size eatimation will be based on the same study 
hypothesis as foreign, that is, median progression‑free survival (mPFS) is 9 months in the test 


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group and 6 months in the control group. Hazard ratio (HR) of the test group to the control 
group is 0.667. If the study keeps ≥50% of the overall effect size of study INTRIGUE, that is, 
point estimate of HR should be ≤ 0.833, it will be considered that results of this study are 
consistent with those of study INTRIGUE. If 58 cases of PFS events occur, a 80% probability 
will be obtained and athe conclusion of consistency will be drawn with a probability of 80%. 
Assumeing the subjects annual drop-out rate of subjects of the total study population is 5%, 
approximately 98 subjects (49 for the test group and the control group, respectively) are 
enrolled within 7 months and followed up for 7 months, and 58 cases of PFS events will occur. 
Main Primary analysis based on ITT will be carried outperformed when 58 cases of PFS events 
occur and it is estimated that the data cutoff of the analysis will be 7 months after completing 
enrollment. 
In population with KIT exon 11 mutation, it was assumed in the foreign study that mPFS of 
the test group was 9 months and mPFS of the control group was 5 months, and HR of the test 
group to the control group was 0.556. If the study keeps ≥a 50% and of the overall effect size 
of study INTRIGUE in population with KIT exon 11 mutation, that is, point estimate of HR 
should be ≤ 0.778, it will be considered that results based on KIT exon 11 mutation population 
in this study are consistent with those in study INTRIGUE. If 26 cases of PFS events occur in 
population with KIT exon 11 mutation, the conclusion of consistence with study INTRIGUE 
can be drawn with a probability of 80%. 
9.2. 
Study Endpoints 
9.2.1. 
Primary endpoints 
The independent radiologic review will assess PFS according to “RECIST v1.1-GIST-specific 
Criteria ” (Appendix 16.1). “RECIST v1.1-GIST-specific Criteria” assessment criteria include: 
• 
No lymph nodes chosen as target lesions; enlarged lymph nodes will be followed as 
non-target lesions. 
• 
No bone lesions chosen as target lesions; 
• 
Positron emission tomography (PET) not acceptable for radiological evaluation;  
• 
A progressively growing new tumor nodule within a pre-existing 
tumor mass must meet the following criteria to be considered as 
unequivocal evidence of progression according to the modification 
of RECIST Version 1.1: (a) the lesion is at least 2 cm in size and 
definitively a new active GIST lesion (e.g. enhancing with contrast 
or other criteria to rule out artefact); or (b) the lesion has to be 
expanding on at least 2 sequential imaging studies. 
9.2.2. 
Secondary endpoints 
9.2.2.1. 
Effectiveness 


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• ORR (confirmed CR + confirmed PR) based on independent radiologic review 
• Disease control rate (DCR) at months 6, 9 and 12, assessed by independent radiologic 
review 
• PFS assessed by the investigator according to “RECIST v1.1-GIST-specific Criteria” 
• Overall survival (OS) 
9.2.2.2. 
Safety 
• 
Incidence of treatment emergent adverse event (TEAE), adverse event of special 
interest (AESI) and serious adverse event (SAE); severity of adverse event will be 
assessed (based on NCI CTCAE 5.0); 
• 
Incidence of adverse events resulting in dose adjustment of the study drug or 
termination of the study; 
• 
Changes in each parameter like ECOG score, vital signs, electrocardiogram, left 
ventricular ejection fraction, dermatologic examination and laboratory indicators from 
baseline. 
9.2.2.3. 
Pharmacokinetic characteristics 
Descriptive statistics and summary of drug concentration at relevant time points will be carried 
out according to plasma concentration of DCC-2618 (ripretinib, ZL-2307). If necessary, 
pharmacokinetic data of this study will be included into population PK analysis with industrial 
standard software. Population PK report will be drafted independently and not taken as the 
appendix of the study report. 
9.2.3. 
Exploratory endpoint 
• KIT/PDGFRA mutation of tumor tissues at baseline and specific time points (e.g., resection 
of metastasis or progressive disease during the study). 
• KIT/PDGFRA mutations and mutant allele frequency at baseline and the treatment effect 
of DCC-2618 (ripretinib, ZL-2307) on KIT/PDGFRA mutant allele frequency (MAF). 
9.3. 
Analysis Population 
The following populations will be used for analysis: all patients intent-to-treat (ITT) 
population, KIT exon 11 mutation intent-to-treat (Ex11 ITT) population, safety population, PK 
population, all patients per-protocol (PP) population and KIT exon 11 mutation per-protocol 
(Ex11 PP) population. 
ITT population is defined as all randomized patients. Patients in the population will be analyzed 
according to treatment they will receive. 
KIT exon 11 mutation intent-to-treat (Ex11 ITT) population is defined as all patients with KIT 
exon 11 mutation at randomization. Patients in the population will be analyzed according to 


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treatment they will receive. 
Safety analysis population is defined as all subjects who were randomly assigned and received 
at least one dose of study drug. Safety population will be used for all safety analyses and 
treatment assignment will be based on the actually received initial study treatment. 
PK population will include all randomized subjects who have received at least one dose of 
DCC-2618 (ripretinib, ZL-2307) and have at least a non-missing plasma PK concentration 
report of DCC-2618 (ripretinib, ZL-2307) and DP-5439. 
PP population is defined as all patients in ITT population who have at least one tumor 
assessment after baseline, meet all inclusion criteria, don’t violate any exclusion criteria and 
don’t have any significant study protocol violation/deviation that are considered to influence 
the integrity of the study. Efficacy analysis in the PP population is supportive and the analysis 
in treatment groups will be based on the actually received treatment. Patients who violate the 
study protocol and excluded from the PP population will be identified and recorded before 
locking the database. 
KIT exon 11 mutation per-protocol (Ex11 PP) population is defined as all patients in Ex11 ITT 
population who have at least one tumor assessment after baseline, meet all inclusion criteria, 
don’t violate any exclusion criteria and don’t have any significant study protocol 
violation/deviation that are considered to influence the integrity of the study. Efficacy analysis 
in the Ex11 PP population is supportive and the analysis in treatment groups will be based on 
the actually received treatment. Patients who violate the study protocol and excluded from the 
Ex11 PP population will be identified and recorded before locking the database. 
Note: If a patient has exon 11 mutation with 1) exon 9 and/or PDGFRA mutation, the patient 
will be considered with exon 11 mutation at randomization. Mutation type of the patient will 
be defined according to a mutation with a higher MAF if the patient has mutation allele 
frequency (MAF) data; 2) other KIT exon mutation, the patient will be considered with exon 
11 mutation at randomization. 
9.4. 
Processing procedures of missing data, unused data and false data 
Calculation of interpolating or missing date is shown in Table 166. Interpolate AE end date to 
calculate the duration of AE. 
Table 166:  
Calculation of some or missing date 
Variables 
Missing Day 
Missing date and 
month 
Missing date, month 
and year 
Date of the last 
treatment/initial 
diagnosis 
Assigned 1 day 
Please assign January 1 if 
before 
the 
date 
of 
informed consent, or else 
use the date of informed 
consent 
Missing (don’t 
interpolate) 
AEs/Starting date 
Assign the first day of the Assign January 1, unless  Assign the date of the 


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month, unless the first dose 
of the study drug is given in 
this month. 
Or else, assign the date of 
the first dose of the study 
drug or end date of AE (if 
not 
missing), 
whichever 
occurs first. 
the first dose of the study 
drug is given this year. 
Or else, assign the date of 
the first dose of the study 
drug or end date of AE (if 
not missing), whichever 
occurs first. 
first dose of the study 
drug. 
The end date of 
adverse event 
Assign the last day of this 
month or study end date, 
whichever occurs first. 
Assign December 31 or 
study end date, 
whichever occurs first. 
If the event continues, 
end date will be left 
blank. Otherwise, study 
end date was to be 
assigned. 
9.5. 
Statistical Method 
9.5.1. 
General methods 
Data collected in the study will be documentedwith summary tables and patients data listings. 
Continuous variables will be summarized with descriptive statistics (the number of patients, 
mean, median, standard deviation, minimum and maximum). Categorical variables will be 
summarized with frequency and proportion. Time-to-event datawill be summarized via 
Kaplan-Meier (KM) methodology using the 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals. 
Unless specified otherwise, baseline measurement values should be the latest values prior to 
the first dose of the investigational drug. If the assessement is not available, the last assessment 
before the visit will be used. 
Medical history, AEs and concomitant treatment procedures will be coded with Medical 
Dictionary for Regulatory Activities (MedDRA). Past and concomitant medications will be 
coded according to the World Health Organization Drug Dictionary. 
Unless specified otherwise, Ex11 ITT population and ITT population are used for efficacy 
analysis (primary endpoint and secondary endpoint) and safety population is used for safety 
analysis. 
 


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9.5.2. 
Patients disposition 
Dispositionof all patients entering the study (patients who sign the informed consent form of 
the study and meet the inclusion criteria and don’t meet the exclusion criteria) will be 
summarized. The number of patients in each population (safety, PK, Ex11 ITT, ITT, Ex11 PP, 
PP, if applicable) and the number of patients excluded from each population will be displayed. 
The number and proportionof patients who completethe study, as well as those who discontinue 
the studywill be summarized along with the reason for discontinuation. 
9.5.3. 
Demographic data and baselinecharacteristics 
Demographic and baseline characteristics (including recurrence risk evaluation at enrollment) 
will be summarized. 
Medical history will be summarized for the safety population. 
 
9.5.4. 
Extent of exposure 
Total subjects who receive treatment with the investigational drug will be summarized with n 
and percentage. Moreover, continuous descriptive statistics will be used to display number of 
treatment cycles subjects received. These analyses will be performed for the safety population. 
 
9.5.5. 
Efficacy analysis 
9.5.5.1. 
Primary endpoint: progression-free survival 
The primary endpoint PFS is defined as the time interval from randomization to the earliest 
documented evidence of progressive disease based on assessment of the independent radiology 
review or death due to any causes. PFS analysis in the ITT population will be stratified by the 
randomization stratification factors (KIT exon 11 mutation; KIT exon 9 mutation; other 
(KIT/PDGFRA WT or other KIT [lacking exon 9 or 11]/PDGFRA mutation). Survival curve 
of different treatment groups will be plotted with KM method and the median progression-free 
survival (mPFS) and its 95% CI of different groups will be calculated. Under a two-sided 
significance level of 0.05, stratified log-rank test will be adopted to compare difference in 
survival curve between the two groups. Point estimate of hazard ratio will be obtained by 
stratified Cox regression model and relevant 95% CI will be calculated with Wald method. 
Randomization stratification factor is stratification factor and treatment factor is the covariant. 
 
 
Rules of defining PFS events and censoring PFS will be elaborated in the statistical analysis 
plan (SAP). Sensitivity analysis for PFS will be specified in the SAP. 
ITT population will be used as the primary analysis population in this analysis while the PP 


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population as supportive analysis population. Sensitivity analysis of progression-free survival 
will be performed, which will be further described in SAP. 
9.5.5.2. 
Secondary efficacy endpoints 
9.5.5.2.1. 
Analysis of objective response rate 
ORR is defined as the proportionof patients, which is confirmed as CR or PR, based on 
independent radiology review. ITT population will be used as the primary analysis population 
in this analysis while the PP population as supportive analysis population. Patients with 
unknown or missing response will be considered non-response, that is, they will be included in 
the denominator when calculating proportion. Rate difference of objective response rate (ORR) 
between treatment groups with95% CI will be calculated with stratified Miettinen and 
Nurminen and statistical test will be performed 
9.5.5.2.2. 
Overall survival 
OS is defined as interval, the time from randomized allocation to patient death because of any 
cause. Surviving patients or those lost to follow-up will be censored on the contact day of the 
last assessment. Model similar to that for PFS analysis will be used for OS analysis. 
9.5.5.2.3. 
Disease control rate 
Disease control is defined as patients who obtained CR, PR or SD. DCR will be summarized 
according to n and proportion. Rate difference of disease control rate (DCR) between treatment 
groups and 95% CI will be calculated with stratified Miettinen and Nurminen and statistical 
test will be performed. 
9.5.5.2.4. 
Investigator-assessed progression‑free survival 
Investigator-assessed PFS is defined as the time interval from randomization to the earliest 
documented evidence of progressive disease based on assessment of the investigator or death 
due to any causes. Differences between treatment groups will be assessed with the same method 
as the primary endpoint. 
 
9.5.6. 
Safety Analysis 
9.5.6.1. 
AEs 
AEs in the safety population will be summarized with the number of events and proportionof 
patients according to system organ class (SOC) and preferred term. All tables will only include 
TEAE. “Treatment emergent” is defined as any AEs occurring during the first dose of the 
investigational drug and up to 30 days after the last dose of the investigational drug. However, 
the listing will include all AEs collected. 
Toxicity grade of AE will be classified with NCI-CTCAE V5.0 (See Table 12). If a patient has 
the same SOC or preferred term evet for several times, only the most severe event will be 


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summarized in the tables for that SOC and preferred term. AEs grade ≥ 3 will be summarized. 
Missing toxicity grade will not be imputed. 
SAEs, AEs and AESIs that lead to dose reduction or discontinuation and AEs will be also 
analyzed. 
Formal hypothesis test of incidence of AE will not be performed. 
9.5.6.2. 
Eastern Cooperative Oncology Group Performance Status 
Descriptive statistics will be provideded and baseline value, value after baseline and changes 
in value from baseline will be summarized by time points. Formal hypothesis test will not be 
performed. 
9.5.6.3. 
Vital signs 
Continuous descriptive statistics will be provided and assessment results will be summarized 
overall by time points. In addition, changes in continuous parameters from baseline will be 
summarized. For categorical parameters, n and proportionwill be presented. Formal hypothesis 
test will not be performed. 
9.5.6.4. 
Echocardiogram 
Continuous descriptive statistics will be provided and assessment results will be summarized 
overall by time points. In addition, changes in continuous parameters from baseline will be 
summarized. For categorical parameters, n and proportion will be presented. Formal hypothesis 
test will not be performed. 
9.5.6.5. 
Dermatologic examination evaluation results 
Descriptive statistics will be provided for summary of evaluation results of dermatologic 
examination. Formal hypothesis test will not be performed. 
9.5.6.6. 
Clinical laboratory parameters 
Continuous descriptive statistics will be provided and assessment results will be summarized 
overall by time points. In addition, changes in continuous parameters from baseline will be 
summarized. For categorical parameters, n and proportion will be presented. Formal hypothesis 
test will not be performed. 
9.5.7. 
Pharmacokinetic analysis 
Plasma concentration of DCC-2618 (ripretinib, ZL-2307) and its metabolite DP-5439 will be 
summarized by descriptive statistics. If the dose changes, plasma concentration can be 
summarized by dose level. 
9.5.8. 
Biomarkers and pharmacodynamics analysis 
Observe baseline KIT and PDGFRA mutation in plasma and features of mutation allele 
frequency change during the study 


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The Mann-Whitney U test will be used to analyze statistical difference between treatment 
groups in terms of treatment effectof DCC-2618 (ripretinib, ZL-2307) and sunitinib on 
mutation frequency tested using ctDNA at all time points. Formal hypothesis test will not be 
performed. 
9.5.9. 
Procedures to report deviations from the original statistical plan 
All information of deviation from source SAP will be provided in the final clinical study report. 
10. 
Quality Control and Assurance 
10.1. 
Monitoring visit at each study site 
The sponsor or its representative will periodically carry out monitoring visit during the study 
to ensure the study is in compliance with the study protocol and ICH GCP requirements. The 
monitor will review source documents to ensure data recorded in the eCRF are accurate. The 
investigator and the study institution will allow the sponsor’s monitor or designated personnel 
and corresponding regulators to directly access to source documents to implement validation. 
Study site may receive IRB/IEC review, and/or quality assurance audit by the sponsor or 
cooperative company of the sponsor or representative company of the sponsor, and/or 
inspection by corresponding regulators. 
What’s more, the investigator and other relevant personnel should invest enough time in the 
procedure during monitoring visit and potential audit or inspection. 
10.2. 
Compliance of the study protocol 
The investigator should conduct the study in compliance with the study protocol provided by 
the Sponsor and obtain the approval/assenting view of IRB/IEC and corresponding regulatory 
authorities. The protocol should not be changed without the unite approval of the investigator 
and sponsor. Written approval/assenting view of IRB/IEC and corresponding regulators should 
be obtained before implementing changes to the study protocol, unless changes that must be 
made to eliminate direct harm to patients. If applicable regulator allows, IRB/IEC can provide 
expedited review and approval/assenting view for minor changes in the ongoing study if 
IRB/IEC approval/assenting view has been obtained. The sponsor must ensure all changes to 
the study protocol are submitted to regulatory authorities according to regulatory requirements. 
If it is necessary to deviate from the procedure specified by the study protocol due to other 
unexpected conditions, the investigator must discuss with the sponsor (and IRB, IEC, as 
required) to confirm appropriate action steps that can be taken. 
Study site must record all protocol deviations in corresponding source documents of patients. 
Study site must inform the sponsor (and IRB, IEC, as required) of any major deviations. Major 
protocol deviations include but are not limited to behaviors involving fraud or misconduct, 
increasing risks to patients’ health or interpretations confusing the main study assessment 
result. 


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11. 
Data handling and record storage 
11.1. 
Electronic case report form 
The sponsor or designated personnel will provide security access rights of electronic data 
capture program to study sites and carry out adequate training of the program to make personnel 
of study sites able to enter or change information of the responsible patients in the eCRF. 
The eCRF should be filled out for each randomized patient. 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. 
It must be clarified in source documents that prove eCRF data that patients have participated 
in the study. In addition, study procedure, AE, other observation results, date of patient status 
and detailed information should be recorded. 
The investigator or designated representative should fill out eCRF as soon as possible after 
collecting information. 
Audit tracing results will show identification information of users and any changed date and 
time. The eCRF should be signed by investigator in an electronic form to prove data in the 
eCRF (including any changes in the eCRF) are correct, which will be used to support the final 
data admitted by the patients charged by the investigator. 
A completed 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 
personnel of the sponsor or relevant regulatory authority. 
11.2. 
Recording storage 
To make it convenient for regulatory authorities or the sponsor to carry out assessment and/or 
review, investigator must agree to retain the identity (including adequate connective 
information of records, e.g., the connect between an eCRF and hospital record) of all patients, 
all original signed ICFs, eCRF, SAE forms,source documents, detailed records of treatment 
management and relevant correspondence proof documents (e.g., letters, minutes and 
telephone reports). The investigator should retain records according to ICH, local regulations 
or regulations in the clinical study protocol, whichever is longer. 
If the investigator cannot keep study archives to the specified time limit for some reasons (such 
as retirement and transfer), it is necessary to notify the sponsor in advance. Study records 
should be transferred to the acceptable personnel designated by the sponsor, e.g., another 
investigator, other institutions or the sponsor. The investigator should obtain written 
permission of the sponsor before destroying any records, even if the retention timeline has 
passed. 
12. 
Ethics 
12.1. 
Ethical implementationof the study 


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The study will be carried out according to “ethical principles for medical research involving 
human subject” in the Declaration of Helsinki of World Medical Association[26]. 
In addition, the study will be conducted according to the study protocol and ICH GCP. 
12.2. 
Subject information and informed consent 
All parties involved should ensure to protect patients’ personal data and not disclose patients’ 
name in any forms, reports, publications or any other disclosure of the sponsor, unless 
otherwise required by laws. The sponsor should keep high-standard confidentiality and 
protection of patients’ individual data during data transmission. 
ICF must comply with ICH GCP requirements. 
ICF used in this study and any changes during the study should obtain prospective approval 
before use of the IRB/IEC and the sponsor. 
The investigator should ensure each study patient fully understands property and objectives of 
the study as well as possible risks of participation in the study. The investigator or personnel 
designated by the investigator must obtain written informed consent document of each patient 
before carrying out any specific activities of the study. The investigator must keep a original 
copy of the signed ICF of each patient. 
12.3. 
IRB/IEC 
The investigator has the responsibility to obtain the prospective approval from IRB/IEC of 
study protocol, protocol amendment, ICF and other related documents (e.g., recruitment 
advertisement, if applicable) in advance. All correspondences with IRB/IEC should be kept in 
investigator's study site file. 
Amendment can be implemented before obtaining IRB/IEC approval only when it is necessary 
to eliminate obvious direct harm to patients. In such case, the investigator should notify the 
IRB/IEC and the sponsor in written immediately after implementation. 
12.4. 
Keeping confidentiality for patient 
The sponsor and personnel designated by the sponsor confirm and maintain the patients’ 
privacy right from being violated. 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 follow the requirements of ICH GCP and confirm the compliance of the protocol, 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/IEC to review patients’ original medical record (source data or document), including but 


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not limited to any gene/genome data at testing before patients were enrolled into the 
investigation, laboratory test result reports, ECG reports, patients' admittance and discharge 
summary generated during hospitalization while participating in the investigation as well as 
autopsy reports. 
Some personal identity information (that is, name of patient, address and other identifiers not 
collected in the patient’s eCRF) should be deleted from copies of any patient-sourced 
documents supplied to the sponsor. 
12.5. 
Report of safety issues or conditions seriously violating the study 
protocol or Good Clinical Practice of ICH 
If the applicable competent authority issues any prohibition or order (that is, order to suspend 
the clinical study) to the study or if the investigator is informed of any new information that 
may influence risk/benefit analysis of the study drug, it is necessary to notify the sponsor 
immediately. 
In addition, when the investigator takes any emergent safety measures to protect patients from 
suffering any immediate danger and finds any behaviors seriously violating the study protocol 
or ICH GCP, it is necessary to notify the sponsor immediately. 
13. 
Termination of study 
If the sponsor has learned about information of quality, efficacy and safety of the study drug 
and other important information that may influence the correct conduct of the clinical study, 
the sponsor may discontinue the clinical study and send a written notice to the investigator to 
notify study discontinuation and reasons for discontinuation. 
If the investigator wishes to discontinue participation in the study, the sponsor must be 
informed immediately and the reason for discontinuation must be informed. 


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13.1. 
Criteria for suspension or premature termination of the study 
Criteria for suspension or premature termination of the study include: 
1. Obtaining new information of safety or efficacy of the study drug indicates that the known 
risk/benefit characteristics of the compound have changed and are not suitable for patients 
taking part in the study. 
2. Seriously violate GCP and damage the ability to realize the primary objective or threaten 
patients’ safety. 
3. The sponsor may suspend or prematurely terminate the study for reasons unrelated to the 
conduct of 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 and agreement or is unable to ensure normal conduct of the study, the participation of 
the study site in this investigation may be prematurely terminated or suspended. 
13.3. 
Procedures for early termination or suspension of the study or 
participation of study site 
If the sponsor chooses to terminate or suspend the study or participation of study site, the 
sponsor will provide a specific procedure for premature termination or suspension. Applicable 
study sites will comply with the procedures during study termination or suspension. 
14. 
Publication of research results 
Zai Lab (Shanghai) Co., Ltd., as the sponsor, has exclusive rights to this study. The author and 
manuscript 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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Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, et al. 
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Kee D, Zalcberg JR. Current and emerging strategies for the management of imatinib-
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KIT hyperactivation in imatinib-resistant GIST: implications for salvage therapies. 
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in the Phase 1 Study of DCC-2618. Abstract# 11511, American Society for Clinical 
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003 
 
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16. 
Appendix 
16.1. 
“RECIST v1.1-GIST-specific Criteria” response Evaluation 
Criteria In Solid Tumours  
“RECIST v1.1-GIST-specific Criteria” include: 
• 
No lymph nodes chosen as target lesions; enlarged lymph nodes will be followed as 
non-target lesions. 
• 
No bone lesions chosen as target lesions; 
• 
Positron emission tomography (PET) not acceptable for radiological evaluation;  
• 
A progressively growing new tumor nodule within a pre-existing 
tumor mass must meet the following criteria to be considered as 
unequivocal evidence of progression according to the modification 
of RECIST Version 1.1: (a) the lesion is at least 2 cm in size and 
definitively a new active GIST lesion (e.g. enhancing with contrast 
or other criteria to rule out artefact); or (b) the lesion has to be 
expanding on at least 2 sequential imaging studies. 
 
From: 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).