Conditions: Gastrointestinal Stromal Tumors
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 129
Healthy volunteers: no

Brief summary:
This is a 2-arm, randomized, placebo-controlled, double-blind, international, multicenter study comparing the efficacy of ripretinib (DCC-2618) to placebo in patients who have received treatment with prior anticancer therapies. Prior anticancer therapies must include imatinib, sunitinib, and regorafenib (3 prior therapies). Approximately 120 patients were randomized in a 2:1 ratio to ripretinib 150 mg QD or placebo

Detailed description:

Arms:
arm 1: 150 mg QD DCC-2618 arm 2: Placebo

Interventions: intervention 1: DCC-2618 intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Oral KIT/PDGFRA kinase inhibitor intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
Protocol DCC-2618-03-001 (INVICTUS) 
A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to Assess the Safety 
and Efficacy of DCC-2618 In Patients with AdvanCed Gastrointestinal Stromal TUmorS 
who have Received Treatment with Prior Anticancer Therapies 
NCT Number: 03353753 
Document Date: Amendment 5 (30 October 2018) 


Deciphera Pharmaceuticals, LLC. 
CONFIDENTIAL 
Page 1 of 97 
CLINICAL STUDY PROTOCOL 
Protocol DCC-2618-03-001 (invictus) 
A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to 
Assess the Safety and Efficacy of DCC-2618 In Patients with AdvanCed 
Gastrointestinal Stromal TUmorS who have Received Treatment with 
Prior Anticancer Therapies  
This study will be conducted according to the protocol and in compliance with  
Good Clinical Practice, the ethical principles stated in the Declaration of Helsinki,  
and other applicable regulatory requirements. 
Study Sponsor: 
Deciphera Pharmaceuticals, LLC 
Headquarters: 
500 Totten Pond Road, 6th Floor 
Waltham, MA 02451 
Phone: 
Fax: 
Research Facility: 
643 Massachusetts St., Suite 200 
Lawrence, KS 66044 
Phone: 
Fax: 
IND Number: 
125279 
EudraCT: 
2017-002446-76 
Document Version (Date): 
Original (10 AUG 2017) 
Amendment 1 (07 NOV 2017) 
Amendment 2 (01 MAR 2018) 
Amendment 3 (22 MAR 2018) 
Amendment 4 (27 AUG 2018) 
Amendment 5 (30 OCT 2018) 
164
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PI
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Clinical Study Protocol DCC-2618-03-001, Amendment 5 
SPONSOR SIGNATURE 
Deciphera Pharmaceuticals, LLC. 
CONFIDENTIAL 
30 OCT2018 
 o ocd(Jtp,r ?to I
 
Date 
Page 2 of97 
165
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INVESTIGATOR STATEMENT 
I understand that all documentation provided to me by Deciphera Pharmaceuticals, LLC or its 
designated representative(s) concerning this study that has not been published previously will be kept 
in the strictest confidence. This documentation includes the study protocol, Investigator brochure, case 
report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted Institutional 
Review Board/Independent Ethics Committee/Research Ethics Board. No changes will be made to the 
study protocol without the prior written approval of Deciphera Pharmaceuticals, LLC and the 
Institutional Review Board, except where necessary to eliminate an immediate hazard to the patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained in this 
protocol. 
 
Investigator Name 
 
Investigator Signature 
 
Date 
 
 
 
 
 
Name of Investigational Site 
 
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CLINICAL STUDY SYNOPSIS 
Protocol Title: A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to 
Assess the Safety and Efficacy of DCC-2618 In Patients with AdvanCed 
Gastrointestinal Stromal TUmorS who have Received Treatment with Prior 
Anticancer Therapies 
Protocol Number: DCC-2618-03-001 
Protocol Name: Invictus 
Study Phase: 3 
Study Centers: Approximately 35 centers globally 
Number of 
Patients Planned: 
Approximately 120 patients (approximately 80 randomized to DCC-2618 
and approximately 40 randomized to placebo) 
Objectives: Primary Objectives: 
• 
To assess the efficacy (progression-free survival [PFS]) of DCC-2618 by 
independent radiologic review in patients with advanced gastrointestinal 
stromal tumors (GIST) who have received prior therapies 
Key Secondary Objectives: 
• 
To assess objective response rate by independent radiologic review 
Secondary Objectives: 
• 
To assess other parameters of efficacy, including but not limited to time 
to progression (TTP) and overall survival (OS) 
• 
To assess the PD/PK relationship of DCC-2618 
• 
To assess the robustness of efficacy using a sensitivity analysis 
• 
To assess improvement of disease-related symptoms and quality of life 
• 
To assess the safety of DCC-2618 
Exploratory Objectives: 
• 
To assess the efficacy of DCC-2618 in patients after dose escalation to 
DCC-2618 150 mg twice daily (BID) 
• 
To characterize KIT and PDGFRA gene resistance mutations (and 
potentially other gene mutations) and their DCC-2618-driven 
longitudinal mutation allele frequency changes in plasma cell-free DNA 
(cfDNA) 
• 
To retrospectively correlate KIT and PDGFRA mutation/s and/or their 
frequency (as well as of potentially other gene mutations) in baseline 
cfDNA with clinical benefit 
• 
To understand potential tyrosine kinase inhibitor- (TKI) resistance 
mechanisms of GIST at time of progression 
• 
To determine concordance between KIT, PDGFRA, and other mutations 
in tumor and cfDNA at baseline 
• 
To assess healthcare utilization in patients with advanced GIST who 
have received approved therapies 
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Study Design: This is a 2-arm, randomized, placebo-controlled, double-blind, international, 
multicenter study comparing the efficacy of DCC-2618+best supportive care 
(hereafter referred to as “DCC-2618”) to placebo+best supportive care 
(hereafter referred to as “placebo”) in patients with advanced gastrointestinal 
stromal tumors (GIST) who have received treatment with prior anticancer 
therapies. Prior anticancer therapies must include treatment with imatinib, 
sunitinib, and regorafenib (3 prior therapies). Up to 40% of enrolled patients 
may have received prior treatment with imatinib, sunitinib, regorafenib, and 
other drugs (≥4 prior therapies). Approximately 120 patients will be 
randomized in a 2:1 ratio to DCC-2618 150 mg once daily (QD) or placebo 
(see Figure 1). Randomization will be stratified by: 
• 
Patients who have received 3 prior anticancer treatments versus patients 
who have received ≥4 prior anticancer treatments  
o It should be noted that enrollment for patients who have received 
≥4 prior anticancer treatments will be limited to 40% of the overall 
sample size. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
(PS)=0 versus ECOG PS=1 or 2  
The primary response for the study will be evaluated using the modified 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - 
GIST-specific (hereafter referred to as “modified RECIST”) based on 
independent radiologic review. 
Upon disease progression by modified RECIST based on independent 
radiologic review, study drug treatment will be unblinded. At that time:  
• 
Patients randomized to DCC-2618 150 mg QD will be given the 
option to:  
o continue DCC-2618 at an increased dose of 150 mg BID, or  
o continue treatment on study with the same dose if the Investigator 
feels the patient is receiving benefit from DCC-2618 or if dose 
escalation may not be tolerable for the patient (dose escalation is not 
permitted at a later time during the study), or 
o discontinue DCC-2618. 
• 
Patients randomized to placebo will be given the option to:  
o cross over to receive DCC-2618 150 mg QD, or 
o discontinue the study. 
Patients randomized to placebo who cross over to receive DCC-2618 
150 mg QD and have disease progression by modified RECIST based on 
Investigator assessment will be given the option to: 
o continue DCC-2618 at an increased dose of 150 mg BID, or 
o continue treatment on study with the same DCC-2618 dose if the 
Investigator feels the patient is receiving benefit from DCC-2618 or 
if dose escalation may not be tolerable for the patient (dose 
escalation is not permitted at a later time during the study), or 
o discontinue DCC-2618. 
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Study Population: 
Inclusion Criteria 
 
Patients must meet all of the following criteria to be eligible to enroll in the 
study: 
1. Male or female patients ≥18 years of age at the time of informed consent 
2. Histologic diagnosis of GIST  
3. Patients must have progressed on imatinib, sunitinib, and regorafenib or have 
documented intolerance to any of these treatments despite dose modifications. 
4. ECOG PS of 0 to 2 at screening. 
5. Able to provide an archival tumor tissue sample if no anticancer therapy was 
administered since the sample was collected; otherwise, a fresh tumor tissue 
sample is required prior to the first dose of study drug. 
6. Female patients of childbearing potential must have a negative serum 
beta-human chorionic gonadotrophin (β-hCG) pregnancy test at screening and a 
negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug. 
7. Patients of reproductive potential must agree to follow the contraception 
requirements outlined in Section 6.11.10. 
8. The patient is capable of understanding and complying with the protocol and 
has signed the informed consent document. A signed informed consent form 
must be obtained before any study-specific procedures are performed. 
9. At least 1 measurable lesion according to modified RECIST Version 1.1 
(non-nodal lesions must be ≥1.0 cm in the long axis or ≥double the slide 
thickness in the long axis) within 21 days prior to the first dose of study drug. 
10. Adequate organ function and bone marrow reserve as indicated by the following 
laboratory assessments performed at screening. 
• 
Absolute neutrophil count ≥1000/µL 
• 
Hemoglobin ≥8 g/dL 
• 
Platelet count ≥75,000/µL 
• 
Total bilirubin ≤1.5 x the upper limit of normal (ULN) 
• 
Aspartate transaminase and alanine transaminase ≤3 x ULN (≤5x ULN in 
the presence of hepatic metastases)  
• 
Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min based on 
either urine collection or Cockcroft Gault estimation.  
• 
Prothrombin time (PT), international normalized ratio (INR), and partial 
thromboplastin time ≤1.5 x 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 x 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. 
11. 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). 
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Exclusion Criteria Patients meeting any of the following criteria will be excluded from the 
study: 
1. Treatment with anticancer therapy, including investigational therapy, or 
investigational procedures within 14 days or 5 x the half-life (whichever is 
longer) prior to the first dose of study drug. For prior biological therapies, eg, 
monoclonal antibodies with a half-life longer than 3 days, the interval must be 
at least 28 days prior to the first dose of study drug. 
2. Prior treatment with DCC-2618 
3. Prior or concurrent malignancy whose natural history or treatment have the 
potential to interfere with the safety or efficacy assessment of DCC-2618. 
Patients receiving adjuvant cancer treatment are not eligible if those 
medications are potentially active against GIST or excluded per protocol (refer 
to Section 5.12.3). 
4. Patient has known active central nervous system metastases. 
5. New York Heart Association class II - IV heart disease, active ischemia or any 
other uncontrolled cardiac condition such as angina pectoris, clinically 
significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or 
congestive heart failure. 
6. Arterial thrombotic or embolic events such as cerebrovascular accident 
(including ischemic attacks) or hemoptysis within 6 months before the first dose 
of study drug. 
7. Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial 
events (eg, pulmonary embolism) within 3 months before the first dose of study 
drug. Patients with venous thrombotic events ≥3 months before the first dose of 
study drug on stable anticoagulation therapy are eligible. 
8. 12-lead electrocardiogram (ECG) demonstrating QT interval corrected by 
Fridericia’s formula >450 ms in males or >470 ms in females at screening or 
history of long QT interval corrected syndrome. 
9. Left ventricular ejection fraction (LVEF) <50% at screening. 
10. Use of proton-pump inhibitors within 4 days prior to the first dose of study 
drug. Other medications that increase gastric pH, ie, histamine H2 receptor 
antagonists and antacids may be taken provided they are not administered 
within 2 hours before or after administration of study drug. 
11. Use of strong or moderate inhibitors and inducers of cytochrome P450 (CYP) 
3A4, including certain herbal medications (eg, St. John’s Wort) and 
consumption of grapefruit or grapefruit juice within 14 days or 5 x the half-life 
(whichever is longer) prior to the first dose of study drug. Please refer to the 
Indiana University Department of Medicine website 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) for guidance on 
medications that inhibit CYP3A4 enzymes. 
12. 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. Please refer to the US Food and Drug 
Administration’s (FDA) website 
 
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(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResour
ces/DrugInteractionsLabeling/ucm093664.htm) for inhibitors and substrates. 
13. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of 
study drug. Following major surgeries, >4 weeks prior to the first dose of study 
drug, all surgical wounds must be healed and free of infection or dehiscence.  
14. 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. 
15. Known human immunodeficiency virus or hepatitis C infection only if the 
patient is taking medications that are excluded per protocol (refer to 
Section 5.12.3), active hepatitis B, or active hepatitis C infection. 
16. If female, the patient is pregnant or lactating. 
17. Known allergy or hypersensitivity to any component of the investigational drug 
product. Patients with a history of Stevens-Johnson syndrome on a prior TKI 
are excluded. 
18. Gastrointestinal abnormalities including but not limited to: 
• 
inability to take oral medication 
• 
malabsorption syndromes 
• 
requirement for intravenous alimentation. 
19. Any active bleeding excluding hemorrhoidal or gum bleeding. 
Study Drug: DCC-2618 or matching placebo 
Formulation: Tablets 
Dose: 
Route of 
Administration: 
150 mg QD or 0 mg QD 
Oral 
Study Endpoints: Primary Endpoint: 
PFS based on independent radiologic review using modified RECIST (1; 
Appendix 17.1). Modified RECIST criteria includes: 
• 
No lymph nodes chosen as target lesions; enlarged lymph nodes 
followed as non-target lesions;  
• 
No bone lesions chosen as target lesions;   
• 
Positron emission tomography 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 (eg, 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. 
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Key Secondary Efficacy Endpoint: 
• 
Objective response rate (confirmed CR + confirmed PR) 
 
Secondary Efficacy Endpoints: 
• 
TTP based on independent radiologic review 
• 
OS 
• 
Time to best response 
• 
PFS based on Investigator assessment 
• 
Quality of life as determined by changes from baseline in European 
Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire for Cancer 30-item and EuroQol 5-Dimension 5-Level 
• 
Disease control rate (complete response [CR] + partial response [PR] + 
stable disease) at 12 weeks 
 
Safety: 
Treatment-emergent adverse events, adverse events of special interest, 
serious adverse events, dose reduction or discontinuation of study drug due 
to toxicity; and changes from baseline in ECOG PS, vital signs, ECGs, 
LVEF, dermatologic examinations, and clinical laboratory parameters. 
 
Pharmacokinetics (PK): 
• 
Correlation of PK with efficacy/safety 
• 
Population PK 
 
Exploratory Endpoints: 
Efficacy: 
• 
PFS by Investigator assessment after dose escalation to DCC-2618 
150 mg BID 
Biomarkers and Pharmacodynamics: 
• 
Type and burden of mutations in plasma cfDNA 
• 
Treatment effect of DCC-2618 on cfDNA mutation allele frequency 
• 
Potential TKI-resistance mechanisms of GIST at time of progression 
• 
Concordance between KIT, PDGFRA and other mutations in tumor and 
cfDNA 
Healthcare Utilization: 
• 
Changes over time in healthcare utilization 
Statistical 
Considerations: 
• 2:1 randomization to DCC-2618 versus placebo  
• Primary endpoint is PFS based on independent radiologic review 
• Total sample size of approximately 120 patients (approximately 80 
patients randomized to DCC-2618,  and approximately 40 patients 
randomized to placebo) is expected to have at least 90% power assuming: 
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• 
9 months of recruitment and 6 additional months of follow-up (total 
study duration of 15 months)  
• 
A two-sided 5% significance level in testing the hypothesis of no 
difference between DCC-2618 and placebo. 
• 
Assumes a 15% dropout rate 
Independent Data 
Monitoring 
Committee: 
An independent data monitoring committee will monitor the safety data from 
this study on a periodic basis to help ensure the ongoing safety of study 
patients. 
Duration of 
Study: 
Patients will be treated on their assigned arm until they develop progressive 
disease, experience unacceptable toxicity, or withdraw consent. At the time 
of progressive disease by modified RECIST based on independent radiologic 
review and following unblinding of study drug treatment, patients receiving 
DCC-2618 will be allowed to dose escalate, continue on the same dose, or 
discontinue DCC-2618; and patients receiving placebo will be allowed to 
cross over to receive DCC-2618 and can dose escalate, continue on the same 
dose, or discontinue DCC-2618 upon further progression by Investigator 
assessment. 
Patients will be eligible to receive study drug for up to 2 years or until 
commercial supply of the drug is available. This will be extended by 
agreement between the Sponsor and Investigator for patients who exhibit 
evidence of clinical benefit and tolerability to the drug, and who adhere to 
the study procedures. The study will end following the last patient last visit. 
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Figure 1: 
Study Schema 
 
NOTE: Patients will be randomized ONLY at the start of the study. Following disease progression by independent radiologic review/unblinding, the 
decision on how to proceed in the study will be by patient choice.  
 
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Table 1: 
Schedule of Assessments 
Assessments / Procedures1 
Screening2 
Cycle 1 
Cycles ≥2 
EOT Visit 
(within 
7 days after 
last dose) 
Safety 
Follow Up 
Overall 
Survival  
Follow Up3 
(±1 month) 
Cycle Day 
-28 to -1 
1 
(Baseline) 
15  
(±1 day) 
1  
(±3 days) 
30 Days Post 
Last Dose 
(+5 days) 
Site Visit 
X 
X 
X 
X 
X 
 
 
Phone Call 
 
 
 
 
 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical and Cancer History 
X 
 
 
 
 
 
 
Prior Medications/Procedures4 
X 
 
 
 
 
 
 
Pregnancy Test5 
X 
X 
 
X 
X 
 
 
Randomization6 
 
X 
 
 
 
 
 
Clinical Laboratory Tests 
 
Hematology 
X 
X 
X 
X 
X 
 
 
Serum Chemistries 
X 
X 
X 
X 
X 
 
 
Coagulation7 
X 
X 
X7 
X 
X 
 
 
Urinalysis8 
X 
 
 
X8 
X 
 
 
Thyroid Testing (TSH, Free T3, Free T4) 
 
X 
 
 
 
 
 
Physical Examination 
X
9 
Examinations will be driven by clinical findings and/or patient complaints 
ECOG PS10 
X 
X 
X 
X 
X 
 
 
Vital Signs and weight11 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
12-lead ECG12 
X 
X 
 
X 
X 
 
 
Echocardiogram/MUGA13 
X 
 
 
X
13 
X 
 
 
Dermatologic Examination14 
X 
 
 
X14 
X 
 
 
Ophthalmologic Examination15 
X 
 
 
 
 
 
 
Adverse Event Reporting 
Continuous from signing informed consent through safety follow up
Concomitant Medications/Procedures 
Continuous from on or after the first day of study drug dose through safety follow up
EORTC-QLQ-C3016 
  
X 
X 
X 
X 
 
 
EQ-5D-5L16 
  
X 
X 
X 
X 
 
 
Healthcare Utilization16 
  
X 
 
X 
X 
 
 
Study Drug Administration17 
 
X 
X 
X 
 
 
 
Study Drug Dispensation18 
 
X 
 
X 
 
 
 
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Assessments / Procedures1 
Screening2 
Cycle 1 
Cycles ≥2 
EOT Visit 
(within 
7 days after 
last dose) 
Safety 
Follow Up 
Overall 
Survival  
Follow Up3 
(±1 month) 
Cycle Day 
-28 to -1 
1 
(Baseline) 
15  
(±1 day) 
1  
(±3 days) 
30 Days Post 
Last Dose 
(+5 days) 
Study Drug Count 
 
 
X 
X 
X 
 
 
PK Sampling19 
 
X 
X 
X
19 
X 
 
 
Pharmacogenomics 
 
X 
 
 
 
 
 
Tumor Tissue Sample20 
X20 
 
 
 
 
 
 
Radiologic Imaging21 
X2 
 
 
X21 
X 
 
 
Biomarker and PD Sampling (Plasma) 22 
 
X 
 
X22 
X 
 
 
CT=computed tomography; ECG=electrocardiogram; ECOG= Eastern Cooperative Oncology Group; EOT=End of treatment; EORTC-QLQ-C30=European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire for Cancer 30-item; EQ-5D-5L= EuroQol 5-Dimension 5-Level; MRI=magnetic resonance imaging, 
MUGA=multigated acquisition; PD=pharmacodynamic; PK=pharmacokinetic; PS=performance status; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating 
hormone 
1. 
All assessments must be performed predose, unless otherwise specified. Additional unscheduled safety or efficacy assessments may be performed at any time as 
clinically indicated to determine the relevance of specific findings and/or the duration of events. 
2. 
Screening must occur within 28 days prior to the first dose of study drug. Radiologic imaging must be performed within 21 days prior to the first dose of study drug. 
Radiologic imaging performed as standard of care prior to informed consent may be used as the Screening assessment as long as the imaging was performed within 21 
days prior to the first dose of study drug. 
3. 
All patients will be followed until withdrawal of consent or death from any cause. After the Safety Follow-Up Visit, patients will be contacted every 3 months 
(±1 month) to collect long-term survival data. 
4. 
Any medication or non-drug therapy or procedure taken or performed within 30 days prior to screening and before the first dose of study drug. 
5. 
A serum pregnancy test will be performed by a central laboratory at screening. Urine pregnancy tests will be performed at all other visits, except Cycle 1 Day 15. Serum 
pregnancy test may be performed instead of urine, if it is the site’s standard practice and results are received prior to the patient being dosed in the clinic. 
6. 
Randomization may occur up to 3 days prior to Cycle 1 Day 1. 
7. 
Patients taking anticoagulants will also have a test at Cycle 1 Day 15. Monitoring of coagulation tests must be increased for as long as deemed clinically appropriate 
following a change in anticoagulant dose during the study. 
8. 
Urinalysis testing will be performed at screening, Day 1 of Cycles 2, 3, and 4, and at the EOT Visit. If any result is abnormal, a microscopic analysis will be performed 
by the central laboratory. 
9. 
A full physical examination as defined in Section 6.11.1 will be performed at screening. 
10. ECOG PS may be performed post dose. 
11. Vital sign measurements will be collected after the patient has been at rest (seated or supine position) for at least 5 minutes. In addition, weight will be collected at each 
visit. 
12. All 12-lead ECGs will be performed after the patient has been at rest (supine or semi-recumbent position) for at least 15 minutes. The rest period begins after the 
placement of the ECG leads. 
13. An echocardiogram or MUGA will only be performed at screening, Cycle 3 Day 1, and every third cycle thereafter (ie, Cycle 6, 9, 12, etc), and the EOT Visit, unless 
deemed clinically appropriate at other times. The same modality (echocardiogram or MUGA) must be used throughout the study. Echocardiogram or MUGA performed 
as standard of care prior to informed consent may be used as the Screening assessment as long as the echocardiogram or MUGA was performed within 28 days prior to 
the first dose of study drug. 
14. All patients will be assessed by a consulting dermatologist for skin lesions, especially for squamous cell carcinoma, actinic keratosis, and keratoacanthomas, within 
21 days prior to Cycle 1 Day 1 (baseline). Subsequently, patients will be assessed at Cycle 3 Day 1 and then every third cycle thereafter (ie, Cycle 6, 9, 12, etc.), at the 
EOT Visit, and as clinically indicated. Dermatologic exam that meets the protocol criteria that was performed as standard of care prior to informed consent may be used 
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as the Screening assessment as long as the exam was performed within 21 days prior to the first dose of study drug. Dermatologic examination may be performed up to 7 
days prior to the corresponding study visit or post dose at the study visit. See Section 6.11.6 for further details. 
15. Ophthalmologic examination will be performed at Screening and if clinically indicated during treatment with study drug. This examination does not have to be repeated 
if there is documentation of an examination that met protocol criteria within 28 days before the Screening Visit and after the last dose of previous anticancer treatment. 
16. The EORTC QLQ-C30 and EQ-5D-5L questionnaires must be performed before the patient sees the Investigator or designee on the day of the scheduled visit. If the 
dermatologic examination or imaging assessments are completed within 7 days of the scheduled visit and the patient does not see the Investigator or designee, the 
questionnaires do not need to be completed on that day. The EORTC QLQ-C30 will be performed prior to the EQ-5D-5L, followed by the Healthcare Utilization 
Questionnaire. Questionnaires are collected via an electronic patient reported outcome system on provided tablet computers. 
17. Patients should be instructed to take the study drug at approximately the same time each day. On days of planned study visits, patients will be informed to take the study 
drug at the study site after predose assessments are completed.   
18. At the time of dose escalation, the patient must come to the site for study drug to be dispensed. 
19. PK sampling will be performed at the following time points: Cycle 1 Day 1 predose and 6 hours after dosing, Cycle 1 Day 15 predose, and 2 and 6 hours after dosing, 
Cycle 2 Day 1 and Cycle 3 Day 1 predose, predose at every other cycle (eg, Cycle 5, 7, etc.), at disease progression, and at the EOT Visit. All predose samples must be 
collected within 60 minutes before dosing and all post dose samples must be collected ±30 minutes of the nominal time point. An unscheduled PK sample may be taken 
at the time of the onset of a new suspected, treatment-related adverse event when requested by the Sponsor. 
20. Archival tumor tissue samples will be collected at screening as long as no anticancer therapy was administered since the sample was collected. Fresh tumor tissue sample 
will only be collected if a patient qualifies for the study based on all other entry criteria and archival tissue is not available or not collected after the last anticancer 
therapy.  
All Patients (optional): Additional tumor tissue samples may be collected for patients undergoing medical procedures including resection of metastases while on study 
or for patients that have disease progression if the patient consents and these samples will be used for further molecular testing of the cancer while treated with study 
drug. 
21. CT scans of the pelvis, abdomen, and chest will be performed at screening (within 21 days of Cycle 1 Day 1). Subsequently, CT scans of the pelvis and abdomen will be 
performed every cycle through and including Cycle 4, and then every other cycle thereafter (ie, Cycle 6, 8, 10, etc.). CT scans of the chest will only be performed 
subsequently if the patient had lung metastases at screening or in case of lung symptoms (per the Investigator’s discretion). Radiologic imaging may be performed up to 
7 days prior to the corresponding study visit or post dose at the study visit. An initial indication of a partial or complete response based on investigator assessment must 
be confirmed ≥4 weeks later. 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. Additionally, for patients whose local regulatory authority and/or ethics committee has not approved use of CT scans, MRIs may be used. Throughout the 
study, the same assessment technique must be used. Ultrasound scanning is not an acceptable substitute for CT scanning. See Section 6.10.1 for further details. 
Confirmation of No Disease Progression: If the independent radiologic reviewer confirms that there is no disease progression, the patient will continue to receive study 
drug unless there is a medical need (ie, rapid progression or clinical deterioration) that requires the study drug to be discontinued. If the Investigator determines 
progression based upon clinical deterioration, a scan must be performed and reviewed by the independent radiologic reviewer to determine if the patient progressed. The 
basis for determination of progression per clinical deterioration must be documented in the patient’s source documents and electronic case report form. 
Disease Progression: Following confirmation of disease progression by modified Response Evaluation Criteria in Solid Tumors based on independent radiologic review, 
the patient's treatment assignment will be unblinded via the Interactive Response Technology system. 
• 
Patients randomized to DCC-2618 150 mg QD will be given the option to continue DCC-2618 at an increased dose of 150 mg twice daily, continue treatment on 
study with the same dose if the Investigator feels the patient is receiving benefit from DCC-2618 or if dose escalation may not be tolerable for the patient (dose 
escalation is not permitted at a later time during the study), or discontinue DCC-2618. At the time of dose escalation, the patient must come to the site for study drug 
to be dispensed. 
• 
Patients randomized to placebo will be given the option to cross over to receive DCC-2618 150 mg once or discontinue the study. Crossover patients must follow 
the schedule of assessments in Table 2. 
22. Biomarker and PD plasma samples will be collected predose at Cycle 1 Day 1 (baseline), every other cycle (ie, Cycle 3, 5, 7, etc.), and at the EOT Visit. 
 
 
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Table 2: 
Schedule of Assessments for Crossover 
CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC-QLQ-C30=European Organisation for Research and Treatment 
of Cancer Quality of Life Questionnaire for Cancer 30-item; EOT=End of treatment; EQ-5D-5L= EuroQol 5-Dimension 5-Level; MRI=magnetic resonance imaging, 
MUGA=multigated acquisition; PD=pharmacodynamic; PK=pharmacokinetic; PS=performance status 
1. 
All assessments must be performed predose, unless otherwise specified. Additional unscheduled safety or efficacy assessments may be performed at any time as clinically 
indicated to determine the relevance of specific findings and/or the duration of events. 
Assessments / Procedures1 
Cycle 1 
Cycles ≥2 
EOT Visit  
(within 7 days after 
last dose) 
Safety Follow Up 
Overall 
Survival  
Follow Up3 
(±1 month) 
Cycle Day 
1 
15  
(±1 day) 
1  
(±3 days) 
30 Days Post Last Dose  
(+5 days) 
Site Visit 
X 
X 
X 
X 
 
 
Phone Call 
 
 
 
 
X 
X 
Pregnancy Test4 
X 
 
X 
X 
 
 
Clinical Laboratory Tests 
 
Hematology 
X2 
X 
X 
X 
 
 
Serum Chemistries 
X2 
X 
X 
X 
 
 
Coagulation5 
X2 
X5 
X 
X 
 
 
Urinalysis6 
X2 
 
X6 
X 
 
 
Physical Examination 
Examinations will be driven by clinical findings and/or patient complaints 
ECOG PS7 
X2 
X 
X 
X 
 
 
Vital Signs and weight8 
X2 
X 
X 
X 
 
 
12-lead ECG9 
X2 
 
X 
X 
 
 
Echocardiogram/MUGA10 
X2 
 
X
10 
X 
 
 
Dermatologic Examination11 
X2 
 
X
11 
X 
 
 
Ophthalmologic Examination 
Examinations will be performed if clinically indicated 
Adverse Event Reporting 
Continuous through Safety Follow Up
Concomitant Medications/Procedures 
Continuous through Safety Follow Up
EORTC-QLQ-C3012 
X2 
X 
X 
X 
 
 
EQ-5D-5L12 
X2 
X 
X 
X 
 
 
Healthcare Utilization12 
X2 
 
X 
X 
 
 
Study Drug Administration13 
X 
X 
X 
 
 
 
Study Drug Dispensation14 
X 
 
X 
 
 
 
Study Drug Count 
 
X 
X 
X 
 
 
PK Sampling15 
X 
X 
X
15 
X 
 
 
Tumor Tissue Sample (Optional)16  
Additional tumor tissue samples may be collected through EOT  
Radiologic Imaging17 
 
 
X17 
X 
 
 
Biomarker and PD Sampling (Plasma)18 
X2 
 
X18 
X 
 
 
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2. 
If the patient had an assessment/procedure at the cycle visit when they progressed, then the assessment/procedure does not need to be performed at the Cycle 1 Day 1 
Visit. 
3. 
All patients will be followed until withdrawal of consent or death from any cause. After the Safety Follow-Up Visit, patients will be contacted every 3 months (±1 month) 
to collect long-term survival data. 
4. 
Urine pregnancy tests will be performed at all visits, except Cycle 1 Day 15. Serum pregnancy test may be performed instead of urine, if it is the site’s standard practice 
and results are received prior to the patient being dose in the clinic. 
5. 
Patients taking anticoagulants will also have a test at Cycle 1 Day 15. Monitoring of coagulation tests must be increased for as long as deemed clinically appropriate 
following a change in anticoagulant dose during the study. 
6. 
Urinalysis testing will be performed at Day 1 of Cycles 1, 2, 3 and 4, and at the EOT Visit. If any result is abnormal, a microscopic analysis will be performed by the 
central laboratory. 
7. 
ECOG PS may be performed post dose. 
8. 
Vital sign measurements will be collected after the patient has been at rest (seated or supine position) for at least 5 minutes. In addition, weight will be collected at each 
visit.  
9. 
All 12-lead ECGs will be performed after the patient has been at rest (supine or semi-recumbent position) for at least 15 minutes. The rest period begins after the 
placement of the ECG leads. 
10. An echocardiogram or MUGA will only be performed at Cycle 1 Day 1, Cycle 3 Day 1, every third cycle thereafter (ie, Cycle 6, 9, 12, etc.) and the EOT Visit, unless 
deemed clinically appropriate at other times. The same modality (echocardiogram or MUGA) must be used throughout the study. 
11. All patients will be assessed, within 7 days of the scheduled visit or post dose on the day of the visit, by a consulting dermatologist for skin lesions, especially for 
squamous cell carcinoma, actinic keratosis, and keratoacanthomas at Cycle 1 Day 1, Cycle 3 Day 1 and then every third cycle thereafter (ie, Cycle 6, 9, 12, etc.), at the 
EOT Visit, and as clinically indicated. See Section 6.11.6 for further details. Note: If the patient had a recent dermatologic examination in the cycle when they 
progressed, then a dermatologic examination does not need to be performed at the Cycle 1 Day 1 visit. 
12. The EORTC QLQ-C30 and EQ-5D-5L questionnaires must be performed before the patient sees the Investigator or designee on the day of the scheduled visit. If the 
dermatologic examination or imaging assessments are completed within 7 days of the scheduled visit and the patient does not see the Investigator or designee, the 
questionnaires do not need to be completed on that day. The EORTC QLQ-C30 will be performed prior to the EQ-5D-5L, followed by the Healthcare Utilization 
Questionnaire. Questionnaires are collected via an electronic patient reported outcome system on provided tablet computers. 
13. Patients should be instructed to take study drug at approximately the same time each day. On days of planned study visits, patients will take the study drug at the study site 
after predose assessments are completed. 
14. At the time of dose escalation, the patient must come to the site for study drug to be dispensed. 
15. PK sampling will be performed at the following time points: Cycle 1 Day 1 predose and 6 hours after dosing, Cycle 1 Day 15 predose, and 2 and 6 hours after dosing, 
Cycle 2 Day 1 and Cycle 3 Day 1 predose, predose at every other cycle (eg, Cycle 5, 7, etc.), at disease progression, and at the EOT Visit. All predose samples must be 
collected within 60 minutes before dosing and all post dose samples must be collected ±30 minutes of the nominal time point. An unscheduled PK sample may be taken at 
the time of the onset of a new suspected, treatment-related adverse event when requested by the Sponsor. 
16. All Patients (optional): Additional tumor tissue samples may be collected for patients undergoing medical procedures including resection of metastases while on study or 
for patients that have disease progression if the patient consents and these samples will be used for further molecular testing of the cancer while treated with study drug. 
17. CT scans of the pelvis and abdomen will be performed every other cycle. CT scans of the chest will only be performed subsequently if the patient had lung metastases at 
screening or in case of lung symptoms (per the Investigator’s discretion). Radiologic imaging may be performed up to 7 days prior to the corresponding study visit or post 
dose at the study visit. An initial indication of a partial or complete response based on investigator assessment must be confirmed ≥4 weeks later. 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. Additionally, for patients whose local 
regulatory authority and/or ethics committee has not approved use of CT scans, MRIs may be used. Throughout the study, the same assessment technique must be used. 
Ultrasound scanning is not an acceptable substitute for CT scanning. See Section 6.10.1 for further details. 
Disease Progression: Following confirmation of disease progression by modified Response Evaluation Criteria in Solid Tumors based on Investigator review, patients 
will be given the option to continue DCC-2618 at an increased dose of 150 mg twice daily according to the rules in Section 5.2.1, continue DCC-2618 at the same dose if 
the Investigator feels the patient is receiving benefit from DCC-2618 or if dose escalation may not be tolerable for the patient (dose escalation is not permitted at a later 
time during the study), or discontinue DCC-2618. At the time of dose escalation, the patient must come to the site for study drug to be dispensed. 
18. Biomarker and PD plasma samples will be collected predose at Cycle 1 Day 1, every other cycle (ie, Cycle 3, 5, 7, etc.), and at the EOT Visit. 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AML 
Acute myeloid leukemia 
ASM 
Aggressive systemic mastocytosis 
ATP 
Adenosine triphosphate 
AUC 
Area under the concentration-time curve 
AUC0-24 
Area under the concentration-time curve during 24 hours 
β-hCG 
Beta-human chorionic gonadotropin 
BCRP 
Breast cancer resistance protein 
BID 
Twice daily 
BP 
Blood pressure 
BSEP 
Bile salt export pump 
cfDNA 
Cell-free DNA 
Cmax 
Maximum observed concentration 
CMH 
Cochran Mantel-Haenszel 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CT 
Computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EORTC 
European Organisation for Research and Treatment of Cancer 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire for Cancer 30 item 
EOT 
End of Treatment 
ePRO 
Electronic patient reported outcome 
EQ-VAS 
EuroQol visual analogue scale 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level 
ER 
Efflux ratio 
FDA 
Food and Drug Administration 
FDG-PET 
18F-Fluorodeoxyglucose positron emission tomography 
FSH 
Follicle stimulating hormone 
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fu 
Fraction unbound 
GBM 
Glioblastoma multiforme 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GIST 
Gastrointestinal stromal tumor 
GLP 
Good Laboratory Practice 
HCUQ 
Healthcare Utilization Questionnaire 
HDPE 
High density polyethylene 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IC50 
Half maximal inhibitory concentration 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent To Treat 
IV 
Intravenous 
KM 
Kaplan-Meier 
LVEF 
Left ventricular ejection fraction 
MAF 
Mutation allele frequency 
MDR1 
Multidrug resistance protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition 
NADPH 
Nicotinamide adenine dinucleotide phosphate 
NCI 
National Cancer Institute 
NGS 
Next generation sequencing 
NOAEL 
No observed adverse effect level 
OAT 
Organic anion transporter 
OCT 
Organic cation transporter 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PMR 
Partial metabolic response 
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PP 
Per protocol 
PR 
Partial response 
PS 
Performance status 
PT 
Prothrombin time 
QD 
Once daily 
QOL 
Quality of life 
QTc 
QT interval corrected 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected by Fridericia’s formula 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SM 
Systemic mastocytosis 
SOC 
System organ class 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
Tmax 
Time to maximum observed concentration 
TSH 
Thyroid Stimulating Hormone 
TTP 
Time to tumor progression 
T1/2 
Half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
ULN 
Upper limit of normal 
WCT PVG 
Worldwide Clinical Trials Pharmacovigilance 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE ......................................................................25 
1.1. 
Introduction ............................................................................................................25 
1.2. 
Clinical Indications ................................................................................................26 
1.3. 
Study Drug .............................................................................................................27 
1.3.1. 
Nonclinical Experience ....................................................................................27 
1.3.2. 
Clinical Experience ..........................................................................................31 
1.4. 
Rationale ................................................................................................................35 
1.4.1. 
Study Rationale ................................................................................................35 
1.4.2. 
Dose, Regimen, and Treatment Duration Rationale ........................................36 
2. 
STUDY OBJECTIVES ................................................................................................40 
2.1. 
Primary Objective ..................................................................................................40 
2.2. 
Secondary Objectives.............................................................................................40 
2.2.1. 
Key Secondary Objectives ...............................................................................40 
2.2.2. 
Secondary Objectives.......................................................................................40 
2.3. 
Exploratory Objectives ..........................................................................................40 
3. 
STUDY DESIGN.........................................................................................................41 
3.1. 
Overview of Study Design .....................................................................................41 
3.2. 
Number of Patients ................................................................................................42 
3.3. 
Duration of Study ...................................................................................................42 
4. 
STUDY POPULATION ..............................................................................................43 
4.1. 
Inclusion Criteria ...................................................................................................43 
4.2. 
Exclusion Criteria ..................................................................................................44 
5. 
STUDY DRUG ADMINISTRATION AND MANAGEMENT .................................46 
5.1. 
Study Drug Description .........................................................................................46 
5.2. 
Study Drug Dose and Administration ....................................................................46 
5.2.1. 
Intra-patient Dose Escalation ...........................................................................47 
5.2.2. 
Crossover .........................................................................................................47 
5.3. 
Dose Interruption and Modification.......................................................................47 
5.3.1. 
Dose Interruption due to Planned Medical Procedures....................................47 
5.3.2. 
Dose Interruption and Modification Due to Toxicity ......................................48 
5.4. 
Packaging and Labeling .........................................................................................52 
5.5. 
Storage Conditions .................................................................................................52 
5.6. 
Study Drug Compliance .........................................................................................52 
5.7. 
Study Drug Accountability ....................................................................................52 
5.8. 
Disposal, Return, or Retention of Unused Study Drug ..........................................53 
5.9. 
Method of Assigning Patients to Treatment ..........................................................53 
5.10. 
Blinding and Unblinding........................................................................................53 
5.10.1. 
Blinding............................................................................................................53 
5.11. 
Unblinding .............................................................................................................54 
5.12. 
Prior and Concomitant Treatment and Procedures ................................................54 
5.12.1. 
Prior Medications and Procedures ...................................................................54 
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5.12.2. 
Prior Anticancer Medications and Procedures .................................................54 
5.12.3. 
Concomitant Medications ................................................................................54 
5.12.4. 
Concomitant Procedures ..................................................................................56 
5.13. 
Other Precautions ...................................................................................................56 
6. 
STUDY ASSESSMENTS ...........................................................................................57 
6.1. 
Screening................................................................................................................57 
6.2. 
Rescreening ............................................................................................................57 
6.3. 
Treatment Period ....................................................................................................57 
6.4. 
Follow Up ..............................................................................................................57 
6.5. 
Lost to Follow Up ..................................................................................................57 
6.6. 
Study Assessments .................................................................................................57 
6.6.1. 
Timing of Assessment......................................................................................58 
6.7. 
Informed Consent Procedure .................................................................................58 
6.8. 
Assigning Patient Number .....................................................................................58 
6.9. 
Demographics and Medical History ......................................................................58 
6.10. 
Efficacy ..................................................................................................................59 
6.10.1. 
Radiologic Imaging ..........................................................................................59 
6.10.2. 
Overall Survival Follow-Up by Phone Call .....................................................60 
6.10.3. 
Patient Reported Outcome Measurements .......................................................60 
6.11. 
Safety .....................................................................................................................61 
6.11.1. 
Physical Examinations .....................................................................................61 
6.11.2. 
Eastern Cooperative Oncology Group Performance Status .............................61 
6.11.3. 
Vital Signs, and Weight and Height ................................................................61 
6.11.4. 
Electrocardiograms ..........................................................................................62 
6.11.5. 
Echocardiograms/Multigated Acquisition Scans .............................................62 
6.11.6. 
Dermatologic Examination ..............................................................................62 
6.11.7. 
Ophthalmologic Examination ..........................................................................63 
6.11.8. 
Clinical Laboratory Tests .................................................................................63 
6.11.9. 
Pregnancy Test .................................................................................................64 
6.11.10. 
Contraception and Pregnancy Avoidance Measures ........................................65 
6.11.11. 
Adverse Events ................................................................................................67 
6.11.12. 
Safety Follow Up .............................................................................................67 
6.12. 
Pharmacokinetics ...................................................................................................67 
6.12.1. 
Sample Collection ............................................................................................67 
6.12.2. 
Sample Assessment ..........................................................................................67 
6.13. 
Biomarkers and Pharmacodynamics ......................................................................68 
6.13.1. 
Sample Collection ............................................................................................68 
6.13.2. 
Sample Assessments ........................................................................................68 
6.14. 
Pharmacogenomic Measurements .........................................................................68 
6.14.1. 
Sample Collection ............................................................................................68 
6.14.2. 
Sample Assessment ..........................................................................................68 
6.15. 
Healthcare Utilization ............................................................................................68 
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6.15.1. 
Healthcare Utilization Questionnaire (HCUQ) ................................................68 
7. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT DOCUMENTATION, 
SEVERITY GRADING, AND REPORTING .......................................................70 
7.1. 
Adverse Events ......................................................................................................70 
7.2. 
Severity Assessment ..............................................................................................70 
7.3. 
Causality Assessment.............................................................................................71 
7.4. 
Study Drug Action Taken ......................................................................................71 
7.5. 
Adverse Event Outcome ........................................................................................71 
7.6. 
Treatment Given ....................................................................................................72 
7.7. 
Additional Points to Consider for Adverse Events ................................................72 
7.7.1. 
Clinically Significant Assessments ..................................................................72 
7.8. 
Serious Adverse Events .........................................................................................73 
7.9. 
Adverse Events of Special Interest ........................................................................73 
7.10. 
Adverse Event Reporting Periods ..........................................................................74 
7.11. 
Adverse Event, Serious Adverse Event, and Adverse Event of Special Interest 
Reporting Requirements ........................................................................................74 
7.12. 
Abuse, Misuse, Overdose, and Medication Error ..................................................74 
8. 
WITHDRAWAL AND REPLACEMENT OF PATIENTS ........................................76 
8.1. 
Withdrawal of Patients ...........................................................................................76 
8.2. 
Replacement of Patients .........................................................................................76 
9. 
STATISTICAL CONSIDERATIONS.........................................................................77 
9.1. 
Determination of Sample Size ...............................................................................77 
9.2. 
Analysis Endpoints ................................................................................................77 
9.2.1. 
Primary Endpoint .............................................................................................77 
9.2.2. 
Secondary Endpoints .......................................................................................77 
9.2.3. 
Exploratory Endpoints .....................................................................................78 
9.3. 
Populations for Analysis ........................................................................................78 
9.4. 
Procedures for Handling Missing, Unused, and Spurious Data.............................79 
9.5. 
Interim Analyses ....................................................................................................80 
9.6. 
Adjustment for Multiple Comparisons ..................................................................80 
9.7. 
Blinding..................................................................................................................80 
9.8. 
Statistical Methods .................................................................................................80 
9.8.1. 
General Methods ..............................................................................................80 
9.8.2. 
Disposition of Patients .....................................................................................81 
9.8.3. 
Demographic and Baseline Characteristics .....................................................81 
9.8.4. 
Extent of Exposure ...........................................................................................81 
9.8.5. 
Efficacy Analysis .............................................................................................81 
9.8.6. 
Safety Analysis ................................................................................................84 
9.8.7. 
Pharmacokinetic Analysis ................................................................................85 
9.8.8. 
Biomarker and Pharmacodynamic Analysis ....................................................85 
9.8.9. 
Pharmacogenomic Analysis .............................................................................85 
9.8.10. 
Healthcare Utilization ......................................................................................85 
9.8.11. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan ....85 
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10. 
STUDY COMMITTEES .............................................................................................86 
10.1. 
Independent Data Monitoring Committee .............................................................86 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ...........................................87 
11.1. 
Study Site Monitoring Visits .................................................................................87 
11.2. 
Protocol Compliance ..............................................................................................87 
12. 
DATA HANDLING AND RECORD KEEPING .......................................................88 
12.1. 
Electronic Case Report Form .................................................................................88 
12.2. 
Record Retention ...................................................................................................88 
13. 
ETHICS........................................................................................................................89 
13.1. 
Ethical Conduct of the Study .................................................................................89 
13.2. 
Patient Information and Consent ...........................................................................89 
13.3. 
IRB/IEC/REB ........................................................................................................89 
13.4. 
Patient Confidentiality ...........................................................................................89 
13.5. 
Reporting of Safety Issues or Serious Breaches of the Protocol or International 
Conference on Harmonization Good Clinical Practice ..........................................90 
13.6. 
Liability and Insurance ..........................................................................................90 
14. 
STUDY TERMINATION ...........................................................................................91 
14.1. 
Criteria for Suspension or Premature Termination of the Study ...........................91 
14.2. 
Criteria for Premature Termination or Suspension of Investigational Sites ..........91 
14.3. 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................91 
15. 
PUBLICATION OF STUDY RESULTS ....................................................................92 
16. 
REFERENCES ............................................................................................................93 
17. 
APPENDICES .............................................................................................................96 
17.1. 
Modified Response Evaluation Criteria in Solid Tumors (RECIST) ....................96 
17.2. 
Healthcare Utilization Questionnaire .....................................................................97 
 
LIST OF TABLES IN THE TEXT 
Table 1: 
Schedule of Assessments .................................................................................12 
Table 2: 
Schedule of Assessments for Crossover ..........................................................15 
Table 3: 
Transporter Interactions of DCC-2618 and Metabolite DP-5439....................30 
Table 4: 
Summary of TEAEs Occurring in >10% of Patients (All Grades) ..................32 
Table 5: 
In vitro Inhibition of Recombinant KIT and KIT Mutants ..............................36 
Table 6: 
Model-predicted Typical Steady-State Pharmacokinetic Exposure of 
DCC-2618 and DP-5439 in Patients with Advanced Malignancies ................38 
Table 7: 
Dose Reduction Steps for Study Drug .............................................................48 
Table 8: 
Dose Reduction Steps for Patients Who Progressed and Dose Escalated to 
150 mg BID......................................................................................................48 
Table 9: 
Dose Modifications for Dermatologic Toxicities and Arthralgia/Myalgia ......49 
Table 10: 
Dose Modifications and Management of Hypertension ..................................50 
Table 11: 
Dose Modifications for Treatment Related Adverse Events Other than 
Dermatologic Toxicities, Arthralgia/Myalgia, and Hypertension ...................51 
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Table 12: 
Safety Laboratory Tests ...................................................................................64 
Table 13: 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) Version 4.03 Severity Grading Scale ..........................70 
Table 14: 
Relationship to Study Drug Criteria ................................................................71 
Table 15: 
Classification for Study Drug Action Taken with Regard to an Adverse 
Event ................................................................................................................71 
Table 16: 
Classifications for Outcome of an Adverse Event ...........................................72 
Table 17: 
Partial or Missing Date Algorithms .................................................................79 
Table 18: 
Imputation Rules for Questionnaires ...............................................................79 
 
LIST OF FIGURES IN THE TEXT 
Figure 1: 
Study Schema...................................................................................................11 
Figure 2: 
Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumor 
Patients Span Exon Regions 13-18 ..................................................................25 
Figure 3: 
Best Radiographic Response per RECIST in KIT and PDGFRA GIST 
Patients (N=37) ................................................................................................34 
Figure 4: 
Pharmacokinetic Model of DCC-2618 and DP-5439 in Patients with 
Advanced Malignancies ...................................................................................37 
 
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1. 
INTRODUCTION AND RATIONALE 
1.1. 
Introduction 
Activating mutations in the receptor tyrosine kinases KIT or PDGFRA have been identified 
in multiple cancer types such as gastrointestinal stromal tumors (GIST), subsets of 
melanoma, testicular seminomas and acute myeloid leukemia (AML), and in 
myeloproliferative neoplasms such as systemic mastocytosis (SM) that include aggressive 
SM (ASM) and mast cell leukemia (2, 3, 4, 5, 6). In addition, aberrant wt KIT and/or 
PDGFRA overexpression is found in GIST, melanoma, AML, gliomas and neuroendocrine 
tumors (7, 8, 9, 10). 
Most gastrointestinal stromal tumors are driven by activating mutations in KIT (~80%) or the 
related PDGFRA (~10%) receptor tyrosine kinases (1, 23). In GIST patients at presentation, 
mutations in the KIT gene are usually found in exon 9 or 11. Primary mutations in exon 11 
disrupt the auto-inhibited form of the kinase, and those in exon 9 increase receptor 
dimerization. Both mechanisms cause ligand-independent receptor activation, which leads to 
uncontrolled cell growth and transformation. Several KIT-targeted therapies have been 
approved for the treatment of GIST, but there are limitations to their therapeutic success.  
Upon treatment with targeted therapies, secondary resistance mutations in KIT usually arise 
in the catalytic domain of the kinase, and frequently these mutations map to the embedded 
conformational switch control mechanism that regulates KIT activity (Figure 2). Secondary 
mutations in KIT typically occur in exons 13 and 14 (near the adenosine triphosphate 
(ATP)-binding pocket) that sterically disrupt drug binding or conformationally activate KIT, 
and in the activation loop (conformation-controlling switch) encoded by exons 17 and 18 
(11, 12). Activation loop mutations act by shifting the kinase into an activated conformation 
that is less amenable to drug binding by any of the approved therapies (13). Other diseases 
that have primary mutations in the KIT (or PDGFRA) activation loop include SM, AML, and 
PDGFRA-driven GIST (7, 14, 15). 
Figure 2: 
Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumor 
Patients Span Exon Regions 13-18 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
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Imatinib was the first KIT inhibitor approved as a therapy for advanced GIST in 2002 (16). 
Imatinib therapy is usually not curative in unresectable and/or metastatic disease with 
complete responses (CRs) seen in ~5% of patients and an objective response rate (ORR) of 
68% (17). More than 80% of GIST patients will receive clinical benefit from imatinib 
monotherapy, but as development of imatinib-resistance is essentially inevitable, more than 
half will develop progressive disease by 2 years (18). Progression is largely due to secondary 
mutations in the KIT kinase domain that cause resistance to imatinib (12). Although imatinib 
is effective against exon 11 mutations in KIT, and has some efficacy against exon 9 
mutations when the dose is increased to 800 mg, little to no response to imatinib is seen for 
other mutations in KIT and PDGFRA, particularly those that mediate the conformational 
dynamics of switch activation (18, 19). 
Sunitinib was approved in 2006 as a second-line therapy for GIST patients who had disease 
progression on or intolerance to imatinib. Sunitinib has greater activity against exon 
9 mutations compared to imatinib and less activity against exon 11 mutations (15, 18). 
Additionally, sunitinib shows activity against KIT exon 13 and 14 mutations, but only half 
the patients show benefit and median progression-free survival (PFS) is 5.5 months (18). 
Sunitinib is not effective against KIT exon 17/18 and PDGFRA exon 18 activation loop 
mutations.  
Regorafenib was approved in 2013 as a third-line therapy for adult patients with metastatic 
and/or unresectable GIST who have had disease progression on or intolerance to imatinib and 
sunitinib treatment. In addition to being active against KIT exon 11 mutations, regorafenib is 
the only approved therapy with activity against a subset of exon 17 mutations in KIT and for 
patients who respond, PFS approaches 5 months. Some patients present with mutations in 
KIT that are not effectively treated by regorafenib, and additionally, other or multiple 
secondary mutations arise and cause resistance to therapy (12). Tumor heterogeneity has 
been found with multiple secondary mutations in KIT arising within an individual patient in 
different areas of 1 tumor or distinct sites of metastasis (12).  
The complex heterogeneity of KIT mutations within individual patients is a major cause of 
resistance to therapy (12). A kinase inhibitor that could broadly inhibit clinically relevant 
KIT mutations or multiple mutations in KIT within an individual GIST patient could be of 
high therapeutic value in the treatment of refractory GIST patients. Importantly, determining 
whether such an inhibitor could delay development of resistance mutations within KIT is an 
important therapeutic objective with DCC-2618. 
At present, there are no approved targeted therapies that broadly inhibit secondary 
drug-resistant mutations in GIST. Thus, a high medical need remains for developing kinase 
inhibitors that are effective against these mutant forms of KIT and PDGFRA.  
1.2. 
Clinical Indications 
DCC-2618, an inhibitor of KIT and PDGFRA kinases, is being developed for the treatment 
of patients with GIST, in addition to other advanced malignancies driven by proto-oncogene 
tyrosine-protein kinases. In addition to KIT and PDGFRA, the drug inhibits CSF1R (FMS), 
VEGFR2, and TIE2, which are less frequently documented to initiate tumor development.  
Gastrointestinal stromal tumors represent the most common form of sarcoma, a relatively 
rare subset of cancers arising from mesenchymal cells in the body (20). Adult GIST occurs 
with an incidence rate of ~3,000-6,000 new cases per year in the US (21, 22, 23), generally 
presents around age 50-70, and occurs in men and women at similar rates (24). Surgery is the 
primary treatment for localized GIST and can be curative, though local and/or distant 
recurrence occurs in more than half of patients (25). For metastatic or unresectable GIST, 
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which is present in about half of patients at diagnosis, radiotherapy and traditional 
chemotherapy are not effective (20, 25). The era of targeted cancer therapies has ushered in 
several new effective treatments for metastatic and recurrent GIST, though CRs are rarely 
achieved (20). Resistance to therapy occurs in a large majority of patients within a few 
months to years depending on treatment (21), similar to that observed in other cancers 
successfully treated with targeted therapies. 
1.3. 
Study Drug 
DCC-2618 is a novel, oral inhibitor of KIT kinase and PDGFRA kinases, developed by 
Deciphera Pharmaceuticals, LLC (hereafter referred to as the “Sponsor”), using its 
proprietary kinase switch control inhibitor technology platform. DCC-2618 comprehensively 
and potently inhibits a broad range of primary and secondary mutants of KIT and PDGFRA 
kinases, including KIT primary mutations in exons 9 and 11 and secondary resistance 
mutations in exon 13 and 14 of the KIT ATP binding/switch pocket region and primary or 
secondary mutations in exons 17 and 18 of the activation loop conformation-controlling 
switch region. DCC-2618 also inhibits the PDGFRA primary exon 18 mutation D842V in the 
conformation-controlling switch region and exon 12 mutations in the auxiliary inhibitory 
switch. DCC-2618 exhibits this broad profile of mutant KIT/PDGFRA inhibition by binding 
as an advanced Type II kinase inhibitor that penetrates the embedded KIT/PDGFRA switch 
pockets. 
1.3.1. 
Nonclinical Experience 
Please refer to the Investigator’s Brochure (IB) for a more detailed summary of the 
nonclinical experience with DCC-2618. 
1.3.1.1. 
Pharmacology 
DCC-2618, and its active metabolite, DP-5439, were evaluated in vitro in recombinant 
kinase assays and in cellular assays with GIST cell lines from treatment-resistant patients, 
AML and mastocytosis cell lines, or cell lines transfected with KIT or PDGFRA mutants. 
These studies provided a comprehensive profile of inhibition versus clinically relevant KIT 
and PDGFRA mutations that cause either de facto refractoriness to existing therapies or 
resistance to existing therapies. Results from evaluation in cancer cell lines guided further 
evaluation of DCC-2618 in refractory/resistant in vivo xenograft models. 
A variety of cancer model systems were employed to evaluate the pharmacology of 
DCC-2618 in vivo, including the evaluation of efficacy in human tumor xenografts in nude 
mice and pharmacokinetic (PK)/pharmacodynamic (PD) studies in tumor-bearing mice to 
evaluate exposures required for durable mutant KIT inhibition in vivo. 
In vivo, DCC-2618 exhibited potent anti-tumor effects in mutant KIT GIST models. 
Additionally, DCC-2618 showed potent inhibition of KIT phosphorylation in GIST models. 
In a PK/PD study performed in a human GIST xenograft mouse model, a single oral dose of 
50 mg/kg resulted in a DCC-2618 exposure (area under the concentration × time curve from 
0 to 24 hours [AUC0-24hr]) of 2500 ng•h/mL (5000 ng•h/mL when active metabolite DP-5439 
is included) that led to 69-88% inhibition of KIT kinase in vivo through 8-hours post dose 
and ~40% inhibition at 12-hours post dose. This exposure led to 90% inhibition of tumor 
growth in the GIST T1 model when dosed at 50 mg/kg twice daily (BID; 10,000 ng•h/mL 
daily exposure) in a multiple-dose efficacy study. This PK/PD derived exposure was used to 
guide identification of toxicology formulations capable of achieving exposures as multiples 
of this durable inhibition of KIT in vivo. 
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Metabolite identification studies in hepatocytes revealed that the major metabolic pathway of 
DCC-2618 is N-demethylation to form an active metabolite known as DP-5439. In 
preclinical animal studies, significant fractions of DP-5439 were measured in mouse, rat, and 
dog plasma in preclinical studies. The metabolite was produced most extensively in mice and 
the PK parameters suggest that mice may be exposed to an approximately equal amount of 
DCC-2618 and DP-5439 when measured as AUC0-24hr. The total active drug exposure in 
mice (AUC0-24hr), as measured by the combined exposure of DCC-2618 and metabolite 
DP-5439, is therefore regarded as 5000 ng•h/mL following a single oral 50 mg dose or 
10,000 ng•h/mL after a 50 mg/kg BID administration, a value which will be referenced in the 
analysis of nonclinical safety studies. Metabolite DP-5439 has been shown to be formed in 
the Phase 1 dose-escalation study. At clinically effective doses the exposure to metabolite is 
greater than exposure to parent DCC-2618. 
DCC-2618 was selected for clinical development based on the efficacy and tolerability 
observed in these model systems. 
1.3.1.1.1. Safety Pharmacology 
DCC-2618 exhibits negligible binding to human ether-à-go-go related gene potassium 
channel components. 
DCC-2618 given at 15, 60, or 300 mg/kg had no effect on any component of the modified 
Irwin battery of behavioral testing at any measured time point in rats. DCC-2618 given at 15, 
60, or 300 mg/kg mildly decreased tidal volume by 10% at 15 mg/kg and up to 17% at 
300 mg/kg in rats. The observed changes in tidal volume were not considered physiologically 
important because they were transient and of small magnitude. 
Cardiovascular safety was assessed by electrocardiogram (ECG), blood pressure (BP), and 
troponin I measurements in the dog 4-week repeat dose toxicology study. No significant 
effects on blood pressure, heart rate, ECG intervals, or troponin I levels were noted. In a 
stand-alone cardiovascular safety study in Beagle dogs, single doses of DCC-2618 resulted in 
increased diastolic pressure and mean arterial pressure (2-6 hours post dose) that were 
generally correlative with the anticipated time to reach the maximum plasma concentration 
(Tmax). Diastolic pressures were higher (12, 12, and 17%) than control at 7, 20, and 75 mg/kg, 
respectively. DCC-2618-related increases in mean arterial pressure were higher (up to 12, 10, 
and 14 mmHg) than control at 7, 20, and 75 mg/kg, respectively. There were no changes to 
systolic pressure or arterial pulse pressure. 
Increases in heart rate and lower QT- and PR-intervals (likely secondary to changes in heart 
rate) were seen at 9 to 19-hours post dose during the dark phase of the study. There were no 
changes in corrected QT interval (QTc) values. Heart rate values were elevated throughout 
the dark phase with maximal differences occurring between 13 and 17-hours post dose when 
heart rates were 45%, 70%, and 129% higher than concurrent controls at 7, 20, and 
75 mg/kg, respectively. The mechanism of these changes is not understood; BP and heart rate 
are being closely monitored in clinical studies. The magnitude of BP and heart rate changes 
was considered noteworthy, but not to represent severe toxicity. 
1.3.1.2. 
Pharmacokinetics and Absorption, Distribution, Metabolism, and 
Excretion Profile 
In vitro studies were performed to characterize the absorption, distribution, metabolism, and 
excretion properties of DCC-2618 and metabolite DP-5439 in human and other mammalian 
species relevant to drug development. In vivo PK studies (both oral and intravenous [IV] 
routes) were conducted in rodents (mice, rats) and non-rodents (dogs, cynomolgus monkeys). 
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DCC-2618 exhibited oral bioavailability in all species, confirming the potential for 
development as an oral therapeutic agent. 
Total exposures (AUC0-24hr) for DCC-2618 achieved in dogs and rats were 1.9-2.6 × the 
target area under the curve (AUC) of 10,000 ng•h/mL for DCC-2618 and metabolite 
DP-5439 in the murine GIST efficacy model. The elimination half-life (T1/2) after a single IV 
dose was comparable in dogs (2.7 hours) and rats (2.0 hours). 
Metabolite identification studies demonstrated that all observed human metabolites were also 
detected in the Sprague-Dawley rat and/or Beagle dog, supporting the relevance of these 
species for toxicology studies. The major metabolite observed in all species of hepatocytes is 
the N-desmethyl metabolite (DP-5439) and it was determined that DP-5439 inhibited wild 
type and mutant KIT and PDGFRA with potency comparable to DCC-2618. In a broad range 
of 19 single and double-mutant KIT assays performed in transfected Chinese Hamster Ovary 
cells, DCC-2618 inhibited mutant KIT phosphorylation with half maximal inhibitory 
concentration (IC50) values ranging from 6 nM to 221 nM. Similarly, the metabolite 
DP-5439 inhibited mutant KIT phosphorylation in these assays with IC50 values ranging from 
21 nM to 191 nM. 
The in vitro metabolism of DCC-2618 and active metabolite DP-5439 by human liver 
microsomes was studied to determine which human cytochrome P450 (CYP) enzymes 
contribute to the metabolism of DCC-2618. The metabolism of DCC-2618 was found to be 
dependent on the presence of nicotinamide adenine dinucleotide phosphate (NADPH), 
reduced form. Blocking the metabolism of DCC-2618 in cultured human liver microsomes 
by the co-administration of specific direct-acting or metabolism-dependent CYP inhibitors 
revealed that CYP3A4/5 is the major metabolizer of DCC-2618 (ketoconazole, 63% 
inhibition; troleandomycin, 79% inhibition); CYP2C8 (gemfibrozil glucoronide, 24% 
inhibition) and CYP2D6 (quinidine, 26% inhibition) were implicated as only minor 
metabolizers. In recombinant human CYP enzyme preparations, however, CYP2D6 and 
CYP2C8 were also found to be strong metabolizers of DCC-2618. Inhibition of DP-5439 
metabolism was observed in microsomal incubations with direct-acting inhibitor 
ketoconazole (CYP3A4/5, 72% inhibition), and with metabolism-dependent inhibitors 
gemfibrozil glucuronide (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). Incubations of DP-5439 with other direct or metabolism-dependent inhibitors 
evaluated resulted in less than 14% inhibition. This study revealed that CYP3A4/5 is the 
major metabolizer of DP-5439, but that significant metabolism is also possible by CYP2C8, 
CYP2E1, and CYP2D6. DCC-2618 did not appreciably inhibit CYP3A4, CYP1A2, or 
CYP2B6 in in vitro metabolism studies. DCC-2618 inhibited CYP2C8, CYP2C9, CYP2C19, 
and CYP2D6 with IC50 values ranging from 0.12 to 1.8 µM. DCC-2618 exhibited little or no 
evidence of time- or metabolism-dependent inhibition of any of the 7 major CYP enzymes 
evaluated. 
Similarly, metabolite DP-5439 was also found to inhibit CYP2C8, CYP2C9, CYP2C19, and 
CYP2D6 with IC50 values ranging from 0.30 to 2.0 µM. DP-5439 did not appreciably inhibit 
CYP3A4, CYP1A2 or CYP2B6 in a direct manner. After a 30-minute pre-incubation with 
pooled human liver microsomes in the presence of NADPH, however, DP-5439 
demonstrated evidence of metabolism-dependent (time-dependent and NADPH-dependent) 
inhibition of CYP3A4/5-mediated testosterone 6β-hydroxylation. The inhibition observed in 
the presence of 7.0 µM DP-5439 increased 41% after pre-incubation. There was little or no 
evidence of metabolism-dependent (time- and NADPH-dependent) inhibition of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 by DP-5439. DCC-2618 and DP-5439 
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exhibit potential for DDIs with other agents dependent on CYP2C8, CYP2C9, CYP2C19, or 
CYP2D6 for their metabolism. 
In the presence of 10 µM DCC-2618 or 7 µM DP-5439, organic anion transporter (OAT) 
OAT1, OAT3, organic cation transporter (OCT) OCT1, and OCT2 were slightly to 
moderately inhibited by ≤55%. OATP1B3 was inhibited 78% by DCC-2618, whereas 
OATP1B1 was inhibited 73% by DP-5439 (Table 3). 
DCC-2618 and DP-5439 were found to inhibit the breast cancer resistance protein (BCRP) 
efflux transporter in an in vitro vesicular transport assay with IC50 values of 0.04 µM and 
1.26 µM, respectively. While DCC-2618 was not a substrate for the BCRP transporter (efflux 
ratio [ER] 2.36), the metabolite DP-5439 exhibited significant substrate activity (ER 85.0), 
indicating the potential for drug-metabolite interactions wherein DCC-2618 is a potential 
perpetrator (BCRP IC50 0.04 µM) and metabolite DP-5439 is a potential victim (BCRP 
ER 85.0) of drug-drug interaction. DCC-2618 also has the potential for drug-drug-interaction 
with other agents that are substrates or inhibitors of the BCRP efflux transporter. 
DCC-2618 and DP-5439 were moderate to weak inhibitors of the Multidrug resistance 
protein 1 (MDR1) efflux transporter, exhibiting IC50 values of 1.95 µM and >7 µM, 
respectively. While DCC-2618 was a moderate substrate for the MDR1 transporter 
(ER 12.9), the metabolite DP-5439 exhibited significant substrate activity (ER 72.4), 
indicating low to moderate potential for drug-metabolite interactions wherein DCC-2618 is a 
potential perpetrator (MDR1 IC50 1.95 µM) and metabolite DP-5439 is a potential victim 
(MDR1 ER 72.4) of drug-drug-interaction (Table 3).  
Table 3: 
Transporter Interactions of DCC-2618 and Metabolite DP-5439 
 
Inhibition of Transporter 
Substrate of Transporter 
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 
54% inhibition @ 7 µM 
NT 
ER <2 
OATP1B1 
32% inhibition @ 10 µM 
73% inhibition @ 7 µM 
NT 
ER <2 
OATP1B3 
78% inhibition @ 10 µM 
43% inhibition @ 7 µM 
NT 
ER <2 
OCT1 
30% inhibition @ 10 µM 
NT 
NT 
NT 
OCT2 
55% inhibition @ 10 µM 
6% inhibition @ 10 µM 
NT 
ER<2 
OAT1, 
OAT3,  
≤15% inhibition @ 10 µM 
≤13% inhibition @ 7 µM 
NT 
ER <2 
IC50=half maximal inhibitory concentration; ER=efflux ratio; NT=not tested 
 
1.3.1.3. 
Toxicology 
The toxicity profile of DCC-2618 was evaluated in vitro in the bacterial mutagenicity assay 
and in vivo in nude mice, Sprague-Dawley rats and Beagle dogs. There was no evidence of 
bacterial mutagenicity up to the maximum tested concentration of 3000 µg/plate 
(concentration resulting in precipitation), with or without metabolic activation, in a 
non-Good Laboratory Practice (GLP) compliant assessment. 
A pivotal, GLP-compliant 4-week oral study was conducted in rats at 0, 15, 60, and 
300 mg/kg/day DCC-2618. Recovery animals were held for an additional 4 weeks following 
the dosing phase. There were no drug related deaths or adverse clinical observations in this 
study. A higher prevalence of thinning hair coat was noted at 300 mg/kg/day. A decrease in 
body weight and food consumption was seen in DCC-2618 treated animals. Body weight and 
food consumption changes reversed during the recovery phase, and neither had any effect on 
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the animals’ overall body condition. Several minor clinical pathology findings were observed 
on Day 29. These changes were of small magnitude, lacked microscopic correlates, exhibited 
reversibility at the end of the recovery phase, and were not considered adverse. DCC-2618 
related increased lung weights (15% to 33%) were noted in males given 300 mg/kg/day and 
females given ≥15 mg/kg/day. There were no correlating microscopic changes and the lung 
weight increases partially reversed during the recovery phase. Microscopic changes were 
limited to the non-glandular stomach (diffuse hyperplasia/hyperkeratosis) of rats given 
≥60 mg/kg/day and the change partially reversed during the recovery phase. Since humans do 
not have this anatomic feature, the changes have no relevance to humans. Based on these 
results, 300 mg/kg/day was the no observed adverse effect level (NOAEL) after 4 weeks of 
dosing. 
A pivotal, GLP compliant 4-week oral study was conducted in Beagle dog at 0, 7, 20, and 
75 mg/kg/day. Recovery animals were held for an additional 4 weeks following the dosing 
phase. Dosing was suspended in several animals at 20 and 75 mg/kg/day during Week 2 or 3 
due to DCC-2618-related adverse clinical observations. Three males given 75 mg/kg/day 
were sacrificed on Day 13, and 7 additional animals at both the 20 mg/kg dose (2 males and 
2 females) and the 75 mg/kg dose (3 females) underwent early sacrifice during Week 4, due 
to DCC-2618-related adverse clinical observations. Clinical observations in these animals 
included erythema of feet, inside of ears, muzzle, periorbital area, and ventral thorax, and 
thinning of cranial hair coat. Some dogs also exhibited dry and flaky skin, otitis, 
erythematous external ear canals, excessive salivation, emesis, and non-formed/liquid feces. 
In dogs administered 7 mg/kg/day, skin changes were of lesser severity and judged not to be 
adverse. The skin lesions at 20 and 75 mg/kg/day were partially or completely resolved 
during the recovery phase. Decreased body weights were noted in males given 20 or 
75 mg/kg/day. Animals at 7 mg/kg/day had small changes in body weight that were not 
considered adverse. No alterations in blood pressure or ECG intervals were noted at any dose 
of DCC-2618. Mild hematology, clinical biochemistry, and/or coagulation findings occurred 
in animals given ≥20 mg/kg/day and all changes exhibited evidence of reversibility by the 
end of the recovery phase. Troponin I levels in DCC-2618-treated animals were unaffected 
by drug treatment. Microscopic findings of hyperkeratosis, cytoplasmic rarefaction of 
hepatocytes consistent with increased glycogen, decreased lymphocytes in lymphoid tissues, 
and one instance of an intra-epidermal pustule were seen at ≥20 mg/kg/day. The only test 
article-related microscopic finding at the recovery sacrifice was minimal cytoplasmic 
rarefaction of liver cells in some animals given 75 mg/kg/day, indicating partial recovery of 
this finding. 
Based on these results, the NOAEL is 7 mg/kg/day. This dose also is considered the highest 
non-severely toxic dose. 
1.3.2. 
Clinical Experience 
There is 1 ongoing clinical study with DCC-2618, Clinical Study DCC-2618-01-001. This is 
an open-label, first-in-human, dose-escalation study in patients with advanced malignancies 
with a molecular rationale for activity. This study has 2 parts: (1) Dose-Escalation Phase and 
(2) Expansion Phase. 
In the Escalation Phase, sequentially increasing dose levels of oral DCC-2618 dosed BID in 
repeated 28-day cycles are being evaluated for safety based on pharmacologically guided 3+3 
escalation rules until a maximum tolerated dose has been identified or a recommended 
expansion dose/regimen(s) is declared. Sequentially increasing dose levels of oral DCC-2618 
dosed once daily (QD) were introduced based on the suspected long plasma half-life of an 
active metabolite (30-60 hours), that support a QD dosing regimen. 
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Upon determination of the single-agent recommended Phase 2 dose (RP2D) in the Escalation 
Phase, patients will be enrolled into the Expansion Phase of the study. Expansion will enroll 
several cohorts including patients with KIT- and PDGFRA-mutant GIST, SM and other 
hematologic malignancies, malignant gliomas, and other solid tumors. 
As of 28 July 2017, 70 patients have been enrolled as follows: 57 patients with advanced 
GIST cancer, and 13 patients with non-GIST.  
The clinical data represent a broad patient population with GIST patients having received 
various numbers of prior therapy ranging from a single prior therapy to patients who have 
received seven prior therapies. 
In the Escalation Phase, 9 cohorts have been evaluated: 20 mg BID, 30 mg BID, 50 mg BID, 
100 mg BID, 150 mg BID, 200 mg BID, 100 mg QD, 150 mg QD, and 250 mg QD. In the 
dose escalation phase of the study, there were three dose limiting toxicities (DLTs): two 
events of Grade 3 lipase elevation in the 100 mg BID and 200 mg BID cohorts (one in each 
cohort) and one event of Grade 4 CPK elevation in the 150 mg QD cohort. Both the lipase 
and CPK elevations, although DLTs per protocol, were considered clinically insignificant by 
the Investigator and Sponsor due to the events being asymptomatic.  
The RP2D was determined to be 150 mg QD, and different expansion cohorts have been 
opened. 
The following sections present clinical data for the 70 patients that have been enrolled as of 
28 July 2017. 
1.3.2.1. 
Clinical Safety 
DCC-2618 has been well tolerated with no clear safety signal observed to-date. Table 4 
summarizes the most frequently reported treatment-emergent adverse events (TEAEs) in 
>10% of patients in Clinical Study DCC-2618-01-001. 
Table 4: 
Summary of TEAEs Occurring in >10% of Patients (All Grades) 
  
<100 mg/d (N = 8) 
≥ 100 mg/d (N = 62)5 
Event Term 
Total 
Events 
G1/2 
G3/4 
G1/2 
G3/4 
Lipase increased 
33 
5 
1 
15 
123 
Fatigue 
32 
6 
0 
25 
1 
Anaemia 
29 
1 
1 
9 
18 
Decreased appetite1 
20 
1 
0 
17 
1 
Diarrhoea 
16 
1 
0 
15 
0 
Alopecia 
15 
1 
0 
14 
0 
Hypertension 
15 
0 
1 
9 
5 
Amylase increased 
14 
3 
0 
10 
1 
Myalgia 
14 
2 
0 
12 
0 
Weight decreased 
14 
1 
0 
13 
0 
Dyspnoea2 
13 
4 
0 
8 
1 
Abdominal pain 
11 
3 
0 
7 
1 
Constipation 
11 
4 
0 
7 
0 
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<100 mg/d (N = 8) 
≥ 100 mg/d (N = 62)5 
Event Term 
Total 
Events 
G1/2 
G3/4 
G1/2 
G3/4 
Nausea 
11 
2 
0 
9 
0 
Palmar-plantar 
erythrodysaesthesia syndrome 
11 
0 
0 
11 
0 
Arthralgia 
10 
2 
0 
8 
0 
Blood bilirubin increased4 
10 
1 
0 
7 
2 
Rash 
8 
2 
0 
6 
0 
101-005 has a "Decreased appetite" AE with no severity grade. This is included in the total events column but 
nowhere else; 203-010 has a "Dyspnoea" AE that resulted in death (severity G5). This is included in the G3/4 
column for the ≥ 100 mg/d group; 3Two events of G3 lipase elevation at 100 mg & 200 mg BID were 
considered DLTs per protocol, although they were not deemed clinically significant by the Investigator and 
Sponsor; 4Unconjugated bilirubin, both patients are homozygous for 28 *(TA)7/(TA)7 UGT1A1 polymorphism; 
21 of the 62 patients were treated with RP2D of 150 mg QD. 
 
Skin abnormalities, including confirmed SCCs (N=3) have been observed. Events of SCC, 
keratoacanthoma, and actinic keratosis are considered adverse events of special interest 
(AESIs).   
1.3.2.2. 
Clinical Pharmacokinetics and Pharmacodynamic Markers 
Nonclinical studies had identified DP-5439 as an active metabolite of DCC-2618 with similar 
activity profile to its parent compound. 
The long plasma T1/2 of the metabolite (30-60 hours) suggests that QD dosing is feasible. The 
food effect sub-study has shown that taking DCC-2618 with food should not have a negative 
impact on absorption. See Section 1.4.2 for further details on the dose, regimen, and 
treatment duration rationale for the present study. 
DCC-2618 leads to rapid clearance of a broad spectrum of KIT mutations from plasma 
cfDNA in patients with heavily pretreated GIST. Overall, a high total plasma concentration, 
determined as Cmax, was observed exceeding 5 μM (3,000 ng/mL) starting at 100 mg BID at 
Cycle 1 Day 15; the observed mean exposure exceeds targeted plasma levels by far, 
including exposures required for inhibition of the KIT mutations least sensitive to DCC-2618 
(V654A and T670I). 
Next-generation sequencing of plasma cell-free DNA (cfDNA) was performed in all GIST 
patients at baseline and every 2 cycles while a patient is on study. Mutations were detected 
and quantitated by Guardant 360 v2.9 or v2.10. Only amino acid-altering mutations in KIT 
and PDGFRA were considered resistance mutations. Cell-free DNA was not detected in all 
patients. Based on the preliminary data, 19 mutations in unique genes were observed in 
11/29 patients with KIT-mutant GIST. Across exons 9, 11, 13, 14, 17, and 18, a total of 
43 mutations were detected in the KIT gene. The PDGFRA D842V-mutation was detected in 
only 1 cfDNA patient sample out of 4 PDGFRA D842V-mutant patients enrolled (confirmed 
by archival testing). 
1.3.2.3. 
Clinical Efficacy  
Efficacy data (measured by Response Evaluation Criteria in Solid Tumors [RECIST] 
Version 1.1) are available for 37 patients with KIT- or PDGFRA-known mutant GIST. The 
waterfall plot (Figure 3) is representative of the 37 GIST patients. Data are based on local 
review of CT scans. Data show patients who were treated at doses <100 mg daily and doses 
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≥100 mg daily. Patients who received the RP2D of 150 mg QD are noted an ‘#’ in the figure. 
In the ≥100 mg daily dose cohorts there were 5 partial responses (PR), 25 stable disease 
(SD), and 3 progressive disease (PD). In the <100 mg dose cohorts there were 3 SD, 1 PD 
and zero PR. 
Figure 3: 
Best Radiographic Response per RECIST in KIT and PDGFRA GIST 
Patients (N=37) 
 
 
 
18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) scans were performed in 
GIST patients as an early marker of tumor activity and treatment response to DCC-2618. 
Scans were obtained at baseline and during Cycle 1 approximately 21 days after the start of 
continuous dosing. Response was assessed according to European Organization for Research 
and Treatment of Cancer (EORTC) PET response criteria by a central imaging review. As of 
Amendment 3, the Sponsor no longer requires FDG-PET scans to be performed in the 
Escalation Phase because sufficient data supporting an impression of strong antitumor 
metabolic activity in KIT-mutant GIST patients are available. In the Expansion Phase, 
FDG-PET scans will be performed for GIST patients that progress and dose escalate 
(ie, intra-patient dose escalation). 
Across the dose levels examined to date, no clear evidence for increased activity at higher 
dose levels was observed based on PD markers. Partial metabolic responses (PMRs) 
determined by FDG uptake in PET scans were observed as early as 30 mg BID in 1 GIST 
patient treated at that dose level and a baseline PET scan. 
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1.4. 
Rationale 
1.4.1. 
Study Rationale 
Once patients have received imatinib, sunitinib, and regorafenib, there are no other approved 
treatment options for patients with advanced or unresectable GIST. For patients who have 
progressed on the approved agents, progression of KIT-driven tumors is primarily based on 
development of further KIT resistance mutations that are highly heterogeneous. In studying 
patients who have failed prior approved treatment options and whom may have acquired 
multiple resistance mutations, the ability to conduct a study with an acceptable active 
comparator is difficult. There are limited data to support that rechallenge with prior failed 
treatment options may offer minor benefit. A Korean, single-center, randomized, placebo-
controlled study (ie, ‘RIGHT Trial’) demonstrated that a rechallenge with imatinib provides a 
small benefit (median PFS of 1.8 months) to some patients compared to placebo (median 
PFS of 0.9 months) (26). Nevertheless, the study did not show any accompanied symptom 
palliation based on a health-related quality of life sub analysis using the European 
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer 
30-item (EORTC QLQ-C30) (27). The RIGHT Trial generally excluded patients who had a 
limited benefit from initial treatment with imatinib (defined as a PFS of ≤6 months), and thus 
the patient population was skewed towards ensuring enrollment of patients who had greater 
initial success on imatinib. A rechallenge with imatinib is not an approved treatment option 
anywhere in the world, and some treating physicians would rather choose sunitinib 
depending on the patient history.  
DCC-2618 was developed as a pan-KIT and PDGFRA inhibitor. Patients with GIST in the 
Phase 1 first-in-human study, DCC-2618-01-001, are heavily pre-treated and considered to 
be tyrosine kinase inhibitor (TKI) resistant. DCC-2618 shows compelling activity in this 
mutationally diverse KIT patient population based on a high incidence of PMRs, 3 PRs, and 
20 patients with SD per RECIST Version 1.1. Initial plasma cfDNA data obtained in the 
Phase 1 study are in line with nonclinical data demonstrating activity against all KIT and 
PDGFRA mutations tested. The Guardant 360 panel was used to detect and monitor mutation 
allele frequency in cfDNA. In patients with heavily pre-treated TKI-resistant GIST, 
DCC-2618 has led to notable decreases in mutation allele frequency (MAF) of resistance 
mutations in KIT exons 13, 14, 17 and 18 as well as PDGFRA D842V. The observed clinical 
activity and the reduction of MAF supports DCC-2618 activity in patients who failed up to 
7 prior anticancer treatments. 
A double-blinded Phase 3 placebo-controlled study provides the best option to adequately 
assess the benefit of DCC-2618 in this difficult to treat, highly heterogeneous patient 
population. Study DCC-2618-03-001 is a Phase 3, interventional, double-blind, 
placebo-controlled study to assess the safety and efficacy of DCC-2618 in patients with 
advanced GIST who have received treatment with prior anticancer therapies. Patients will be 
randomized to the active arm, DCC-2618 + best supportive care (hereafter referred to as 
“DCC-2618”), or and the control arm, placebo + best supportive care (hereafter referred to as 
“placebo”). 
To address the ethical concern of patients with advanced cancer receiving placebo, the study 
will allow for crossover of patients on the placebo arm who radiographically progress per 
modified RECIST by independent radiologic review. Tumor assessments are scheduled 
initially after each cycle to allow for an early detection of disease progression. 
Additionally, the study will include a 2:1 randomization scheme to the study, which will also 
minimize the number of patients that receive placebo. The study will randomize 
approximately 120 patients, randomized 2:1 (DCC-2618:placebo). This sample size was 
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selected based on considerations for PFS, objective response rate (ORR), and rate to detect 
rare safety events and overall exposure to DCC-2618, recommended by FDA. 
1.4.2. 
Dose, Regimen, and Treatment Duration Rationale 
1.4.2.1. 
Nonclinical Pharmacology and Clinical Pharmacokinetic Analyses to 
Support Optimal Phase 3 Dose Selection 
This section addresses the scientific justification for the selection of a 150 mg QD dose 
regimen for the Phase 3 study of DCC-2618 in patients with advanced GIST. The dose 
recommendation is based on nonclinical pharmacology, clinical PK assessment, and PD 
results of the ongoing Phase 1 study (up to 01 June 2017). Upon completion of the Phase 1 
study, clinical PK analysis and evaluation of the exposure-response relationship shall be 
updated. 
1.4.2.1.1. In Vitro Pharmacology 
The in vitro pharmacology studies demonstrated DCC-2618 and its active metabolite 
DP-5439 potently inhibit the wild-type and oncogenic KIT variants with IC50 values in the 
range of 3-20 nM (Table 5). Data for the currently available KIT inhibitors, imatinib, 
sunitinib, and regorafenib, are shown for reference. Imatinib, sunitinib, regorafenib and 
DCC-2618 all have active metabolites. The following dose considerations are primarily 
based on the pharmacological properties of the parent compounds.  
Table 5: 
In vitro Inhibition of Recombinant KIT and KIT Mutants 
 
The reported fraction unbound (fu) of imatinib and sunitinib are the same (5%), while in vitro 
potency of sunitinib is approximately 6-fold higher (wt KIT). Correspondingly the daily 
dosage of sunitinib for GIST (125 µmol, 50 mg) is 6.5-fold lower (based on molar dose ratio) 
than imatinib (810 µmol, 400 mg). At 0.5% the reported fu of regorafenib is 10-fold lower 
than sunitinib, while the in vitro potency is 2-fold higher. However, the daily dose of 
regorafenib (331 µmol, 160 mg) is only 2.6-fold greater (based on molar dose ratio) than 
sunitinib for GIST, likely due to the inhibition of more KIT mutants. 
The measured in vitro fu of DCC-2618 was 0.2% for albumin and 0.6-1.4% for α-1 acid 
glycoprotein, closer to that of regorafenib (fu=0.5%) than imatinib or sunitinib (fu=5%). The 
molecular weight of DCC-2618 (510.4 Dalton) is slightly greater than that of regorafenib 
(482.8 Dalton). As such the projected daily dose of DCC-2618 for GIST (294 µmol, 150 mg) 
is similar to regorafenib (331 µmol, 160 mg), although the optimal dose could be lower given 
more potent inhibition of KIT mutants exon 17 and 11 by DCC-2618. 
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1.4.2.1.2. In vivo Pharmacology  
In an exon 11 mutant KIT GIST T1 cell line xenograft mouse model, KIT signaling was 
suppressed by 69-88% out to 8 hours after administration of a single oral dose of 50 mg/kg 
DCC-2618 and sustained at ~40% inhibition at 12 hours post dose. After oral, BID dosing in 
the GIST T1 xenograft model, DCC-2618 significantly inhibited tumor growth, with 90% 
suppression at 50 mg/kg. In an imatinib-resistant GIST patient-derived xenograft model, 
100 mg/kg QD or 50 mg/kg BID DCC-2618 completely stopped the tumor growth. In the 
Kasumi-1 AML xenograft model expressing a primary exon 17 KIT mutation (N822K KIT), 
both 100 mg/kg and 50 mg/kg doses of DCC-2618 exhibited robust efficacy while imatinib 
was ineffective at a dose of 50 mg/kg BID.  
From in vivo pharmacology studies, the target PK exposure for tumor growth inhibition was 
determined to be 10,000 ng⋅h/mL for AUC0-24hr of DCC-2618 and DP-5439 at steady-state. 
1.4.2.1.3. Clinical Pharmacokinetics Assessment 
A population PK analysis was performed on pooled BID and QD data collected from the 
ongoing Phase 1 study of DCC-2618 in patients with advanced malignancies 
(Protocol DCC-2618-01-001). The model structure is shown in Figure 4. The PK profiles of 
DCC-2618 and DP-5439 are both described by two-compartment models. Depot represents 
the GI tract for orally administered DCC-2618. KA is the first-order absorption rate constant 
of DCC-2618 and K23 is the first-order rate constant for the metabolism of DCC-2618 to its 
active metabolite DP-5439 by CYP3A4/5. CL and CLM represent the clearance of 
DCC-2618 by other enzymatic pathways and the clearance of DP-5439, respectively. To 
avoid overparameterization, the central and peripheral distribution volumes of DP-5439 were 
assumed to be the same as those of DCC-2618. 
Figure 4: 
Pharmacokinetic Model of DCC-2618 and DP-5439 in Patients with 
Advanced Malignancies 
 
 
 
 
 
 
 
 
Despite the small number of patients in each cohort, population analysis of pooled data 
across BID and QD cohorts (n=44 total) indicated dose-proportional PK for both DCC-2618 
and DP-5439 in cancer patients. The model-predicted steady-state PK exposure as shown in 
Table 6. 
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Table 6: 
Model-predicted Typical Steady-State Pharmacokinetic Exposure of 
DCC-2618 and DP-5439 in Patients with Advanced Malignancies 
Dosing 
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 
Combined 
338 
396 
8947 
30 
DCC-2618 
197 
257 
5603 
DP-5439 
310 
337 
7816 
Combined 
507 
594 
13419 
50 
DCC-2618 
328 
428 
9339 
DP-5439 
517 
561 
13027 
Combined 
845 
989 
22366 
100 
DCC-2618 
655 
857 
18678 
DP-5439 
1034 
1123 
26054 
Combined 
1689 
1980 
44732 
150 
DCC-2618 
983 
1285 
28017 
DP-5439 
1551 
1684 
39081 
Combined 
2534 
2969 
67098 
200 
DCC-2618 
1311 
1714 
37356 
DP-5439 
2068 
2246 
52108 
Combined 
3379 
3960 
89464 
QD 
100 
DCC-2618 
249 
510 
9348 
DP-5439 
457 
609 
13041 
Combined 
706 
1119 
22389 
150 
DCC-2618 
373 
766 
14021 
DP-5439 
685 
914 
19562 
Combined 
1058 
1680 
33583 
Ctrough=concentration at the end of a dosing interval; Cmax=maximum concentration; AUC0-24hr=area under the concentration 
× time curve from 0 to 24 hours; BID=twice daily; QD=once daily 
 
The population PK analysis indicated that at DCC-2618 dose regimens of 30-200 mg BID or 
100-150 mg QD in a typical cancer patient, the combined steady-state PK exposure 
(AUC0-24hr) of DCC-2618 and DP-5439 exceeds the 10,000 ng⋅h/mL threshold for efficacy 
identified from xenograft mouse studies. However, the observed PK of both DCC-2618 and 
DP-5439 were highly variable among patients.  
Using the population PK model, a simulation was conducted based on 100 clinical studies, 
each including 100 patients, in order to estimate the proportion of patients achieving the 
10,000 ng⋅h/mL threshold for efficacy. Results showed that a dose of 150 mg QD (estimated 
from comparative in vitro pharmacology) is predicted to maintain the PK exposure above 
10,000 ng⋅h/mL in 93.6% of patients. The simulation was repeated with a dose of 100 mg 
QD, at which 87.9% of patients are predicted to reach the efficacy threshold. 
1.4.2.1.4. Summary 
An oral QD dose of 150 mg DCC-2618 is recommended as the optimal dose regimen for the 
treatment of GIST based on the following considerations: 
• Comparison of in vitro pharmacological properties of DCC-2618 and 3 approved targeted 
therapies for GIST suggests an efficacious daily dose of ≤160 mg for DCC-2618 in 
patients with GIST 
• In vivo pharmacology studies in xenograft mouse models indicated a target combined PK 
exposure (AUC0-24hr =10,000 ng⋅h/mL) of DCC-2618 and DP-5439 for tumor growth 
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inhibition. A daily oral dose of 150 mg is predicted to maintain the PK above this 
threshold in 93.6% of patients. 
• Both in vitro and in vivo pharmacology data are consistent in predicting that 150 mg QD 
will be an efficacious dose. 
• Safety data collected from the Phase 1 study support administration of 150 mg QD as a 
tolerable dose. 
Further points of consideration are listed below: 
• Comparing with BID regimens that are predicted to achieve the exposure target for 
efficacy, daily dosing is more convenient and may improve treatment adherence. 
Therefore, the 150 mg QD regimen is preferred over a similar daily dose given BID. 
• Due to the large PK interindividual variability, doses lower than 150 mg will result in PK 
exposure falling below the efficacy threshold in more patients. On the other hand, further 
improvement in efficacy is likely incremental at a higher dose.  
• A dose of 100 mg QD is predicted to reach the exposure target for efficacy in a large 
majority (87.9%) of patients. If individual patients experience lack of tolerance at 
150 mg QD, the dose could be lowered to 100 mg QD potentially without compromising 
efficacy.  
• Further PK-efficacy and PK-safety assessments are being conducted to confirm the 
selection of 150 mg QD as the optimal regimen for DCC-2618 in patients with GIST. 
1.4.2.2. 
Intra-patient Dose Escalation After Disease Progression 
Dose escalation of other TKIs (imatinib) is already a therapeutic option for patients with 
primary, as well as secondary resistance to standard doses of imatinib. 
Based on the population PK model simulations, by using the 150 mg QD regimen, around 
93% of patients are predicted to achieve the exposure target for efficacy. Due to the large PK 
inter-individual variability, doses lower than 150 mg will result in PK exposure falling below 
the efficacy threshold in more patients. On the other hand, further improvement in efficacy is 
likely incremental at a higher dose. 
The Sponsor acknowledges the challenges of dosing optimization and regards well monitored 
dose escalation at the time of disease progression as an innovative approach to avoid the 
selection of an effective but intolerable dose. 
Dose escalation at the time of disease progression allows for an exploratory 
exposure-outcome comparison in individual patients originally assigned to an active dose 
level and should provide important information for an integrated safety and efficacy analysis. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To assess the efficacy (PFS) of DCC-2618 by independent radiologic review in patients 
with advanced GIST who have received prior anticancer therapies 
2.2. 
Secondary Objectives 
2.2.1. 
Key Secondary Objectives 
• To assess objective response rate (ORR) by independent radiologic review 
2.2.2. 
Secondary Objectives 
• To assess other parameters of efficacy, including but not limited to time to progression 
(TTP) and overall survival (OS) 
•  To assess the pharmacokinetics/pharmacodynamics (PK/PD) relationship of DCC-2618 
• To assess the robustness of efficacy using a sensitivity analysis 
• To assess improvement of disease-related symptoms and quality of life 
• To assess the safety of DCC-2618 
2.3. 
Exploratory Objectives 
• To assess the efficacy of DCC-2618 in patients after dose escalation to DCC-2618 
150 mg BID 
• To characterize KIT and PDGFRA gene resistance mutations (and potentially other gene 
mutations) and their DCC-2618-driven longitudinal mutation allele frequency changes in 
plasma cfDNA 
• To retrospectively correlate KIT and PDGFRA mutation/s and/or their frequency (as well 
as of potentially other gene mutations) in baseline cfDNA with clinical benefit 
• To understand potential TKI-resistance mechanisms of GIST at time of progression 
• To determine concordance between KIT, PDGFRA, and other mutations in tumor and 
cfDNA at baseline 
• To assess healthcare utilization in patients with advanced GIST who have received 
approved therapies 
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3. 
STUDY DESIGN 
3.1. 
Overview of Study Design 
This is a 2-arm, randomized, placebo-controlled, double-blind, international, multicenter 
study comparing the efficacy of DCC-2618 to placebo in patients who have received 
treatment with prior anticancer therapies. Prior anticancer therapies must include treatment 
with imatinib, sunitinib, and regorafenib (3 prior therapies). Up to 40% of enrolled patients 
may have received prior treatment with imatinib, sunitinib, regorafenib, and other drugs (≥4 
prior therapies). Approximately 120 patients will be randomized in a 2:1 ratio to DCC-2618 
150 mg QD or placebo (see Figure 1). Randomization will be stratified by: 
• Patients who have received 3 prior anticancer treatments versus patients who have 
received ≥4 prior anticancer treatments  
• It should be noted that enrollment for patients who have received ≥4 prior anticancer 
treatments will be limited to 40% of the overall sample size. 
• Eastern Cooperative Oncology Group (ECOG) performance status (PS)=0 versus ECOG 
PS=1 or 2 
The primary response for the study will be evaluated using the modified RECIST Version 1.1 
- GIST-specific (hereafter referred to as “modified RECIST”) based on independent 
radiologic review. 
Upon disease progression by modified RECIST based on independent radiologic review, 
study drug treatment will be unblinded. At that time:  
• Patients randomized to DCC-2618 150 mg QD will be given the option to:  
• continue DCC-2618 at an increased dose of 150 mg BID (See Section 5.2.1 for more 
details on intra-patient dose escalation), or  
• continue treatment on study with the same dose if the Investigator feels the patient is 
receiving benefit from DCC-2618 or if dose escalation may not be tolerable for the 
patient (dose escalation is not permitted at a later time during the study), or  
• discontinue DCC-2618. 
• Patients randomized to placebo will be given the option to:  
• cross over to receive DCC-2618 150 mg QD, or 
• discontinue the study. 
Patients randomized to placebo who cross over to receive DCC-2618 150 mg QD and 
have disease progression by modified RECIST based on Investigator assessment will be 
given the option to: 
• continue DCC-2618 at an increased dose of 150 mg BID (See Section 5.2.1 for more 
details on intra-patient dose escalation),  
• continue treatment on study with the same DCC-2618 dose if the Investigator feels 
the patient is receiving benefit from DCC-2618 or if dose escalation may not be 
tolerable for the patient (dose escalation is not permitted at a later time during the 
study), or,  
• discontinue DCC-2618.  
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3.2. 
Number of Patients 
Approximately 120 patients (approximately 80 randomized to DCC-2618 and approximately 
40 randomized to placebo) will be enrolled in this study at approximately 35 centers globally. 
3.3. 
Duration of Study 
Patients will be treated on their assigned arm until they develop progressive disease, 
experience unacceptable toxicity, or withdraw consent. At the time of progressive disease by 
modified RECIST based on independent radiologic review and following unblinding of study 
drug treatment, patients receiving DCC-2618 will be allowed to dose escalate, continue on 
the same dose, or discontinue DCC-2618; and patients receiving placebo will be allowed to 
cross over to receive DCC-2618 and can dose escalate, continue on the same dose, or 
discontinue DCC-2618 upon further progression by Investigator assessment. 
Patients will be eligible to receive study drug for up to 2 years or until commercial supply of 
the drug is available. This will be extended by agreement between the Sponsor and 
Investigator for patients who exhibit evidence of clinical benefit and tolerability to the drug, 
and who adhere to the study procedures. The study will end following the last patient last 
visit. 
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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible to enroll in the study: 
1. Male or female patients ≥18 years of age at the time of informed consent 
2. Histologic diagnosis of GIST  
3. Patients must have progressed on imatinib, sunitinib, and regorafenib or have 
documented intolerance to any of these treatments despite dose modifications. 
4.  ECOG PS of 0 to 2 at screening. 
5. Able to provide an archival tumor tissue sample if no anticancer therapy was 
administered since the sample was collected; otherwise, a fresh tumor tissue sample is 
required prior to the first dose of study drug. 
6. Female patients of childbearing potential must have a negative serum beta-human 
chorionic gonadotrophin (β-hCG) pregnancy test at screening and a negative pregnancy 
test at Cycle 1 Day 1 prior to the first dose of study drug. 
7. Patients of reproductive potential must agree to follow the contraception requirements 
outlined in Section 6.11.10. 
8. The patient is capable of understanding and complying with the protocol and has signed 
the informed consent document. A signed informed consent form must be obtained 
before any study-specific procedures are performed. 
9. At least 1 measurable lesion according to modified RECIST Version 1.1 (non-nodal 
lesions must be ≥1.0 cm in the long axis or ≥ double the slide thickness in the long axis) 
within 21 days prior to the first dose of study drug. 
10. Adequate organ function and bone marrow reserve as indicated by the following 
laboratory assessments performed at screening. 
• ANC ≥1000/µL 
• Hemoglobin ≥8 g/dL 
• Platelet count ≥75,000/µL 
• Total bilirubin ≤1.5 x the upper limit of normal (ULN) 
• Aspartate transaminase and alanine transaminase ≤3 x ULN (≤5x ULN in the presence of 
hepatic metastases)  
• Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min based on either urine 
collection or Cockcroft Gault estimation  
• Prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin 
time ≤1.5 x 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 x 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. 
11. 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). 
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4.2. 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study:  
1. Treatment with anticancer therapy, including investigational therapy, or investigational 
procedures within 14 days or 5 x the half-life (whichever is longer) prior to the first dose 
of study drug. For prior biological therapies, eg, monoclonal antibodies with a half-life 
longer than 3 days, the interval must be at least 28 days prior to the first dose of study 
drug. 
2. Prior treatment with DCC-2618 
3. Prior or concurrent malignancy whose natural history or treatment have the potential to 
interfere with the safety or efficacy assessment of DCC-2618. Patients receiving adjuvant 
cancer treatment are not eligible if those medications are potentially active against GIST 
or excluded per protocol (refer to Section 5.12.3). 
4. Patient has known active central nervous system metastases. 
5. New York Heart Association class II - IV heart disease, active ischemia or any other 
uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac 
arrhythmia requiring therapy, uncontrolled hypertension, or congestive heart failure. 
6. Arterial thrombotic or embolic events such as cerebrovascular accident (including 
ischemic attacks) or hemoptysis within 6 months before the first dose of study drug. 
7. Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events 
(eg, pulmonary embolism) within 3 months before the first dose of study drug. Patients 
with venous thrombotic events ≥3 months before the first dose of study drug on stable 
anticoagulation therapy are eligible. 
8. 12-lead ECG demonstrating QT interval corrected by Fridericia’s formula (QTcF) 
>450 ms in males or >470 ms in females at screening or history of long QT interval 
corrected (QTc) syndrome. 
9. Left ventricular ejection fraction (LVEF) <50% at screening. 
10. Use of proton-pump inhibitors within 4 days prior to the first dose of study drug. Other 
medications that increase gastric pH, ie, histamine H2 receptor antagonists and antacids 
may be taken provided they are not administered within 2 hours before or after 
administration of study drug. 
11. Use of strong or moderate inhibitors and inducers of CYP3A4, including certain herbal 
medications (eg, St. John’s Wort) and consumption of grapefruit or grapefruit juice 
within 14 days or 5 x the half-life (whichever is longer) prior to the first dose of study 
drug. Please refer to the Indiana University Department of Medicine website 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) for guidance on medications that 
inhibit CYP3A4 enzymes. 
12. Use of known substrates or inhibitors of BCRP transporters within 14 days or 5 x the 
half-life (whichever is longer) prior to the first dose of study drug. Please refer to the 
FDA’s website 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm093664.htm) for inhibitors and substrates. 
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13. Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study 
drug. Following major surgeries >4 weeks prior to the first dose of study drug, all 
surgical wounds must be healed and free of infection or dehiscence.  
14. 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. 
15. Known human immunodeficiency virus or hepatitis C infection only if the patient is 
taking medications that are excluded per protocol (refer to Section 5.12.3), active 
hepatitis B, or active hepatitis C infection. 
16. If female, the patient is pregnant or lactating. 
17. Known allergy or hypersensitivity to any component of the investigational drug product. 
Patients with a history of Stevens-Johnson syndrome on a prior TKI are excluded. 
18. Gastrointestinal abnormalities including but not limited to: 
o inability to take oral medication 
o malabsorption syndromes  
o requirement for IV alimentation. 
19. Any active bleeding excluding hemorrhoidal or gum bleeding. 
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5. 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
Study drug refers to DCC-2618 and matching placebo. 
5.1. 
Study Drug Description 
DCC-2618 will be supplied as 50 mg strength tablets for oral administration. The tablets 
contain the active pharmaceutical ingredient formulated as a 
% w/w
on a hydroxypropyl methylcellulose acetate succinate, 
 
%). 
Other excipients include microcrystalline cellulose 
) 
%), lactose 
 
%), cross-linked polyvinylpyrrolidone 
%), fumed silica 
) 
%), and 
magnesium stearate 
%). 
Placebo will be supplied as identically sized and color-matched tablets. 
5.2. 
Study Drug Dose and Administration 
Study drug may be dispensed only under the supervision of the Investigator or an authorized 
designee and only for administration to study patients. Patients will be randomized to receive 
150 mg QD of DCC-2618 or placebo in repeated 28-day cycles. 
The Investigator or designee must instruct the patient to take the study drug as per protocol. 
• Patients should be instructed to take their assigned dose at the same time each day.  
• Patients should take their study drug dose with a 6-ounce glass of water with or without 
food.  
• Patients must be instructed to swallow the tablets whole. Tablets must not be crushed, 
chewed, or dissolved in liquid or food.  
• The date, amount taken, and time of study drug administration must be recorded for the 
3 days prior to PK sample collections and on the days of PK sample collection. 
• On days of scheduled visits, the dose of study drug must be administered at the site after 
pre-dose assessments have been completed. The date, amount taken and time of study 
drug administration must be recorded.  
If a patient dose escalates to 150 mg BID of DCC-2618, the Investigator or designee must 
instruct the patient to take the study drug as per protocol. 
• Patients should be instructed take the study drug twice a day, at least 6 hours apart, and at 
the same time each day. 
• Patients should take their study drug dose with a 6-ounce glass of water with or without 
food.  
• Patients must be instructed to swallow the tablets whole. Tablets must not be crushed, 
chewed, or dissolved in liquid or food.  
• The date, amount taken, and time of study drug administration must be recorded for the 
3 days prior to PK sample collections and on the days of PK sample collection. 
• On days of scheduled visits, the dose of study drug must be administered at the site after 
pre-dose assessments have been completed. The date, amount taken and time of study 
drug administration must be recorded. 
If a patient forgets to take a dose at the scheduled time, the patient can take the scheduled 
dose if taken within 8 hours of the scheduled time that was missed for QD dosing and within 
4 hours of the scheduled time that was missed for BID dosing. If more than 8 hours (for QD 
dosing) or 4 hours (for BID dosing) have passed after the scheduled time, then that missed 
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dose must be omitted and the patients must continue treatment with the next scheduled dose. 
On days of planned study visits, patients will be informed to take the study drug at the study 
site as per the Schedule of Assessments. 
If vomiting occurs immediately after taking a dose, that dose must not be “made up,” and the 
patient may be offered prophylactic anti-emetics prior to their next dose. 
For information on overdose, refer to Section 7.12. 
5.2.1. 
Intra-patient Dose Escalation 
• Patients who are randomized to DCC-2618 150 mg QD and have disease progression by 
modified RECIST based on independent radiologic review may continue DCC-2618 at an 
increased dose of 150 mg BID. 
• Patients who are randomized to placebo who cross over to receive DCC-2618 150 mg 
QD and have disease progression by modified RECIST based on Investigator assessment 
may continue DCC-2618 at an increased dose of 150 mg BID.  
Upon disease progression, patients must be counseled on any other available treatment 
options. At the time of dose escalation, the patient must return to the site for study drug to be 
dispensed. Detailed instructions will be provided in the Study Reference Manual. 
5.2.2. 
Crossover 
Patients randomized to placebo who have disease progression by modified RECIST based on 
independent radiologic review will be given the option to cross over to receive DCC-2618 
150 mg QD. Once the independent radiologic review has confirmed disease progression, the 
patient's study drug treatment will be unblinded and either the patient may start the crossover 
procedures, or discontinue if the patient declines to enter the crossover.  
The initiation of crossover will start with the assessments described in Cycle 1 Day 1 of 
Table 2 (Schedule of Assessments for Crossover). Following crossover, if a patient has 
disease progression by modified RECIST based on Investigator assessment, then the patient 
may continue DCC-2618 with the same dose if the Investigator feels the patient is receiving 
benefit from DCC-2618, may dose escalate according to the rules in Section 5.2.1, or may 
discontinue DCC-2618. Detailed instructions will be provided in the Study Reference 
Manual. 
5.3. 
Dose Interruption and Modification  
Study drug may be interrupted or modified (ie, dose reduction) at the discretion of the 
Investigator at any time due to adverse event (AE), to accommodate palliative treatment, or 
for other reasons after consultation with the Sponsor. An interruption must be limited to no 
more than 1 cycle (28 days). Upon resumption following a dose interruption, the Investigator 
must continue with the patient’s original visit schedule calculated from Cycle 1 Day 1. 
5.3.1. 
Dose Interruption due to Planned Medical Procedures 
For surgeries that occur while the patient is on study, the extent of the procedure and rate of 
healing following the procedure must be taken into consideration. The following guidance 
applies: 
• Planned minimally invasive surgery: study drug must be interrupted for 3 days prior to 
and 3 days after surgery.  
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• Planned major surgeries: study drug must be interrupted for a minimum of 5 days prior to 
surgery and continuation of study drug must be determined after consultation with the 
Sponsor. 
• Unplanned surgery: study drug must be interrupted immediately and continuation of 
study drug must be determined after consultation with the Sponsor. 
5.3.2. 
Dose Interruption and Modification Due to Toxicity 
Study drug may be interrupted or reduced as described in Table 7 at the discretion of the 
Investigator at any time due to AEs and according to the guidelines described in Table 8, 
Table 9, and Table 10. Whenever possible, dose reductions must be prospectively discussed 
with the Sponsor. If study drug is interrupted and then study drug is restarted, the patient 
should remain on their original cycle schedule.   
If any patient requires a dose lower than 50 mg QD or if a patient has had their dose reduced 
and has disease progression confirmed by the independent radiologic reviewer, the patient 
must be discontinued from study drug, the End-of-Treatment (EOT) Visit and Safety Follow 
up Visit must be conducted, and the patient must be followed for overall survival. 
Table 7: 
Dose Reduction Steps for Study Drug 
Starting Dose of Study Drug 
1ST  
Dose Reduction 
2ND  
Dose Reduction 
150 mg QD 
100 mg QD 
50 mg QD 
 
Following disease progression by modified RECIST, patients who dose escalate to 150 mg 
BID and have toxicity must be dose reduced according to the steps outlined in Table 8. 
Table 8: 
Dose Reduction Steps for Patients Who Progressed and Dose Escalated to 
150 mg BID 
Starting Dose of Study Drug 
1ST  
Dose Reduction 
2ND 
Dose Reduction 
150 mg BID 
100 mg BID 
150 mg QD 
 
If the AE returns to Grade 1 or baseline, the patient may be re-escalated. Efforts must be 
made to re-escalate the patient to the dose level at which the AE occurred. If the dose level is 
reduced to the 1st dose reduction level and the AE returns to Grade 1 or baseline, the patient 
may be re-started at the starting dose level. If a patient has two sequential dose reductions 
and the AE returns to Grade 1 or baseline at the 2nd dose reduction level, the patient may be 
re-started at the 1st dose reduction level and must remain at this dose level for 1 cycle without 
interruption before escalating to the starting dose level.   
If the AE leading to dose modification does not return to Grade 1 or baseline within 1 cycle 
(28 days), then the study drug must be discontinued, unless the event is considered not 
clinically significant by the Investigator, in which case the possibility of restarting the patient 
at a reduced dose level may be made after consultation with the Sponsor. 
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Table 9: 
Dose Modifications for Dermatologic Toxicities and Arthralgia/Myalgia 
Toxicity Grade 
Dose Modification Guide 
Grade 1 
Institute support measures and continue the study drug at the current dose 
Grade 2 
Institute support measures and continue the study drug at the current dose 
If no improvement within 7 days, then interrupt the study drug 
• 
If the event returns to Grade 1 or baseline within 7 days, resume the study drug at the same dose level 
• 
If the event returns to Grade 1 or baseline after 7 days, resume the study drug at a reduced dose level 
If this is a recurrence, after event returns to Grade 1 or baseline, resume the study drug at a reduced dose level regardless of 
time to improvement 
If after a dose reduction the event is maintained at Grade 1 or baseline for at least 1 cycle (28 days) of dosing, consider re-
escalating the study drug by 1 dose level 
Grade 3 
Institute support measures 
Interrupt study drug for at least 7 days or until the event returns to Grade 1 or baseline (maximum 28 days) 
• 
Resume study drug at a reduced dose level 
If after a dose reduction the event is maintained at Grade 1 or baseline for at least 1 cycle (28 days) of dosing, consider re-
escalating the study drug by 1 dose level 
Grade 4 
Discontinue study drug unless the event is not considered life-threatening. Patients may continue study drug with non-life 
threatening events upon discussion with the Sponsor. 
Any Grade 
Stevens-Johnson Syndrome: 
If a patient experiences Stevens-Johnson syndrome (SJS), study drug must be permanently discontinued. The patient should 
be immediately referred to a hospital for clinical evaluation and supportive care/management per institutional guidelines. 
Re-administration of study drug is not allowed due to the risk of recurrent SJS. Caution for recurrence of SJS with other 
similar agents (TKIs for GIST) is advised, as the one patient who has been diagnosed with SJS while being treated with 
DCC-2618 had a similar reaction while being treated with regorafenib prior to DCC-2618. 
 
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Table 10: 
Dose Modifications and Management of Hypertension 
Toxicity Grade 
Management Guideline* 
Grade 1 
Prehypertension (systolic BP 120 - 139 mm Hg or 
diastolic BP 80 - 89 mm Hg) 
Continue BP monitoring  
Continue the study drug at the current dose level 
Grade 2  
Systolic BP 140 - 159 mm Hg or 
diastolic BP 90 - 99 mm Hg 
 Or 
Symptomatic increase by 
>20 mm Hg (diastolic) or to 
>140/90 mm Hg if previously within normal limits 
Treat BP to achieve diastolic BP ≤90 mmHg and or systolic BP ≤140 mmHg 
• 
If BP was previously within normal limits, start antihypertensive monotherapy 
• 
If patient is already on antihypertensive medication, titrate dose up 
Continue the study drug at the current dose level 
Hold study drug if symptomatic increase by 20 mmHg (diastolic BP) until symptoms resolve 
and diastolic BP ≤90 mmHg 
On resuming study drug, continue at the same dose level 
Grade 3  
Systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg) 
Or  
More than 1 drug or more intensive therapy than 
previously indicated 
Treat to achieve diastolic BP ≤90 mmHg and or systolic BP ≤140 mmHg 
• 
Start antihypertensive medication 
and/or 
• 
Increase current antihypertensive medication 
and/or 
• 
Add additional antihypertensive medication 
If symptomatic, hold study drug until diastolic BP ≤90 mmHg and/or systolic BP 
≤140 mmHg, and symptoms resolve 
On resuming study drug, continue at the same dose level 
If BP is not controlled with addition of a new or more intensive therapy, reduce the study drug 
by 1 dose level 
If Grade 3 hypertension recurs despite study drug dose reduction and antihypertensive therapy, 
reduce the study drug by 1 additional dose level 
Grade 4 
Life-threatening consequences (eg, malignant 
hypertension, transient or permanent neurologic 
deficit, hypertensive crisis) 
Treat BP per institutional guidelines 
Discontinue study drug 
BP=blood pressure 
*If BP remains controlled for at least 1 full cycle (28 days), study drug dose re-escalation is permitted at the Investigator’s discretion. 
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Table 11: 
Dose Modifications for Treatment Related Adverse Events Other than Dermatologic Toxicities, 
Arthralgia/Myalgia, and Hypertension 
Toxicity Grade 
Management Guideline1 
Any Grade 3 or 4 
Interrupt study drug dosing until event has resolved to Grade 1 or baseline 
Once the AE returns to Grade 1 or baseline, reduce study drug by 1 dose level 
If a patient tolerates the reduced dose without recurrence of the event for at least one cycle, consider re-escalating the dose 
of study drug to the prior dose level 
Asymptomatic/Not clinically 
significant Grade 3 or 4 
laboratory AEs (including 
CPK and lipase) that persist 
≤10 days 
Closely monitor for clinical symptoms and continue the study drug at the current dose level 
Repeat labs within 10 days. 
Asymptomatic/Not clinically 
significant Grade 3 or 4 
laboratory AEs (including 
CPK and lipase) that persist 
>10 days 
Closely monitor for clinical symptoms; for Grade 4 events, interrupt study drug until the event returns to Grade 3 
• 
Asymptomatic Grade 3 or Grade 4 elevations of plasma enzyme: lipase or CPK do not require dose interruption 
Once the AE returns to Grade 3, resume the study drug at the current dose level or consider reducing by 1 dose level per 
Investigator discretion after discussion with the Sponsor. 
Clinically Significant Grade 
3 or 4 laboratory AEs 
(including CPK and lipase) 
Interrupt study drug. If the Investigator assesses that restarting study drug is in the patient’s best interest, the Sponsor must 
be contacted for discussion and determination if restarting is allowed. 
AE=adverse event; CPK=creatine phosphokinase 
1. The rules for dose modifications for laboratory AEs will be based on local laboratory results.  
 
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5.4. 
Packaging and Labeling 
DCC-2618 will be supplied by the Sponsor as formulated drug in tablets for oral 
administration containing 50 mg of study drug in 30-count high-density polyethylene 
(HDPE) bottles with child resistant caps.  
Placebo tablets of matching size, shape, and color, will be supplied by the Sponsor in 
matching 30-count HDPE bottles with child resistant caps. 
Study drug labeling will be in accordance with applicable local and national regulations. 
Study drug will be provided and replaced via the Interactive Response Technology (IRT). 
Study drug dispensation instructions will be provided in the Pharmacy Manual. 
5.5. 
Storage Conditions 
Study drug bottles must be stored tightly closed between 5°C/41°F and 25°C/77°F, away 
from sunlight and areas of high humidity (ie, near showers in bathrooms) and according to 
the instructions provided in the Pharmacy Manual. Excursions between 2°C/35.6°F and 
27°C/80.6°F are allowed. While at the clinical site, the study drug must be stored in a secure, 
temperature-monitored area of limited access and only at the location(s) listed on the Form 
FDA 1572. 
Instructions regarding the storage and handling of study drug after dispensation to patients 
will be provided to site in the Pharmacy Manual. 
5.6. 
Study Drug Compliance 
To ensure study drug compliance, the Investigator or designee must supervise all study drug 
dosing that occurs at the site. At each visit, site personnel must review that the patient is 
compliant with study drug dosing and remind the patient of study drug dosing requirements. 
Compliance must also be assessed by ongoing study drug count. 
If a patient demonstrates continued noncompliance of study drug dosing despite educational 
efforts, the Investigator must contact the Sponsor to discuss discontinuation of the patient 
from the study.  
5.7. 
Study Drug Accountability 
Accountability for the study drug at the study site is the responsibility of the Investigator. 
The Investigator must ensure that the study drug is used only in accordance with this 
protocol. Where allowed, the Investigator may choose to assign drug accountability 
responsibilities to a pharmacist or other appropriate individual. Drug accountability records 
indicating the study drug’s delivery date to the site, study drug inventory at the site, study 
drug dispensed to each patient, study drug returned by each patient, and study drug returned 
to the Sponsor or study drug destruction on site must be maintained by the clinical site. 
Accountability records must include dates, quantities, bottle numbers, and patient numbers. 
The Sponsor or its designee must review drug accountability at the site on an ongoing basis 
during monitoring visits. If any dispensing errors or discrepancies are discovered, the 
Sponsor must be notified immediately. 
Patients must be instructed to return all unused, partially used, and used study drug bottles to 
the site at each visit. The study monitor must verify study drug records and inventory 
throughout the study. 
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5.8. 
Disposal, Return, or Retention of Unused Study Drug 
Patients must be instructed to return all used, partially used, and full study drug bottles. The 
site staff or pharmacy personnel (as appropriate) must retain all materials returned by the 
patients until returned to Sponsor/designee or destroyed by the study site. If the study drug 
will be destroyed at the study site, the Investigator or designee, must ensure that the materials 
are destroyed in compliance with applicable environmental regulations, institutional policy, 
and any special instructions provided by the Sponsor. Destruction must be adequately 
documented. 
5.9. 
Method of Assigning Patients to Treatment 
Patients will be randomized in a 2:1 ratio to DCC-2618 150 mg or placebo. Randomization 
will be stratified by: 
• Patients who have received 3 prior anticancer treatments versus patients who have 
received ≥4 prior anticancer treatments  
o It should be noted that enrollment for patients who have received ≥4 prior 
anticancer treatments will be limited to 40% of the overall sample size. 
o Prior anticancer treatments are only counted once and without regard to when 
the patient received treatment, unless they were given as combination 
treatments.   
• ECOG=0 versus ECOG=1 or 2  
The IRT will be used to assign study drug treatment. Detailed instructions for randomization 
will be provided separately. 
5.10. 
Blinding and Unblinding 
This is a double-blind study. 
5.10.1. 
Blinding 
The patients and all site personnel, including the Investigator, the site monitor, and the study 
team must be blinded, with the exception of the following: 
• Any site personnel for whom this information is important to ensure the safety of the 
patient in the event of a life threatening medical emergency 
• Any site personnel for whom this information is important to ensure the safety of the 
patient and their fetus in the event of a pregnancy 
• Vendors responsible for pharmacovigilance and regulatory personnel at the Sponsor to 
satisfy serious adverse event (SAE) processing and reporting regulations 
• Clinical Supply Chain  
• Unblinded statistician and programmer preparing the final (production) randomization 
list and unblinded analyses for the independent data monitoring committee (IDMC) 
• IDMC 
• Vendors analyzing PK and biomarker samples 
• Vendor conducting the population PK analysis 
• IRT vendor 
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• The Investigator, patient, site personnel, site monitor and study team will become 
unblinded to a specific patient's treatment assignment, if the patient has disease 
progression based on independent radiologic review. 
5.11. 
Unblinding 
Instructions for unblinding through IRT will be provided in the Study Reference Manual. 
Unblinding of the individual patient’s study drug assignment by the Investigator must be 
limited to the following: medical emergencies in which knowledge of the patient’s study 
drug is necessary for clinical management. In cases of medical emergencies, the Investigator 
must use their best judgment as to whether to unblind. If the Investigator deems it is not 
necessary to unblind immediately, the Investigator must first attempt to contact the Sponsor 
to discuss and agree to the need for unblinding. If the Investigator has tried but is unable to 
reach the Sponsor, the Investigator must use their best judgment, based on the nature and 
urgency of the clinical situation, and may proceed with unblinding without having 
successfully reached and discussed the situation with the Sponsor. 
If a patient’s study drug assignment has been unblinded for a medical emergency, the 
Sponsor must be notified within 24 hours of the unblinding event. The reason and the date of 
the unblinding must be documented clearly in the patient's source documents. Information 
regarding the study drug assignment obtained from the unblinding must be maintained in a 
secure location with controlled access and must not be shared with the Sponsor, contract 
research organization, or any site personnel (other than the physician treating the patient). In 
addition, the Investigator must consider whether the clinical event that prompted unblinding 
must be considered an SAE, according to the regulatory definitions or criteria for SAEs, and 
if so, submit an SAE report, per Section 7.11. If a patient’s study drug assignment is 
unblinded for a medical emergency or urgent clinical situation, the patient must discontinue 
study drug. 
The Sponsor or designee may also unblind any SAE reports in compliance with regulatory 
reporting requirements. In addition, the Sponsor may, for matters relating to safety concerns, 
unblind individual patients at any time. 
5.12. 
Prior and Concomitant Treatment and Procedures 
5.12.1. 
Prior Medications and Procedures 
Information regarding any medication or non-drug therapy or procedure taken or performed 
within 30 days prior to screening and before the first dose of study drug must be documented 
in the patient’s source documents and the electronic case report form (eCRF). 
5.12.2. 
Prior Anticancer Medications and Procedures 
Any prior anticancer medication or procedure must be documented in the patient’s source 
documents and the eCRF. 
5.12.3. 
Concomitant Medications 
All medications, including vitamin supplements, over-the-counter medications, and oral 
herbal preparations; non-drug therapies taken on or after the first day of study drug dose 
through and including 30 days after the last dose of study drug must be documented in the 
patient’s source documents and the eCRF. In addition, any new treatments taken after the last 
dose of study drug through 30 days after the last dose must be documented in the patient's 
source documents and the eCRF. 
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The date and time of concomitant H2 receptor antagonist and antacid administration must be 
recorded 3 days prior to the study visit and on the day of the visit in the patient’s source 
documents and the eCRF. 
5.12.3.1. 
Permitted Medication 
Patients may receive medications for symptomatic relief (eg, analgesics, laxatives, 
antiemetics). 
Medications that increase gastric pH (eg, antacids), with the exception of proton pump 
inhibitors, may be taken provided they are not administered within 2 hours before or after 
administration of study drug. 
5.12.3.2. 
Medications to Avoid or Take with Caution 
The following medications must be avoided or taken with caution following discussion with 
the Sponsor: 
• Strong or moderate inhibitors or inducers of CYP2D6, CYP2C8, or CYP2E1 during 
treatment with study drug. Please refer to the Indiana University Department of Medicine 
website (http://medicine.iupui.edu/clinpharm/ddis/main-table/) for guidance on 
medications that inhibit or induce CYP2D6, CYP2C8, or CYP2E1 enzymes. 
• Known substrates or inhibitors of P-glycoprotein 1 (permeability glycoprotein, also 
known as multidrug resistance protein 1 or MDR1). Please refer to the FDA’s website for 
inhibitors 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm#table5-2 and substrates 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm#table5-1 for MDR1.  
• Medications that are known substrates of OATP1B1 and OATP1B3. Please refer to the 
FDA’s website 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm#table5-1) for known substrates of OATP1B1 and 
OATP1B3. 
• Medications dependent on CYP2C8, CYP2C9, CYP2C19, or CYP2D6 for their 
metabolism. Please refer to the Indiana University Department of Medicine website 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) for guidance on medications. For 
example: 
o Warfarin may be given but be monitored carefully due to CYP2C9 inhibition 
by study drug. 
o Plavix (clopidogrel) should be avoided.  Plavix is a pro-drug dependent on 
CYP2C19 for its activity. Co-administration can lead to reduced effects of 
Plavix. 
Patients taking any of the above listed medications must be closely monitored for any 
potential drug-drug interactions. 
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5.12.3.3. 
Prohibited Medications and Substances 
Prohibited medications and certain foods are not allowed in this study (from screening 
through the Safety Follow-up Visit). The following medications must be excluded during the 
study:  
• Proton pump inhibitors must be discontinued at least 4 days prior to the first dose of 
study drug 
• Strong or moderate inhibitors or inducers of CYP3A4, including certain herbal 
medications (eg, St. John’s Wort) must be discontinued at least 14 days or 5 x the 
half-life (whichever is longer) prior to the first dose of study drug. Please refer to the 
Indiana University Department of Medicine website 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/) for guidance on medications that 
inhibit CYP3A4 enzymes. 
• Grapefruit or grapefruit juice at least 14 days prior to the first dose of study drug. 
• Known substrates or inhibitors of BCRP transporters must be discontinued at least 
14 days or 5 x the half-life (whichever is longer). Please refer to the FDA’s website 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm) for inhibitors and substrates for BCRP.  
• Anticancer therapies, including investigational therapy, must be discontinued at least 
14 days or 5 x the half-life of the drug, whichever is longer, prior to the first dose of 
study drug. For prior biological therapies, eg, monoclonal antibodies with a half-life 
longer than 3 days, the interval must be at least 28 days prior to the first dose of study 
drug. 
5.12.4. 
Concomitant Procedures 
All procedures performed on or after the first dose of study drug through and including 
30 days after the last dose of study drug must be documented in the patient’s source 
documents and the eCRF. 
Surgical resection or palliative radiotherapy during study treatment must be discussed with 
the Sponsor prior to implementation. If the Investigator and Sponsor agree it is in the best 
interest of the patient, surgical resection or palliative radiotherapy may be performed; 
however, the patient must be censored in the PFS analysis from the time surgery or 
radiotherapy was performed. 
5.13. 
Other Precautions 
In order to mitigate the potential risk of photoirritation/phototoxicity, patients must be 
instructed to avoid strong sunlight, sunlamps, and other sources of ultraviolet radiation for 
the duration of the study. Prophylactic skin care recommendations for all patients on study 
drug include sunscreen with SPF ≥30, hypoallergenic moisturizing creams or ointments for 
dry skin, and gentle skincare with fragrance-free soaps and detergents. 
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6. 
STUDY ASSESSMENTS 
6.1. 
Screening 
Screening must occur within 28 days prior to the first dose of study drug to confirm that 
patients meet the selection criteria for the study. Radiologic imaging must be performed 
within 21 days prior to the first dose of study drug. The assessments to be conducted at 
screening are provided in Table 1 (schedule of assessments). 
6.2. 
Rescreening 
Patients may only be rescreened with the approval of the Sponsor. If a patient is rescreened, 
all screening assessments must be repeated except tumor tissue sample (as applicable) and 
ophthalmologic examination. Imaging assessments and dermatologic examination do not 
need to be repeated if performed within 21 days of the first dose of study drug. Patients may 
only be rescreened once. If a patient is rescreened, the screening window will begin once the 
first rescreening assessment has been initiated.  
6.3. 
Treatment Period 
Patients will be randomized in the study after confirmation of all eligibility criteria. The first 
dose of study drug must be administered in the clinic on Cycle 1 Day 1. Study visits during 
the Treatment Period will occur as shown in Table 1 (schedule of assessments) and Table 2 
(schedule of assessments for crossover). Patients will be outpatients during the Treatment 
Period. All visits must occur within the windows specified. 
Patients who prematurely discontinue study drug must return for an EOT Visit within 7 days 
after the last dose of study drug. 
6.4. 
Follow Up 
Patients will be contacted by phone call for the Safety Follow-up Visit within 30 days 
(+5 days) after the last dose of study drug to assess AEs; medications, including anticancer 
treatments; and procedures (see Section 6.11.12 for further details). Patients will be contacted 
by phone call for overall survival (see Section 6.10.2 for further details). 
6.5. 
Lost to Follow Up 
A patient will be considered lost to follow up if both of the following occur: 
• Patient misses 2 consecutive study visits and is subsequently unable to be contacted by 
phone call (3 documented attempts by phone within 2 weeks following the second missed 
visit). 
• Patient does not respond within 2 weeks to a registered letter sent after the 3 attempted 
phone contacts. 
6.6. 
Study Assessments 
The study specific assessments are detailed in this section and the schedule of assessments 
are outlined in Table 1 (schedule of assessments) and Table 2 (schedule of assessments for 
crossover). 
Additional unscheduled safety or efficacy assessments may be performed at any time as 
clinically indicated to determine the relevance of specific findings and/or the duration of 
events. 
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6.6.1. 
Timing of Assessment 
The EORTC QLQ-C30 and EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaires must 
be performed before the patient sees the Investigator or designee on the day of the scheduled 
visit. If the dermatologic examination or imaging assessments are completed within 7 days of 
the scheduled visit and the patient does not see the Investigator or designee, the 
questionnaires do not need to be completed on that day. The EORTC QLQ-C30 must be 
performed prior to the EQ-5D-5L, followed by the Healthcare Utilization Questionnaire 
(HCUQ).  
All other assessments may be completed in any order as shown in Table 1 (schedule of 
assessments) and Table 2 (schedule of assessments for crossover). 
6.7. 
Informed Consent Procedure 
Each patient must sign and date a study-specific informed consent form (ICF) before any 
study specific procedures can be performed. The ICF will comply with all applicable 
regulations governing the protection of patients. An ICF, approved by the Sponsor and the 
site's Institutional Review Board (IRB)/Independent Ethics Committee (IEC)/Research 
Ethics Board (REB) must be used. The Investigator or designee must document the 
consenting process, including the date when the informed consent form was signed in the 
patient’s source document. 
6.8. 
Assigning Patient Number 
A unique patient identification number (patient number) will be assigned to each patient once 
informed consent is obtained. Detailed instructions on assigning patient numbers will be 
provided in the Study Reference Manual. If a patient is rescreened, the patient retains the 
original patient number. 
6.9. 
Demographics and Medical History 
Demographic information must be collected at screening. 
Cancer history and prior treatment (including reason for discontinuation), must be obtained 
during screening. Cancer history will include: 
• Known histologic diagnosis of GIST 
• Tumor mutational status 
• All prior cancer treatment regimens, including: 
• Surgery (including tumor tissue sample[s]): include date(s), site(s), and extent of 
resection (eg, tumor tissue sample only, R0, R1, or R2) 
• Systemic therapy: include dates of treatment, agents (including dose and dosing 
regimen), reason for treatment (eg, adjuvant therapy or for metastatic disease), best 
response, date of disease progression or date and reason for treatment discontinuation 
other than disease progression. 
• Radiation therapy: include the site(s) treated, total dose(s), date(s) of treatment, and 
response(s) 
• Other procedures, such as radiofrequency ablation (if applicable) 
Medical history, including any significant conditions or diseases that stopped at or prior to 
informed consent, must be elicited from each patient during screening. Based on the medical 
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history, the patient must be assessed for any disqualifying medical conditions as specified in 
the inclusion and exclusion criteria. The medical history shall include a complete review of 
systems, past medical and surgical histories, and any allergies. Ongoing conditions are 
considered concurrent medical conditions; if possible, the start date for these comorbidities 
must be documented. 
6.10. 
Efficacy 
6.10.1. 
Radiologic Imaging 
All patients will have radiographic tumor evaluation by computed tomography (CT) scans of 
the pelvis, abdomen, and chest according to the schedule of study assessments in Table 1 
(schedule of assessments) and Table 2 (schedule of assessments for crossover).  Radiologic 
imaging performed as standard of care prior to informed consent may be used as the 
Screening assessment as long as the imaging was performed within 21 days prior to the first 
dose of study drug. Radiologic imaging may be performed up to 7 days prior to the 
corresponding study visit or post dose at the study visit. An initial indication of a PR or CR 
based on independent radiologic review must be confirmed ≥4 weeks later. Magnetic 
resonance imaging (MRI) scans of the abdomen/pelvis and CT scan without contrast of the 
chest may be used for patients who are allergic to radiographic contrast media. Additionally, 
for patients whose local regulatory authority and/or ethics committee has not approved use of 
CT scans, MRIs may be used. Throughout the study, the same assessment technique must be 
used. Ultrasound scanning is not an acceptable substitute for CT scanning. 
Copies of all imaging scans must be obtained and sent to an independent imaging vendor 
designated by the Sponsor as outlined in a separate protocol specific manual. The 
independent imaging vendor will assess the quality of the images and be responsible for 
performing an independent radiologic review. 
The independent imaging vendor must ensure that the independent radiologic reviewer 
remains blinded to the local assessment from the Investigator and other unblinding 
information. This and all other imaging procedures will be documented in a protocol specific 
review charter agreed upon between the Sponsor and the independent imaging vendor before 
initiation of any independent radiologic reviews. 
The independent radiologic reviewer and Investigator will assess tumor response using 
modified RECIST (see Section 9.2.1.1). Response as determined by the Investigator will be 
recorded in the eCRF. Data from the independent radiologic review will be used for the 
primary endpoint analysis. 
Confirmation of No Disease Progression: If the independent radiologic reviewer confirms 
that there is no disease progression, the patient will continue to receive study drug unless 
there is a medical need (ie, rapid progression or clinical deterioration) that requires the study 
drug to be discontinued. If the Investigator determines progression based upon clinical 
deterioration, a scan must be performed and reviewed by the independent radiologic reviewer 
to determine if the patient progressed. The basis for determination of progression per clinical 
deterioration must be documented in the patient’s source documents and eCRF. 
Confirmation of Disease Progression: Following confirmation of disease progression by 
modified RECIST based on independent radiologic review, the patient's treatment 
assignment will be unblinded via the IRT.  
• Patients randomized to DCC-2618 150 mg QD will be given the option continue at an 
increased dose of 150 mg BID, to continue treatment on study with the same dose if the 
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Investigator feels the patient is receiving benefit from DCC-2618, or discontinue 
DCC-2618. If a patient continues treatment at the same dose, dose escalation is not 
allowed at a future time. At the time of dose escalation, the patient must come back to the 
site for study drug to be dispensed. 
• Patients randomized to placebo will be given the option to cross over to receive 
DCC-2618 150 mg QD, or discontinue the study. Crossover patients must follow the 
schedule of assessments in Table 2. 
Confirmation of Disease Progression Following Crossover: Following confirmation of 
disease progression by modified RECIST based on Investigator review, patients will be given 
the option to dose escalate according to the rules in Section 5.2.1, continue DCC-2618 at the 
same dose if the Investigator feels the patient is receiving benefit from DCC-2618, or 
discontinue DCC-2618. If a patient continues treatment at the same dose, dose escalation is 
not allowed at a future time. At the time of dose escalation, the patient must come back to the 
site for study drug to be dispensed. 
More details on image acquisition guidelines and radiographic assessment will be provided in 
a separate protocol specific manual. 
6.10.2. 
Overall Survival Follow-Up by Phone Call 
All patients will be followed until withdrawal of consent or death from any cause. After the 
Safety Follow-Up Visit, patients will be contacted every 3 months (±1 month) to collect 
long-term survival data.  
6.10.3. 
Patient Reported Outcome Measurements 
6.10.3.1. 
European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire for Cancer 30-item (EORTC QLQ-C30) 
The EORTC QLQ-C30 is a validated, standardized, patient-completed questionnaire used 
extensively in international clinical studies and developed to assess health-related quality of 
life in patients with cancer (28). The time required for completion is approximately 
3-5 minutes. Validated translations will be provided for sites in non-English-speaking 
countries. 
The questionnaire is composed of multi-item and single-item scales. These include 
5 functional scales (physical functioning, role functioning, emotional functioning, social 
functioning, cognitive functioning), 9 symptom scales (fatigue, nausea and vomiting, pain, 
dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a 
global health status/quality of life (QOL) scale. 
The functioning and symptoms scales ask the patient to rate his or her experience for a 
particular item during the last week by selecting Likert scale response options of “not at all,” 
“a little,” “quite a bit,” or “very much.” The 2 items comprising the global health status scale 
also evaluate the patient’s experience over the past week using numerical rating scales with 1 
representing “very poor” and 7 representing “excellent.” 
Patients will be asked to complete EORTC-QLQ-C30 in their native language using an 
electronic patient reported outcome (ePRO) system on provided tablet computers before 
dosing at the visits indicated in Table 1 (schedule of assessments) and Table 2 (schedule of 
assessments for crossover). 
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6.10.3.2. 
EuroQol 5-Dimension 5-Level (EQ-5D-5L) 
The EQ-5D-5L is a validated, standardized, patient-completed questionnaire developed by 
the EuroQol group and used commonly in clinical studies to provide a measure of patient 
utility for clinical and economic appraisals (29). The time required for completion is 
approximately 2-3 minutes. Validated translations of the EQ-5D-5L will be provided for sites 
in non-English-speaking countries.  
The first 5 items of the EQ-5D-5L measure the health dimensions of mobility, ability to 
conduct self-care, ability to conduct usual activities, pain/discomfort, and anxiety/depression. 
The patient will select from 5 response levels (no problems, slight problems, moderate 
problems, severe problems, extreme problems) to rate their level of difficulty on that 
dimension that day. The EQ-5D-5L represents a revision to the original EQ-5D-3L (with 
3 response levels per item) and has been shown to significantly increase reliability and 
sensitivity (discriminatory power) while maintaining ease of completion. 
The sixth item is a EuroQol visual analogue scale (EQ-VAS). The EQ-VAS records the 
patient’s self-rated health on a vertical scale with endpoints labeled “the best health you can 
imagine” and “the worst health you can imagine.” This information can be used as a 
quantitative measure of health as judged by the individual patient. A patient is asked to 
“mark an X on the scale to indicate how your health is TODAY” and “write the number you 
marked on the scale in the box below.” 
Patients will be asked to complete EQ-5D-5L after the EORTC-QLQ-C30 in their native 
language using an ePRO system on provided tablet computers before dosing at the visits 
indicated in Table 1 (schedule of assessments) and Table 2 (schedule of assessments for 
crossover). 
6.11. 
Safety 
The safety profile will be assessed based on physical examinations; ECOG PS; changes from 
baseline in vital signs, ECGs, LVEF based on echocardiogram/multigated acquisition scan 
(MUGA), dermatologic examination, and clinical laboratory tests; and the reporting of AEs. 
6.11.1. 
Physical Examinations 
A full physical examination will be performed at screening. A full physical examination 
includes a review of the following systems: head/neck/thyroid, eyes/ears/nose/throat, 
respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal, and neurological. 
Breast, anorectal, and genital examinations will be performed when medically indicated. At 
all other visits, examinations will be driven by clinical findings and/or patient complaints. 
After screening, any clinically significant abnormal findings in physical examinations must 
be reported as AEs. 
6.11.2. 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group PS (30) will be assessed according to the schedule of 
assessments in Table 1 (schedule of assessments) and Table 2 (schedule of assessments for 
crossover). ECOG may be performed pre or post dose. 
6.11.3. 
Vital Signs, and Weight and Height 
Vital sign measurements, height, and weight will be performed according to the schedule of 
assessments in Table 1 (schedule of assessments) and Table 2 (schedule of assessments for 
crossover). Vital sign measurements will include sitting blood pressure, pulse, respiratory 
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rate, and body temperature. These will be assessed following a 5-minute rest (seated or 
supine position). 
6.11.4. 
Electrocardiograms 
Digital, 12-lead ECGs will be performed with central over-reading according to the schedule 
of assessments in Table 1 (schedule of assessments) and Table 2 (schedule of assessments for 
crossover). All sites will be provided with an ECG machine and associated materials by the 
central ECG diagnostic service. 
Performance of all ECGs must adhere to the following guidelines: 
• All standard digital ECGs must be performed after the patient has been in the supine or 
semi-recumbent position for at least 15 minutes. The 15-minute rest period will start after 
the placement of the ECG leads. 
• The ECG must be performed before the dose of study drug. 
A hard copy of the ECG must be printed and signed by the Investigator at the site.  
ECG data will be transmitted to the central ECG diagnostic service and all interval 
measurements will be reviewed and adjusted using the central ECG core labs methodology 
by a trained ECG analyst. A cardiologist at the central ECG diagnostic service will then 
review each ECG to confirm if intervals were calculated correctly and to provide an 
interpretation. A report containing this information will be provided to the site for review and 
signature by the Investigator. This report will be filed with the machine ECG report for each 
visit in the patient’s source documents. The values reported by the central ECG diagnostic 
service will be used for data analysis. 
Heart rate and the following ECG intervals will be captured in the database: 
• PR interval 
• QT, QTcB (Bazett’s corrected QT interval [QTcB = QT/RR0.50]) and QTcF 
(QTcF = QT/RR1/3) intervals 
• QRS duration 
• RR interval  
The central ECG diagnostic service's standard reference ranges will be used throughout the 
study. 
6.11.5. 
Echocardiograms/Multigated Acquisition Scans 
Echocardiograms or multigated acquisition scans (MUGAs) will be performed according to 
the schedule of assessments in Table 1 (schedule of assessments) and Table 2 (schedule of 
assessments for crossover). Echocardiogram or MUGA performed as standard of care prior 
to informed consent may be used as the Screening assessment as long as the echocardiogram 
or MUGA was performed within 28 days prior to the first dose of study drug. The same 
modality (echocardiogram or MUGA) must be used throughout the study. Left ventricular 
ejection fraction (LVEF) must be documented in the patient’s source documents and eCRF. 
6.11.6. 
Dermatologic Examination 
All patients will be assessed by a consulting dermatologist for skin lesions, especially for 
SCC, actinic keratosis, and keratoacanthomas, according to the schedule of assessments in 
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Table 1 (schedule of assessments) and Table 2 (schedule of assessments for crossover) and as 
clinically indicated. The examinations must include the entire skin. Dermatologic exam that 
meets the protocol criteria that was performed as standard of care prior to informed consent 
may be used as the Screening assessment as long as the exam was performed within 21 days 
prior to the first dose of study drug. Any new or changing skin lesions noted during the 
course of treatment must be documented in the patient’s source documents and eCRF. In case 
of suspected SCC or keratoacanthomas, a skin biopsy must be taken for confirmation of 
diagnosis by a certified pathologist at the clinical site. Samples with confirmed SCC or 
keratoacanthoma lesions will be sent to a central laboratory for histopathological and/or 
molecular analysis. 
6.11.7. 
Ophthalmologic Examination 
Ophthalmologic examinations will be performed by a licensed ophthalmologist according to 
the schedule of assessments in Table 1 (schedule of assessments) and Table 2 (schedule of 
assessments for crossover) and if clinically indicated during treatment with study drug. 
Examinations will include examination of anterior structures (including cornea, anterior 
chamber, iris, and lens) and posterior structures (including optic nerve, macula, retinal 
vessels, the retinal periphery, and the vitreous); assessment of intraocular pressure in each 
eye; assessment of visual acuity. 
This examination does not have to be repeated if there is documentation of an examination 
that met protocol criteria within 28 days before the Screening Visit and after the last dose of 
previous anticancer treatment. 
6.11.8. 
Clinical Laboratory Tests 
Blood and urine samples will be collected according to the schedule of assessments in 
Table 1 (schedule of assessments) and Table 2 (schedule of assessments for crossover) and 
analyzed at a central laboratory. All blood samples must be collected while patients are in a 
seated or supine position. Specific instructions for the collection, processing and shipment of 
samples will be provided in a separate laboratory manual. Laboratory test results that are 
abnormal and considered clinically significant must be reported as AEs (Section 7.7.1). 
Screening laboratory results must be available before randomization. All samples must be 
collected in accordance with acceptable laboratory procedures and graded for toxicity as 
defined by the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE), Version 4.03. 
Available local laboratory test results will be used for treatment management decisions (eg, 
dose modifications [Section 5.3.2]) and initial assignment of CTCAE grading. Every effort 
must be made to discuss any changes to study drug dosing with the Sponsor before 
implementation, and only if not feasible beforehand, to inform the Sponsor within the same 
day. Central laboratory results will be used for final assignment of CTCAE grading. In the 
case of different grades associated with local versus central laboratory results for AEs, the 
central laboratory results must be used for documenting AEs. 
The safety laboratory tests are provided in Table 12. 
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Table 12: 
Safety Laboratory Tests 
Serum Chemistry 
Hematology 
Urinalysis2 
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Magnesium 
Phosphorus  
Total and direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase  
Alanine aminotransferase 
Lactate dehydrogenase 
Total protein 
Albumin 
Creatine Phosphokinase 
Globulin 
Triglycerides 
Lipase 
Amylase 
Hemoglobin 
• Mean corpuscular hemoglobin 
• Mean corpuscular hemoglobin 
concentration 
• Mean corpuscular volume 
Hematocrit 
Platelets 
Leukocytes 
Reticulocytes 
Differential (absolute): 
• Eosinophils 
• Basophils 
• Neutrophils 
• Lymphocytes  
• Monocytes 
Coagulation Studies1 
Activated partial thromboplastin time  
Prothrombin time 
International Normalized Ratio 
Urine protein  
Urine blood 
Specific gravity  
Urine ketones  
Urine glucose  
Thyroid Testing 
Thyroid stimulating hormone (TSH) 
Free triiodothyronine (T3) 
Free thyroxine (T4) 
1. For patients taking anticoagulants, testing will be performed according to Table 1 (schedule of 
assessments) and Table 2 (schedule of assessments for crossover). Monitoring of coagulation tests must 
be increased for as long as deemed clinically appropriate following a change in anticoagulant dose 
during the study. 
2. If any result is abnormal, a microscopic analysis must be performed by the central laboratory. 
 
6.11.9. 
Pregnancy Test 
A serum β-hCG test to rule out pregnancy in women of childbearing potential will be 
obtained at screening and analyzed at a central laboratory. A urine pregnancy test will be 
completed at all other visits as outlined in Table 1 (schedule of assessments) and Table 2 
(schedule of assessments for crossover). A serum pregnancy test may be performed instead 
of urine if it is the site’s standard practice and the results are received prior to the patient 
being dosed in the clinic. Pregnancy testing will not be required for patients who are 
non-childbearing females, defined as one who is post-menopausal (amenorrheic for 
≥12 months with a follicle stimulation hormone (FSH) ≥40 mIU/mL) or has documented 
complete oophorectomy or hysterectomy. 
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6.11.10. 
Contraception and Pregnancy Avoidance Measures 
6.11.10.1. 
Contraception 
The effects of DCC-2618 on sperm, conception, pregnancy, and lactation are not known. 
Participation in this study requires patients to agree to use 2 methods of contraception with 
one of the methods being highly effective. Methods of contraception must be in successful 
use from at least 14 days prior to the first dose of study drug and until 104 days following the 
last dose of study drug. 
Contraception for the patient is waived for the following: 
• True abstinence for the patient, when this is in line with the preferred and usual lifestyle 
of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, and 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
• If the male has documented bilateral orchiectomy or is considered infertile as 
documented through examination of a semen specimen or by demonstration of the 
absence of the vas deferens by ultrasound before the first dose of the study drug. 
• If the female is of non-childbearing potential, per the following: 
• Postmenopausal: spontaneous amenorrhea for at least 12 consecutive months and 
have a serum FSH level ≥40 mIU/mL 
• Documented hysterectomy or a bilateral oophorectomy/salpingo-oophorectomy 
NOTE: All other female patients (including patients with tubal ligations and patients who do not have 
a documented hysterectomy) will be considered to be of childbearing potential. 
Acceptable highly effective methods of contraception: 
• Vasectomy 6 months or more previously, with a negative post-vasectomy semen analysis 
for sperm. 
• Bilateral tubal ligation performed at least 6 months previously. 
• Continuous use of an intrauterine device (non-hormone-releasing or hormone-releasing) 
for at least 90 days. 
• Combined (estrogen and progestogen containing) or progestogen-only hormonal 
contraception associated with inhibition of ovulation: 
• oral 
• intravaginal 
• transdermal 
• injectable 
• implantable 
NOTE: Hormonal contraceptives can be used as a highly effective method of contraception unless 
they’re one of the prohibited medications as described in Section 5.12.3.3, as the efficacy of the 
hormonal contraceptives may be affected due to potential drug-drug interactions with DCC-2618. 
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Acceptable methods of contraception: 
• Male and female condom with or without spermicide 
• Barrier contraception (such as diaphragm, cervical cap or sponge) and spermicide 
• In countries where spermicide is not available, barrier contraception without 
spermicide is acceptable 
Additional notes: 
Acceptable methods of contraception listed above are examples. Local requirements may prohibit the 
use of some of these examples. Please contact the Sponsor with any questions. 
• Female condom cannot be used with male condom (as a double method of contraception) 
due to risk of tearing. 
• Male and female patients who are not sexually active at the time of screening must agree 
to follow the contraceptive requirements of this study if they become sexually active with 
a partner of the opposite sex. 
• If applicable, additional contraception requirements may need to be followed according 
to local regulations and/or requirements. 
• Male patients must not donate sperm after the first dose of study drug, throughout the 
study, and for 104 days following the last dose of study drug. They should seek advice on 
conservation of sperm prior to the first dose of study drug. 
• Female patients and female partners of male patients must not plan to become pregnant 
during the study through 104 days following the last dose of study drug. 
• Male patients whose female partner becomes pregnant through well-documented in vitro 
fertilization (donated sperm) or banked sperm (collected before the patient received study 
drug), must be compliant with the contraception requirements. In this scenario, the male 
patient must commit to using acceptable methods of contraception (to ensure there is no 
exposure of the fetus to study drug) for the duration of the study and until 104 days after 
the last dose of study drug.  
Unique situations that may not fall within the above specifications must be discussed with the 
Sponsor. 
If there is any question that a woman of childbearing potential or male patient will not 
reliably comply with the requirements for contraception, that patient must not be entered into 
the study. 
6.11.10.2. 
Pregnancy 
Patients must be counseled to inform the Investigator of any pregnancy that occurs during 
study treatment and for 104 days after the last dose of the study drug. An exception is made 
for pregnancies that occur 104 days after the last dose of study drug resulting from donated 
sperm or sperm banked before study drug exposure. 
If a female patient becomes pregnant while participating in the study, study drug must be 
permanently discontinued immediately. If the female partner of a male patient becomes 
pregnant while participating in the study, the patient must notify the Investigator 
immediately. The male patient must to commit to use acceptable methods of contraception 
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(to ensure there is no exposure of the fetus to study drug) for the duration of the study and 
until 104 days after the last dose of study drug. The Investigator must notify the Sponsor and 
Worldwide Clinical Trials Pharmacovigilance (WCT PVG) within 1 business day of the site's 
knowledge of the patient’s (or partner's) pregnancy. 
If confirmed to be on active drug, the patient or partner must be followed until the end of the 
pregnancy and the infant must be followed for 1 year after the birth, provided informed 
consent is obtained. A separate ICF must be provided to explain these follow-up activities. 
Pregnancy itself does not constitute an AE. 
6.11.11. 
Adverse Events 
All AEs will be assessed, documented, and reported in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Section 7 
outlines the definitions, collection periods, criteria and procedures for documenting, grading, 
and reporting AEs. A separate document that details AE eCRF completion guidelines for the 
Investigator, as well as training, will be provided. 
6.11.12. 
Safety Follow Up 
All patients must be followed for AEs; medications, including any anticancer treatments; and 
procedures until 30 days (+5 days) following the last dose of study drug. 
6.12. 
Pharmacokinetics  
6.12.1. 
Sample Collection 
At the visits indicated in Table 1 (schedule of assessments) and Table 2 (schedule of 
assessments for crossover), blood samples will be collected for the determination of the 
concentrations of DCC-2618 and its metabolite, DP-5439. Pre-dose blood samples must be 
collected within 60 minutes before dosing and post dose blood samples must be collected 
±30 minutes of the nominal time point. An unscheduled PK sample may be taken at the time 
of the onset of a new suspected, treatment-related AE when requested by the Sponsor. 
Samples from the PK sampling will be kept frozen by the Sponsor or its designee until all 
analyses have been completed and then disposed of according to the Sponsor or designee 
standard operating procedures. 
For each visit with a PK blood draw, a record of study drug administration must be collected 
as described in Section 5.2. The collection date and time that each PK blood sample is drawn 
must also be recorded. 
Details on sample collection, processing, and shipping will be provided in a separate 
protocol-specific Laboratory Manual. 
6.12.2. 
Sample Assessment 
The following PK parameters will be calculated using non-compartmental methods of plasma 
DCC-2618 and metabolite DP-5439, obtained after single and repeated dose administration. 
The parameters will include, but may not be limited to Cmax, Tmax, AUC, and T1/2. 
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6.13. 
Biomarkers and Pharmacodynamics 
6.13.1. 
Sample Collection 
Biomarker and PD samples will be collected according to the schedule in Table 1 (schedule 
of assessments) and Table 2 (schedule of assessments for crossover). A laboratory manual 
describing the details of obtaining, storing, and shipping the samples will be provided. 
Remaining PD samples, including archival samples, will be stored for up to 15 years. These 
samples will be used for further analysis intended to address scientific questions related to 
study drug and/or cancer. A decision to perform such exploratory biomarker research studies 
will be based on data obtained from DCC-2618 clinical studies, new scientific findings 
related to the drug class or disease, and/or reagent and assay availability. 
6.13.2. 
Sample Assessments 
6.13.2.1. 
Tumor Tissue Samples 
Mandatory archival and/or fresh tumor tissue samples will be collected and analyzed by a 
central laboratory to identify molecular alterations in KIT or PDGFRA or other kinases. At 
screening, an archival tumor tissue sample will be collected as long as no anticancer therapy 
was administered since the sample was collected. Fresh tumor tissue samples will only be 
collected if a patient qualifies for the study based on all other entry criteria and archival 
tissue is not available or not collected after the last anticancer therapy. 
All Patients (optional): Additional tumor tissue samples may be collected for patients 
undergoing medical procedures including resection of metastases while on study or for 
patients that have disease progression if the patient consents and these samples will be used 
for further molecular testing of the cancer while treated with study drug. 
6.13.2.2. 
Plasma Samples 
Biomarker and PD plasma samples will be collected and analyzed by a central laboratory to 
evaluate mutations in KIT or PDGFRA and possibly other genes and their longitudinal 
frequency changes in cfDNA. Samples will be analyzed by NGS. Drug treatment effect on 
additional mutations of interest may also be evaluated. 
6.14. 
Pharmacogenomic Measurements 
6.14.1. 
Sample Collection 
A pharmacogenomic sample will be collected at Cycle 1 Day 1 according to the schedule of 
study assessments in Table 1 (schedule of assessments). A laboratory manual describing the 
details of obtaining, storing, and shipping the sample will be provided. 
6.14.2. 
Sample Assessment 
A single whole blood sample will be collected and may be used to correlate study drug 
response and PK with individual genetic variation. The pharmacogenomic sample will be 
stored and analyzed by a central laboratory and may be stored for up to 15 years. 
6.15. 
Healthcare Utilization 
6.15.1. 
Healthcare Utilization Questionnaire (HCUQ) 
The Healthcare Utilization Questionnaire was designed specifically for this study to collect 
data on the use of healthcare resources. It will be completed via a patient interview conducted 
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by the Investigator or designee participating in this study at the visits indicated in Table 1 
(schedule of assessments) and Table 2 (schedule of assessments for crossover). The required 
time for completion is approximately 3-5 minutes. Certified translations of the HCUQ will be 
provided for sites in non-English-speaking countries. 
The first section of the questionnaire deals with utilization of ambulatory healthcare services, 
with the staff member asking the patient about utilization of each of the services (emergency 
room, ambulance, primary care physician, specialist physician, counseling, other) and 
recording information as to whether the type of service had been used in the past 28 days 
(yes, no) and, if so, the number of times it was utilized. The second section proceeds in a 
similar way with data collection regarding the number of hospital admissions in the past 
28 days, the length of stay, and the reason for each admission (disease/treatment related, 
other). The last section focuses on paid care provided in the patient’s home by a nurse, home 
health aide, hospice worker, or another provider type in the last 28 days, with collection of 
whether service was provided and, if so, the number of days and the number of hours per 
day. 
 
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7. 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
DOCUMENTATION, SEVERITY GRADING, AND REPORTING 
7.1. 
Adverse Events 
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 (eg, 
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. 
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 (eg, 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. 
Elective surgeries or procedures must not be reported as AEs, but must be documented on the 
appropriate eCRF page. 
Each AE must be assessed immediately to determine if it meets the definition of serious 
(Section 7.8). If a serious adverse event (SAE) occurs, expedited reporting must follow local 
and international regulations, as appropriate. 
7.2. 
Severity Assessment 
The Investigator must determine and record the severity of all serious and non-serious AEs. 
The NCI-CTCAE, Version 4.03, must be used for grading the severity of AEs (Cancer 
Therapy Evaluation Program website; available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
The severity of an AE that does not appear in the CTCAE scale must be determined 
according to Table 13. 
Table 13: 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) Version 4.03 Severity Grading Scale 
Grade 1 (Mild) 
Experiences which are usually transient, requiring no special treatment, and 
do not interfere with the patient's daily activities. 
Grade 2 (Moderate) 
Experiences which introduce some level of inconvenience or concern the 
patient, and may somewhat interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures (may include drug therapy). 
Grade 3 (Severe) 
Experiences which are unacceptable or intolerable, significantly interrupt the 
patient's usual daily activity, and require systemic drug therapy or other 
treatment. 
Grade 4 (Life-threatening) 
Experiences which cause the patient to be in imminent danger of death. 
Grade 5 (Death) 
Death related to AE. 
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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 14. 
Table 14: 
Relationship to Study Drug Criteria 
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 the safety analyses, all AEs that are classified as possibly related will be 
considered treatment-related events. 
7.4. 
Study Drug Action Taken 
The Investigator must classify the study drug action taken with regard to the AE. The action 
taken must be classified according to the categories shown in Table 15. 
Table 15: 
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 16. 
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Table 16: 
Classifications for Outcome of an Adverse Event 
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). 
 
7.6. 
Treatment Given 
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, hospitalization, surgery, or physical therapy. "No" indicates the absence of 
any kind of treatment for an AE. 
7.7. 
Additional Points to Consider for Adverse Events 
7.7.1. 
Clinically Significant Assessments 
Study assessments including laboratory tests, ECGs, physical examinations, and vital signs 
must be assessed and those deemed as clinically significant must be documented as an AE. 
When possible, a clinical diagnosis for the study assessment must be provided rather than the 
abnormal test result alone (eg, urinary tract infection, anemia). In the absence of a diagnosis, 
the abnormal study assessment itself may be listed as the AE (eg, bacteria in urine or 
decreased hemoglobin). 
An abnormal study assessment is considered clinically significant if the patient has 1 or more 
of the following: 
• Worsening, from baseline, concomitant signs or symptoms related to the abnormal study 
assessment 
• Further diagnostic testing or medical/surgical intervention is required 
• A change in the dose of study drug, if study drug is withheld, or discontinuation from 
study drug occurs 
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. 
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7.8. 
Serious Adverse Events 
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 
• 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 (ie, 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). 
Clinical outcomes or symptoms related to progressive disease need to be reported as an SAE 
if they meet SAE criteria and occur within 30 days of the last study drug administration. 
They must be reported according to the diagnosis or symptom of event and not by the term 
“progressive disease.”  
Clarification must be made between the terms "serious" and "severe," because they are not 
synonymous. The term "severe" is often used to describe the intensity (severity) of a specific 
event, as in mild, moderate, or severe myocardial infarction. The event itself, however, may 
be of relatively minor medical significance, such as a severe headache. This is not the same 
as "serious," which is based on patient/event outcome or action criteria described above, and 
is usually associated with events that pose a threat to a patient's life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory reporting obligations. 
7.9. 
Adverse Events of Special Interest 
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. Adverse events of special interest may be added or removed during a study 
by a protocol amendment. 
The following AEs are considered AESIs: 
• SCC 
• Actinic keratosis 
• Keratoacanthoma 
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7.10. 
Adverse Event Reporting Periods 
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 administration of the 
study drug for all randomized patients. Patients who are not randomized will have AEs 
collected until the time of screen failure. Any SAE or AESI occurring after the reporting 
period must be promptly reported if a causal relationship to study drug is suspected.  
If a patient begins a new anticancer therapy, the safety reporting period ends at the time the 
new treatment is started; however, death must always be reported when it occurs during the 
safety reporting period irrespective of intervening treatment. 
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 (eg, “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 (eg, 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 to WCT PVG within 24 hours from the point in time when the 
Investigator becomes aware of the SAE or AESI. SAEs and AESIs must be followed until 
resolution, the condition stabilizes, or the Investigator and Sponsor agree that follow up is not 
required. For the purposes of study analysis, if the event has not resolved at the end of the 
study reporting period, it must be documented as ongoing. For purposes of regulatory safety 
monitoring, the Investigator is required to follow the event to resolution and report to the 
Sponsor the outcome of the event. Further instructions on reporting of SAEs will be provided 
in the Study Reference Manual.  
If there are serious, unexpected, suspected adverse drug reactions (SUSARs) associated with 
the use of the study drug, the Sponsor or authorized designee will ensure that the appropriate 
regulatory agency(ies) and all participating investigators are notified on an expedited basis. 
In addition, the Sponsor or authorized designee will be responsible for notification of 
SUSARs to the ethics committee. It is the responsibility of the Investigator to promptly 
notify the local IRB/IEC/REB of SUSARs according to the institutional policy. An 
unexpected event is one that is not reported in the IB. 
7.12. 
Abuse, Misuse, Overdose, and Medication Error 
Occurrences of events of overdose, drug misuse, drug abuse and medication error must be 
reported to the Sponsor.  
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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 (Section 7.1 and Section 7.8). 
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8. 
WITHDRAWAL AND REPLACEMENT OF PATIENTS 
8.1. 
Withdrawal of Patients 
A patient is free to withdraw from the study drug and/or study for any reason and at any time 
without giving reason for doing so and without penalty or prejudice. The Investigator is also 
free to terminate a patient's involvement in the study at any time if the patient's clinical 
condition warrants it. The primary reason for discontinuation or withdrawal of a patient from 
the study must be determined using the following categories: 
• Adverse event 
• Death 
• Lost to follow-up 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Confirmed progressive disease by Investigator assessment 
• Confirmed progressive disease by independent radiologic review 
• Protocol deviation 
• Termination of site by Sponsor 
• Termination of study by Sponsor 
• Withdrawal by patient 
• Any other reason that in the opinion of the Investigator, would justify removing the 
patient from the study, based on the best interest of the patient 
If a patient voluntarily withdraws from the study, the Investigator should attempt to contact 
the patient to determine the reason(s) for discontinuation and request the patient return for an 
EOT Visit and Safety Follow up Visit. If a patient withdraws from the study for any reason 
other than withdrawal by the patient, an EOT Visit and Safety Follow up Visit must be 
conducted, and the patient must be followed for overall survival. . Patients must return all 
used, partially used, and unused study drug bottles. 
8.2. 
Replacement of Patients 
Patients will not be replaced in this study.  
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Determination of Sample Size 
The sample size selection of approximately 120 patients (n=80 DCC-2618, n=40 placebo) 
was based on considerations for powering of the primary endpoint, key secondary endpoint, 
detection of rare safety events and overall exposure to DCC-2618, and assuming 15% patient 
dropout. Patients will be randomized in a 2:1 ratio of DCC-2618 versus placebo. 
This sample size [105 patients (n=70 DCC-2618, n=35 placebo) with 90 events 
(55 DCC-2618, 35 placebo) at the final analysis] will have at least 90% power to detect a 
difference in PFS between DCC-2618 and placebo assuming a median PFS of 4.5 months for 
DCC-2618 and 1 month for placebo. Moreover, this assumes 9 months of uniform 
recruitment and 6 additional months of follow-up (total patient follow-up of 15 months). 
Furthermore, 105 patients (n=70 DCC-2618, n=35 placebo) will have approximately 80% 
power to detect a 0.2 difference in ORR assuming that the ORR for DCC-2618 = 0.22 and 
the ORR for placebo = 0.02. 
In addition, a minimum sample size of 80 DCC-2618 patients allows adequate power to 
detect the incidence of rare safety events. A sample of 80 patients yields 95% probability that 
the study will reveal at least one occurrence of all safety events that occur in patients at a rate 
of 4.0% or greater. This in combination with the exposure to DCC-2618 from other studies 
conducted in this clinical program will meet the recommendations for overall exposure 
recommended by FDA. 
9.2. 
Analysis Endpoints 
9.2.1. 
Primary Endpoint 
9.2.1.1. 
Efficacy 
Progression-free survival based on independent radiologic review using modified RECIST 
(1; Appendix 17.1). Modified RECIST criteria includes: 
• No lymph nodes chosen as target lesions; enlarged lymph nodes followed as non-target 
lesions;  
• No bone lesions chosen as target lesions;   
• 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 (eg, 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. 
Key Secondary Endpoints 
9.2.2.1.1. Efficacy 
• ORR based on independent radiologic review 
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9.2.2.2. 
Additional Secondary Endpoints  
9.2.2.2.1. Efficacy 
• TTP based on independent radiologic review 
• OS 
• Time to best response 
• PFS based on Investigator assessment 
• QOL as determined by changes from baseline in EORTC-QLQ-C30 and EQ-5D-5L 
• Disease control rate (DCR; CR + PR + SD) at 12 weeks 
9.2.2.2.2. Safety 
Safety endpoints that will be evaluated include TEAEs, AESIs, SAEs, dose reduction or 
discontinuation of study drug due to toxicity; and changes from baseline in ECOG PS, vital 
signs, ECG, LVEF, dermatologic examinations, and clinical laboratory parameters. 
9.2.2.2.3. Pharmacokinetics 
• Correlation of PK with efficacy/safety 
• Population PK 
9.2.3. 
Exploratory Endpoints 
9.2.3.1. 
Efficacy 
• PFS by Investigator assessment after dose escalation to DCC-2618 150 mg BID 
9.2.3.2. 
Biomarkers and Pharmacodynamics 
• Type and burden of mutations in plasma cfDNA 
• Treatment effect of DCC-2618 on cfDNA mutation allele frequency 
• Potential TKI-resistance mechanisms of GIST at time of progression 
• Concordance between KIT, PDGFRA and other gene mutations in tumor and cfDNA 
9.2.3.3. 
Healthcare Utilization 
• Changes over time in healthcare utilization 
9.3. 
Populations for Analysis 
The following populations will be used in the analysis: Intent-to-treat (ITT), Safety, PK, and 
Per Protocol (PP). 
The ITT population is defined as all patients who signed the informed consent and were 
randomized. The ITT population will be used for all efficacy analysis as a primary analysis 
set with treatment assignment based on randomization. 
The Safety population is defined as all patients who have received at least 1 dose of study 
drug. The Safety population will be used for all safety analysis with treatment actually 
received. 
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The PK population will include all randomized subjects who received at least 1 dose of 
DCC-2618 and had at least 1 non-missing PK concentration in plasma reported for 
DCC-2618 or DP-5439. 
A PP population may be included if there are patients in the ITT population who do not have 
protocol violations that are expected to compromise the efficacy and/or safety assessments 
(eg, patients enrolled who do not meet key eligibility criteria) during the study. Protocol 
violators resulting in exclusion from the PP population will be identified and documented 
prior to database lock. 
9.4. 
Procedures for Handling Missing, Unused, and Spurious Data 
All available data will be included in data listings.  
Algorithms for imputing partial or missing dates are shown in Table 17. If a period 
determination cannot be made for an adverse event, it will be attributed to the randomized 
blinded period, with missing dates imputed as explained in Table 18. Adverse event end 
dates are imputed to facilitate calculation of AE duration.  
Table 17: 
Partial or Missing Date Algorithms 
Variable 
Missing Day 
Missing Day, Month 
Missing  
Day, Month, Year 
Date of Last 
Therapy/Date of 
Initial Diagnosis 
Assign 1 
Assign January 1 if prior to 
date of informed consent, 
otherwise use date of 
informed consent 
Missing (do not impute) 
Adverse 
Event/Start Date 
Assign first day of month 
unless it is the year/month of 
first dose of study 
medication. 
Otherwise, assign date of first 
dose of study medication or 
AE end date (if not missing) 
whichever is earlier.  
Assign January 1 unless the 
year is year of first dose of 
study medication 
Otherwise, assign date of first 
dose of study medication or 
AE end date (if not missing) 
whichever is earlier. 
Assign date first dose of 
study medication. 
Adverse Event End 
Date 
Assign the last day of the 
month or end of study date, 
whichever is earlier.  
Assign December 31 or end 
of study date, whichever is 
earlier. 
If ongoing, end date is 
missing. Otherwise, 
assign end of study date. 
 
Table 18: 
Imputation Rules for Questionnaires 
Questionnaire 
Number of items missing  
< half 
Number of items missing  
> half 
EORTC-QLQ-C30 
No imputation for missing 
Impute missing values by using the average score from the 
patients with non-missing values from within the same 
randomization strata 
 
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9.5. 
Interim Analyses 
No interim analysis for efficacy will be performed for this study. An IDMC will be used to 
review safety data periodically throughout the course of this study (see Section 10.1 for 
further details).  
9.6. 
Adjustment for Multiple Comparisons 
To control family wise type-I error, the hypothesis tests for treatment difference will be 
performed at two-sided 0.05 level of significance sequentially in the following order:  
1. The primary endpoint PFS 
2. The key secondary endpoint ORR 
3. OS 
4. QOL as determined by changes from baseline to  Day 1 of cycle 2 in EORTC-QLQ-
C30 Role function and Physical function  (each at 0.025 level significance) 
 
Once a hypothesis test is nonsignificant at alpha=0.05 level, the remaining analyses will be 
viewed as descriptive.  
9.7. 
Blinding 
Prior to the unblinding of study data, the Sponsor will approve a comprehensive statistical 
analysis plan (SAP). 
Where required, safety personnel at the Sponsor or designee may be unblinded to a patient’s 
study drug assignment to meet reporting requirements to regulatory agencies. In addition, the 
Investigator, patient, Sponsor, and study team will be unblinded at the time the patient has 
disease progression by modified RECIST based on independent radiology review. 
Additional Sponsor representatives may be unblinded to some data for the purposes of 
ensuring adequacy of study conduct, including proper distribution of study drug. 
At no point in time before official full study unblinding will any aggregate efficacy and 
safety analyses be conducted by the Sponsor or Sponsor representatives, unless there is 
explicit permission to do so, for instance high level efficacy assessment for the purposes of 
IDMC review to determine the adequacy of the risk/benefit profile of the drug as it pertains 
to the conduct of the clinical trial. 
Upon determining the results based on the primary PFS analysis, all remaining patients will 
be unblinded to their treatment assignment and patients assigned to placebo will be allowed 
to cross-over to active therapy. 
9.8. 
Statistical Methods 
9.8.1. 
General Methods 
Data collected in this study will be documented using summary tables and patient data 
listings. Continuous variables will be summarized using descriptive statistics (number of 
patients, mean, median, standard deviation, minimum, and maximum). Categorical variables 
will be summarized using frequencies and proportions. Time-to-event data will be 
summarized via Kaplan-Meier (KM) methodology using the 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% confidence intervals. 
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Unless specified otherwise, baseline measurements must be the most recent value prior to 
receiving the first dose of study medication. If an assessment is not available, then the last 
assessment prior to that visit would be used.  
Medical history, adverse events, and concurrent procedures will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA). Prior and concomitant medications will be 
coded using the World Health Organization Drug Dictionary. 
This study will be broken into 2 periods: the randomized blinded period and the open-label 
portion which occurs after the study treatment unblinding at the time of disease progression 
based on the independent radiologic review.  
The data cut-off for the primary analysis will occur when 90 PFS events have occurred. It is 
expected that the final analysis will occur within 6 months after the last patient is enrolled 
into the trial. 
Unless specified, the ITT population is used for efficacy analysis and the Safety population is 
used for the safety analysis. 
9.8.2. 
Disposition of Patients 
Patient disposition will be summarized overall for all patients who entered the study 
(ie, signed the informed consent for the study). The number and proportion of patients who 
entered the open-label portion of the study will be displayed. In addition, the number of 
patients in each population (ITT, Safety, and PP if applicable) and patients were removed 
from a population. The number and proportion of patients who complete the study, as well as 
those who discontinue the study will be summarized along with the reason for 
discontinuation. 
9.8.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics at study entry will be summarized for the ITT, 
Safety, and PP populations. 
Medical history will be summarized overall for the Safety population. 
9.8.4. 
Extent of Exposure 
The total number of patients who received study medication will be summarized by n and 
percentage. In addition, the number of cycles received will be displayed using continuous 
descriptive statistics. These analyses will be performed for the Safety population. 
9.8.5. 
Efficacy Analysis 
9.8.5.1. 
Primary Endpoint: Progression-free Survival Analysis 
The primary endpoint of PFS (reported in weeks) is defined as the interval between the date 
of randomization and the earliest documented evidence of disease progression based on the 
independent radiologic review, or death due to any cause. Patients who undergo surgical 
resection of target or non-target lesions, who have received other anticancer treatments, or 
patients who do not have a documented date of progression or death due to any cause will be 
censored at the date of the last assessment. Analysis for PFS will be stratified by the 
randomization stratification factors [prior lines of therapy (3 versus ≥4) and ECOG (0 versus 
1 or 2)]. The p-value will be from a 2-sided stratified Log-rank test at 0.05 significant level 
for evaluation of treatment difference. Point estimate of hazard ratio will be obtained from a 
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Cox regression model with the treatment and the randomization stratification factors as fixed 
factors and it’s 95% CI will be obtained using the Wald method.    
Analysis will be using the ITT population as the primary analysis and PP as supportive. 
Progression-free survival will have sensitivity analyses performed which will be further 
detailed in the SAP. 
9.8.5.2. 
Key Secondary Endpoint 
The key secondary endpoint is ORR. 
9.8.5.2.1. Objective Response Rate Analysis 
Objective response rate is defined as the proportion of patients with a confirmed CR or PR 
based on the independent radiologic review. This analysis will be performed in the ITT 
population as the primary analysis and the PP population as supportive analysis. To be 
assigned a status of a CR or PR, changes in tumor measurements must be confirmed by 
repeat assessments that must be performed at least 4 weeks after the criteria for response are 
first met. Patients with unknown or missing response will be treated as non-responders, that 
is, they will be included in the denominator when calculating the proportion. Time to 
confirmed response (CR or PR) (reported in weeks) is defined as the interval between the 
date of first dose of study medication and the earliest date of first documented confirmed CR 
or confirmed PR. Patients who do not have a confirmed PR or CR will be censored at the 
date of the last adequate assessment. An unstratified two-sided Fisher’s Exact test at a 0.05 
significance level will be used to investigate statistical differences between treatment groups. 
A 95% confidence interval of treatment rate difference in ORR will be calculated by the 
Wald method. 
9.8.5.3. 
Secondary Endpoints 
9.8.5.3.1. Time to Tumor Progression  
The secondary endpoint of TTP (reported in weeks) is defined as the interval between the 
date of randomization and the earliest documented evidence of disease progression based on 
the independent radiologic review. Patients who undergo surgical resection of target or non-
target lesions, who have received other anticancer treatments, who do not have a documented 
date of progression or death due to any cause, or who die prior to tumor progression will be 
censored at the date of the last assessment. P-value for treatment difference will be obtained 
using the log rank test. Hazard ratio will be from a Cox regression model and it’s 95% 
confidence intervals will use Wald method. 
9.8.5.3.2. Overall Survival 
Overall survival (reported in weeks) is defined as the interval between the date of 
randomization and date of death from any cause. Patients who are still alive or who are lost 
to follow-up will be censored at the date of last contact. Differences between treatment 
groups will be evaluated using a model similar to that used for PFS. 
9.8.5.3.3. Time to Best Response Analysis 
The time to best response, as defined by the independent radiologic review, will be 
summarized and displayed using KM methods in a manner similar to the PFS analysis as 
described above. 
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9.8.5.3.4. Progression-free Survival based on Investigator Assessment 
PFS (reported in weeks) is defined as the interval between the date of randomization and the 
earliest documented evidence of disease progression based on Investigator assessment, or 
death due to any cause. Patients who undergo surgical resection of target or non-target 
lesions, who have received other anticancer treatments, or patients who do not have a 
documented date of progression or death due to any cause will be censored at the date of the 
last assessment. Differences between treatment groups will be evaluated using a model 
similar to that used for the primary endpoint. . 
9.8.5.3.5. EORTC-QLQ-C30 
The EORTC-QLQ-C30 will be summarized by scale. In all scales, a high scale score 
represents a higher response level. The scoring for this questionnaire will be done in 2 steps. 
The first step is to estimate the average of the items that contribute to the scale. This will be 
considered the raw score for the scale. After the raw score has been calculated, a linear 
transformation will be used to standardize the raw score, so that scores range from 0 to 100. 
An analysis of covariance with treatment, KIT/PDGFRA fourth line/KIT/PDGFRA fifth 
line/PDGFRA D842V status, and ECOG status at baseline will be performed. 
9.8.5.3.6. EQ-5D-5L 
The EQ-5D-5L will be summarized overall by n and percentage for each level of each 
dimension. The Cochran–Mantel–Haenszel test will be used to test differences between 
DCC-2618 and placebo. The EQ-VAS will be summarized using continuous descriptive 
statistics.  
9.8.5.3.7. Disease Control Rate Analysis 
Disease control rate will be calculated and summarized with n and percentage at 12 weeks. 
Disease control will be defined as having a response (complete or partial) or stable disease. 
This analysis will be performed by time point. Fisher’s Exact test will be used to investigate 
statistical differences between treatment groups and the Cochran-Mantel-Haenszel (CMH) 
will be utilized to assess the effect of strata. 
9.8.5.4. 
Exploratory endpoint 
9.8.5.4.1. Progression-free Survival by Investigator Assessment after Dose Escalation 
to DCC-2618 150 mg BID 
Progression-free survival (reported in weeks) after dose escalation to 150 mg BID is defined 
as the interval between the date of first dose of DCC-2618 150 mg BID and the earliest 
documented evidence of disease progression after dose escalation to 150 mg BID, or death 
due to any cause. Patients who undergo surgical resection of target or non-target lesions, who 
have received other anticancer treatments, or patients who do not have a documented date of 
progression or death due to any cause will be censored at the date of the last assessment post 
the first dose of DCC-2618 150 mg BID or if there are no assessments post the first dose, the 
first dose will be used as the censor date. 
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9.8.6. 
Safety Analysis 
9.8.6.1. 
Adverse Events 
Adverse events will be summarized utilizing the number and proportion of patients overall 
and by period (randomized/open-label), system organ class and preferred term for the Safety 
population. All tables will only include TEAEs, where treatment emergent is defined as any 
AE that occurs after administration of the first dose of study drug and through 30 days after 
the last dose of study drug, but listings will include all AEs.  
Adverse event toxicity grade will be classified using NCI-CTCAE Version 4.03 criteria (See 
Table 13). If a patient has multiple occurrences of the same system organ class (SOC) or 
preferred term, then only the most severe event will be summarized in the tables for that SOC 
and preferred term. Adverse events of ≥Grade 3 will also be summarized. A missing toxicity 
grade will not be imputed. 
The AE analysis will be repeated for SAEs, AEs leading to dose reduction or discontinuation, 
and AESIs.  
No formal hypothesis-testing analysis of AE incidence rates will be performed.  
9.8.6.2. 
Eastern Cooperative Oncology Group Performance Status 
Assessments will be summarized overall by time point utilizing continuous descriptive 
statistics. In addition, the change from baseline will be summarized for continuous 
parameters. For categorical parameters, the n and percentage will be displayed. No formal 
hypothesis-testing analysis will be performed. 
9.8.6.3. 
Vital Signs 
Assessments will be summarized overall by time point utilizing continuous descriptive 
statistics. In addition, the change from baseline will be summarized for continuous 
parameters. For categorical parameters, the n and percentage will be displayed. No formal 
hypothesis-testing analysis will be performed. 
9.8.6.4. 
Echocardiogram/Multigated Acquisition Scans 
Assessments will be summarized overall by time point utilizing continuous descriptive 
statistics. In addition, the change from baseline will be summarized for continuous 
parameters. For categorical parameters, the n and percentage will be displayed. No formal 
hypothesis-testing analysis will be performed. 
9.8.6.5. 
Dermatologic assessments  
Dermatologic assessments will be summarized by n and percent. No formal 
hypothesis-testing analysis will be performed. 
9.8.6.6. 
Clinical Laboratory Parameters 
Assessments will be summarized overall by time point utilizing continuous descriptive 
statistics. In addition, the change from baseline will be summarized for continuous 
parameters. For categorical parameters, the n and percentage will be displayed. No formal 
hypothesis-testing analysis will be performed. 
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9.8.7. 
Pharmacokinetic Analysis 
Pharmacokinetic concentrations will be summarized utilizing continuous descriptive 
statistics. 
9.8.8. 
Biomarker and Pharmacodynamic Analysis 
The Mann-Whitney U test will be used to examine the statistical difference between 
treatment groups in terms of treatment effect of DCC-2618 on cfDNA mutation frequency 
over all time point tested. No formal hypothesis-testing analysis will be performed. 
9.8.9. 
Pharmacogenomic Analysis 
Pharmacogenomic analysis to explore the impact of variations in genes encoding for drug 
metabolism enzymes and drug transporters on patient’s response to study drug. 
9.8.10. 
Healthcare Utilization 
Data collected on the HCUQ will be summarized using n and percentage or continuous 
descriptive statistics as appropriate based on the item collected. These data will be compared 
between treatment groups over time as applicable using the appropriate statistical test. 
9.8.11. 
Procedures for Reporting Deviations to Original Statistical Analysis Plan 
All deviations from the original SAP will be provided in the final clinical study report. 
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10. STUDY COMMITTEES 
10.1. 
Independent Data Monitoring Committee 
An IDMC will monitor the safety data from this study on a periodic basis to help ensure the 
ongoing safety of study patients. The IDMC will consist of an experienced biostatistician and 
two qualified clinicians, who are not employees of the Sponsor, with combined scientific 
expertise in general oncology and GIST and practical experience conducting clinical studies 
and monitoring safety and efficacy of clinical studies. The IDMC or Sponsor may request an 
ad hoc meeting for any reason, including significant unexpected safety event, unplanned 
unblinding of study results, follow-up of an observation during a planned IDMC meeting, or 
a report external to the study, such as publication of study results from a competing product. 
The IDMC objectives and operational details will be defined in a separate document (IDMC 
Charter), which will be finalized before the first patient is randomized in the study. 
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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. 
Study Site Monitoring Visits 
During study conduct, the Sponsor or its agent will conduct periodic monitoring visits to 
ensure that the protocol and GCPs are being followed. The monitors will review source 
documents to confirm that the data recorded on eCRFs is accurate. The Investigator and 
institution will allow the Sponsor’s monitors or designees and appropriate regulatory 
authorities direct access to source documents to perform this verification. 
The study site may be subject to review by the IRB/IEC/REB, and/or to quality assurance 
audits performed by the Sponsor, or companies working with or on behalf of the Sponsor, 
and/or to inspection by appropriate regulatory authorities. 
It is important that the Investigator and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11.2. 
Protocol Compliance 
The Investigator must conduct the study in compliance with the protocol provided by the 
Sponsor and given approval/favorable opinion by the IRB/IEC/REB and the appropriate 
regulatory authority(ies). Modifications to the protocol must not be made without agreement 
between both the Investigator and the Sponsor. Changes to the protocol will require written 
IRB/IEC/REB and the appropriate regulatory authority(ies) approval/favorable opinion prior 
to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients. The IRB/IEC/REB may provide, if applicable regulatory authority(ies) 
permit, expedited review and approval/favorable opinion for minor change(s) in ongoing 
studies that have the approval/favorable opinion of the IRB/IEC/REB. The Sponsor must 
ensure that all protocol modifications are submitted to the regulatory authority(ies) in 
accordance with the governing regulations.  
If other unexpected circumstances arise that require deviation from protocol-specified 
procedures, the Investigator must consult with the Sponsor (and IRB, IEC, or REB, as 
required) to determine the appropriate course of action. 
The site must document all protocol deviations in the patient’s source documents. In the 
event of a significant deviation, the site must notify the Sponsor (and IRB, IEC, or REB, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary 
study assessments. 
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12. DATA HANDLING AND RECORD KEEPING 
12.1. 
Electronic Case Report Form 
The Sponsor or designee will provide the study sites with secure access to and training on the 
electronic data capture application sufficient to permit site personnel to enter or correct 
information in the eCRFs on the patients for which they are responsible. 
An eCRF is required and must be completed for each randomized patient. The Investigator 
has ultimate responsibility for the accuracy, authenticity, and timely collection and reporting 
of all clinical, safety, and laboratory data entered on the eCRFs and any other data collection 
forms. Source documentation supporting the eCRF data must indicate the patient’s 
participation in the study and must document the dates and details of study procedures, AEs, 
other observations, and patient status. 
The Investigator, or designated representative, must complete the eCRF as soon as possible 
after information is collected. 
The audit trail will show the user’s identification information and the date and time of the 
any correction. The eCRFs must be signed electronically by the Investigator to attest that the 
data contained on the eCRFs, including any changes made to the eCRFs, is correct and 
endorse the final submitted data for the patients for whom the Investigator is responsible. 
The completed eCRFs are the sole property of the Sponsor and must not be made available in 
any form to third parties, except for authorized representatives of the Sponsor or appropriate 
regulatory authorities, without written permission from the Sponsor. 
The Sponsor will retain the eCRF data and corresponding audit trails. A copy of the final 
archival eCRF in the form of a compact disc or other electronic media will be provided to the 
site for placement in the Investigator’s study file. 
12.2. 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the 
Investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, eCRFs and hospital records), all original signed 
informed consent forms, eCRFs, SAE forms, source documents, detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (eg, letters, meeting 
minutes, telephone calls reports). The records must be retained by the Investigator according 
to the ICH, local regulations, or as specified in the Clinical Study Agreement, whichever is 
longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), the Sponsor must be prospectively notified. The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor. The Investigator must obtain the 
Sponsor's written permission before disposing of any records, even if retention requirements 
have been met. 
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13. ETHICS 
13.1. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical 
Principles for Medical Research Involving Human Subjects, adopted by the General 
Assembly of the World Medical Association (31). 
In addition, the study will be conducted in accordance with the protocol, ICH GCP, and 
applicable local regulatory requirements and laws. 
The Investigator must ensure that this study is conducted in full conformity with Regulations 
for the Protection of Human Subjects of Research codified in 21 CFR Part 50, 21 CFR Part 
54, 21 CFR Part 56, 21CFR Part 312, 21 CFR Part 314 and ICH GCP E6. 
13.2. 
Patient Information and Consent 
All parties must ensure protection of patient personal data and must not include patient 
names on any Sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. In case of data transfer, the Sponsor must maintain high standards of 
confidentiality and protection of patient personal data. 
The informed consent form must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. 
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC/REB and the Sponsor before 
use. 
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. The Investigator, or a 
person designated by the Investigator, must obtain written informed consent from each 
patient or the patient's legally acceptable representative before any study-specific activity is 
performed. The Investigator must retain the original of each patient's signed consent form. 
13.3. 
IRB/IEC/REB 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (eg, 
recruitment advertisements, if applicable) from the IRB/IEC/REB. All correspondence with 
the IRB/IEC/REB must be retained in the Investigator Site File. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC/REB 
approval is where the change is necessary to eliminate apparent immediate hazards to the 
patients. In that event, the Investigator must notify the IRB/IEC/REB and the Sponsor in 
writing immediately after the implementation. 
13.4. 
Patient Confidentiality 
The Sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data must only be 
linked to the Sponsor’s clinical study database or documentation via a unique identification 
number. As permitted by all applicable laws and regulations, limited patient attributes, such 
as sex, age, or date of birth may be used to verify the patient and accuracy of the patient’s 
unique identification number. 
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To comply with ICH GCP and to verify compliance with this protocol, the Sponsor requires 
the Investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA), the Sponsor’s designated auditors, and the appropriate IRBs 
and IECs to review the patient’s original medical records (source data or documents), 
including, but not limited to, any genetic/genomic data the patient might have from testing 
done prior to entering the study, laboratory test result reports, ECG reports, admission and 
discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports. Access to a patient’s original medical records requires the specific 
authorization of the patient as part of the informed consent process (Section 13.2). 
Copies of any patient source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, patient name, address, and other identifier 
fields not collected on the patient’s eCRF). 
13.5. 
Reporting of Safety Issues or Serious Breaches of the Protocol or 
International Conference on Harmonization Good Clinical 
Practice 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the study drug, the Sponsor must be 
informed immediately.  
In addition, the Investigator must inform the Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the study patients against any immediate 
hazard, and of any serious breaches of this protocol or of ICH GCP that comes to the 
attention of the Investigator. 
13.6. 
Liability and Insurance 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its 
legal liability for injuries caused to participating persons and arising out of this research 
performed strictly in accordance with the scientific protocol as well as with applicable law 
and professional standards. 
 
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14. STUDY TERMINATION 
When the Sponsor is aware of information on matters concerning the quality, efficacy, and 
safety of the study drug, as well as other important information that may affect proper 
conduct of the clinical study, the Sponsor may discontinue the clinical study and send a 
written notice of the discontinuation along with the reason to the Investigator.  
If an Investigator intends to discontinue participation in the study, the Investigator must 
immediately inform the Sponsor of the discontinuation and the reason for it. 
14.1. 
Criteria for Suspension or Premature Termination of the Study 
Criteria for either temporary suspension or premature termination of the study include: 
1. New information regarding the safety or efficacy of the study drug that indicates a change 
in the known risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for patients participating in the study. 
2. Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises patient safety. 
3. The Sponsor may suspend or prematurely terminate the study for reasons not related to 
the conduct of the study. 
14.2. 
Criteria for Premature Termination or Suspension of 
Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the 
Investigator) is found to be in significant violation of GCP, protocol, contractual agreement, 
or is unable to ensure adequate performance of the study. 
14.3. 
Procedures for Premature Termination or Suspension of the 
Study or the Participation of Investigational Site(s) 
In the event that the Sponsor elects to terminate or suspend the study or the participation of 
an investigational site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension. 
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15. PUBLICATION OF STUDY RESULTS 
Any and all scientific, commercial, and technical information disclosed by the Sponsor in 
this protocol or elsewhere must be considered the confidential and proprietary property of the 
Sponsor. The Investigator shall hold such information in confidence and shall not disclose 
the information to any third party except to such of the Investigator's employees and staff as 
have been made aware that the information is confidential and who are bound to treat it as 
such and to whom disclosure is necessary to evaluate that information. The Investigator shall 
not use such information for any purpose other than determining mutual interest in 
performing the study and, if the parties decide to proceed with the study, for the purpose of 
conducting the study. 
The Investigator understands that the information developed from this clinical study will be 
used by the Sponsor in connection with the development of the study drug and therefore may 
be disclosed as required to other clinical investigators, business partners and associates, the 
FDA, and other government agencies. The Investigator also understands that, to allow for the 
use of the information derived from the clinical study, the Investigator has the obligation to 
provide the Sponsor with complete test results and all data developed in the study. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between the Sponsor and the Investigator and/or 
the Investigator's institution. 
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Force. NCCN Task Force Report: Optimal management of patients with 
gastrointestinal stromal tumor (GIST) – update of the NCCN clinical practice 
guidelines. J Natl Compr Canc Netw 2007;5(2):S1-29. 
20. 
Aubin F and Blanke CD. Metastatic gastrointestinal stromal tumors. Cancer 
Chemother Pharmacol. 2011;67(Suppl 1):S9-S14. 
21. 
Blay J-Y. A decade of tyrosine kinase inhibitor therapy: Historical and current 
perspectives on targeted therapy for GIST. 2010. 
http://dx.doi.org/10.1016/j.ctrv.2010.11.00. 
22. 
Corless CL, Fletcher JA, and Heinrich MC. Biology of gastrointestinal stromal 
tumors. J Clin Oncol. 2004;22(18):3813-25. 
23. 
Corless CL, Barnett CM, and Heinrich MC. Gastrointestinal stromal tumours: origin 
and molecular oncology. Nature Reviews. Cancer. 2011;11:865-78. 
24. 
Emile JF, Brahimi S, Coindre JM, et.al. Frequencies of KIT and PDGFRA mutations 
in the MolecGIST prospective population-based study differ from those of advanced 
GISTs. Med Oncol. 2011. 
25. 
Eisenberg BL and Smith KD. Adjuvant and neoadjuvant therapy for primary GIST. 
Cancer Chemother Pharmacol. 2011;67 (Suppl 1):S3–S8. 
26. 
Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, et al. Resumption of Imatinib 
dosing to control metastatic Gastrointestinal Stromal Tumors (GIST) after failure of 
Imatinib and Sunitinib: Results of a randomised, placebo-controlled, phase 3 trial 
(RIGHT). Lancet Oncol. 2013 November;14(12):1175–82. 
 
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Page 95 of 97 
                                                                                                                                                                    
27. 
Yoo C, Ryu MH, Nam BH, Ryoo BY, Demetri GD, Kang YK. Impact of imatinib 
rechallenge on health-related quality of life in patients with TKI-refractory 
gastrointestinal stromal tumours: Sub-analysis of the placebo-controlled, randomised 
phase III trial (RIGHT). Eur J Cancer. 2016 Jan;52:201-8. 
28. 
EORTC QLQ-C30. [Internet]. European Organisation for Research and Treatment of 
Cancer. [cited 05 July 2017]. Available from: 
http://groups.eortc.be/qol/sites/default/files/img/slider/specimen_qlq-c30_english.pdf 
29. 
van Reenen M and Janssen B. EQ-5D-5L User Guide. [Internet]. The EuroQol Group. 
2015 [cited 05 July 2017]. Available from: https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf 
30. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
31. 
World Medical Association. World Medical Association Declaration of Helsinki: 
ethical principles for medical research involving human subjects. JAMA. 2013 Nov 
27;310(20):2191-4. 
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Page 96 of 97 
17. APPENDICES 
17.1. 
Modified Response Evaluation Criteria in Solid Tumors 
(RECIST) 
Modified RECIST criteria includes: 
• No lymph nodes chosen as target lesions; enlarged lymph nodes 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 (eg, 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. 
Source: Demetri GD, Jeffers M, Reichardt P, Kang Y-K, Blay J-Y, Rutkowski P, et al. Mutational analysis of plasma DNA 
from patients (pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI) 
refractory GIST: Correlating genotype with clinical outcomes. J Clin Oncol 31, 2013 (suppl; abstr 10503). 
 
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17.2. 
Healthcare Utilization Questionnaire 
Healthcare Utilization Questionnaire Instructions 
 
Administration: The questionnaire should be completed via a patient interview by a healthcare 
provider participating in the study. 
 
Healthcare Utilization Questionnaire 
A.  Healthcare Visits 
Other than what was required for this study, did you use any 
of the following health care services during the last 28 days (4 
weeks)? 
Yes   No 
Number during the 
last 28 days 
Emergency room visit 
□   □ 
 
Use of an ambulance 
□   □ 
 
Outpatient primary care physician visit  
□   □ 
 
Outpatient specialist visit (e.g., oncologist, surgeon) 
□   □ 
 
Outpatient counseling visit (e.g., psychiatrist, psychologist, 
therapist, mental health specialist) 
□   □ 
 
Other  
□   □ 
 
 
B. Inpatient Visits   
Did you spend any days in the 
following facilities during the last 
28 days (4 weeks)? 
Yes   No 
Length of Stay 
(days) 
Reason for Stay 
Inpatient hospital 
□   □ 
 
□ Disease/treatment related 
□ Other 
Rehabilitation facility 
□   □ 
 
□ Disease/treatment related 
□ Other 
Hospice facility 
□   □ 
 
□ Disease/treatment related 
□ Other 
Respite care 
(eg, caregiver relief) 
□   □ 
 
□ Disease/treatment related 
□ Other 
Skilled nursing facility/nursing 
home 
□   □ 
 
□ Disease/treatment related 
□ Other 
 
C. Care in the home 
Did any healthcare worker provide 
services to you in your home during the 
last 28 days (4 weeks)? 
Yes       No 
Number of days 
Number of hours 
per day 
Nurse 
□     □ 
 
 
Home health aide 
□     □ 
 
 
Hospice worker 
□     □ 
 
 
Other 
□     □ 
 
 
 
 
260

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Protocol DCC-2618-03-001 (INVICTUS) 
A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to Assess the Safety 
and Efficacy of DCC-2618 In Patients with AdvanCed Gastrointestinal Stromal TUmorS 
who have Received Treatment with Prior Anticancer Therapies 
NCT Number: 03353753 
Document Date: Version 2.0 (08 August 2019) 


Deciphera Pharmaceuticals, LLC 
STATISTICAL ANALYSIS PLAN 
Protocol No. DCC-2618-03-001 
A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to Assess the Safety 
and Efficacy of DCC-2618 In Patients with AdvanCed Gastrointestinal Stromal TUmorS 
who have Received Treatment with Prior Anticancer Therapies 
Deciphera Pharmaceuticals, LLC 
500 Totten Pond Road, 6th Floor 
Waltham, MA 02451 
Final 2.0 
08 Aug 2019 
6


Pro1ocol Kumbe.: DCC-2618-03-001 
Plan Versioo: 0SAug2019, Final 2.0 
APPROVALS 
By signing this document. I acknowledge that I ha,e n:ad the document and approve of
the planned statistical analyses described herein. I agree that the planned statistical 
analys1.-s are appropriate for this study, are in accordance with the study objcc1ivcs, and
are consisten1 wilh the Ç1a1istical methodology described in 1he s1udy. and all applicable
regulmory guidance and guidelines.
Prepared by:
Deciphcra Pharmaceuticals. LLC' 
Reviewed an
ppro,·ed by:
Deciphera Pharmaceu1icals. L LC 
Deciphera PhannaceuticaJs, lLC. 
CONFIDEN!lAL 
Page 3 of29 
7
PI
PI
PI
PI
PI
PI
PI


Protocol Number: DCC-2618-03-001 
 
Plan Version: 08Aug2019, Final 2.0 
 
Deciphera Pharmaceuticals, LLC. 
CONFIDENTIAL 
Page 3 of 29 
TABLE OF CONTENTS 
ABBREVIATIONS ............................................................................................................... 5 
SUMMARY OF MAJOR CHANGES ................................................................................... 7 
1 
INTRODUCTION ................................................................................................... 11 
2 
OVERALL STUDY DESIGN AND OBJECTIVES ................................................ 11 
2.1 
Study Objectives ................................................................................................ 11 
2.1.1 
Primary Objective ........................................................................................ 11 
2.1.2 
Key Secondary Objective ............................................................................. 11 
2.1.3 
Additional Secondary Objectives.................................................................. 11 
2.1.4 
Exploratory Objectives ................................................................................. 11 
2.2 
Trial Design and Study Procedures..................................................................... 12 
2.2.1 
Study Design ................................................................................................ 12 
2.2.2 
Treatments and Assignment to Treatments ................................................... 12 
2.3 
Determination of Sample Size ............................................................................ 13 
3 
GENERAL ANALYSIS CONVENTIONS .............................................................. 14 
3.1 
Statistical Analysis Periods ................................................................................ 14 
3.2 
Visit Windows ................................................................................................... 15 
3.3 
Baseline ............................................................................................................. 15 
3.4 
Handling of Repeated and Unscheduled Assessments ........................................ 15 
3.5 
Coding Dictionaries ........................................................................................... 15 
3.6 
General Analysis Conventions ........................................................................... 16 
4 
ANALYSIS POPULATIONS .................................................................................. 16 
4.1 
Intention-to-treat Population .............................................................................. 16 
4.2 
Safety Population ............................................................................................... 16 
4.3 
Per Protocol Population ...................................................................................... 16 
4.4 
PK Population .................................................................................................... 16 
5 
PATIENT DISPOSITION ....................................................................................... 17 
6 
PROTOCOL DEVIATIONS .................................................................................... 17 
7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................. 17 
7.1 
Demographic Characteristics .............................................................................. 17 
7.2 
Medical History ................................................................................................. 18 
7.3 
Cancer History and Prior Cancer Therapy .......................................................... 18 
8 
EFFICACY ANALYSIS .......................................................................................... 18 
8.1 
Primary Efficacy Analysis .................................................................................. 18 
8.2 
Key Secondary Endpoint .................................................................................... 19 
8.3 
Secondary Efficacy Analysis .............................................................................. 19 
8.3.1 
Time to Progression ..................................................................................... 19 
8.3.2 
Overall Survival ........................................................................................... 20 
8.3.3 
Time to Response ......................................................................................... 20 
8.3.4 
PFS Based on Investigator Assessment ......................................................... 20 
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8.3.5 
Quality of Life.............................................................................................. 21 
8.3.6 
Disease Control Rate .................................................................................... 22 
8.3.7 
Duration of Response ................................................................................... 22 
8.4 
Handling of Missing Data .................................................................................. 22 
8.5 
Multiple Comparisons/Multiplicity .................................................................... 23 
8.6 
Examination of Subgroups ................................................................................. 23 
8.7 
Interim Analysis and Data Monitoring ............................................................... 23 
9 
PHARMACOKINETICS ......................................................................................... 23 
10 
SAFETY ANALYSIS .............................................................................................. 24 
10.1 
Study Drug Exposure ......................................................................................... 24 
10.2 
Adverse Events .................................................................................................. 24 
10.3 
Eastern Cooperative Oncology Group Performance Status ................................. 25 
10.4 
Clinical Laboratory Data .................................................................................... 25 
10.5 
Vital Signs ......................................................................................................... 27 
10.6 
Electrocardiograms ............................................................................................ 27 
10.7 
Echocardiograms/Multigated Acquisition Scans ................................................. 27 
10.8 
Dermatologic assessments .................................................................................. 27 
10.9 
Ophthalmologic assessments .............................................................................. 27 
10.10 
Prior and Concomitant Medications and Procedures ........................................... 27 
11 
STATISTICAL ANALYSIS DURING THE OPEN-LABEL ANALYSIS PERIOD 28 
11.1 
Analysis Sub-periods ......................................................................................... 28 
11.2 
Baseline ............................................................................................................. 28 
11.3 
Analysis Populations .......................................................................................... 28 
11.4 
Efficacy Analysis ............................................................................................... 28 
11.5 
Safety Analysis .................................................................................................. 29 
12 
QUALITY CONTROL ............................................................................................ 29 
13 
REFERENCES ........................................................................................................ 29 
 
LIST OF TABLES IN THE TEXT 
Table 1 
Imputation Rules for Partially Missing Dates ..................................................... 22 
Table 2. 
Safety Laboratory Tests ..................................................................................... 26 
 
9


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Page 5 of 29 
ABBREVIATIONS 
Below is the list of acronyms that will be used throughout this document. 
Abbreviation 
Definition 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC-2 
Anatomical Therapeutic Chemical 2nd level 
BID 
Twice Daily 
cfDNA 
Cell-Free DNA 
CR 
Complete Response 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire for Cancer 30 item 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level 
EQ-VAS 
EuroQol visual analogue scale 
GIST 
Gastrointestinal Stromal Tumors 
IDMC 
Independent Data Monitoring Committee 
KM 
Kaplan-Meier 
ICH 
International Conference on Harmonisation 
ITT 
Intent to Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PR 
Partial Response 
PT 
Preferred Term 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PP 
Per Protocol 
QD 
Once daily 
QOL 
Quality of Life 
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Page 6 of 29 
Abbreviation 
Definition 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TKI 
Tyrosine Kinase Inhibitor 
TTP 
Time to Progression  
VAS 
Visual analogue scale 
WHO 
World Health Organization 
11


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Page 7 of 29 
SUMMARY OF MAJOR CHANGES 
Section(s)  Version 1 Language  
Version 2 Language  
Rationale for 
Change  
3.1 
 
Double-blind treatment analysis 
period 
from the randomization date to the 
last follow-up date for patients who 
discontinued from the study upon 
disease progression by independent 
radiologic review on initial treatment 
or discontinuation from initial 
treatment due to other cause 
from the randomization date to the 
first disease progression date for 
patients who continued to receive 
DCC-2618 at 150mg QD or an 
escalated dose and those who 
crossed over from placebo to receive 
DCC-2618 at150mg QD after 
disease progression on initial 
treatment 
Open-label analysis period 
from the day immediately after the 
first disease progression on initial 
treatment to the last follow-up date 
for patients who continued to receive 
DCC-2618 150mg QD or at an 
escalated dose and those who 
crossed over from placebo to receive 
DCC-2618 150mg QD after disease 
progression on initial treatment 
 
• 
Double-blind treatment analysis period 
o 
from the randomization date to the last follow-up 
date,  
 
if a patient did not have disease progression 
based on independent radiologic review, or, 
 
if a placebo patient did not cross over to DCC-
2618 treatment, or, 
 
if a patient was initially treated with DCC-
2618 and did not continue to receive DCC-
2618 at 150mg QD or escalate to 150mg BID 
after disease progression based on independent 
radiologic review. 
o 
from the randomization date to the first disease 
progression date if a patient was initially treated 
with DCC-2618 and continued to receive DCC-
2618 at 150mg QD after disease progression based 
on independent radiologic review. 
o 
from the randomization date to the day immediately 
before the first dose of DCC-2618 150mg BID if a 
patient was initially treated with DCC-2618 and 
escalated to DCC-2618 150mg BID after disease 
progression based on independent radiologic 
review.   
o 
from the randomization date to the day immediately 
before the first dose of DCC-2618 150mg QD if a 
patient crossed over from placebo to receive DCC-
2618 at150mg QD after disease progression based 
on independent radiologic review.   
• 
Open-label analysis period 
o 
from the day immediately after the first disease 
progression based on independent radiologic review 
to the last follow-up date if a patient was initially 
treated with DCC-2618 and continued to receive 
DCC-2618 150mg QD after disease progression 
based on independent radiologic review.  
o 
from the first dose date of DCC-2618 150mg BID 
to the last follow-up date if a patient was initially 
treated with DCC-2618 and escalated to DCC-2618 
150mg BID after disease progression based on 
independent radiologic review.   
o 
from the first dose date of DCC-2618 150mg QD to 
the last follow-up date if a patient crossed over 
from placebo to receive DCC-2618 150mg QD 
after disease progression based on independent 
radiologic review.   
Revision for more 
specific 
definitions 
3.5 
 
Handling of Repeated and Unscheduled Assessments 
In general, for by-visit summaries, data recorded at nominal 
visits will be presented.  
Laboratories, vital signs, ECG, and ECHO/MUGA results at 
unscheduled visits and repeated assessments will not be 
included in the by-visit summaries however will contribute to 
the best/worst case value, and last on-treatment visit, where 
applicable.  
Tumor assessments at unscheduled visits will be used for the 
derivation of the primary endpoint and other efficacy 
endpoints. 
Addition of a new 
section. 
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Section(s)  Version 1 Language  
Version 2 Language  
Rationale for 
Change  
4.3 
A Per Protocol (PP) population may 
be included if there are patients in 
the ITT population who have 
protocol violations that are expected 
to compromise the efficacy and/or 
safety assessments (eg, patients 
enrolled who do not meet key 
eligibility criteria during the study).  
At the primary efficacy analysis, 
protocol violators resulting in 
exclusion from the PP population 
will be identified by the sponsor and 
documented prior to the database 
freeze. 
The Per Protocol (PP) population is defined as randomized 
patients who do not have important protocol deviations that 
are expected to compromise the efficacy and/or safety 
assessments as follows, 
• 
Inclusion/exclusion criteria deviations 
• 
Patient receiving wrong treatment 
• 
Patient receiving incorrect dose 
• 
Patient receiving prohibited medications 
The criteria for the important protocol deviations will be 
determined by the sponsor and documented in a separate file. 
Revision of the 
definition to align 
with ICH E3 R1 
Guidelines 2013 
6 
A major protocol deviation is a 
deviation that may significantly 
impact the completeness, accuracy, 
and/or reliability of the trial data; 
that may significantly affect a 
subject's rights, safety, or well-being 
(ICH E3 R1 Guidelines 2013). All 
major deviations related to trial 
inclusion or exclusion criteria, 
conduct of the trial, patient 
management or patient assessment 
will be described in the clinical study 
report.  
In addition, the sponsor will determine the important protocol 
deviations that may significantly impact the completeness, 
accuracy, and/or reliability of the trial data; that may 
significantly affect a subject's rights, safety, or well-being 
(ICH E3 R1 Guidelines 2013). Patients who have important 
deviations will be excluded from the Per-protocol population. 
All the important deviations will be summarized and 
described in the clinical study report. 
Revision of the 
definition to align 
with ICH E3 R1 
Guidelines 2013 
8.1 
For patients who have first disease 
progression or die after two or more 
consecutive missed/non-evaluable 
assessments , the patient will be 
censored at the time of the evaluable 
radiologic assessment immediately 
prior to the two or more consecutive 
missed/non-evaluable  radiologic 
assessments. 
For patients who have first disease progression or die after 
two or more consecutive missed/non-evaluable assessments , 
the patient will be censored at the time of the evaluable 
radiologic assessment immediately prior to the two or more 
consecutive missed/non-evaluable  radiologic assessments. 
The missed/non-evaluable assessments include both the 
scheduled assessments when a patient was on treatment and 
the hypothetical assessments (the expected assessments as if 
the patient was still on treatment) after a patient discontinued 
treatment or withdrew for reasons other than progressed 
disease. 
Addition to the 
handling rule of 
missing 
assessments in a 
hypothetic 
situation. 
8.3.5 
An analysis of covariance with study 
treatment, KIT/PDGFRA fourth 
line/KIT/PDGFRA fifth 
line/PDGFRA D842V status, and 
ECOG status at baseline will be 
performed. 
 
 
Remove of the 
originally planned 
analysis of 
EORTC-QLQ-
C30 which was 
not appropriate. 
Addition of new 
analysis to EQ-
5D-5L. 
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Section(s)  Version 1 Language  
Version 2 Language  
Rationale for 
Change  
8.3.5 
Score sets are available for Denmark, 
France, Germany, Japan, 
Netherlands, Spain, UK, US and 
Zimbabwe. For countries in which 
no score set exists (Canada, 
Hungary, Israel, Romania, and 
Sweden) the closest neighboring 
country will be used as a proxy 
(EuroQol Group, 2015). EQ-5D-5L 
will be summarized overall by n and 
percentage for each level of each 
dimension. The Cochran–Mantel–
Haenszel test will be used to test 
differences between DCC-2618 and 
placebo.  
The EuroQol visual analogue scale 
(EQ-VAS) is a measure of overall 
self-rated health status, used and 
analyzed separately from the index 
score. The EQ-VAS recorded the 
subject’s self-rated health on a 20 cm 
vertical VAS with endpoints labelled 
“the best health you can imagine” 
and “the worst health you can 
imagine.” The EQ-VAS score ranges 
from 0 to 100, with higher scores 
indicative of better overall health. 
EQ-VAS will be summarized using 
continuous descriptive. statistics. 
 
Score sets are available for Denmark, France, Germany, 
Japan, Netherlands, Spain, UK, US and Zimbabwe. For 
countries in which no score set exists (Canada, Hungary, 
Israel, Romania, and Sweden) the closest neighboring 
country will be used as a proxy (EuroQol Group, 2015), eg, 
UK value set for Australia, France value set for Belgium, 
USA value set for Canada and Singapore, and Germany 
value set for Poland. If scale is missing for one of the 
dimensions, the index (utility) score will have a missing 
value.  
EQ-5D-5L will be summarized overall by number and 
percentage for each level of each dimension. For 
pain/discomfort and usual activities, the Cochran–Mantel–
Haenszel test will be used to test the change in response scale 
at Day 1 of Cycle 2 from baseline between DCC-2618 and 
placebo. For EQ-5D-5L index (utility) score, an ANCOVA 
model with the stratification factors as factors will be used to 
compare the change at Day 1 of Cycle 2 from baseline 
between the two treatment arms.  
The EuroQol visual analogue scale (EQ-VAS) is a measure 
of overall self-rated health status, used and analyzed 
separately from the index score. The EQ-VAS recorded the 
subject’s self-rated health on a 20 cm vertical VAS with 
endpoints labelled “the best health you can imagine” and “the 
worst health you can imagine.” The EQ-VAS score ranges 
from 0 to 100, with higher scores indicative of better overall 
health. EQ-VAS will be summarized using continuous 
descriptive statistics. Change in EQ-VAS score at Day 1 of 
Cycle 2 from baseline between the two treatment arms will 
be tested with a t-test.  
Addition of the 
use of value sets 
and corresponding 
new analyses to 
EQ-5D-5L. 
8.3.7 
 
8.3.7 Duration of Response 
Duration of response is defined as the time interval from the 
first assessment of confirmed CR or PR until the first disease 
progression or death. In the case that the PFS is censored,  
duration of response will be censored at the last evaluable 
progression-free radiologic assessment in an analogous 
manner. 
Duration of response based on the independent radiologic 
review will be analyzed with Kaplan-Meier method using the 
25th, 50th (median), and 75th percentiles and survival 
probability at pre-specified timepoints, each with associated 
2-sided 95% confidence intervals. Duration of response 
based on the Investigator assessment will be analyzed in a 
similar fashion as well. 
Addition of new 
efficacy endpoint 
and analysis. 
10.4 
 
Numeric laboratory values recorded as “<x” or “>x” will be 
handled as follows, 
• 
In the listings, “<x” and “>x” will be presented as 
recorded 
• 
In the summary tables of observed values and 
changes from the baseline and those for shifts in 
CTCAE grade, “<x” and “>x” will be converted to 
numeric values before the analysis, 
o 
 “<x” will be converted to “x – 1e-6”  
o 
 “>x” will be converted to “x + 1e-6” 
In the summary tables of numeric values, the convention is to 
present 1 decimal place beyond those used in raw data for 
median and mean and 2 more decimal places beyond those 
Addition to handle 
the data that are 
not entered in a 
normal way. 
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Section(s)  Version 1 Language  
Version 2 Language  
Rationale for 
Change  
used in raw data for standard deviation and standard error. 
There will be no deviation from this convention to display 6 
or more decimals due to any conversion using the above 
rules. 
11.4 
Efficacy data during the open-label 
analysis period will be presented in 
listings only.  
 
Efficacy analysis during the open-label analysis period will 
be explored by analysis sub-periods.  
For patients who initially received placebo and subsequently 
crossed over to DCC-2618 treatment, PFS in the “Prior to 
intra-patient dose escalation” sub-period will be defined as 
the time interval between the date of first dose of DCC-2618 
and the earliest documented evidence of disease progression. 
PFS will be re-defined or censored as needed, and analyzed 
in a similar fashion to the primary efficacy endpoint. 
For patients in the “Intra-patient dose escalation” sub-period, 
efficacy assessment data will be presented in listings only.  
Addition of new 
efficacy analysis. 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the methods to be used in the analysis of study 
data from clinical protocol DCC-2618-03-001 (invictus) in order to answer the study 
objectives, and is based on Amendment 5 of the study protocol, dated 30Oct2018. 
Populations for analysis, data handling rules, and statistical methods are described within this 
document. The statistical analyses and summary tabulations described in this SAP will 
provide the basis for the results sections of the clinical study report (CSR) for this trial. 
Pharmacokinetic (PK) analysis, pharmacodynamic (PD) and bioanalytical data analysis is not 
in the scope of this SAP. These analyses will be separately planned and reported. The SAP 
outlines any differences in data analysis methods relative to those planned in the study 
protocol.  Any changes to the data analysis methods after the SAP is finalized will be 
described in the CSR. 
2 
OVERALL STUDY DESIGN AND OBJECTIVES 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
To assess the efficacy (progression-free survival [PFS]) of DCC-2618 by independent 
radiologic review in patients with advanced gastrointestinal stromal tumors (GIST) who have 
received prior therapies 
2.1.2 
Key Secondary Objective 
To assess objective response rate (ORR) by independent radiologic review 
2.1.3 
Additional Secondary Objectives 
• To assess other parameters of efficacy, including but not limited to time to 
progression (TTP) and overall survival (OS) 
• To assess the PD/PK relationship of DCC-2618 
• To assess the robustness of efficacy using a sensitivity analysis 
• To assess improvement of disease-related symptoms and quality of life (QOL) 
• To assess the safety of DCC-2618 
2.1.4 
Exploratory Objectives 
• To assess the efficacy of DCC-2618 in patients after dose escalation to DCC-2618 
150 mg twice daily (BID) 
• To characterize KIT and PDGFRA gene resistance mutations (and potentially other 
gene mutations) and their DCC-2618-driven longitudinal mutation allele frequency 
changes in plasma cell-free DNA (cfDNA) 
• To retrospectively correlate KIT and PDGFRA mutation/s and/or their frequency (as 
well as of potentially other gene mutations) in baseline cfDNA with clinical benefit 
• To understand potential tyrosine kinase inhibitor- (TKI) resistance mechanisms of 
GIST at time of progression 
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• To determine concordance between KIT, PDGFRA, and other genetic mutations in 
tumor and cfDNA at baseline 
• To assess healthcare utilization in patients with advanced GIST who have received 
approved therapies 
2.2 
Trial Design and Study Procedures 
2.2.1 
Study Design 
This is a 2-arm, randomized, placebo-controlled, double-blind, international, multicenter 
study comparing the efficacy of DCC-2618+best supportive care to placebo+best supportive 
care in patients with advanced GIST who have received treatment with prior anticancer 
therapies. Prior anticancer therapies must include treatment with imatinib, sunitinib, and 
regorafenib (3 prior therapies). Up to 40% of enrolled patients may have received prior 
treatment with imatinib, sunitinib, regorafenib, and other drugs (≥4 prior therapies). 
Approximately 120 patients will be randomized in a 2:1 ratio to DCC-2618 150 mg once 
daily (QD) or placebo. Randomization will be stratified by the number of prior anticancer 
treatments (3 versus ≥4) and Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) (0 versus 1 or 2). 
The primary response to study treatment for the study will be evaluated using the modified 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - GIST-specific 
(hereafter referred to as “modified RECIST”) based on independent radiologic review. 
2.2.2 
Treatments and Assignment to Treatments 
Approximately 120 patients will be randomized to 2:1 to 150 mg QD of DCC-2618 versus 
placebo. Randomization will be stratified by: 
• Patients who have received 3 prior anticancer treatments versus patients who have 
received ≥4 prior anticancer treatments. 
• ECOG performance status=0 versus ECOG performance status=1 or 2. 
Patients will continue on the current treatment until the time of disease progression by 
modified RECIST from the independent radiological review, unacceptable toxicity, or 
withdraw of consent. Upon progression confirmation by independent radiological review, 
study treatment will be unblinded.  
At that time:  
Patients randomized to DCC-2618 150 mg QD will be given the option to:  
• continue DCC-2618 at an increased dose of 150 mg BID, or  
• continue treatment on study with the same dose if the Investigator feels the patient is 
receiving benefit from DCC-2618 or if dose escalation may not be tolerable for the 
patient (dose escalation is not permitted at a later time during the study), or  
• discontinue DCC-2618. 
Patients randomized to placebo will be given the option to:  
• cross over to receive DCC-2618 150 mg QD, or 
• discontinue the study 
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Patients randomized to placebo who cross over to receive DCC-2618 150 mg QD and 
have disease progression by modified RECIST based on Investigator assessment will be 
given the option to: 
• continue DCC-2618 at an increased dose of 150 mg BID 
• continue treatment on study with the same DCC-2618 dose if the Investigator feels 
the patient is receiving benefit from DCC-2618 or if dose escalation may not be 
tolerable for the patient (dose escalation is not permitted at a later time during the 
study) or 
• discontinue DCC-2618.  
2.3 
Determination of Sample Size  
The sample size selection of approximate 120 patients (n=80 DCC-2618, n=40 placebo) was 
based on considerations for powering of the primary endpoint, key secondary endpoint, 
detection of rare safety events and overall exposure to DCC-2618, and assuming 15% patient 
dropout. Patients will be randomized in a 2:1 ratio of DCC-2618 versus placebo. 
This sample size [105 patients (n=70 DCC-2618, n=35 placebo) with 90 events 
(55 DCC-2618, 35 placebo) at the final analysis] will have at least 90% power to detect a 
difference in PFS between DCC-2618 and placebo assuming a median PFS of 4.5 months for 
DCC-2618 and 1 month for placebo. Moreover, this assumes 9 months of uniform 
recruitment and 6 additional months of follow-up (total patient follow-up of 15 months). 
Furthermore, 105 patients (n=70 DCC-2618, n=35 placebo) will have approximately 80% 
power to detect a 0.2 difference in ORR assuming that the ORR for DCC-2618 = 0.22 and 
the ORR for placebo = 0.02. 
In addition, a minimum sample size of 80 DCC-2618 patients allows adequate power to 
detect the incidence of rare safety events. A sample of 80 patients yields 95% probability that 
the study will reveal at least one occurrence of all safety events that occur in patients at a rate 
of 4.0% or greater. This in combination with the exposure to DCC-2618 from other studies 
conducted in this clinical program will meet the recommendations for overall exposure 
recommended by FDA. 
Where required, safety personnel at the Sponsor or designee may be unblinded to a patient’s 
study drug assignment to meet reporting requirements to regulatory agencies. In addition, the 
Investigator, patient, Sponsor, and study team will be unblinded at the time the patient has 
disease progression by modified RECIST based on independent radiology review.  
At no point in time before official full study unblinding will any efficacy and safety analyses 
be conducted by the Sponsor or Sponsor representatives, unless there is explicit permission to 
do so, for instance high level efficacy assessment for the purposes of an Independent Data 
Monitoring Committee (IDMC) review to determine the adequacy of the risk/benefit profile 
of the drug as it pertains to the conduct of the clinical trial. 
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3 
GENERAL ANALYSIS CONVENTIONS 
Statistical analysis will be performed using SAS® (version 9.4 or newer). 
3.1 
Statistical Analysis Periods 
Based on the study design, two main analysis periods will be defined as follows: 
• Double-blind treatment analysis period 
o from the randomization date to the last follow-up date  
 if a patient did not have disease progression based on independent radiologic 
review or 
 if a placebo patient did not cross over to DCC-2618 treatment or 
o if a patient was initially treated with DCC-2618 and did not continue to receive 
DCC-2618 at 150mg QD or escalate to 150mg BID after disease progression based 
on independent radiologic review from the randomization date to the first disease 
progression date if a patient was initially treated with DCC-2618 and continued to 
receive DCC-2618 at 150mg QD after disease progression based on independent 
radiologic review 
o from the randomization date to the day immediately before the first dose of 
DCC-2618 150mg BID if a patient escalated to DCC-2618 150mg BID after 
disease progression based on independent radiologic review  
o from the randomization date to the day immediately before the first dose of 
DCC-2618 150mg QD  if a patient crossed over from placebo to receive 
DCC-2618 at150mg QD after disease progression based on independent 
radiologic review  
• Open-label analysis period 
o from the day immediately after the first disease progression based on independent 
radiologic review to the last follow-up date if a patient was initially treated with 
DCC-2618 and continued to receive DCC-2618 150mg QD after disease 
progression based on independent radiologic review 
o from the first dose date of DCC-2618 150mg BID to the last follow-up date if a 
patient was initially treated with DCC-2618 and escalated to DCC-2618 150mg 
BID after disease progression   
o from the first dose date of DCC-2618 150mg QD to the last follow-up date if a 
patient crossed over from placebo to receive DCC-2618 150mg QD after disease 
progression based on independent radiologic review  
The primary efficacy endpoint, progression-free survival, will be defined and analyzed only 
during the double-blind treatment analysis period.  
Overall survival will be defined and analyzed throughout patients’ entire on study period. 
The data cut-off for the primary analysis will occur when 90 PFS events have occurred. It is 
expected that the primary analysis will occur approximately 6 months after the last patient is 
enrolled into the trial.  
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As of the primary efficacy analysis, the evaluation of the efficacy and safety of DCC-2618 
against the placebo will be mainly based on the data collected during the double-blind 
treatment analysis period. The analysis during this period will be detailed in Sections 3.2 to 
10.10.  
For data collected during the open-label analysis period and entered in the database by the 
data cut-off date or at the final database lock, statistical analysis will be described in 
Section 11. 
3.2 
Visit Windows 
The protocol visit windows are defined the same for blinded treatment and open label 
treatment phases. Visits will be analyzed per the electronic case report form (eCRF) 
collection.  Unscheduled visits will be mapped to a scheduled visits if possible, using a 
window based on all the available actual visit dates for the scheduled visits. 
Reference start date will be defined as  Cycle 1 Day 1 visit date. Study Day will be calculated 
from the reference start date and used to show start/stop day of the assessments and events as 
follows, 
• For assessments/events on/after the reference start date:  
       Study Day= (date of assessment/event – reference start date ) +1 
• For assessments/events before the reference start date:  
       Study Day= (date of assessment/event – reference start date ) 
3.3 
Baseline 
Unless specified otherwise, baseline measurements will be the most recent (ie, last non-
missing) value collected from screening until prior to receiving the first dose of study 
medication  (Cycle 1 Day 1).  
3.4 
Handling of Repeated and Unscheduled Assessments 
In general, for by-visit summaries, data recorded at nominal visits will be presented.  
Laboratories, vital signs, ECG, and ECHO/MUGA results at unscheduled visits and repeated 
assessments will not be included in the by-visit summaries however will contribute to the 
best/worst case value, and last on-treatment visit, where applicable.  
Tumor assessments at unscheduled visits will be used for the derivation of the primary 
endpoint and other efficacy endpoints. 
3.5 
Coding Dictionaries 
Medical history and adverse events (AE) will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA), Version  21.1 or higher. Prior and concomitant 
medications and procedures will be coded using the World Health Organization (WHO) Drug 
Dictionary (SEP 2018) or higher. 
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3.6 
General Analysis Conventions  
Continuous variables will be summarized using descriptive statistics (number of patients, 
mean, median, standard deviation, minimum, and maximum). Categorical variables will be 
summarized using frequencies and proportions. Time-to-event data will be summarized via 
Kaplan-Meier (KM) methodology using the 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% confidence intervals.  
4 
ANALYSIS POPULATIONS 
4.1 
Intention-to-treat Population 
The Intention-to-treat Population (ITT) population is defined as all patients who signed the 
informed consent and were randomized.  
The ITT population will be used for all efficacy analysis as a primary analysis set with 
treatment assignment based on randomization. 
4.2 
Safety Population 
The Safety population is defined as all patients who have received at least 1 dose of study 
drug.  
The safety population will be used for all safety analyses with treatment actually received. 
4.3 
Per Protocol Population 
The Per Protocol (PP) population is defined as randomized patients who do not have 
important protocol deviations that are expected to compromise the efficacy and/or safety 
assessments as follows, 
• Inclusion/exclusion criteria deviations 
• Patient receiving wrong treatment 
• Patient receiving incorrect dose 
• Patient receiving prohibited medications 
The criteria for such important protocol deviations will be determined by the sponsor and 
documented in a separate file. At the primary efficacy analysis, protocol deviations resulting 
in exclusion from the PP population will be identified by the sponsor and documented prior 
to the database lock. 
4.4 
PK Population 
The PK population will include all randomized subjects who received at least 1 dose of 
DCC-2618 and had at least 1 non-missing PK concentration in plasma reported for 
DCC-2618 or DP-5439. 
The PK population will be used for all PK analyses. 
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5 
PATIENT DISPOSITION  
Patient disposition will be summarized overall for all patients who enrolled in the study 
(ie, signed the informed consent for the study and were randomized). In addition, the number 
of patients in each population (ie, ITT, safety,  PK, and PP) will be displayed. The number 
and proportion of patients among the safety population  who have discontinued from 
treatment and the study will be summarized along with the reason for discontinuation. 
6 
PROTOCOL DEVIATIONS 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the clinical protocol.  Protocol deviations will be classified by medical 
review prior to primary analysis and major protocol deviations will be identified.  
The Sponsor or designee will be responsible for producing the final protocol deviation file 
(formatted as a Microsoft Excel file). This file will include a description of each protocol 
deviation and whether or not this deviation is classified as a major protocol deviation. This 
file will be finalized prior to database lock and study unblinding. 
In addition, the sponsor will determine the important protocol deviations that may 
significantly impact the completeness, accuracy, and/or reliability of the trial data; that may 
significantly affect a subject's rights, safety, or well-being (ICH E3 R1 Guidelines 2013). 
Patients who have important deviations will be excluded from the Per-protocol population. 
All the important deviations will be summarized and described in the clinical study report. 
7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
7.1 
Demographic Characteristics 
Demographic and baseline characteristics at study entry will be summarized for the safety 
and intention-to-treat populations.  
Demographic and baseline variables to be summarized are: 
• Continuous variables  
− Age (years) at time of consent 
− Height (cm) 
− Weight (kg) 
• Categorical variables  
− Gender 
− Race 
− Ethnicity 
− Screening ECOG (stratification variable) 
− Number of prior therapies (stratification variable) 
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7.2 
Medical History 
The number and percentage of patients with each medical history condition will be 
summarized for the safety population by system organ class and preferred term as coded 
using MedDRA Version 21.1 or higher. 
7.3 
Cancer History and Prior Cancer Therapy 
Histologic diagnosis of GIST, tumor mutation status, histology, stage at initial diagnosis, and 
time since the initial diagnosis in years (calculated from the informed consent date) will be 
summarized for the Safety Population. For prior cancer therapy, the number of patients and 
the type of systemic therapy, surgery, and radiation will be summarized along with the 
number of systemic therapy regimens per patient for the safety population. 
8 
EFFICACY ANALYSIS 
8.1 
Primary Efficacy Analysis 
The primary endpoint of PFS (reported in weeks) is defined as the interval between the date 
of randomization and the earliest documented evidence of the first disease progression based 
on the independent radiologic review or death due to any cause on initially assigned study 
treatment, whichever comes earlier. In the following situations, PFS will be re-defined 
otherwise or censored: 
• For patients who do not have evaluable radiologic assessment (including those 
randomized but untreated due to death or any other cause), PFS will be censored at 
randomization date (PFS=1 day) unless they die within 2 cycles of treatment (8 weeks 
plus 3 days allowing for a late radiologic assessment within the visit window). If 
patients die within 2 cycles of treatment (8 weeks plus 3 days), they are considered to 
have a PFS event at death date 
• For patients who only have non-measurable lesion according to modified RECIST 
Version 1.1 (non-nodal lesions must be ≥1.0 cm in the long axis or ≥double the slide 
thickness in the long axis) within 21 days prior to the first dose of study treatment, 
PFS will be censored at the date of latest evaluable progression-free radiologic 
assessment or patients will be considered to have disease progression at the date of 
new lesion(s) or unequivocal progression in non-target disease 
• For patients who undergo surgical resection of target or non-target lesions, who have 
received other anticancer treatments than the study treatment before documented date 
of the first disease progression, PFS will be censored at the date of the latest 
evaluable progression-free radiologic assessment  
• For patients who have not progressed and have not died, PFS will be censored at the 
time of the latest date of evaluable progression-free radiologic assessment if at most 
one missed/non-evaluable assessment prior to this assessment 
• For patients who have first disease progression or die after two or more consecutive 
missed/non-evaluable assessments , the patient will be censored at the time of the 
evaluable radiologic assessment immediately prior to the two or more consecutive 
missed/non-evaluable  radiologic assessments. The missed/non-evaluable assessments 
include both the scheduled assessments when a patient was on treatment and the 
hypothetical assessments (the expected assessments as if the patient was still on 
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treatment) after a patient discontinued treatment or withdrew for reasons other than 
progressed disease. For patients who have first disease progression documented 
between scheduled assessments, progression date is defined as the date of new lesion 
(if progression is due to new lesions) or defined as the earliest of the scan dates of the 
components that triggered the progression per independent radiologic review (if 
progression is due to increase in sum of measured lesions).    
Analysis for PFS will be stratified by the randomization stratification factors [prior lines of 
therapy (3 versus ≥4) and ECOG (0 versus 1 or 2)] . The p-value will be from a 2-sided 
stratified Log-rank test at 0.05 significant level for evaluation of treatment difference. Point 
estimate of hazard ratio will be obtained from a Cox regression model with treatment and the 
randomization stratification factors as fixed factors and it’s 95% CI will be obtained using 
Wald method.  PFS time will be summarized via KM methodology using the 25th, 50th 
(median), and 75th percentiles and pre-specified timepoints, each with associated 2-sided 
95% confidence intervals.  
Analyses will be performed using the ITT population as the primary efficacy analysis and PP 
population as supportive.  
Sensitivity analyses maybe performed if deemed necessary. 
8.2 
Key Secondary Endpoint 
ORR is defined as the proportion of patients with a confirmed complete response (CR) or 
partial response (PR) based on the independent radiologic review and during the initial 
assigned study treatment. This analysis will be performed in the ITT population as the main 
analysis and the PP population as supportive analysis. To be assigned a status of a CR or PR, 
changes in tumor measurements must be confirmed by repeat assessments that must be 
performed at least 4 weeks (allowing a minus 3 day window) after the criteria for response 
are first met. This analysis will include assessments prior to an event or censoring under the 
primary PFS analysis. Patients with unknown or missing response will be categorized as non-
responders and will be included in the denominator when calculating the proportion. An 
unstratified two-sided Fisher’s Exact test at a 0.05 significance level will be used to 
investigate statistical differences between treatment groups.  
A 95% Newcombe score confidence interval will be constructed for the treatment rate 
difference in ORR (Newcombe, 1998) 
A sensitivity analysis will be performed for ORR without requiring confirmation of CR and 
PR.  
8.3 
Secondary Efficacy Analysis 
8.3.1 
Time to Progression 
TTP (reported in weeks) is defined as the interval between the date of randomization and the 
earliest documented evidence of first disease progression on initial treatment based on the 
independent radiologic review. Since dying without progression is a competing risk of 
progression, TTP is censored at death date for patients who died without disease progression. 
Additionally, in the following situations, PFS will be re-defined otherwise or censored: 
• For patients who do not have evaluable radiologic assessment, TTP will be censored 
at randomization date (TTP=1 day) unless they die within 2 cycles of treatment (8 
weeks plus 3 days allowing for a late radiologic assessment within the visit window). 
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If patients die within 2 cycles of treatment (8 weeks plus 3 days), TTP will be 
censored at death date 
• For patients who only have none measurable lesion according to modified RECIST 
Version 1.1 (non-nodal lesions must be ≥1.0 cm in the long axis or ≥double the slide 
thickness in the long axis) within 21 days prior to the first dose of study treatment, 
TTP will be censored at the date of latest evaluable progression-free radiologic 
assessment or patients will be considered to have disease progression at the date of 
new lesion(s) or unequivocal progression in non-target disease 
• For patients who undergo surgical resection of target or non-target lesions, who have 
received other anticancer treatments than the study treatment before documented date 
of the first disease progression, TTP will be censored at the date of the latest 
evaluable progression-free radiologic assessment 
• For patients who have not progressed, TTP will be censored at the time of the latest 
date of evaluable progression-free radiologic assessment if at most one missed/non-
evaluable assessment prior to this assessment 
• For patients who have first disease progression after two or more consecutive 
missed/non-evaluable scheduled or hypothetical assessments , TTP will be censored 
at the time of the evaluable radiologic assessment immediately prior to the two or 
more consecutive missed/non-evaluable scheduled or hypothetical radiologic 
assessments 
• For patients who have first disease progression documented between scheduled 
assessments, progression date is defined as the date of new lesion (if progression is 
due to new lesions) or defined as the earliest of the scan dates of the components that 
triggered the progression per independent radiologic review (if progression is due to 
increase in sum of measured lesions)   
TTP will be analyzed in a similar fashion to PFS.  
8.3.2 
Overall Survival 
Overall survival (OS, reported in weeks) is defined as the interval between the date of 
randomization and date of death from any cause. Patients who are still alive or who are lost 
to follow-up will be censored at the date of last contact. As mentioned in Section 3.1, OS will 
be analyzed during the entire study period in a similar fashion toPFS.  
8.3.3 
Time to Response 
The time to response, based on the independent radiologic review, is defined as the interval 
between the date of randomization and the earliest date of first documented confirmed CR or 
earliest date of first documented confirmed PR if the patient does not have confirmed CR. 
Patients who do not have a confirmed PR or CR will be censored at the date of the last 
assessment during the double-blind treatment analysis period. Time to response will be 
summarized and displayed using KM methods in a manner similar to the primary analysis of 
PFS. 
8.3.4 
PFS Based on Investigator Assessment 
As a sensitivity analysis to the primary efficacy analysis, PFS (reported in weeks) is defined 
as the interval between the date of randomization and the earliest documented evidence of 
disease progression based on Investigator assessment or death on initial study treatment due 
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to any cause. In the situations mentioned in Section 8.1, PFS based on investigator 
assessment will be defined or censored in a manner analogous to which is used for PFS based 
on independent radiologic review.   
PFS based on investigator assessment will be analyzed in similar fashion to PFS based on 
independent radiologic review. 
8.3.5 
Quality of Life 
Quality of life (QOL) will be based on European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire for Cancer 30-item (EORTC-QLQ-C30) and the 
EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaires.  
The EORTC-QLQ-C30 will be summarized by scale. In all scales, a high scale score 
represents a higher response level. The scoring for this questionnaire will be done in 2 steps. 
1. Calculate the average of the items that contribute to the scale. This will be used as the 
raw score for the scale, and 
2. Apply a linear transformation to standardize the raw score, so that scores range from 
0 to 100. 
Changes from baseline to Day 1 of Cycle 2 in EORTC-QLQ-C30 Role function and Physical 
function will be compared between the two treatment arms using analysis of covariance 
(ANCOVA) model with the stratification factors as factors. If Day 1 of Cycle 2 value is 
missing, then the change from baseline to the end of initial study treatment will be used in the 
analysis. 
The EQ-5D-5L is a standardized measure of health status comprised of a descriptive system 
including five health-related QOL states (ie, mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and a visual analogue scale (VAS) of overall health. 
Each dimension is rated on a 5-point response scale indicating severity of problems, where 1 
is “no problems”, 2 “slight problems”, 3 “moderate problems”, 4 “severe problems”, and 5 is 
“extreme problems”. The five questions are scored and together contribute to the EQ-5D-5L 
index (utility) score between 0 and 1 (1 being perfect health), which will be calculated using 
the developers’ algorithm based on country-specific reference score sets (Van Hout et al., 
2012). Score sets are available for Denmark, France, Germany, Japan, Netherlands, Spain, 
UK, US and Zimbabwe. For countries in which no score set exists (Canada, Hungary, Israel, 
Romania, and Sweden) the closest neighboring country will be used as a proxy (EuroQol 
Group, 2015), eg, UK value set for Australia, France value set for Belgium, USA value set 
for Canada and Singapore, and Germany value set for Poland. If scale is missing for one of 
the dimensions, the index (utility) score will have a missing value.  
EQ-5D-5L will be summarized overall by number and percentage for each level of each 
dimension. For pain/discomfort and usual activities, the Cochran–Mantel–Haenszel test will 
be used to test the change in response scale at Day 1 of Cycle 2 from baseline between DCC-
2618 and placebo. For EQ-5D-5L index (utility) score, an ANCOVA model with the 
stratification factors as factors will be used to compare the change at Day 1 of Cycle 2 from 
baseline between the two treatment arms.  
The EuroQol visual analogue scale (EQ-VAS) is a measure of overall self-rated health status, 
used and analyzed separately from the index score. The EQ-VAS recorded the subject’s self-
rated health on a 20 cm vertical VAS with endpoints labelled “the best health you can 
imagine” and “the worst health you can imagine.” The EQ-VAS score ranges from 0 to 100, 
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with higher scores indicative of better overall health. EQ-VAS will be summarized using 
continuous descriptive statistics. Change in EQ-VAS score at Day 1 of Cycle 2 from baseline 
between the two treatment arms will be tested with a t-test.  
8.3.6 
Disease Control Rate 
Disease control rate (DCR) will be calculated and summarized with n and percentage. 
Disease control will be defined as having a response (complete or partial) or stable disease 
lasting at least 12 weeks. Other time points (6, 9, 12 months) may be added on an exploratory 
basis. 
8.3.7 
Duration of Response 
Duration of response is defined as the time interval from the first assessment of confirmed 
CR or PR until the first disease progression or death. In the case that the PFS is censored,  
duration of response will be censored at the last evaluable progression-free radiologic 
assessment in an analogous manner. 
Duration of response based on the independent radiologic review will be analyzed with 
Kaplan-Meier method using the 25th, 50th (median), and 75th percentiles and survival 
probability at pre-specified timepoints, each with associated 2-sided 95% confidence 
intervals. Duration of response based on the Investigator assessment will be analyzed in a 
similar fashion as well. 
8.4 
Handling of Missing Data 
For the analysis of efficacy endpoints, handling of missing data has been specified in 
Sections 8.1, 8.2, and 8.3. 
Algorithms for imputing partial or missing dates are shown below in Table 1. If a period 
determination cannot be made for an adverse event, it will be attributed to the randomized 
blinded period. AE end dates are imputed to facilitate calculation of AE duration. 
Table 1 
Imputation Rules for Partially Missing Dates 
Variable 
Missing Day 
Missing Day, Month 
Missing Day, Month, Year 
Date of Last 
Therapy/Date of 
Initial Diagnosis 
Assign 1 
Assign January 1 if prior to 
date of informed consent, 
otherwise use date of 
informed consent 
Missing (do not impute) 
Adverse 
Event/Start 
Date 
Assign first day of month 
unless it is the month of first 
dose of study medication. 
Otherwise, assign date of 
first dose of study 
medication or AE end date 
(if not missing) whichever is 
earlier 
Assign January 1 unless 
the year is year of first 
dose of study medication 
Otherwise, assign date of 
first dose of study 
medication or AE end date 
(if not missing) whichever 
is earlier. 
Assign date first dose of 
study medication. 
Adverse Event 
End Date 
Assign the last day of the 
month or death date or data 
cut-off date (or end of study 
date), whichever is earliest. 
Assign December 31 or 
death date or data cut-off 
date (or end of study date), 
whichever is earliest. 
If ongoing, end date is 
missing.  
Otherwise, assign death date 
or data cut-off date (or end 
of study date), whichever is 
earlier. 
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8.5 
Multiple Comparisons/Multiplicity 
To control familywise type-I error, the hypothesis tests for treatment difference between 
DCC-2618 and placebo will be performed at two-sided 0.05 level of significance sequentially 
in the following order: 
1. The primary endpoint PFS based on independent radiologic review 
2. The key secondary endpoint ORR based on independent radiologic review 
3. OS 
4. QOL as determined by changes from baseline to Day 1 of Cycle 2 in EORTC-QLQ-
C30 Role function and Physical function (each at 0.025 level of significance) 
 
If any hypothesis test is not significant at alpha=0.05 level, the subsequently listed analyses 
will be viewed as descriptive. 
8.6 
Examination of Subgroups 
Subgroup analysis will be performed for the primary and key secondary efficacy endpoints 
defined by the following variables: 
• Age (18 – 64 vs 65 – 74 vs 75 years or older) 
• Gender (Male vs female) 
• Race (White vs non-White vs not-reported) 
• Region (US vs non-US) 
• Screening ECOG (0 vs 1/2) 
• Number of prior therapies (3 vs ≥4) 
8.7 
Interim Analysis and Data Monitoring 
No interim analysis for efficacy will be performed for this study. An IDMC will be used to 
review safety data periodically throughout the course of this study. 
The IDMC will consist of an experienced biostatistician and two qualified clinicians, who are 
not employees of the Sponsor, with combined scientific expertise in general oncology and 
GIST and practical experience conducting clinical studies and monitoring safety and efficacy 
of clinical studies. The IDMC or Sponsor may request an ad hoc meeting for any reason, 
including significant unexpected safety event, unplanned unblinding of study results, follow-
up of an observation during a planned IDMC meeting, or a report external to the study, such 
as publication of study results from a competing product. The IDMC objectives and 
operational details will be defined in the IDMC Charter.  
9 
PHARMACOKINETICS 
Individual patient’s raw concentrations of DCC-2618 and actual sampling time will be listed 
by nominal sampling time point. Raw concentrations for each nominal sampling time point 
will be summarized with descriptive statistics such as number of subjects, geometric mean, 
median, arithmetic mean, standard deviation, coefficient of variation, and geometric 
coefficient of variation, minimum and maximum.  
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10 SAFETY ANALYSIS 
10.1 Study Drug Exposure  
The duration of initial assigned study treatment in weeks, total dose, average daily dose, and 
relative dose intensity will be displayed using continuous descriptive statistics. In addition, 
the number and percent of patients in categories based on treatment duration and patients 
with dose increase, reduction, and interruption will be summarized.  
The treatment duration will be calculated as (the date of last treatment before Open label or 
discontinuation treatment – date of first treatment of study drug + 1 day)/7. If the date of last 
treatment is missing because the true last treatment date is unknown or patients are still on 
treatment at the time of analysis, the earliest of the end of treatment (EOT) date, end of study 
date, death date, and data cut-off date will be used. The average daily dose will be calculated 
as the total dose received divided by treatment duration in days. The relative dose intensity 
(%) is the total dose received divided by the total planned dose and multiplied by 100%. 
These analyses will be performed for the Safety population. 
10.2 Adverse Events 
Adverse events tables will summarize the number and proportion of patients overall and by 
treatment arm with an event by each system organ class (SOC) and preferred term (PT) for 
the Safety population. All tables will only include treatment emergent adverse events 
(TEAEs), where TEAEs are defined as any AE that occurs that occurs after administration of 
the first dose of study drug and through 30 days after the last dose of study drug. In the case 
of missing start and/or stop date, non-missing date parts will be used to determine if an AE is 
treatment-emergent or not. An AE will be categorized as TEAE if a determination cannot be 
made using the non-missing date parts as to when the event occurred relative to study drug 
administration. Adverse event toxicity grade will be classified using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 
criteria. For incidence summaries, a missing toxicity grade of a TEAE will be conservatively 
imputed as severe; for a TEAE missing causal relationship to study treatment, a causality of 
“related” will be assigned. Listings will include all reported AEs, flagging events that were 
TEAEs and displaying missing severity grades and causalities as they were entered in the 
clinical database. 
An overall summary of the number of subjects with TEAEs as well as the number of event 
will be presented, including the number and percentage of subjects with any TEAEs, 
treatment-emergent serious adverse events (SAE), drug-related TEAEs  and TEAEs leading 
to treatment discontinuation, study discontinuation, and death. 
The number and percentage of patients reporting TEAEs, as well as the number of events, in 
each treatment group will be tabulated by SOC and PT; by SOC, PT, and maximum severity. 
If a patient has multiple occurrences of the same SOC and PT, then the patient will be 
counted only once for the SOC and PT using the most severe occurrence for the 
summarization by maximum severity. Presentation by SOC and PT will display SOC sorted 
alphabetically and PT by descending frequency within SOC. 
TEAEs and drug-related TEAEs will be summarized by PT by descending frequency. 
Treatment-emergent SAEs, TEAEs leading to study treatment discontinuation and study 
discontinuation, and treatment-emergent SAEs leading to death will be summarized by SOC, 
PT, and treatment arm. 
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Adverse events of special interest (AESI) are serious or nonserious AEs of scientific and 
medical concern specific to study drug, for which ongoing monitoring and immediate 
notification by the Investigator to the Sponsor is required. AESIs will be flagged on the 
eCRF by the investigator. The following AEs are considered AESIs: squamous cell 
carcinoma of skin (SCC), actinic keratosis, and keratoacanthoma. 
The number and percentage of patients by treatment arm with the following categories of 
TEAEs will be summarized in tables by SOC and PT: 
• Any TEAE 
• Any TEAE by toxicity grade 
• Any TEAE Grade 3/4 
• Any drug-related TEAE  
• Any treatment-emergent SAE  
• Any drug-related treatment-emergent SAE  
• Any TEAE leading to dose modification(dose reduction or interruption) 
• Any TEAE leading to treatment discontinuation 
• Any TEAE leading to study discontinuation 
• Any TEAE leading to death 
• Any AESI  
• Any AESI by toxicity grade 
• Any AESI Grade ≥ 3 
• Any drug-related AESI  
10.3 Eastern Cooperative Oncology Group Performance Status 
The Eastern Cooperative Oncology Group (ECOG) Performance Status Assessments will be 
summarized for each visit.  
10.4 Clinical Laboratory Data 
Clinical laboratory measurements will be collected from screening until the EOT visit (within 
7 days of the last dose). Laboratory values will be graded for toxicity as defined by the NCI-
CTCAE, Version 4.03 or higher. 
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Table 2. 
Safety Laboratory Tests 
Serum Chemistry 
Hematology 
Urinalysis 
Glucose 
Blood urea nitrogen 
Creatinine 
Sodium 
Potassium 
Calcium 
Magnesium 
Phosphorus 
Total and direct bilirubin 
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
Lactate dehydrogenase 
Total protein 
Albumin 
Creatine Phosphokinase 
Globulin 
Triglycerides 
Lipase 
Amylase 
TSH 
T3 
T4 
Hemoglobin 
• 
Mean corpuscular hemoglobin 
• 
Mean corpuscular hemoglobin 
concentration 
• 
Mean corpuscular volume 
Hematocrit 
Platelets 
Leukocytes 
Reticulocytes 
Differential (absolute): 
• 
Eosinophils 
• 
Basophils 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
 
Coagulation Studies (for patients 
taking anticoagulants) 
• 
Activated partial thromboplastin 
time 
• 
Prothrombin time 
• 
International Normalized Ratio 
Urine protein 
Urine blood 
Specific gravity 
Urine ketones 
Urine glucose 
 
Assessments will be summarized overall by time point utilizing continuous descriptive 
statistics. In addition, the change as well as shift in toxicity grade from baseline will be 
summarized for continuous parameters. For categorical parameters, the n and percentage will 
be displayed.  
Numeric laboratory values recorded as “<x” or “>x” will be handled as follows, 
• In the listings, “<x” and “>x” will be presented as recorded 
• In the summary tables of observed values and changes from the baseline and those for 
shifts in CTCAE grade, “<x” and “>x” will be converted to numeric values before the 
analysis, 
o  “<x” will be converted to “x – 1e-6”  
o  “>x” will be converted to “x + 1e-6” 
In the summary tables of numeric values, the convention is to present 1 decimal place beyond 
those used in raw data for median and mean and 2 more decimal places beyond those used in 
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raw data for standard deviation and standard error. There will be no deviation from this 
convention to display 6 or more decimals due to any conversion using the above rules. 
10.5 Vital Signs  
Summary and change from baseline for weight, temperature, heart rate, respiratory rate, and 
blood pressure will be summarized overall by time point utilizing continuous descriptive 
statistics.  
10.6 Electrocardiograms 
PR, QRS, QT, QTc (ie, QTcB and QTcF) and RR intervals and their change from baseline 
will be summarized for each treatment group by scheduled visit.  Patients will be categorized 
into > 450, > 480, and > 500 ms per their maximum post-baseline absolute QTc interval and 
> 30 and > 60 ms per their maximum change from baseline QTc interval. Additionally, 
patients will be classified into the following categories: HR ≤50 bpm and/or decrease from 
baseline ≥20 bpm; HR ≥120 bpm and/or increase from baseline ≥20 bpm; PR ≥220 ms and/or 
increase from baseline ≥20 ms.  The number and percentage of subjects in each category will 
be summarized for each treatment group.   
10.7 Echocardiograms/Multigated Acquisition Scans 
Summary and change from baseline for left ventricular ejection fraction (LVEF) will be 
summarized overall by time point utilizing descriptive statistics. Change from baseline in 
LVEF will be summarized with number and percentage of patients who have a >20% 
absolute decrease from baseline as well. 
10.8 Dermatologic assessments 
The number and percentage of subjects with new suspicious skin lesions  will be summarized 
overall and by location.  
10.9 Ophthalmologic assessments 
The ophthalmologic assessments at baseline and any clinically indicated exams will be listed.  
10.10 Prior and Concomitant Medications and Procedures 
Prior medications and procedures taken or performed within 30 days prior to screening and 
prior to the first dose will be documented.  
All concomitant medications and procedures (those taken or performed on or after the day of 
the first dose to 30 days after the last dose of study drug) will be documented.  
Prior and concomitant medications will be summarized by the WHO Drug Dictionary 
Anatomical Therapeutic Chemical  2nd level (ATC-2) and preferred  term (pharmacological 
subgroup ATC level 5), for the safety population. If the 2nd  level term is not available, the 
next available level (eg, ATC-2) will be used.   
The number and proportion of the patients who took each medication will be tabulated by the 
ATC-2 level and preferred name for concomitant medications. A patient will only be counted 
once within each ATC-2 code and within each preferred name. 
All prior and concomitant medication data will be listed by patient. 
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11 STATISTICAL ANALYSIS DURING THE OPEN-LABEL 
ANALYSIS PERIOD 
In general, the analysis methods and conventions specified in Section 3.2 to 10.10 will be 
applied to the open-label analysis period, with exceptions described as below.  
11.1 Analysis Sub-periods 
The open-label analysis period will be further split into 2 sub-periods:  
• Prior to intra-patient dose escalation 
• Post intra-patient dose escalation 
Days on DCC-2618 treatment within the open-label analysis period for patients that crossed 
over to DCC-2618 will be defined from the first dose date after crossover. 
11.2 Baseline 
During the open-label analysis period, Study Day will be calculated using the same reference 
start date as defined in Section 3.3.  
For the “Prior to intra-patient dose escalation” sub-period, baseline will be defined as the last 
non-missing value prior to the first administration of DCC-2618 150mg QD. 
For the “Post intra-patient dose escalation” sub-period, baseline will be defined as the last 
non-missing value prior to the first administration of DCC-2618 150mg BID. 
11.3 Analysis Populations 
For the “Prior to intra-patient dose escalation” sub-period, the analysis population will be the 
safety population, including patients who have been treated with DCC-2618 but not yet at 
150mg BID in the open-label period. 
For the “Post intra-patient dose escalation” sub-period, the analysis population will be the 
safety population, consisting of patients who have been treated with DCC-2618 at 150mg 
BID in the open-label period. 
For each sub-period, the PK population will include patients who received at least 1 dose of 
DCC-2618 at 150mg QD or 150mg BID and had at least 1 non-missing PK concentration in 
plasma reported for DCC-2618. 
ITT and PP populations are not applicable to the open-label analysis period. 
11.4 Efficacy Analysis  
Efficacy analysis during the open-label analysis period will be explored by analysis sub-
periods.  
For patients who initially received placebo and subsequently crossed over to DCC-2618 
treatment, PFS in the “Prior to intra-patient dose escalation” sub-period will be defined as the 
time interval from the date of the first dose of DCC-2618 to the earliest documented evidence 
of disease progression. PFS will be re-defined or censored as needed, and analyzed in a 
similar fashion to the primary efficacy endpoint. 
For patients in the “Intra-patient dose escalation” sub-period, efficacy assessment data will 
be presented in listings only.  
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11.5 Safety Analysis  
Exposure to DCC-2618 will be summarized by analysis sub-periods. The duration of DCC-
2618 in weeks, total dose, average daily dose, and relaive dose intensity will be displayed 
using continuous descriptive statistics. In addition, the number and percent of patients in 
categories by treatment duration and patients with a dose increase, reduction, and interruption 
will be summarized.  
All the AEs and the other safety data collected during the open-label analysis period will be 
analyzed. All the AEs in the open-label analysis period will be analyzed as TEAEs.  
TEAEs and the other safety endpoints will be analyzed by treatment groups as defined by 
patients’ initial treatment in the double-blind treatment period, for all patients who entered in 
the open-label analysis period overall and separately for each sub-period. 
12 QUALITY CONTROL 
All data displays and analyses will adhere to the International Conference on Harmonisation 
(ICH) Harmonized Tripartite Guideline: Structure and Content of Clinical Study Reports 
(ICH Topic E3). 
The sponsor will review all tables, listings, and figures prior to final database lock. Final SAS 
datasets, programs and outputs will be transferred to the sponsor at project completion. 
13 REFERENCES 
Newcombe, R. G. 1998. Interval Estimation for the Difference Between Independent 
Proportions: Comparison of Eleven Methods. Statistics in Medicine, 17, pp. 873-890. 
 
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