Conditions: GIST
Keywords: Other Relapsed or Refractory Solid Tumors BLU-285 BLU 285 BLUE-285 BLUE 285 Avapritinib GIST imatinib relapse GIST gleevec relapse GIST KIT GIST relapse GIST refractory GIST imatinib intolerance GIST TKI treatment GIST tyrosine kinase inhibitor treatment GIST TKI GIST tyrosine kinase inhibitor Advanced GIST GIST mutations GIST treatments Blueprint GIST Relapsed GIST clinical trial Refractory GIST clinical trial KIT-mutant GIST cancer gist gastrointestinal stromal tumor gist cancer PDGFRA
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 476
Healthy volunteers: no

Brief summary:
This is an open-label, randomized, Phase 3 study in patients with locally advanced unresectable or metastatic GIST (advanced GIST) of avapritinib (also known as BLU-285) versus regorafenib in patients previously treated with imatinib and 1 or 2 other TKIs.

Detailed description:

Arms:
arm 1: 300 mg PO QD arm 2: 160 mg PO QD

Interventions: intervention 1: avapritinib intervention 2: regorafenib
Intervention descriptions: intervention 1: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously. intervention 2: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).

Protocol document:
Prot_000.pdf: 
Clinical Protocol  BLU-285-1303  
Avapritinib 
 
ClinicalTrials.gov Document Cover Page 
 
Clinical Protocol  
 
Study BLU-285-1303 
 
Study Title: An International, Multicenter, Open-label, Randomized, Phase 3 Study of BLU-285 vs 
Regorafenib in Patients With Locally Advanced Unresectable or Metastatic Gastrointestinal Stromal 
Tumor (GIST) 
 
Document Date: 20 June 2019 
 
NCT Number: NCT03465722 


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CLINICAL RESEARCH PROTOCOL 
DRUG: 
Avapritinib (formerly BLU-285) 
STUDY NUMBER: 
BLU-285-1303 
PROTOCOL TITLE: 
An International, Multicenter, Open-label, 
Randomized, Phase 3 Study of BLU-285 vs 
Regorafenib in Patients with Locally Advanced 
Unresectable or Metastatic Gastrointestinal 
Stromal Tumor (GIST)  
IND NUMBER: 
125379 
EudraCT NUMBER 
2017-003497-14 
SPONSOR: 
Blueprint Medicines Corporation 
Cambridge, MA 02139 
ORIGINAL PROTOCOL DATE: 
25 October 2017 
VERSION NUMBER: 
Amendment 3 
VERSION DATE: 
20 June 2019 
CONFIDENTIALITY STATEMENT 
The information contained herein is confidential and the proprietary property of 
Blueprint Medicines and any unauthorized use or disclosure of such information 
without the prior written authorization of Blueprint Medicines is expressly prohibited. 




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STUDY SUMMARY 
Title: 
An International, Multicenter, Open-label, Randomized, Phase 3 Study of 
BLU-285 vs Regorafenib in Patients with Locally Advanced Unresectable 
or Metastatic Gastrointestinal Stromal Tumor (GIST) 
Study Centers: 
The study will be conducted at multiple centers in North America, Europe, 
Australia, and Asia. 
Rationale: 
Approximately 90% of patients with GIST have a tumor that is dependent 
on a mutation in either V-kit Hardy-Zuckerman 4 feline sarcoma viral 
oncogene homolog (KIT) (75%-80%) or the highly related protein platelet-
derived growth factor receptor alpha (PDGFRα) (10%-15%). On a 
molecular level, the most common sites for oncogenic mutations at the 
time of diagnosis are in the juxtamembrane domain (exon 11 [60%-70%]) 
and extracellular domain (exon 9 [5%-15%]) for KIT and in the activation 
loop (Exon 18) for PDGFRα where the most common activation loop 
mutation is D842V. The current treatment paradigm for advanced GIST 
involves successive use of tyrosine kinase inhibitors (TKIs) that target KIT 
or PDGFRα. 
Avapritinib (formerly BLU-285), a highly potent and selective oral kinase 
inhibitor, was designed to treat imatinib-resistant GIST by targeting 
KIT/PDGFRα activation loop mutants. Avapritinib has potent activity on 
the KIT and PDGFRα activation loop mutants (exon 17/18), including the 
D842V mutation, with biochemical half-maximal inhibitory concentration 
(IC50) against all activation loop mutants of less than 2 nM. In addition, 
avapritinib has demonstrated considerable potency across a wide array of 
disease-relevant KIT mutants found in patients with GIST including those 
that appear as secondary mutants after imatinib treatment and those found 
as primary mutants in imatinib-naïve GIST. 
No currently approved TKI selectively and potently inhibits activation loop 
mutations of KIT and PDGFRα. Thus, GISTs linked to either of these 
mutations represent an important medical need especially in patients who 
did not respond to imatinib and 1 other TKI and who have not been treated 
with regorafenib. 
Number of 
Patients: 
Approximately 460 patients will be enrolled and randomized in a 1:1 ratio, 
stratified by TKI treatment (third vs. fourth), geographic region (Asia vs. 
rest of the world), and mutation status (PDGFRα D842V mutation present 
vs. absent) including: 
•
Approximately 230 patients randomized to receive avapritinib
(Arm A).
•
Approximately 230 patients randomized to receive regorafenib
(Arm B).
At least 70% of the patients enrolled should be receiving their third distinct 
TKI treatment for GIST, ie, no more than 30% of patients should be 
receiving a fourth distinct TKI treatment for GIST. Enrollment will be 
restricted to include only patients receiving their third distinct TKI 
treatment once 30% of the targeted 460 patients who are receiving their 


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fourth distinct TKI treatment have been enrolled. 
Objectives: 
Primary Objective: 
•
The primary objective is to demonstrate the efficacy of avapritinib
based on progression-free survival (PFS) determined by central
radiological assessment per modified Response Evaluation Criteria in
Solid Tumors (mRECIST), version 1.1 in patients with advanced GIST
following 2 or 3 prior TKI therapies, including imatinib, compared to
patients treated with regorafenib.
Secondary Objectives: 
The key secondary objectives are: 
•
To evaluate objective response rate (ORR) determined by central
radiology assessment per mRECIST, version 1.1 in patients with
advanced GIST treated with avapritinib compared to patients treated
with regorafenib.
•
To evaluate overall survival (OS) in patients with advanced GIST
treated with avapritinib compared to patients treated with regorafenib.
To preserve study-wide Type I error, the key secondary objectives will be 
tested in the order presented, as part of the sequential testing scheme for 
the study if the primary analysis is significant. 
Additional secondary objectives are: 
•
To evaluate the European Organisation for Research and Treatment of 
Cancer Quality of Life (EORTC-QLQ-C30) individual scores in patients 
with advanced GIST treated with avapritinib compared to patients treated 
with regorafenib.
•
To evaluate the safety and tolerability of avapritinib compared to 
regorafenib.
•
To evaluate disease response rate as assessed by the Investigator per 
mRECIST, version 1.1 and determined by central radiological assessment 
per Choi criteria in patients with advanced GIST treated with avapritinib 
compared to patients treated with regorafenib.
•
To evaluate disease control rate (DCR) per mRECIST, version 1.1 in 
patients with advanced GIST treated with avapritinib compared to patients 
treated with regorafenib.
•
To evaluate duration of response (DOR) per mRECIST, version 1.1 in 
patients with advanced GIST treated with avapritinib compared to patients 
treated with regorafenib.
•
To determine steady state systemic exposure of avapritinib.
•
To assess the patient-reported perception of abdominal pain. 
 


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Study Design: 
This is an open-label, randomized, Phase 3 study in patients with locally 
advanced unresectable or metastatic GIST (advanced GIST) of avapritinib 
versus regorafenib in patients previously treated with imatinib and 1 or 2 
other TKIs.  
All study visits are intended to be conducted on an outpatient basis. After 
provision of written informed consent, patients will be evaluated for study 
eligibility during the screening period within 4 weeks (28 days) before 
study drug administration on Cycle 1 Day 1 (C1D1). During the screening 
period, eligibility will be confirmed; management of baseline concomitant 
conditions will be recorded and stabilized; and baseline symptoms will be 
assessed. Hematology, blood chemistry, mutation status, brain imaging 
(computed tomography [CT] scan or magnetic resonance imaging [MRI]), 
and baseline tumor assessments (CT scan or MRI) will be performed 
within 28 days of C1D1.  
Patients will be randomly assigned, in a 1:1 ratio, to 1 of 2 treatment arms: 
Arm A (avapritinib) or Arm B (regorafenib) stratified by TKI treatment 
(third vs. fourth), geographic region (Asia vs. rest of the world), and 
mutation status measured in ctDNA or a tumor sample (PDGFRα D842V 
mutation present vs. absent). Patients randomized to Arm A will receive 
avapritinib 300 mg orally (PO) once daily (QD). Patients who experience 
disease progression on avapritinib, based on central review, will be offered 
the opportunity to continue taking treatment with avapritinib if there is no 
clinical evidence of disease progression (including worsening of laboratory 
values); the patient is not experiencing rapid progression of disease or a 
progressive tumor requiring urgent alternative medical intervention at 
critical anatomical sites (eg, spinal cord compression); and there has been 
no decline in Eastern Cooperative Oncology Group Performance Status 
(ECOG PS). Patients randomized to Arm A must consent to continue 
avapritinib treatment after disease progression. 


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Patients randomized to Arm B will receive regorafenib 160 mg PO QD for 
3 weeks out of every 4 weeks (28 days) cycle (ie, 3 weeks on/1 week off). 
Patients who experience disease progression on regorafenib (Arm B), as 
confirmed by central radiology review, may be offered the opportunity to 
cross over to the avapritinib treatment arm (Arm A) after an evaluation of 
their disease progression and a washout period of 7 to 28 days after their 
last dose of regorafenib. Patients randomized to Arm B must consent to 
cross over to avapritinib treatment after disease progression. 
At least 70% of the patients enrolled should be receiving the study drug as 
their third distinct TKI treatment for GIST, ie, no more than 30% of 
patients should be receiving the study drug as their fourth distinct TKI 
treatment for GIST. In addition, patients will receive best supportive care, 
excluding any additional anticancer therapy such as any systemic 
antineoplastic therapy (including kinase inhibitors and chemotherapy), 
radiation therapy, or surgery. 
All patients will present to the study center on C1D1 for the first dose of 
study drug, vital sign measurements, safety monitoring, quality-of-life 
(QoL) assessment, PRO assessments, electrocardiogram (ECG) 
assessment, and AE recording. On Cycle 2 Day 1 (C2D1) and Cycle 3 
Day 1 (C3D1), patients will present to study centers for physical 
examination, laboratory assessments, QoL assessments, PRO assessments, 
and AE/concomitant medication recording. For all subsequent cycles, all 
patients will attend study center visits every other cycle on Day 1 of odd 
cycles (ie, C5D1, C7D1 etc.) for safety monitoring including ECG, 
hematology, blood chemistry, QoL assessments, PRO assessments, and AE 
recording. At any point in time between treatment cycles patients should 
attend or contact the study center for AE reporting, evaluation, and medical 
intervention. 
Tumor assessments will be performed at Baseline and then every 8 weeks 
(± 1 week) counting from C1D1, regardless of the scheduled treatment 
cycles, ie, if study treatment is interrupted or discontinued for any reason, 
tumor imaging should continue according to an 8-week schedule until 
tumor progression is confirmed by central radiology review. Computed 
tomography with intravenous contrast is the preferred imaging modality, 
unless a site of disease is better evaluated by MRI. 
All patients will attend an End-of-Treatment (EOT) visit within 
14 (±7) days after the last dose of study drug. A safety Follow-up visit for 
resolution of any ongoing AE will be made on Day 30 (±7 days) after the 
last dose of study drug, or at the time the patient initiates another 
antineoplastic therapy. Patients who discontinue study treatment before 
disease progression will undergo tumor assessments every 8 weeks until 
disease progression, death, or patient withdrawal of consent. After 
documentation of disease progression by central radiology review, patients 
are to be followed for subsequent antineoplastic therapy and survival 
approximately every 2 months until death, withdrawal of consent or 
closure of the study by the Sponsor. 
Duration of 
Treatment: 
It is anticipated that patients will receive at least 1 cycle of avapritinib if 
randomized to Arm A and regorafenib if randomized to Arm B; no 


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maximum treatment duration has been set. After C1, patients may continue 
to receive study drug until precluded by toxicity, noncompliance, 
pregnancy, withdrawal of consent, physician decision, progressive disease 
(PD), death, or closure of the study by the Sponsor. 
Duration of 
Patient 
Participation: 
The minimum duration of patient participation is approximately 3 months, 
including a screening period to assess study eligibility up to 4 weeks 
(28 days); a treatment period of at least 1 cycle (28 days); an EOT visit at 
least 14 ± 7 days after the last dose of study drug; and a Safety Follow-up 
visit in the clinic for physical examination and resolution of any AEs 
30 days (± 7 days) after the last dose of study drug. Thereafter, patients are 
to be followed for tumor imaging every 8 weeks (± 7 days) until disease 
progression, death, initiation of new anti-GIST therapy, withdrawal of 
consent, or closure of the study by the Sponsor and then survival 
approximately every 2 months until death, withdrawal of consent or 
closure of the study by the Sponsor. 
Duration of 
Study: 
The expected enrollment period is approximately 18 months, and the 
expected duration of the study to reach the primary analysis timepoint is 
approximately 24 months until a total number of 264 PFS events are 
reached. The study will be completed when all patients are no longer 
receiving study drug and follow-up for OS has been concluded. 
Target 
Population: 
Inclusion Criteria: 
1.
Patients who are ≥18 years of age.
2.
Patients who have histologically confirmed metastatic or unresectable
GIST. Unresectable GIST must be confirmed to be unresectable by a
qualified surgeon.
3.
Patients who have received imatinib and 1 or 2 other TKIs for the
treatment of GIST, including TKIs used for adjuvant therapy. Each
different TKI is counted once regardless of how often it was used, and
if 2 different TKIs are used in combination, both TKIs are counted.
Patients must have objective disease progression, inadequate clinical
benefit, or intolerance to the prior TKIs. Patients must have disease
progression prior to enrollment. Prior use of other systemic and local
therapies is not restricted.
4.
Patients who have an Eastern Cooperative Oncology Group
Performance Status (ECOG PS) of 0 to 1.
5.
Patient, or legal guardian if permitted by local regulatory authorities,
who provides informed consent to participate in the study.
Primary 
Endpoints: 
•
The primary endpoint is PFS, based on central radiological assessment
per mRECIST, version 1.1, in patients with advanced GIST.
Progression-free survival is defined as time from randomization to
disease progression, or death due to any cause, whichever occurs first.
Secondary 
Endpoints: 
The key secondary endpoints are: 
•
Objective response rate defined as the percentage of patients whose
best response is CR or PR as assessed by central radiology using
mRECIST, version 1.1.


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•
Overall survival defined as the time from date of randomization to
death due to any cause.
Additional secondary endpoints include: 
Exploratory 
Endpoints 
•
All individual EORTC QLQ-C30 scores, eg, physical functioning 
score, pain score, role functioning score, appetite loss score, etc.
•
Adverse events, serious AEs, and changes in safety laboratory 
parameters, 12-lead ECG evaluations, and ECOG PS. The intensity of AEs 
will be assessed by the National Cancer Institute Common Terminology 
Criteria for Adverse Events, version 5.0.
•
Response as assessed by Investigator per mRECIST, version 1.1. and 
assessed by central radiology per Choi criteria.
•
Disease control is defined as the rate of CR or PR of any duration, or 
stable disease (SD) lasting for at least 16 weeks per mRECIST, version 1.1.
•
Duration of response defined as the time from first documentation of 
tumor response to disease progression or death due to any cause.
•
Plasma drug concentration at specified time points.
•
Abdominal pain as measured by a numeric rating scale (0-10).
 
 
 
 
Pharmacokinetics Blood samples will be collected to determine circulating plasma 
concentrations (including any relevant metabolites) of avapritinib. 
Statistical 
Methods and 
Data Analysis 
The primary endpoint of PFS is defined as the time from randomization to 
disease progression or death due to any cause, whichever occurs first. The 
primary analysis for PFS is based on the central radiological assessment of 
PD per mRECIST, version 1.1 in the ITT population. 
Patients without disease progression or death at the time of analysis will be 
censored at their last date of tumor evaluation. Patients who withdraw from 
the study and receive subsequent antineoplastic therapy without 
documented PD will be censored at the time of the last adequate (CT or 
MRI scan available) disease assessment. For PD documented between 
scheduled evaluations, the actual date of PD will be used, not the date of 
the next scheduled evaluation. For death or PD after no more than 1 missed 
evaluation, the date of the event will be the date of PD or death, whichever 
occurs first. For death or PD after more than 1 missed evaluation, the date 
of the event will be censored at the last adequate disease assessment. 


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Detailed censoring methods will be described in the statistical analysis 
plan. 
The Kaplan-Meier method will be used to estimate the distribution of PFS 
for each treatment group. The primary treatment comparison is based on a 
stratified log-rank test in the intent-to-treat population. The hazard ratio, 
and its 95% confidence interval (CI), are to be estimated based on a 
stratified Cox’s model with treatment as the explanatory variable. 
Stratification factors include TKI treatment (third vs. fourth), geographic 
region (Asia vs. rest of the world), and mutation status measured in ctDNA 
or a tumor sample (PDGFRα D842V mutation present vs. absent). 
The key secondary endpoints are: ORR and OS. The ORR, as assessed by 
central radiological assessment according to mRECIST, version 1.1, will 
be evaluated and analyzed for the intent-to-treat population. A stratified 
Cochran-Mantel-Haenszel test will be performed to test treatment 
difference. A logistic regression model will be used to estimate the 
treatment effect measured in terms of odds ratios. 
The primary treatment comparison for OS will be based on a rank 
preserving structural failure time model to account for treatment crossover 
effects from regorafenib to avapritinib. The survival time gained/lost by 
receiving avapritinib after crossover in the regorafenib group will be 
estimated. Rank preserving structural failure time reconstructs the survival 
duration of patients as if they had never received avapritinib, assuming 
treatment is acting by multiplying survival time by a given factor once a 
patient starts receiving avapritinib (Korhonen et al, 2012). If the patient is 
alive or the vital status is unknown at the time of analysis, OS will be 
censored at the date the patient is last known to be alive. The Kaplan-
Meier method will be used to estimate the distribution of OS for each 
treatment group. The hazard ratio and its 95% confidence interval will be 
estimated based on Cox’s regression model with stratification factors as 
covariates. 
A gate-keeping method will be implemented to control Type I error. The 
ORR will be analyzed when superiority is demonstrated for PFS. The OS 
will be analyzed when superiority is demonstrated for both PFS and ORR. 
Safety will be evaluated by the incidence of AEs, causality, intensity, 
seriousness, and type of AEs, and by the patient’s vital signs, ECOG PS 
scores, clinical laboratory test results, and ECG data. All safety data will 
be listed by patient and summarized by treatment arm. 
 


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STUDY SCHEMATIC 
Abbreviations:  GIST = gastrointestinal stromal tumor; N = number of patients; R = randomized; 
TKI = tyrosine kinase inhibitor. 


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TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ..........................................................................1 
CLINICAL PROTOCOL ..................................................................................................2 
AMENDMENT 3 RATIONALE ......................................................................................3 
AMENDMENT 2 RATIONALE ......................................................................................5 
AMENDMENT 1 RATIONALE ......................................................................................9 
STUDY SUMMARY ........................................................................................................12 
TABLE OF CONTENTS ................................................................................................20 
LIST OF TABLES ...........................................................................................................23 
LIST OF FIGURES .........................................................................................................23 
LIST OF ABBREVIATIONS .........................................................................................24 
1 
BACKGROUND AND RATIONALE ....................................................................27 
1.1 
Background on Gastrointestinal Stromal Tumors ...........................................27 
1.1.1 
Molecular Pathology of GIST .......................................................................27 
1.1.2 
Treatment of GIST ........................................................................................27 
1.2 
Avapritinib............................................................................................................29 
1.2.1 
Overview .........................................................................................................29 
1.2.2 
Summary of Nonclinical Information ..........................................................30 
1.2.3 
Summary of Clinical Studies.........................................................................33 
1.3 
Study Rationale ....................................................................................................36 
1.4 
Benefit/Risk Assessment ......................................................................................37 
2 
STUDY OBJECTIVES ............................................................................................38 
2.1 
Primary Objective ................................................................................................38 
2.2 
Secondary Objectives...........................................................................................38 
2.3 
Exploratory Objectives ........................................................................................39 
3 
STUDY ENDPOINTS ..............................................................................................40 
3.1 
Primary Endpoints...............................................................................................40 
3.2 
Secondary Endpoints ...........................................................................................40 
3.3 
Exploratory Endpoints ........................................................................................40 
4 
STUDY PLAN ...........................................................................................................41 
4.1 
Study Design .........................................................................................................41 
4.2 
Justification of the Study Design ........................................................................43 
4.3 
Rationale for the Dose Selected ..........................................................................44 
5 
POPULATION ..........................................................................................................45 
5.1 
Number of Patients ..............................................................................................45 
5.2 
Inclusion Criteria .................................................................................................45 
5.3 
Exclusion Criteria ................................................................................................45 
5.4 
Patient Identification and Registration ..............................................................48 
5.5 
Randomization .....................................................................................................48 
5.6 
Study Completion.................................................................................................49 
5.7 
Patient Withdrawal Criteria ...............................................................................49 
6 
STUDY CONDUCT ..................................................................................................50 
6.1 
General Conduct ..................................................................................................50 
6.2 
Early Termination ...............................................................................................50 
6.3 
Dose and Administration .....................................................................................51 


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6.3.1 
Dose Modification Recommendations for Adverse Events ........................52 
6.3.2 
Dose Re-escalation After Resolution of Adverse Drug Reactions .............54 
6.4 
Prior and Concomitant Therapy ........................................................................54 
6.4.1 
Prohibited Concomitant Therapy ................................................................55 
6.4.2 
Concomitant Therapy to be used with Caution ..........................................55 
6.4.3 
Permitted Concomitant Therapy ..................................................................56 
6.5 
Schedule of Assessments ......................................................................................57 
6.6 
Additional Considerations...................................................................................61 
6.6.1 
Precautions .....................................................................................................61 
6.6.2 
Contraception Requirements ........................................................................61 
7 
DESCRIPTION OF STUDY PROCEDURES .......................................................62 
7.1 
Screening ...............................................................................................................62 
7.2 
Safety Assessments ...............................................................................................63 
7.2.1 
Physical Examination ....................................................................................63 
7.2.2 
Eastern Cooperative Oncology Group Performance Status ......................63 
7.2.3 
Brain Imaging.................................................................................................63 
7.2.4 
Vital Signs .......................................................................................................63 
7.2.5 
ECGs ...............................................................................................................64 
7.2.6 
Clinical Laboratory Tests..............................................................................64 
7.2.7 
Adverse Events and Concomitant Medications ..........................................64 
7.3 
Pharmacokinetic Assessment ..............................................................................65 
7.4 
Blood Samples for Biomarker Assessment ........................................................65 
7.5 
Efficacy Assessments ...........................................................................................65 
7.5.1 
Disease Response Assessment .......................................................................65 
7.5.2 
Central Radiology Review .............................................................................66 
7.5.3 
Quality-of-Life Instruments ..........................................................................66 
7.5.4 
Patient-Reported Outcome Instruments......................................................66 
7.6 
Crossover From Regorafenib to Avapritinib ....................................................67 
7.7 
Continuing Avapritinib After Disease Progression ..........................................67 
7.8 
End-of-Treatment, Safety Follow-up and Progression-Free Survival 
Follow-up ..............................................................................................................67 
7.9 
Survival Follow-up ...............................................................................................68 
7.10 
Sample Processing, Storage, and Shipment .......................................................68 
8 
STUDY DRUG MANAGEMENT ...........................................................................68 
8.1 
Description ............................................................................................................68 
8.1.1 
Avapritinib......................................................................................................68 
8.1.2 
Regorafenib ....................................................................................................69 
8.2 
Accountability ......................................................................................................69 
8.3 
Compliance ...........................................................................................................69 
8.4 
Overdose ...............................................................................................................70 
9 
ADVERSE EVENTS ................................................................................................70 
9.1 
Definitions .............................................................................................................70 
9.1.1 
Adverse Event.................................................................................................70 
9.1.2 
Adverse Event due to Protocol Procedures .................................................71 
9.1.3 
Serious Adverse Event ...................................................................................71 
9.2 
Grading of Severity Using NCI CTCAE ............................................................72 


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9.3 
Relationship to Study Drug (Causality Assessment) ........................................72 
9.4 
Adverse Event Monitoring Period ......................................................................73 
9.5 
Eliciting Adverse Event Information .................................................................73 
9.6 
Adverse Event Reporting Conventions and Principles ....................................73 
9.6.1 
Laboratory Values .........................................................................................73 
9.6.2 
Preexisting Conditions ...................................................................................73 
9.6.3 
Pre-Planned Therapeutic Procedures ..........................................................74 
9.6.4 
Disease Progression ........................................................................................74 
9.6.5 
Lack of Efficacy..............................................................................................74 
9.6.6 
Adverse Events NCI CTCAE Grade 5 .........................................................74 
9.6.7 
Second Malignancies ......................................................................................74 
9.6.8 
Special Situations ...........................................................................................74 
9.6.9 
Exposure in Utero and Pregnancy................................................................75 
9.7 
Adverse Event Collection and Reporting ..........................................................76 
9.8 
Adverse Event Electronic Data Capture ............................................................76 
9.8.1 
Follow-Up of Unresolved Events ..................................................................77 
9.9 
Reporting Serious Adverse Events .....................................................................77 
9.10 
Regulatory and Institutional Reporting Responsibilities .................................78 
10 STATISTICS .............................................................................................................78 
10.1 
General Procedures .............................................................................................78 
10.2 
Sample Size Estimation .......................................................................................78 
10.3 
Analysis Populations ............................................................................................79 
10.4 
Randomization and Stratification ......................................................................80 
10.5 
Statistical Methods ...............................................................................................80 
10.5.1 
Disposition ......................................................................................................80 
10.5.2 
Demographic and Baseline Characteristics .................................................80 
10.5.3 
Efficacy Analysis ............................................................................................80 
10.5.4 
Exposure and Safety Analyses ......................................................................83 
10.5.5 
Pharmacokinetics Analyses ...........................................................................84 
10.5.6 
Analyses of the Exploratory Endpoints .......................................................85 
11 ETHICS AND RESPONSIBILITIES .....................................................................85 
11.1 
Good Clinical Practice .........................................................................................85 
11.2 
Independent Data Monitoring Committee ........................................................85 
11.3 
Institutional Review Board/Independent Ethics Committee ...........................87 
11.4 
Informed Consent ................................................................................................87 
11.5 
Records Management ..........................................................................................88 
11.6 
Source Documentation.........................................................................................88 
11.7 
Study Files and Record Retention ......................................................................88 
11.8 
Liability and Insurance .......................................................................................89 
12 AUDITING AND MONITORING ..........................................................................89 
13 AMENDMENTS .......................................................................................................89 
14 STUDY REPORT AND PUBLICATIONS ............................................................90 
15 STUDY DISCONTINUATION ...............................................................................90 
16 CONFIDENTIALITY ..............................................................................................90 
17 REFERENCES .........................................................................................................91 
18 APPENDICES ...........................................................................................................93 


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18.1 
Appendix 1 ............................................................................................................93 
18.2 
Appendix 2 ............................................................................................................94 
18.3 
Appendix 3 ............................................................................................................99 
18.4 
Appendix 4 ..........................................................................................................101 
18.5 
Appendix 5 ..........................................................................................................103 
18.6 
Appendix 6 ..........................................................................................................104 
18.7 
Appendix 7 ..........................................................................................................105 
18.8 
Appendix 8 ..........................................................................................................106 
18.9 
Appendix 9 ..........................................................................................................108 
18.10 Appendix 10 ........................................................................................................109 
18.11 Appendix 11 ........................................................................................................110 
18.12 Appendix 12 ........................................................................................................113 
18.13 Appendix 13 ........................................................................................................116 
18.14 Appendix 14 ........................................................................................................117 
LIST OF TABLES 
Table 1: 
Dose Modification and Re-escalation Guidelines for Avapritinib-
Related Toxicity .......................................................................................53 
Table 2: 
Schedule of Assessments ..........................................................................57 
LIST OF FIGURES 
Figure 1: 
Biochemical Activity of Avapritinib Against Disease-relevant KIT 
Mutants .....................................................................................................30 
Figure 2: 
Clinical Exposure of Avapritinib Reaches Levels Projected to be 
Efficacious Across Multiple KIT-mutant Genotypes ...........................35 
Figure 3: 
Probability of PFS with Avapritinib in KIT-mutated GIST patients at 
Low and High Dose Levels. .....................................................................36 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the systemic plasma concentration versus -
time curve from zero through 24 hours 
β-hCG 
Beta human chorionic gonadotropin 
BSC 
Best supportive care 
CI 
Confidence interval 
Cmax 
Maximum systemic concentration 
CNS 
Central nervous system 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CxDx 
Cycle x Day x 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance 
Status 
eCRF 
Electronic case report form 
EEG 
Electroencephalogram 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of 
Cancer Quality of Life 
EOT 
End-of-Treatment 
EQ-5D-5L 
EuroQol 5 Dimension 
FACT-Cog 
Functional Assessment of Cancer Therapy-Cognitive 
Function 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 


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Abbreviation 
Definition 
GIST 
Gastrointestinal stromal tumor 
GLP 
Good Laboratory Practice 
HNSTD 
Highest non-severely toxic dose 
IB 
Investigator’s Brochure 
IC50 
Half-maximal inhibitory concentration 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system 
KIT 
V-kit Hardy-Zuckerman 4 feline sarcoma viral 
oncogene homolog 
mRECIST 
Modified Response Evaluation Criteria in Solid 
Tumors 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PDGFRα 
Platelet-derived growth factor receptor alpha 
PFS 
Progression-free survival 
PGI-C 
Patients’ Global Impression of Change 
PGI-S 
Patients’ Global Impression of Severity 
PK 
Pharmacokinetic(s) 
PO 
Orally (per os; by mouth) 
PR 
Partial response  
PRO 
Patient-reported outcome 
QD 
Once daily 
QoL 
Quality-of-life 
QTcF 
QT interval corrected using Fridericia's formula 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 


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Abbreviation 
Definition 
STD10 
Severely toxic dose for 10% of animals 
TKI 
Tyrosine kinase inhibitor 
ULN 
Upper limit of normal 


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1 BACKGROUND AND RATIONALE 
1.1 
Background on Gastrointestinal Stromal Tumors 
Gastrointestinal stromal tumors (GIST) are thought to develop from the interstitial cells 
of Cajal or their stem cell precursors. They are the most common mesenchymal tumors 
occurring in the gastrointestinal (GI) tract, representing approximately 0.1% to 3.0% of 
all GI malignancies (Miettinen and Lasota, 2006; Rammohan et al, 2013). GIST is most 
commonly diagnosed between the ages of 50 and 80 years, with a slight predilection for 
males (Nilsson et al, 2005).  
GIST may develop at any point along the GI tract, with the stomach (60%) and small 
intestine (30%) being the most common locations; the remaining 10% of GIST arise from 
the esophagus, colon, rectum, or the mesentery (Nilsson et al, 2005). GIST most 
commonly presents with GI bleeding, with obstruction or acute tumor rupture occurring 
more rarely (Rammohan et al, 2013). Slightly fewer than half of patients with GIST 
present with high-risk characteristics, such as large size, local infiltration, and/or 
metastasis (Goettsch et al, 2005; Nilsson et al, 2005). GIST typically progresses by local 
extension from its site of origin, intra-peritoneal spread, and metastases to the hepatic 
parenchyma. Metastases to lymph nodes are rare. 
Surgery is the primary treatment for patients with resectable or potentially resectable 
GIST with the goal being to obtain histologically negative margins. GIST is not 
considered sensitive to either systemic cytotoxic chemotherapy or radiation therapy. 
1.1.1 
Molecular Pathology of GIST 
Approximately 90% of patients with GIST have a tumor that is dependent on a mutation 
in either V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) 
(75%-80%) or the highly related protein platelet-derived growth factor receptor alpha 
(PDGFRα) (10%-15%). On a molecular level, the most common sites for oncogenic 
mutations at the time of diagnosis are in the juxtamembrane domain (exon 11 [60%-
70%]) and extracellular domain (exon 9 [5%-15%]) for KIT and in the activation loop 
(Exon 18) for PDGFRα where the most common activation loop mutation is D842V. The 
current treatment paradigm for advanced GIST involves successive use of tyrosine kinase 
inhibitors (TKIs) that target KIT or PDGFRα.  
1.1.2 
Treatment of GIST 
Most patients with GIST present with resectable disease and undergo surgery. Surgery 
followed by adjuvant imatinib has been demonstrated to result in significantly prolonged 
recurrent-free survival (Gleevec, 2016). In metastatic, unresectable GIST the first 
treatment regimen is imatinib, a small molecule oral kinase inhibitor, indicated for the 
treatment of patients with KIT (CD117) positive unresectable and/or metastatic malignant 
GIST. Imatinib was assessed initially in a single, open-label trial involving 1 center in 
Europe and 3 centers in the United States (US). In this randomized study, 73 patients 
received imatinib 400 mg once daily (QD) and 74 patients received imatinib 600 mg QD. 


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An objective response was confirmed in 56 patients; the overall response rate for the 
combined study arms was 38% (95% confidence interval [CI], 30%-46%). These were all 
partial responses (PRs), and there was no statistically significant difference in response 
rates between the 2 dose groups (Dagher et al, 2002). After the initial open-label trial, 
2 large, identical, open-label, randomized, global phase 3 studies were conducted where 
1640 patients were enrolled and randomized to receive imatinib at doses of 400 mg orally 
(PO) QD or 800 mg PO QD. Patients in the 400 mg QD group who experienced disease 
progression were permitted to cross over to receive treatment with 800 mg QD. The 
results showed a response rate of 50% to 69% and a median progression-free survival 
(PFS) of approximately 19 months (Gleevec, 2016). 
Commonly reported adverse events (AEs) included edema, fatigue, nausea, abdominal 
pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Edema most frequently 
included periorbital or lower extremity edema; severe edema was observed in 
182 patients (11.1%). Other AEs included bone marrow suppression, GI bleeding, and 
elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), or 
bilirubin. Imatinib treatment is notably limited by primary resistance among 15% of 
patients and progressive disease (PD) through secondary resistance driven mutations in 
over 80% of patients. 
In the second treatment regimen setting, based upon data from a randomized, 
placebo-controlled trial with supportive evidence from a single-arm study, sunitinib, an 
oral multi-kinase inhibitor, is indicated for the treatment of patients with GIST after 
disease progression or intolerance to imatinib. In patients treated with imatinib who had 
refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was 
superior to that of placebo-treated patients. Median time to tumor progression of 
sunitinib-treated patients was 27.3 weeks, compared to 6.4 weeks for placebo-treated 
patients (p < 0.0001). Partial responses were observed in 6.8% of sunitinib-treated 
patients. The most common AEs related to sunitinib included diarrhea, mucositis, skin 
abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe 
hypertension were also more common in sunitinib-treated patients. Sunitinib has also 
been associated with severe hepatoxicity resulting in liver failure or death. Sunitinib is 
potent against the wild type KIT kinase compared to a first treatment regimen; however, 
resistance to this therapy evolves usually within 1 year of treatment. 
In the third treatment regimen setting, regorafenib, an oral multi-kinase inhibitor, is 
indicated for the treatment of patients with locally advanced unresectable or metastatic 
GIST who have been previously treated with imatinib and sunitinib. The United States 
Food and Drug Administration (US FDA) approved regorafenib in February 2013 based 
upon efficacy and safety evaluated in the GRID study, an international, multicenter, 
randomized, double blind, placebo-controlled trial (Demetri et al, 2013a) in 199 patients 
with unresectable, locally advanced or metastatic GIST, who had been previously treated 
with imatinib and sunitinib.  
The primary efficacy outcome measure of the GRID study was PFS based on disease 
assessment by independent radiological review using modified Response Evaluation 
Criteria in Solid Tumors, version 1.1 (mRECIST, version 1.1). Patients were randomized 


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to receive 160 mg regorafenib PO QD (N=133) plus best supportive care (BSC) or 
placebo (N=66) plus BSC for the first 21 days of each 28-day cycle until disease 
progression or unacceptable toxicity. At the time of disease progression as assessed by 
central review, the study blind was broken, and all patients were offered the opportunity 
to take regorafenib at the Investigator’s discretion. Fifty-six (85%) patients randomized to 
placebo and 41 (31%) patients randomized to regorafenib received open-label 
regorafenib. 
A statistically significant improvement in PFS was demonstrated among patients treated 
with regorafenib (4.8 months) compared to placebo (0.9 months) at a hazard ratio (HR) of 
0.27 and no patients in either group had a complete response (CR), while 6 of the 
133 patients in the regorafenib group and 1 of the 66 patients in the placebo group had a 
PR, giving objective response rates of 4.5% and 1.5%, respectively. Drug-related AEs 
were reported in 130 patients who received regorafenib (98%) and 45 patients who 
received placebo (68%). The most common regorafenib-related AEs of Grade 3 or higher 
were hypertension, hand-foot skin syndrome, and diarrhea. Regorafenib has also been 
associated with severe hepatoxicity resulting in liver failure or death. 
Serious side effects, which occurred in less than 1% of patients, were liver damage, 
severe bleeding events, blistering and peeling of skin, severe hypertension that required 
emergency intervention, acute myocardial infarctions, and intestinal perforations. 
Although imatinib is effective as a first treatment regimen for the majority of patients 
with GIST, primary imatinib resistance is a challenge in a subset of patients, and nearly 
all patients who receive imatinib ultimately develop secondary resistance. Subsequent 
treatment regimens for those who respond initially to imatinib are less effective. This 
diminished efficacy may be related to an acquired resistance to imatinib, which can occur 
due to multiple mutations in KIT, with exon 13 being the most common, and ~23% of 
activations loop mutations, with exon 17 being the most common. Primary resistance to 
all available therapies is most often due to wild type KIT and the D842V mutation in 
exon 18 of PDGFRα (5%-10% in unresectable/metastatic disease). In KIT-mutant GIST, 
activation loop mutations occur at a rate of ~20% after imatinib and ~90% after imatinib 
and sunitinib, and no currently approved TKI selectively and potently inhibits the 
activation loop mutations in KIT (Antonescu et al, 2005; Debiec-Rychter et al, 2006; 
Heinrich et al, 2003; Liegl et al, 2008; Wardelmann et al, 2006). Likewise, there are no 
effective therapies that inhibit D842V mutant PDGFRα (Cassier et al, 2012; Corless et al, 
2005; Yoo et al, 2016). Thus, GIST, dependent on either of these mutations, represents an 
important medical need especially in patients who did not respond to imatinib.  
1.2 
Avapritinib 
1.2.1 
Overview 
Avapritinib (formerly BLU-285), a highly potent and selective oral kinase inhibitor, was 
designed to treat imatinib-resistant GIST by targeting KIT/PDGFRα activation loop 
mutants (exon 17/18). Avapritinib has potent activity on the KIT and PDGFRα activation 
loop mutants (exon 17/18), including the D842V mutation, with biochemical half-


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maximal inhibitory concentration (IC50) against all activation loop mutants of less than 
2 nM (Figure 1). In addition, avapritinib has demonstrated considerable potency across a 
wide array of disease-relevant KIT mutants found in patients with GIST including those 
that appear as secondary mutants after imatinib treatment as well as the exon 11 mutants 
most commonly observed in imatinib-naïve GIST. 
Figure 1: 
Biochemical Activity of Avapritinib Against Disease-relevant 
KIT Mutants 
 
1.2.2 
Summary of Nonclinical Information 
A summary of the key nonclinical information is provided below. Additional information 
can be found in the Investigator Brochure (IB) for avapritinib. 
1.2.2.1 
Pharmacokinetic Drug Interactions 
In vitro studies with recombinant human cytochrome P450 (CYP) enzymes demonstrated 
that avapritinib phase I metabolism is predominantly mediated by CYP3A4, with 
CYP2C9 playing a minor role. Therefore, CYP3A inhibitors may increase circulating 
levels of avapritinib and CYP3A inducers may reduce circulating levels of avapritinib. 
In vitro, avapritinib is a reversible inhibitor of CYP2C9 and CYP3A4/5 at clinically 
relevant concentrations. The R1 values for CYP2C9 and CYP3A4 inhibition and R1,gut 
value for CYP3A4 inhibition are ≥1.02 and >11, respectively. Avapritinib also 
demonstrated time-dependent inhibition of CYP3A4/5 in vitro with an estimated Kinact 
and KI of 0.0301 min-1 and 12.3 μM, respectively and estimated R2 value of ≥1.25. 
Therefore, clinical drug interactions with comedications for which CYP2C9, or CYP3A-
mediated metabolism constitutes the primary mechanism of clearance are likely.  


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In vitro, avapritinib, at concentrations of 0.3 to 3 μM, induced CYP3A4 mRNA 
expression with a maximal 3.25-fold induction observed at 3 μM.  
In vitro, avapritinib is an inhibitor of P-glycoprotein (P-gp), breast cancer resistance 
protein (BCRP), bile salt export pump (BSEP), and multidrug and toxin extrusion protein 
(MATE1, MATE2K). Therefore, avapritinib may have the potential to increase plasma 
concentrations of co-administered substrates of these transporters.  
1.2.2.2 
Safety Pharmacology 
In an Irwin test to evaluate the effects of avapritinib on the gross behavioral, 
physiological, and neurological state of female Sprague-Dawley rats after 15 days of 
avapritinib administration, no test article–related effects were noted at a dose level of 15 
mg/kg. A dose level of 45 mg/kg resulted in increased touch response, increased corneal 
reflex, increased pinna reflex, head flicking, exophthalmos, increased startle response, 
aggressiveness, vocalization, increased pain response, and/or tremors in 2 of 6 animals. 
These findings show an increase in sensitivity to stimuli and are potentially underlying 
indictors of preconvulsive activity. Although observed in a minority of treated animals 
and noted at lethal doses only, these signs were considered test article-related. 
Avapritinib inhibited the human ether-à-go-go-related gene (hERG) channel with an IC50 
of 2.4 µM (~100× the free mean maximum systemic concentration [Cmax] of 0.0243 µM 
at the human maximum tolerated dose (MTD) of 400 mg QD). However, in an in vivo 
study in radiotelemetry-implanted Beagle dogs, avapritinib did not affect any 
cardiovascular parameter (heart rate, mean arterial blood pressure, and systolic, diastolic, 
and pulse pressure), body temperature, electrocardiogram (ECG) waveform morphology, 
duration of PR, QRS, RR, QT, and heart rate corrected QT intervals, respiratory 
parameters (respiratory frequency, tidal volume, and minute volume), or the clinical 
condition of the animals. The observed Cmax of 1650 ng/mL at the high dose of 45 mg/kg 
in the telemetrized dog study was 1.6-fold higher than the human Cmax of 1009 ng/mL at 
the human MTD of 400 mg QD. 
1.2.2.3 
Toxicology 
Sprague-Dawley rats and Beagle dogs were chosen as the nonclinical test species for 
assessing chemical structure- and pharmacology-mediated toxicity of avapritinib on the 
basis of the following criteria: a) these species are pharmacologically responsive to the 
effects of avapritinib; b) these species have historically been used to assess potential 
human adverse effects; and c) these species are qualitatively similar in hepatocyte 
metabolism profiles to humans. 
Two 28-day Good Laboratory Practice (GLP)-compliant repeated dose toxicology studies 
were conducted in Sprague-Dawley rats. These studies determined that the severely toxic 
dose in 10% of animals (STD10) was 30 mg/kg/day (180 mg/m2/day). The Day last area 
under the systemic plasma concentration versus -time curve from zero through 24 hours 
(AUC0-24) of 208000 h•ng/mL at 30 mg/kg/day in rats is approximately 10-fold higher 
than the steady state (Day 15) AUC0-τ  of 20298 h•ng/mL at the human MTD of 400 mg 


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QD. The toxicities defining the STD10 were inanition and metabolic perturbations 
(including changes in serum and urine chemistries, body weight loss, decreased food 
consumption, tissue effects [including gonad effects] and convulsions). All findings 
reversed after the 2-week recovery period except gonad effect. No morphologic brain 
alterations were observed. 
In a 28-day GLP-compliant toxicology study in male Beagle dogs, the highest 
non-severely toxic dose (HNSTD) was 7.5 mg/kg/day (150 mg/m2/day). The Day last 
AUC0-24 of 6115 h•ng/mL at 7.5 mg/kg/day in dogs is approximately 0.3 times the steady 
state (Day 15) AUC0-τ of 20298 h•ng/mL at the human MTD of 400 mg QD. The 
toxicities defining the HNSTD were inanition, metabolic perturbations (including 
changes in urine electrolytes and serum cholesterol and triglycerides) with vomiting, 
diarrhea, decreased food intake, body weight loss, hematologic and serum chemistry 
alterations, and microscopic alterations in tissues, including single focal brain 
hemorrhage in 3 of 10 dogs treated at doses above the HNSTD, decreased bone marrow 
cellularity, and gonad effects. All findings reversed after the 2-week recovery period, 
except gonad and brain effects.  
GLP-compliant 3-month toxicology studies were conducted to further characterize 
dose-limiting toxicities (DLTs) in the dog and rat. In the rat study, no DLT was identified 
and the highest dose tested was identified as the HNSTD. In dogs, central nervous system 
(CNS) effects including brain hemorrhage were considered dose limiting. The HNSTD in 
dogs was 7.5 mg/kg/day (150 mg/m2/day), consistent with the 28-day toxicology study.  
Due to the occurrence of convulsions in rats, a study was conducted to determine if the 
oral administration of avapritinib evokes changes in electroencephalographic (EEG) 
measures consistent with seizures or altered seizure threshold in rats. Administration of 
avapritinib at the STD10 (30 mg/kg/day) for 9 consecutive days did not result in frank 
seizures or in EEG changes suggestive of lowered seizure threshold. Convulsions 
associated with EEG abnormalities were observed when animals were dosed at 
50 mg/kg/day, a dose that exceeds the STD10.   
In a follow-up, non-GLP-compliant study conducted in the rat, diazepam, a routinely 
used anti-seizure medication, was observed to ameliorate avapritinib-induced CNS 
effects in rats. The ameliorative effects of diazepam on avapritinib-induced altered 
seizure potential were noted in rats at the early stages of pre-seizure effects as well as at 
the onset of a frank seizure. These data in Sprague-Dawley rats suggest that diazepam 
may be effective in preventing avapritinib-induced altered seizure potential. 
Avapritinib did not cause mutagenesis in the Ames bacterial mutagenesis assay. In the in 
vitro chromosome aberration test, in cultured human peripheral blood lymphocytes, 
avapritinib demonstrated minimal potential to cause chromosomal aberrations. However, 
avapritinib did not demonstrate any potential to induce micronuclei in vivo in rats. As the 
in vivo micronucleus assay is considered to be a more physiologically relevant and 
informative indicator of human genotoxicity risk than the in vitro chromosome aberration 
test, the overall risk of genotoxicity with avapritinib is considered to be low. 


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1.2.3 
Summary of Clinical Studies 
The avapritinib clinical development program was initiated in August 2015 and includes 
2 ongoing Phase 1 clinical studies:  
1. BLU-285-1101: A Phase 1 study of BLU-285 in patients with GIST and other 
relapsed and refractory solid tumors. 
2. BLU-285-2101: A Phase 1 Study of BLU-285 in patients with advanced systemic 
mastocytosis and relapsed or refractory myeloid malignancies. 
In addition, the avapritinib clinical pharmacology development program includes a 
completed bioavailability study and other ongoing or planned studies to evaluate food 
effect, drug-drug interaction, and bioequivalence. 
Summaries of the data from studies of avapritinib are provided in the IB. 
1.2.3.1 
Study BLU-285-1101 
Study BLU-285-1101 is assessing the safety, PK and clinical activity of avapritinib in 
adult patients with unresectable GIST. In Part 1 of the study, patients with GIST must 
have had disease that had progressed following imatinib and at least 1 of the following: 
sunitinib, regorafenib, sorafenib, dasatinib, pazopanib or an experimental kinase-inhibitor 
agent, or disease with a D842 mutation in the PDGFRα gene. Patients in Part 1 (dose 
escalation) received avapritinib QD on a 4-week cycle following a 3+3 design, which 
allowed additional accrual to dose levels demonstrated to be safe. In Part 2 of the study, 
expansion cohorts dosed at the recommended Phase 2 dose include the following 
3 groups of patients:  
• Group 1:  Patients with unresectable GIST that has progressed following treatment 
with imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, 
dasatinib, pazopanib, or an experimental kinase-inhibitor therapy and who do not 
have a D842V mutation in PDGFRα. 
• Group 2:  Patients with unresectable GIST harboring a D842V mutation in the 
PDGFRα gene. 
• Group 3:  Patients with unresectable GIST that has progressed and/or those who have 
experienced intolerance after treatment with imatinib (including in the adjuvant 
setting), and have not received additional kinase-inhibitor therapy, and do not have a 
known D842V mutation in PDGFRα.  
Adverse events based on the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03, PK and plasma/tumor mutant DNA levels 
are being assessed. Response is being determined according to mRECIST, version 1.1 
approximately every 8 weeks. This study is currently ongoing. 
As of 11 October 2017, 116 patients with GIST have been treated with avapritinib 


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including 46 patients who were enrolled and treated during the dose escalation part of the 
study, and 70 patients in the expansion part. 
Treatment with avapritinib has been well tolerated in patients with GIST. Most AEs have 
been Grade 1 or 2 in intensity, with the most common (≥ 25%) including nausea (56%), 
fatigue (53%), periorbital edema (43%), vomiting (41%), peripheral edema (34%), 
anemia (31%), diarrhea (31%), cognitive effects (consisting of multiple similar AEs 
aggregated into a single category [30%]), increased lacrimation (30%), and decreased 
appetite (28%). There were no DLTs until the 600 mg dose cohort was reached and DLTs 
were noted in 2 patients: 1 patient experienced Grade 2 hypertension, Grade 2 rash, and 
Grade 2 memory impairment; the other patient experienced Grade 2 hyperbilirubinemia. 
The maximum tolerated dose was determined to be 400 mg QD. 
Overall, 49 patients discontinued avapritinib treatment. Six patients discontinued due to 
AEs, 40 patients discontinued due to disease progression, and 3 patients discontinued 
avapritinib due to patient’s decision. 
The single dose (Cycle 1 Day 1; C1D1) and steady state (Cycle 1 Day 15; C1D15) 
pharmacokinetics of avapritinib have been evaluated in Study BLU-285-1101. 
Preliminary unaudited PK data from the 11 April 2018 datacut are presented. After 
administration of single oral doses of avapritinib ranging from 30 to 400 mg avapritinib, 
the median time to peak concentration (Tmax) ranged from 2 to 4 hours postdose, and the 
mean plasma elimination half-life of avapritinib ranged from 35 hours to 57 hours. After 
a single dose and repeat dosing of avapritinib, systemic exposure was dose proportional 
over the dose range of 30 mg to 400 mg QD. The steady state (C1D15) geometric mean   
Cmax (%CV) of avapritinib at doses of 300 mg QD and 400 mg QD was 774 ng/mL 
(49.4%) and 1009 ng/mL (50.9%), respectively, and the corresponding area under the 
plasma concentration-time curve (AUC0-τ) was 14074 h•ng/mL (45.1%) and 20298 
h•ng/mL (41.5%), respectively. The mean accumulation ratio after repeat dosing of 
avapritinib (dose range: 30 – 400 mg QD) was 3.4 – 5.2. Based on the data collected thus 
far, and the exposures required for antitumor activity in GIST patient-derived xenograft 
models (Figure 2), systemic exposure at 300 mg QD - 400 mg QD is predicted to provide 
broad coverage of the primary (eg, exon 11) and secondary KIT (eg, exon 11/17 and exon 
11/13) mutations. 


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Figure 2: 
Clinical Exposure of Avapritinib Reaches Levels Projected to 
be Efficacious Across Multiple KIT-mutant Genotypes 
 
As of 11 October 2017, 74 patients including 31 patients with a PDGFRα D842V 
mutation and 43 patients with a KIT mutation were evaluable for the analysis of efficacy 
(ie, had at least 1 mRECIST, version 1.1 response determined by radiographic assessment 
and evaluated by blinded central review). The median number of prior kinase inhibitor 
regimens was 4 (ranging from 2 to 11) among patients with a KIT mutation and 1 
(ranging from 0 to 6) among patients with a PDGFRα mutation. 
Of the 31 patients with a PDGFRα D842V mutation who had a radiographic assessment 
evaluated by blinded central review, 21 PDGFRα D842V patients had PR (objective 
response rate [ORR] 71%, 18 confirmed, and 3 pending confirmation) and 9 PDGFRα 
D842V patients had stable disease (SD). Clinical and molecular response was observed in 
heavily pretreated patients with KIT – mutant GIST with a median of 4 prior TKIs. Of 
the 43 efficacy-evaluable patients with a KIT mutation treated at all dose levels, 6 KIT 
patients had PR (5 confirmed and 1 pending confirmation; ORR 14%) and 23 KIT 
patients had SD. Among patients treated at or above the Part 2 starting dose of 300 mg, 
5 patients have had a PR (ORR 16%). In patients with a KIT mutation treated at doses 
≥ 300 mg QD, the median PFS was 11.5 months and in patients treated at doses between 
30 mg and 200 mg the median PFS was 2 months. (Figure 3). Overall, decreases in tumor 
size were observed in patients with a variety of KIT mutations, including mutations in 
exons 9, 11, 13, 17 and 18 (Heinrich et al, 2017). In this heavily pretreated population, 
imatinib rechallenge has shown a median PFS of 1.8 months (Kang et al, 2013). 


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Figure 3: 
Probability of PFS with Avapritinib in KIT-mutated GIST 
patients at Low and High Dose Levels. 
 
Abbreviations: GIST = gastrointestinal stromal tumor; KIT = V-kit Hardy-Zuckerman 4 feline sarcoma 
viral oncogene homolog; PFS = progression-free survival. 
In summary, treatment with avapritinib has demonstrated potent and selective activity 
against KIT and PDGFRα mutants in vitro and growth inhibition in TKI-resistant models 
in nonclinical and clinical studies. It has been shown to be efficacious and tolerable at 
active doses in nonclinical toxicology and safety pharmacology studies, as well in the 
Phase 1 clinical program with dose expansion cohorts. Given the poor prognosis and 
potential risk/benefit of avapritinib for patients with advanced GIST, further development 
of this agent is warranted in a third treatment regimen setting. 
1.3 
Study Rationale 
No currently approved TKI selectively and potently inhibits the activation loop mutations 
of KIT and PDGFRα. Thus, GISTs linked to either of these mutations represent an 
important medical need especially in patients who did not respond to imatinib and 1 other 
TKI and who have not been treated with regorafenib. 
Avapritinib, a highly potent and selective oral kinase inhibitor, was designed to treat 
imatinib-resistant GIST by targeting KIT/PDGFRα activation loop mutants. Avapritinib 
has potent activity on the KIT and PDGFRα activation loop mutants with biochemical 
IC50 against all activation loop mutants less than 2 nM. In addition, avapritinib has 
demonstrated considerable potency across a wide array of disease-relevant KIT mutants 
found in patients with GIST including those that appear as secondary mutants after 


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imatinib treatment and those found as primary mutants in imatinib-naïve GIST; it is also 
potent against D842V mutant PDGFRα, which results in resistance to the available TKIs. 
As of 11 October 2017, preliminary Phase 1 clinical data with avapritinib in patients with 
advanced KIT mutant GIST have shown the compound to be well tolerated with 
clinically meaningful evidence of anti-tumor activity including radiographic response. 
Based on the supportive efficacy and safety data (see Section 1.2.3.1), avapritinib may 
serve as a novel targeted treatment option for patients with previously treated advanced 
GIST. 
Study BLU-285-1303 is an open-label randomized study designed to demonstrate the 
efficacy and safety of avapritinib in patients with locally advanced unresectable or 
metastatic GIST previously treated with at least 2 TKIs including imatinib compared to 
regorafenib. Patients eligible for this study are those who received imatinib and 1 or 2 
other TKIs as prior treatment regimens including adjuvant therapy, with objective disease 
progression, inadequate clinical benefit or intolerance, or had disease progression or 
intolerance to other systemic therapies including investigational agents and radiotherapy, 
and have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 
0 to 2. Patients who experienced intolerance to prior therapies must have objective 
disease progression prior to enrollment onto BLU-285-1303 study. 
As regorafenib is the only approved TKI treatment for patients with GIST who have 
received 2 prior TKIs, patients who experience disease progression on regorafenib during 
this study, as confirmed by central radiology review, may be offered the opportunity to 
cross over to the avapritinib treatment arm (see Section 7.6 for additional details).  
1.4 
Benefit/Risk Assessment 
GIST is a sarcoma of the gastrointestinal tract. It commonly presents with GI bleeding 
and gastrointestinal obstruction. Surgery is the primary therapy for patients with 
resectable disease. GIST that is metastatic or locally advanced and unresectable is treated 
with TKIs that target KIT. Imatinib is the standard first-line therapy for patients with 
metastatic and locally advanced, unresectable GIST. Sunitinib and regorafeninb are the 
standard second-line therapies, respectively; however, other TKIs targeting KIT are also 
used in the second- and third-line setting. Therefore, regorafenib is also often used in the 
fourth-line setting.  
This study includes patients with metastatic and locally advanced, unresectable GIST 
who have been treated with imatinib and one or two other TKIs, but have not received 
regorafenib. Patients will be randomly assigned to treatment with avapritinib (the 
experimental group) or regorafenib (the control group). Following treatment with 
imatinib and a second TKI the outcome for patients with GIST is very poor. Treatment 
with regorafenib following imatinib and sunitinib provides a median PFS of about 
5 months and a response rate of about 5 months. The median survival for patients treated 
with available TKIs in the third- and fourth-line setting is about 1 year (Ozer-Stillman et 
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Avapritinib is a selective and potent inhibitor of KIT and PDGFRα. Activating mutations 
in KIT and PDGFRA are the primary drivers of GIST in about 90% of patients (75-80% 
KIT and 10-15% PDGFRA). As described in Section 1.2.1, avapritinib potently inhibits 
KIT and PDGFRA carrying the activating mutations most commonly found in GIST 
tumors. Avapritinib has demonstrated important clinical activity in an ongoing clinical 
study, BLU-285-1101, in patients with advanced, heavily pre-treated GIST. As described 
in Section 1.2.3.1, the response rate with avapritinib was 16% among patients with KIT-
driven GIST treated at doses of 300-400 mg QD. Importantly, these patients were heavily 
pre-treated, having received a median of 4 prior lines of therapy. The response rate was 
71% among patients with PDGFRA-driven GIST across all dose levels. These patients 
had received a median of 1 prior line of therapy; however, PDGFRA-driven GIST is 
typically not responsive to any of the available TKIs, including imatinib. Based on 
preliminary data from this ongoing study the median PFS in patients with KIT-driven 
GIST was 11.5 months, and the median PFS in patients with PDGFRA-driven GIST was 
not yet reached.  
Overall, avapritinib has been well-tolerated in patients with GIST. Most AEs have been 
Grade 1 or Grade 2 in severity and consistent with the effects of KIT inhibition. Adverse 
events occurring in ≥25% of patients (regardless of relationship to avapritinib) included 
nausea (56%), fatigue (53%), periorbital edema (43%), vomiting (41%), peripheral 
edema (34%), anemia (31%), diarrhea (31%), cognitive effects (consisting of multiple 
similar AEs aggregated into a single category [30%]), increased lacrimation (30%), and 
decreased appetite (28%). Among 116 patients treated with avapritinib in the BLU-285-
1101 study as of the 11 October 2017 data cut-off only 6 (5%) have discontinued 
treatment due to a treatment-related AE.  
Overall, the benefit-risk assessment is favorable and warrants continued development of 
avapritinib in patients with advanced GIST.  
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
•
The primary objective is to demonstrate the efficacy of avapritinib based on PFS
determined by central radiological assessment per mRECIST, version 1.1 in patients
with advanced GIST following 2 or 3 prior TKI therapies, including imatinib,
compared to patients treated with regorafenib.
2.2 
Secondary Objectives 
The key secondary objectives are: 
•
To evaluate ORR determined by central radiology assessment per mRECIST, version
1.1 in patients with advanced GIST treated with avapritinib compared to patients
treated with regorafenib.


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•
To evaluate overall survival (OS) in patients with advanced GIST treated with
avapritinib compared to patients treated with regorafenib.
To preserve study-wide Type I error, the key secondary objectives will be tested in the 
order presented, as part of the sequential testing scheme for the study if the primary 
analysis is significant. 
Additional secondary objectives are: 
•
To evaluate the European Organisation for Research and Treatment of Cancer Quality
of Life (EORTC-QLQ-C30) individual scores in patients with advanced GIST treated
with avapritinib compared to patients treated with regorafenib.
•
To evaluate the safety and tolerability of avapritinib compared to regorafenib.
•
To evaluate disease response rate as assessed by the Investigator per mRECIST,
version 1.1 and determined by central radiological assessment per Choi criteria in
patients with advanced GIST treated with avapritinib compared to patients treated
with regorafenib.
•
To evaluate DCR per mRECIST, version 1.1 in patients with advanced GIST treated
with avapritinib compared to patients treated with regorafenib.
•
To evaluate duration of response (DOR) per mRECIST, version 1.1 in patients with
advanced GIST treated with avapritinib compared to patients treated with
regorafenib.
•
To determine steady state systemic exposure of avapritinib.
•
To assess the patient-reported perception of abdominal pain.
 
 
 
 
 
 
 
 
 


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3 STUDY ENDPOINTS 
3.1 
Primary Endpoints 
•
The primary endpoint is PFS, based on central radiological assessment per
mRECIST, version 1.1, in patients with advanced GIST. Progression-free survival is
defined as time from randomization to disease progression, or death due to any cause,
whichever occurs first.
3.2 
Secondary Endpoints 
The key secondary endpoints are: 
•
Objective response rate defined as the percentage of patients whose best response is
CR or PR as assessed by central radiology using mRECIST, version 1.1.
•
Overall survival defined as the time from date of randomization to death due to any
cause.
Additional secondary endpoints include: 
•
All individual EORTC QLQ-C30 scores, eg, physical functioning score, pain score,
role functioning score, appetite loss score, etc.
•
Adverse events, serious AEs (SAEs), and changes in safety laboratory parameters,
12-lead ECG evaluations, and ECOG PS. The intensity of AEs will be assessed by the
NCI CTCAE, version 5.0.
•
Response as assessed by Investigator per mRECIST, version 1.1. and assessed by
central radiology per Choi criteria.
•
Disease control is defined as the rate of CR, or PR of any duration, or SD lasting for
at least 16 weeks per mRECIST, version 1.1.
•
Duration of response defined as the time from first documentation of tumor response
to disease progression or death due to any cause.
•
Plasma drug concentration at specified time points.
•
Abdominal pain as measured by a numeric rating scale (0-10).
 
 
 
 


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4 STUDY PLAN 
4.1 
Study Design 
This is an open-label, randomized, Phase 3 study in patients with locally advanced 
unresectable or metastatic GIST (advanced GIST) of avapritinib versus regorafenib in 
patients previously treated with imatinib and 1 or 2 other TKIs.  
All study visits are intended to be conducted on an outpatient basis. After provision of 
written informed consent, patients will be evaluated for study eligibility during the 
screening period within 4 weeks (28 days) before study drug administration on Cycle 1 
Day 1 (C1D1). During the screening period, eligibility will be confirmed; management of 
baseline concomitant conditions will be recorded and stabilized; and baseline symptoms 
will be assessed. Hematology, blood chemistry, mutation status, brain imaging (CT scan 
or MRI), and baseline tumor assessments (CT scan or MRI) will be performed within 
28 days of C1D1.  
Patients are to be randomly assigned, in a 1:1 ratio, to 1 of 2 treatment arms: Arm A 
(avapritinib) or Arm B (regorafenib) stratified by TKI treatment (third vs. fourth), 
geographic region (Asia vs. rest of the world), and PDGFRα D842V mutation status 
measured in ctDNA or a tumor sample (PDGFRα D842V mutation present vs. absent). 
Patients randomized to Arm A will receive avapritinib 300 mg PO QD. Patients who 
experience disease progression on avapritinib, based on central review, will be offered 
the opportunity to continue taking treatment with avapritinib if there is no symptomatic 
evidence of disease progression or laboratory abnormalities attributable to disease 
progression, no rapid progression of disease or a progressive tumor requiring urgent 
alternative medical intervention at critical anatomical sites, and no decline in ECOG PS. 
Patients randomized to Arm A must consent to continue avapritinib treatment after 
disease progression; see Section 7.7 for additional details. 
Patients randomized to Arm B will receive regorafenib 160 mg PO QD for 3 weeks out of 
every 4-weeks (28 days) cycle (ie, 3 weeks on/1 week off). Patients who experience 
disease progression on regorafenib, as confirmed by central radiology review, may be 
offered the opportunity to cross over to the avapritinib treatment arm (Arm A); see 
Section 7.6 for additional details. Prespecified dose modification guidance for AEs 
related to regorafenib and to avapritinib are described in Section 6.3.1. 
At least 70% of the patients enrolled should be receiving the study drug as their third 
distinct TKI treatment for GIST, ie, no more than 30% of patients should be receiving the 
study drug as their fourth distinct TKI treatment for GIST. In addition, patients will 


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receive BSC, excluding any additional anticancer therapy such as any systemic 
antineoplastic therapy (including kinase inhibitors and chemotherapy), radiation therapy, 
or surgery. 
All patients will present to the study center on C1D1 for the first dose of study drug, vital 
sign measurements, physical exam, quality-of-life (QoL) assessment, PRO assessments, 
laboratory assessments, ECG and AE recording. In Cycle 2 Day 1 (C2D1), Cycle 3 Day 1 
(C3D1), Cycle 4 Day 1 (C4D1) and Cycle 5 Day 1 (C5D1), patients will present to study 
centers for physical examination, vital signs measurements, laboratory assessments, QoL 
assessments, PRO assessments, ECG, and AE/concomitant medication recording.  On 
C1D15 and C2D15, all patients will attend study center visits for vital sign 
measurements, serum chemistry measurements, and AE reporting. For all subsequent 
cycles, all patients will attend study center visits every other cycle on Day 1 of odd cycles 
(ie, C7D1, C9D1 etc.) for physical examination, vital sign measurements, laboratory 
assessments, QoL assessments, PRO assessments, ECG and AE recording. At any point 
in time between treatment cycles patients should attend or contact the study center for AE 
reporting, evaluation, and medical intervention. 
Tumor assessments will be performed at Baseline and then every 8 weeks (± 1 week) 
counting from C1D1, regardless of the scheduled treatment cycles, ie, if study treatment 
is interrupted or discontinued for any reason, tumor imaging should continue according to 
an 8-week schedule until tumor progression is confirmed by central radiology review. 
Computed tomography with intravenous (IV) contrast is the preferred imaging modality, 
unless a site of disease is better evaluated by MRI. 
It is anticipated that patients will receive at least 1 cycle of avapritinib if randomized to 
Arm A and regorafenib if randomized to Arm B; no maximum treatment duration has 
been set. After C1, patients may continue to receive study drug until precluded by 
toxicity, noncompliance, pregnancy, withdrawal of consent, physician decision, PD, 
death, or closure of the study by the Sponsor. 
All patients will attend an End-of-Treatment (EOT) visit within 14 (±7) days after the last 
dose of study drug. A safety Follow-up visit for resolution of any ongoing AE will be 
made on Day 30 (±7 days) after the last dose of study drug, or at the time the patient 
initiates another antineoplastic therapy. Patients who discontinue study treatment before 
disease progression will undergo tumor assessments every 8 weeks until disease 
progression, death, or patient withdrawal of consent. After documentation of disease 
progression by central radiology review, patients are to be followed for subsequent 
antineoplastic therapy and survival approximately every 2 months until death, withdrawal 
of consent or closure of the study by the Sponsor. 
The expected enrollment period is approximately 18 months, and the expected duration 
of the study to reach the primary analysis timepoint is approximately 24 months until a 
total number of 264 PFS events are reached. The study will be completed when all 
patients are no longer receiving study drug and follow-up for OS has been concluded. 


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Study Schematic 
 
Abbreviations:  GIST = gastrointestinal stromal tumor; N = number of patients; R = randomized; 
TKI = tyrosine kinase inhibitor. 
4.2 
Justification of the Study Design 
The study is designed as a randomized, open-label, efficacy and safety study. Patients 
who meet all study eligibility criteria will be randomly assigned in a 1:1 ratio to receive 
avapritinib or regorafenib. Random assignment of patients minimizes bias and helps 
ensure that both known and unknown risk factors are distributed evenly between 
treatment groups. Eligible patients will continue to receive BSC throughout the duration 
of the study. 
The study is not blinded because the distinct AE profiles of regorafenib and avapritinib 
make effective blinding impossible. In particular, regorafenib treatment is associated with 
palmar-planar erythrodysesthesia (PPE) in 67% of patients, rash in 30% of patients and 
hypertension in 59% of patients (Stivarga, 2017). In addition, the adverse events 
requiring dose modification are very different between regorafenib and avapritinib; 
therefore, appropriate patient care requires that the treating physician and patient know 
which drug is being used. In order to prevent bias in assessing efficacy endpoints, PFS 
and response will be determined by independent, central radiology reviewers blinded to 
treatment group, and the sponsor team responsible for analysis of the study will not have 
access to efficacy and safety data identified by treatment group. 
Demonstration of the efficacy of avapritinib as assessed by PFS is the primary objective 
of the study. Response assessments used to determine PFS for the primary endpoint will 
be based on standard response criteria (mRECIST, version 1.1) evaluated by blinded 
central radiology review to ensure consistent tumor assessments between the 
2 randomized treatment arms. 
Key secondary endpoints including ORR and OS and additional secondary endpoints 
including safety, DCR, DOR, disease response by Choi criteria, EORTC-QLQ-C30 
scores, plasma drug concentration and an abdominal pain assessment will provide 


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important supportive data to help determine whether avapritinib provides a clinically 
relevant improvement in outcome compared to regorafenib.  
An Independent Data Monitoring Committee (IDMC) will be in place to review study 
progress including final primary efficacy outcomes, safety data, adherence to protocol, 
and follow-up assessments. 
4.3 
Rationale for the Dose Selected 
Dose selection for the treatment of unresectable or metastatic GIST patients with 
avapritinib was based on a 3+3 dose escalation study design with a starting dose of 30 mg 
QD (BLU-285-1101). Forty-six patients were enrolled in Part 1 (dose escalation) of the 
study, 23 patients with PDGFRα-mutated GIST and 23 patients with KIT-mutated GIST, 
treated with avapritinib at doses of 30 to 600 mg. 
Preliminary data showed avapritinib to be well tolerated at QD doses of 30 mg to 
400 mg. No DLTs were reported at doses ranging from 30 mg to 400 mg; 2 DLTs were 
observed at 600 mg, including Grade 2 hypertension, Grade 2 rash, and Grade 2 memory 
impairment in 1 patient and Grade 2 hyperbilirubinemia in the other patient in Study 
BLU-285-1101.  
After a single dose and repeat dosing of avapritinib, systemic exposure was dose 
proportional over the dose range of 30 to 400 mg QD. The steady state (C1D15) 
geometric mean Cmax (%CV)  of avapritinib at doses of 300 and 400 mg QD was 774 
ng/mL (49.4%) and 1009 ng/mL (50.9%), respectively, and the corresponding AUC0-τ 
was 14074 h•ng/mL (45.1%) and 20298 h•ng/mL (41.5%). The mean accumulation ratio 
after repeat dosing of avapritinib (dose range: 30 – 400 mg QD) was 3.4 – 5.2. 
On 14 February 2017, the maximum tolerated dose for the BLU-285-1101 study was 
determined to be 400 mg QD and the dose expansion (Part 2) phase of the study started to 
enroll patients at this dose. Subsequently, based on a joint Investigator and Sponsor 
review of the available safety, PK/pharmacodynamics, and clinical activity data observed 
across all cycles of treatment during Part 1 (dose escalation) and Part 2 (dose expansion), 
300 mg QD was selected as the avapritinib starting dose for the remainder of Part 2. 
Exposures in humans who have received avapritinib at 300 mg and 400 mg QD doses are 
active against resistance mutations in patient-derived xenograft models showing an 
overlap covering a broad range of KIT mutations, including exon 11/13 and exon 17/18. 
Hence, 300 mg PO QD is expected to be clinically active and well tolerated.  
As of this 11 October 2017 data cut, 43 patients had initiated treatment in the dose 
expansion part (Part 2) of the study at 400 mg QD and 27 patients initiated at 300 mg 
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5 POPULATION 
5.1 
Number of Patients 
Approximately 460 patients will be enrolled and randomized in a 1:1 ratio, stratified by 
TKI treatment (third vs. fourth), geographic region (Asia vs. rest of the world), and 
mutation status (PDGFRα D842V mutation present vs. absent) including: 
• Approximately 230 patients randomized to receive avapritinib (Arm A). 
• Approximately 230 patients randomized to receive regorafenib (Arm B). 
At least 70% of the patients enrolled should be receiving their third distinct TKI 
treatment for GIST, ie, no more than 30% of patients should be receiving their fourth 
distinct TKI treatment for GIST. Enrollment will be restricted to include only patients 
receiving their third distinct TKI once 30% of the targeted 460 patients who are receiving 
their fourth distinct TKI treatment have been enrolled. 
5.2 
Inclusion Criteria 
Patients meeting the following criteria will be eligible for participation in the study: 
1. Patients who are ≥ 18 years of age. 
2. Patients who have histologically confirmed metastatic or unresectable GIST. 
Unresectable GIST must be confirmed to be unresectable by a qualified surgeon. 
3. Patients who have received imatinib and 1 or 2 other TKIs for the treatment of GIST, 
including TKIs used for adjuvant therapy. Each different TKI is counted once 
regardless of how often it was used, and if 2 different TKIs are used in combination, 
both TKIs are counted. Patients must have disease progression prior to enrollment. 
Prior use of other systemic and local therapies is not restricted. 
4. Patients who have an ECOG PS of 0 to 1.  
5. Patient, or legal guardian if permitted by local regulatory authorities, who provides 
informed consent to participate in the study. 
5.3 
Exclusion Criteria 
Patients meeting any of the following criteria will not be eligible for participation in the 
study: 
1. Patients who have received prior treatment with avapritinib or regorafenib. 
2. Patients who have previously received more than 3 different TKIs for the treatment of 
GIST, including TKIs used for adjuvant therapy. Each different TKI is counted once 


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regardless of how often it was used, and if 2 different TKIs are used in combination, 
both TKIs are counted. 
3. Patients who are known to be both KIT and PDGRFα wild type. 
4. Patients who received any systemic anticancer therapy within 1 week before the first 
dose of study drug. Prior radiotherapy (including stereotactic radiotherapy) to major 
organs within 2 weeks of the first dose of study drug, or focal radiotherapy (including 
stereotactic radiotherapy), such as to bones, limbs, or other areas not involving major 
organs, within 3 days. 
5. Patients who have clinically significant, uncontrolled, cardiovascular disease, 
including congestive heart failure Grades II, III or IV according to the New York 
Heart Association classification, myocardial infarction or unstable angina within the 
previous 6 months, or uncontrolled hypertension. 
6. Patients who have experienced arterial thrombotic or embolic events such as 
cerebrovascular accident (including transient ischemic attacks) within 6 months 
before the first dose of study drug, or venous thrombotic events such as pulmonary 
embolism or deep vein thrombosis within 14 days before the first dose of study drug. 
Patients with venous thrombotic events such as pulmonary embolism or deep vein 
thrombosis ≥ 14 days before the first dose of study drug are not excluded provided 
they are on stable doses of anti-coagulation, or have completed the planned anti-
coagulation regimen.  
7. Patients who have experienced any hemorrhage or bleeding event NCI CTCAE 
version 5.0 Grade 3 or higher within 4 weeks before the first dose of study drug. 
8. Patients who have a known risk of intracranial bleeding, such as a brain aneurysm 
that has not been removed or repaired, or a history of intracranial bleeding within 
1 year prior to the first dose of study drug. 
9. Patients who have a symptomatic non-healing wound, ulcer, gastrointestinal 
perforation, or bone fracture. 
10. Patients who have poor organ function as defined by one or more of the following 
laboratory parameters: 
o Persistent proteinuria of NCI CTCAE version 5.0 Grade 3 or higher  
o Alanine aminotransferase and AST > 3 × upper limit of normal (ULN) if no 
hepatic metastases are present; > 5 × ULN if hepatic metastases are present. 
o Total bilirubin >1.5 × ULN; and in presence of Gilbert’s syndrome, total bilirubin 
> 3 × ULN or direct bilirubin > 1.5 × ULN.  
o Estimated (per institutional standard; eg, Cockcroft-Gault formula or 
Modification of Diet in Renal Disease equation) or measured creatinine clearance 


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< 40 mL/min (if the estimated or measured creatinine clearance is ≥ 40 mL/min 
using any of these methods the patient is not excluded). 
o Platelet count < 90 × 109/L and absolute neutrophil count (ANC) < 1.0 × 109/L. 
o Hemoglobin < 9 g/dL. Transfusion and erythropoietin may be used to reach at 
least 9 g/dL, but must have been administered at least 2 weeks before the first 
dose of study drug. 
11. Patients who have received neutrophil growth factor support within 14 days of the 
first dose of study drug. 
12. Patients who require therapy with a concomitant medication that is a strong inhibitor 
or strong or moderate inducer of CYP3A4. 
13. Patients who have had a major surgical procedure (minor surgical procedures such as 
central venous catheter placement, tumor needle biopsy, and feeding tube placement 
are not considered major surgical procedures) within 14 days of the first dose of study 
drug. Patient has significant traumatic injury within 28 days before the first dose of 
study drug. 
14. Patients who have a history of another primary malignancy that has been diagnosed 
or required therapy within 3 years before the first dose of study drug. The following 
prior malignancies are not exclusionary:  completely resected basal cell and 
squamous cell skin cancer, curatively treated localized prostate cancer, and 
completely resected carcinoma in situ of any site. Patients with a prior or concurrent 
malignancy whose natural history or treatment does not have the potential to interfere 
with the safety or efficacy assessment of the investigational agent may be included 
after approval by medical monitor. 
15. Patients who have a history of a seizure disorder requiring anti-seizure medication. 
16. Patients who have metastases to the brain. 
17. Patients who are unwilling or unable to comply with scheduled visits, drug 
administration plan, laboratory tests, or other study procedures and study restrictions. 
18. Patients who have a QT interval corrected using Fridericia's formula (QTcF) of 
> 450 msec. 
19. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain 
from sexual intercourse or employ highly effective contraception from the time of the 
first dose of study drug and for at least 60 days after the last dose of study drug. Men 
who are unwilling, if not surgically sterile, to abstain from sexual intercourse or 
employ highly effective contraception from the time of the first dose of study drug 
and for at least 90 days after the last dose of study drug. Refer to Section 6.6.2 for 
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20. Women who are pregnant, as documented by a serum beta human chorionic 
gonadotropin (β-hCG) pregnancy test consistent with pregnancy, obtained within 
7 days before the the first dose of study drug. Females with β-hCG values that are 
within the range for pregnancy but are not pregnant (false-positives) may be enrolled 
with written consent of the Sponsor, after pregnancy has been ruled out. Females of 
non-childbearing potential (postmenopausal for more than 1 year; bilateral tubal 
ligation; bilateral oophorectomy; hysterectomy) do not require a serum β-hCG test. 
21. Women who are breastfeeding. 
22. Patients who have prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, or laboratory abnormality that, in the Investigator’s 
opinion, could put the patient at an unacceptably high risk for toxicities, or alter the 
absorption, distribution, metabolism, or excretion of the study drug; or impair the 
assessment of study results. 
23. Patients with a known hypersensitivity to avapritinib, regorafenib, or the excipients in 
either study drug. 
5.4 
Patient Identification and Registration 
Patients who are candidates for enrollment into the study will be evaluated for eligibility 
by the Investigator to ensure that the inclusion and exclusion criteria (see Section 5.2 and 
Section 5.3) have been satisfied.  
Upon identification of an eligible patient, study centers will submit a request to the 
Sponsor or designee to register each patient for enrollment. Further instructions will be 
provided in the study manual. 
The Medical Monitor or designee will confirm eligibility for all patients before 
randomization and administration of the first dose of study drug. 
5.5 
Randomization 
Patients who meet all study eligibility criteria will be randomly assigned in a 1:1 ratio to 
receive avapritinib PO QD or regorafenib PO QD, stratified by TKI treatment (third vs. 
fourth), geographic region (Asia vs. rest of the world), and mutation status measured in 
ctDNA or a tumor sample (PDGFRα D842V mutation present vs. absent). 
At least 70% of the patients enrolled in this study should be receiving study treatment as 
their third distinct TKI treatment for GIST, ie, no more than 30% of patients should be 
receiving their fourth distinct TKI treatment for GIST. Enrollment will be restricted to 
include only patients receiving their third distinct TKI treatment once 30% of the enrolled 
targeted 460 patients who are receiving their fourth distinct TKI treatment have been 
enrolled. 
The randomization assignment will be implemented by an interactive web response 
system (IWRS). 


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5.6 
Study Completion 
It is anticipated that patients will receive at least 1 cycle of avapritinib or regorafenib; no 
maximum treatment duration has been set. After C1, patients may continue to receive 
study drug until precluded by toxicity, or until disease progression, noncompliance, 
pregnancy, withdrawal of consent, death, physician decision, or closure of the study by 
the Sponsor. Patients permanently withdrawn from study participation will not be 
allowed to re-enter the study. 
Patients will be considered to have completed the study if they withdraw from the study 
for any of the criteria listed in Section 5.7. 
5.7 
Patient Withdrawal Criteria 
Patients have the right to withdraw from the study at any time for any reason. 
Patients must withdraw or be withdrawn from study treatment for any of the following 
reasons: 
• Withdrawal of consent 
• Pregnancy 
• Death 
Patients may withdraw or be withdrawn from study treatment for any of the following 
reasons: 
• AE 
• Disease progression 
• Protocol deviation 
• Investigator decision 
• Loss to follow-up 
When a patient discontinues study drug or withdraws from the survival follow-up part of 
the study, the primary reason(s) for discontinuation or withdrawal must be recorded in the 
appropriate sections of the electronic case report form (eCRF) and all efforts will be 
made to complete and report final study observations as thoroughly as possible. 
All related AEs should be monitored until they are resolved, have stabilized, have 
returned to pre-exposure baseline, are determined to be due to another illness, or until a 
subsequent therapy is initiated. For AEs considered not related to study drug, similar 
monitoring guidelines will only be required through 30 days after the last dose of study 
drug. If the patient withdraws from treatment because of an AE, every effort must be 


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made to perform protocol-specified safety follow-up procedures, as outlined in 
Section 7.6. 
In the event a patient is withdrawn from study drug or the follow-up part of the study, the 
Medical Monitor must be informed. If there is a medical reason for withdrawal, the 
patient will remain under the supervision of the Investigator or designee until the 
condition has returned to baseline or stabilized. 
6 STUDY CONDUCT 
6.1 
General Conduct 
The study will be conducted at multiple centers in North America, Europe, Australia, and 
Asia. 
This study will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), and the applicable regulatory requirements. 
Patients may be randomized in the system at any time but must be dosed within 28 days 
of signing of informed consent. 
The schedule of assessments for the study is provided in Table 2. 
The minimum duration of patient participation is expected to be approximately 3 months, 
including a screening period to assess study eligibility up to 4 weeks (28 days); a 
treatment period of at least 1 cycle (28 days); an EOT visit at least 14 ± 7 days after the 
last dose of study drug; and a Safety Follow-up visit in the clinic for physical 
examination and resolution of any AEs 30 days (± 7 days) after the last dose of study 
drug. Thereafter, patients are to be followed for tumor imaging every 8 weeks (± 7 days) 
until disease progression, death, initiation of new anti-GIST therapy, withdrawal of 
consent, or closure of the study by the Sponsor and then survival approximately every 
2 months until death, withdrawal of consent or closure of the study by the Sponsor. 
The end of the study is defined as the time that the last patient completes his/her last visit 
(LPLV), including assessments performed as part of PFS follow-up, if the patient enters 
the PFS follow-up part of the study. See Section 7 for details of all study assessments. 
The expected enrollment period is approximately 18 months and the expected duration of 
the study to reach the primary analysis timepoint is approximately 24 months until a total 
number of 264 PFS events are reached. The study will be completed when all patients are 
no longer receiving study drug and follow-up for OS has been concluded. 
6.2 
Early Termination 
The study may be terminated early at the discretion of the Sponsor, if there is sufficiently 
reasonable cause. In the event of such action, written notification documenting the reason 
for study termination will be provided to each Investigator. 


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Circumstances that may warrant early termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients. 
• Insufficient adherence to protocol requirements. 
• Plans to modify, suspend, or discontinue the development of study drug. 
• Other administrative reasons. 
Should the study be terminated prematurely, all study materials must be returned to the 
Sponsor or Sponsor’s designee. 
6.3 
Dose and Administration 
Avapritinib will be administered PO at a starting dose of 300 mg QD in continuous 
28-day cycles.  
Prespecified dose modifications guidance for AEs related to avapritinib including 
cognitive effects, are described in Section 6.3.1. 
Regorafenib will be administered at 160 mg PO QD for 21 days in 28-day cycles with 
1 week off therapy. Doses of avapritinib or regorafenib may be modified or discontinued 
for toxicity as described in Section 6.3.1. 
Patients receiving regorafenib who experience disease progression may be offered the 
opportunity to cross over to the avapritinib treatment arm after evaluation and 
confirmation of disease progression by central radiology review and a washout period of 
7 to 28 days after their last dose of regorafenib; see Section 7.6 for additional details. 
Prespecified dose modifications guidance for AEs related to regorafenib including hand-
foot skin reaction, hypertension, and AST, ALT, or bilirubin increases are described in 
Section 6.3.1. 
Patients will be dispensed the appropriate number of Sponsor-packaged, labeled bottles 
on D1 of each cycle to allow dosing until D1 of the next cycle, which is expected to be 
within 28 or 56 days. Patients must return all unused tablets (or the empty bottles) at each 
scheduled visit. 
Avapritinib doses should be administered with a glass of water (at least 8 ounces or 
250 mL) in a fasted state, with no food intake from 2 hours before until 1 hour after study 
drug administration. Patients should be instructed to swallow tablets whole and to not 
chew the tablets. Antacids should not be taken within 3 hours before or after study drug 
administration. 
Regorafenib will be provided as 40 mg strength tablets and it should be administered 
after a low-fat meal. See Appendix 1 for additional details. 


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Avapritinib or regorafenib should be administered QD at approximately the same time 
each day. If a patient forgets to take his/her daily dose in the morning, he/she should take 
that dose by 4 pm that day. If the dose has not been taken by 4 pm, then that dose should 
be omitted, and the patient should resume treatment with the next scheduled dose. 
If the patient forgets to take his/her daily dose in the evening, he/she should take the 
study drug dose by 12 am (midnight) that day, and at least 8 hours before the next dose. If 
the dose has not been taken by the specified times, that dose should be omitted, and the 
patient should resume treatment with the next scheduled dose. 
If a patient vomits during or after taking avapritinib or regorafenib, re-dosing is not 
permitted until the next scheduled dose.  
A temporary discontinuation, up to 56 days (8 weeks) in avapritinib or regorafenib dosing 
is allowed for patients who require an interruption (eg, for surgery or another 
interventional procedure) during the treatment period. Avapritinib should be discontinued 
48 hours before the procedure (unless the procedure is required more urgently) and 
resumed at least 48 hours after the procedure is completed. For regorafenib, a vascular 
endothelial growth factor receptor inhibitor that can impair wound healing, treatment 
should be stopped at least 2 weeks before the procedure, if possible, and at least 1 week 
before the procedure, unless the procedure is required more urgently. The decision to 
resume regorafenib after surgery should be based on clinical judgment of adequate 
wound healing. 
6.3.1 
Dose Modification Recommendations for Adverse Events 
Dose modification guidelines are summarized for avapritinib in Table 1, and for 
regorafenib in Appendix 2. These guidelines should be followed by clinical Investigators; 
however, for an individual patient, dose interruptions, reductions, and treatment 
discontinuation should also be based on the clinical circumstance. Deviation from these 
guidelines must be documented and communicated with the sponsor. 
Adverse events are to be graded according to NCI CTCAE version 5.0. When the 
observed toxicity has resolved to ≤ Grade 2 or returned to baseline, the investigator may 
resume dosing if clinically indicated. Guidance for re-escalation after resolution of 
adverse drug reactions is provided in Section 6.3.2. 
Avapritinib dose reductions to below 100 mg QD are not permitted (see Table 1), and 
regorafenib dose reductions to below 80 mg QD are not permitted (See Appendix 2). If a 
patient requires dose reduction below these dose levels, study treatment should be 
discontinued. 
Doses may be interrupted for study-drug related toxicities for up to 56 days (8 weeks). In 
general, if a study drug-related toxicity does not resolve to ≤ Grade 2 or has not returned 
to baseline after dose interruption for more than 56 days, the patient must be discontinued 
from study treatment unless after discussion with the medical monitor, resumption of 
treatment is considered to be in the best medical interest of the patient, and this is 
documented in writing. Additionally, the Sponsor’s medical monitor must be contacted if 


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an AE deemed unrelated to treatment requires a dose interruption for more 56 days; a 
longer recovery period is permitted with written approval by the Sponsor. 
During dose interruptions, study sites should continue to observe the study schedule as 
planned. 
Once adverse drug reactions have resolved after the guidelines below are followed, 
Investigators are encouraged to re-escalate the dose of study drug as described in 
Section 6.3.2. 
Table 1: 
Dose Modification and Re-escalation Guidelines for 
Avapritinib-Related Toxicity 
Toxicity 
Modification 
General 
Grade 1 or Grade 2 
• 
No dose modification required 
Grade 3 - 4  
• 
Occurrence: Hold until event is ≤ Grade 2, or has returned to baseline, and 
then resume by reducing the dose by 100 mg less than the current dose 
o 
 
• 
Occurrence at 100 mg: Discontinue avapritinib 
o 
 
Cognitive or Mood Effects1, 2 
Grade 1 with only 
minor impairment 
No dose modification required 
Grade 1, other than 
minor impairment 
• 
Interrupt dosing for 7 days, and resume dosing without dose reduction  
• 
The dosing interruption may be repeated if the impairment continues to 
worsen after resuming dosing; however, repeated dosing interruption is at the 
discretion of the investigator, and should be balanced with the need to treat 
the underlying GIST 
Grade 2 
• 
Interrupt dosing for a minimum of 7 days 
• 
Resume dosing with a dose reduction of 100 mg when the cognitive effect has 
improved to Grade 1 or less, or still at Grade 2, if continued treatment is 
considered in the best medical interest of the patient due to the underlying 
GIST 
• 
If the patient is already receiving a dose of 100 mg QD, and continued 
treatment is considered in the best medical interest of the patient due to the 
underlying GIST, treatment may be resumed at 100 mg 
Grade 3-4 
• 
Interrupt dosing for a minimum of 14 days 
• 
Resume dosing with a dose reduction of 100 mg when the cognitive effect has 
improved to Grade 1 or less, or when it has improved to Grade 2, if continued 
treatment is considered in the best medical interest of the patient due to the 
underlying GIST 
• 
Occurrence at 100 mg: Discontinue avapritinib  
Intracranial Bleeding2 
Grade 1 
• 
Interrupt dosing for a minimum of 7 days, and re-image the brain 


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• 
Resume dosing without dose reduction, if the bleed is stable or improving, 
and continued treatment is considered in the best medical interest of the 
patient due to the underlying GIST 
Grade 2 
• 
Interrupt dosing for a minimum of 14 days and re-image the brain 
• 
Resume dosing with a dose reduction of 100 mg when the intracranial 
bleeding has improved to Grade 1 or less, or still at Grade 2, if continued 
treatment is considered in the best medical interest of the patient due to the 
underlying GIST 
• 
Occurrence at 100 mg: Discontinue avapritinib  
Grade 3-4 
• 
Discontinue avapritinib  
Abbreviations: CNS = central nervous system; GIST = gastrointestinal stromal tumor; QD = once daily. 
1 Changes in cognition, memory, attention, mood, or speech (thought to originate in the CNS). 
2 If avapritinib treatment is resumed after interruption for a cognitive or mood effect, or for an intracranial 
bleeding event, the investigator must document in writing that resuming avapritinib treatment was 
considered to be in the best medical interest of the patient. 
For regorafenib, dose modification is described in Appendix 2. 
6.3.2 
Dose Re-escalation After Resolution of Adverse Drug Reactions 
Avapritinib and regorafenib doses may be re-escalated from the reduced dose level to the 
immediate previously administered dose level if any of the following criteria are met: 
• All ≥ Grade 2 non-hematologic (other than CNS toxicities) have recovered to 
< Grade 2 for at least 2 weeks. 
• All ≥ Grade 3 hematologic toxicities have recovered to ≤ Grade 2 and are 
manageable with supportive therapy. 
• All ≥ Grade 2 CNS toxicities have recovered to ≤ Grade 1 and are manageable 
with supportive therapy. 
Patients may receive step-wise avapritinib dose re-escalations up to 300 mg QD 
(eg, 100 mg QD to 200 mg QD to 300 mg QD) if the above criteria continue to be met.  
Patients may receive step-wise regorafenib dose escalations up to 160 mg QD (eg, 80 mg 
QD to 120 mg QD to 160 mg QD) if the above criteria continue to be met.  
A patient should be treated and tolerate therapy well for at least 1 cycle at each higher 
dose level before the dose is escalated again. In no circumstances should a patient receive 
a dose higher than 300 mg QD. 
6.4 
Prior and Concomitant Therapy 
All medications administered and procedures conducted within 28 days before C1D1 
should be recorded on the eCRF. In addition, all prior treatments for the underlying 
malignancy should be recorded. 


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6.4.1 
Prohibited Concomitant Therapy 
The following medications and procedures are prohibited during the study: 
• In vitro studies with recombinant human CYP enzymes demonstrated that avapritinib 
phase I metabolism is predominantly mediated by CYP3A4, with CYP2C9 playing a 
minor role. Concomitant treatment with drugs that are strong CYP3A4 inhibitors or 
strong or moderate CYP3A4 inducers are prohibited for patients receiving 
avapritinib. Please refer to Appendix 3 for a list of prohibited medications and foods. 
• Regorafenib is metabolized by CYP3A4 and UGT1A9. Concomitant treatment with 
drugs that are strong inhibitors of CYP3A4, strong inducers of CYP3A4, and strong 
inhibitors of UGT1A9 are prohibited for patients receiving regorafenib. Please refer 
to Appendix 3 for a list of prohibited medications and foods. 
• Any investigational agent or device other than avapritinib or regorafenib, including 
commercially available agents that are investigational for the treatment of the 
patient’s underlying malignancy. 
• Any antineoplastic treatment (including kinase inhibitors, chemotherapy, and 
radiotherapy) other than avapritinib and regorafenib. Patients who experience 
centrally confirmed disease progression but subsequently undergo radiation therapy 
or surgery may continue to receive study treatment with avapritinib, if the treating 
investigator considers it to be in the patient’s best medical interest. 
6.4.2 
Concomitant Therapy to be used with Caution 
Avapritinib 
In vitro, avapritinib is a reversible inhibitor of CYP2C9, and CYP3A4/5 at clinically 
relevant concentrations. Avapritinib also demonstrated time-dependent inhibition of 
CYP3A4/5 in vitro with an estimated Kinact and KI of 0.0301 min-1 and 12.3 μM, 
respectively. Therefore, avapritinib treatment may increase the plasma concentration of 
other medications for which CYP2C9 or CYP3A-mediated metabolism constitutes the 
primary mechanism of clearance. 
In vitro, avapritinib, at concentrations of 0.3 to 3 μM, induced CYP3A4 mRNA 
expression with a maximal 3.25-fold induction observed at 3 μM. In vitro, avapritinib is 
an inhibitor of P-gp, BCRP, BSEP, and MATE1 and MATE2K. Therefore, avapritinib 
may increase the plasma concentration of other medications that are substrates of these 
transporters. Medications that are CYP2C9, CYP3A4 or BCRP substrates, with a narrow 
therapeutic index and moderate inhibitors of CYP3A4 should be used with caution (Refer 
to Appendix 4 for a list of these medications). 
Investigators should ensure patients avoid proton pump inhibitors and H2-receptor 
antagonists during the study. Furthermore, antacids should be taken at a time point that is 
not proximal to study drug administration (at least 3-4 hours before or after study drug 
administration).  


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In addition, medications that are known to increase the risk of seizures should be used 
with caution. 
Regorafenib 
Investigators should ensure patients exercise caution while using concomitant therapies 
with regorafenib as listed in Appendix 4. 
6.4.3 
Permitted Concomitant Therapy 
Medications and treatments other than those specified in Section 6.4.1 and Section 6.4.2, 
including palliative and supportive care for disease-related symptoms are permitted 
during the study.  
Patients should be closely monitored, and treatment is to be instituted for disease-related 
symptoms as appropriate. Supportive care measures for treating AEs should be instituted 
as soon as they are recognized. 
Anti-emetic treatments may be used at the Investigator’s discretion and in accordance 
with the American Society of Clinical Oncology guidelines or equivalent after 
documented nausea or vomiting has occurred without medications having been used. The 
choice of anti-emetic treatment, if required, will be made at the Investigator’s discretion. 
Anti-diarrhea medications may also be used after documented diarrhea has occurred, at 
the Investigator’s discretion.  


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6.5 
Schedule of Assessments 
Table 2: 
Schedule of Assessments 
Study Activitiesa 
Screening 
Study Treatment 
EOTe 
± 7 
days 
Safety 
Follow-
Upf 
± 7 days 
PFS 
Follow-upg 
± 7 days 
Survival 
Follow-
uph
± 30 
days 
Cycle 
C1 
C2 
± 2 days 
C3, C4, 
C5 b,c 
± 3 days 
C7-EOT b,d 
± 7 days 
Study Day 
-28 to -1
D1 
D15 
D1 
D15 
D1 
D1 
14 days 
after 
last 
dose 
30 days 
after last 
dose 
Every 
8 weeks 
after Safety 
F/U 
Every 
2 months 
Window (Days) 
±3 
±7 
±7 
±7 
±7 
±1 
month 
Informed consenti 
X 
Inclusion/exclusion criteria 
X 
Demographics 
X 
Medical historyj 
X 
Physical examinationk 
X 
X 
X 
X 
X 
X 
Vital signsl 
X 
X 
X 
X 
X 
X 
X 
X 
Serum or urine pregnancym 
(β-hCG) test 
X 
X 
X 
X 
X 
X 
Xm 
ECOG PS 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
X 
Hematologyn
X 
Xo 
X 
X 
X 
X 
Coagulationp 
X 
Xo 
X 
Serum chemistryq
X 
Xo 
Xr 
X 
Xr 
X 
Xs 
X 


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Study Activitiesa 
Screening 
Study Treatment 
EOTe 
± 7 
days 
Safety 
Follow-
Upf 
± 7 days 
PFS 
Follow-upg 
± 7 days 
Survival 
Follow-
uph
± 30 
days 
Cycle 
C1 
C2 
± 2 days 
C3, C4, 
C5 b,c 
± 3 days 
C7-EOT b,d 
± 7 days 
Study Day 
-28 to -1
D1 
D15 
D1 
D15 
D1 
D1 
14 days 
after 
last 
dose 
30 days 
after last 
dose 
Every 
8 weeks 
after Safety 
F/U 
Every 
2 months 
Window (Days) 
±3 
±7 
±7 
±7 
±7 
±1 
month 
Urinalysis 
X 
Xo 
X 
Study drug administration 
X 
PK blood samplesc (Arm A: 
avapritinib patients only) 
X 
X 
Xc 
Mutation screening (ctDNA 
sample) 
X 
Plasma sample for biomarkers 
Xo 
X 
X 
X 
X 
Tumor imagingt 
X 
Xt 
X 
X 
X 
Brain imaging (MRI or CT)u 
X 
X 
X 
EORTC-QLQ-C30, 
 
 
X 
X 
Xv
Xv 
AE monitoringw
X 
SAE monitoringx 
X 
Concomitant medicationsx 
X 
Survival assessment 
X 
New antineoplastic therapy 
X 


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Abbreviations: AE = adverse event; C = cycle; CT = computed tomography; ctDNA = circulating tumor deoxyribonucleic acid; D = day; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC-QLQ-C30 = European Organisation for Research 
and Treatment of Cancer Quality of Life Questionnaire; EOT = End-of-Treatment; EQ-5D-5L = EuroQol 5 Dimension Questionnaire; F/U = follow-up; 
FACT-Cog = Functional Assessment of Cancer Therapy-Cognitive Function; GIST = gastrointestinal stromal tumor; IV = intravenous; MRI = magnetic 
resonance imaging; PD = progressive disease; PFS = progression-free survival; MRI = magnetic resonance imaging; PGI-C = Patients' Global Impression of 
Change; PGI-S = Patients’ Global Impression of Severity; PK = pharmacokinetics; SAE = serious adverse event; ULN = upper limit of normal. 
a On days when study drug is to be administered in the clinic, all tests or procedures must be completed pre-dose at each study visit unless otherwise indicated. 
Additional safety tests (eg, hematology, ECG) may be performed whenever clinically indicated, at the Investigator’s discretion. Whenever a test result is 
questionable, it should be repeated immediately.  
b Patients receiving regorafenib who experience disease progression documented by central radiology review may be permitted to cross over to receive 
treatment with avapritinib after disease progression confirmed by central radiology review (see Section 7.6) and a washout period of 7 to 28 days after their 
last dose of regorafenib. At the first study visit after the washout period, the patient will complete the C1D1 assessment schedule except for the following 
tests, which are not required: PK blood sample and biomarker plasma sample. After patients cross over to treatment with avapritinib, ECGs will be performed 
following the same schedule as prior to cross over and AEs will only be assessed for their relationship to avapritinib. 
c Pharmacokinetics samples will be collected before dosing (ie, predose) on Day 1 of Cycles 1, 2, 3, and 5 only from patients in Arm A of the study (those 
receiving avapritinib). There will be no PK samples collected from patients in Arm B of the study (those receiving regorafenib). On C3D1 and C5D1, in 
addition to the predose sample in all patients, samples will be collected at any 1 time point between 1-8 hours postdose. On C2D1, additional samples will be 
collected predose and at 1 hour (±10 minutes), 4 hours (±15 minutes), and 6-8 hours (±15 minutes) postdose in a total of 25 patients at selected centers. Note: 
The predose samples for all patients are to be collected before the day’s dose of avapritinib and should be taken as close as possible to 24 hours after the prior 
dose was taken. 
d Every odd Cycle D1, eg, C7D1, C9D1, etc., moving forward through EOT. Visits may be performed more frequently, if dictated by the local standard of care 
or if needed to adequately monitor individual patients.  
e If an alternative antineoplastic treatment is to be started within 14 days after the last dose of study drug, the EOT visit should be conducted before the dose of 
alternative antineoplastic therapy. Tumor assessment for EOT procedures do not need to be repeated if they were conducted within 7 days (or within 28 days 
for disease response assessments).  
f The Safety Follow-up visit may be performed by clinic visit or a phone call for resolution of any ongoing AEs. 
g After completing the Safety Follow-up assessments, patients are to be followed for tumor imaging every 8 weeks (±7 days) until disease progression, death, 
initiation of new anti-GIST therapy, withdrawal of consent, or closure of the study by the Sponsor. 
h After documentation of disease progression by central radiology review, patients or their designated care giver will be contacted by phone every 2 months 
until withdrawal of consent, death, or closure of the study by the Sponsor to collect the drug name of any new systemic antineoplastic therapy or the date of 
death. 
i 
Patients randomized to Arm A must consent to continue avapritinib treatment after disease progression and patients randomized to Arm B must consent to 
cross over to avapritinib after disease progression; see Section 7.7 for additional details. 
j 
A complete medical history will be obtained at the Screening visit, including a history of GIST and/or other malignancies, prior treatments, response to each 
treatment (if available), and concurrent illnesses. 
k A complete physical examination and a basic neurological assessment will be performed at the Screening visit. Subsequent physical examinations will focus 
on symptoms and signs of GIST, changes from previous physical examinations, and AEs. 
l
Vital signs include weight, temperature, pulse, and systolic/diastolic blood pressure. Height will also be measured at Screening.


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m To be performed for women of childbearing potential. A serum pregnancy test is to be performed at Screening and at C1D1. A serum or urine pregnancy test 
should be performed every 4 weeks, even if a study visit is not specified, through 8 weeks after the last dose of study drug. Pregnancy tests may be performed 
locally during even cycles after C5D1 ± 5 days from expected CXD1 (ie, C6D1, C8D1, etc). 
n Hematology parameters to be measured include hemoglobin, red blood cell count, white blood cell count with differential count (including absolute 
neutrophil count), and platelet count. 
o
Baseline (C1D1) safety laboratory tests and samples for pharmacodynamic markers are to be obtained within 7 days before the first study drug dose (prior to
dosing on the first day of dosing permitted). If Screening tests occur within 7 days of C1D1, they do not need to be repeated.
p Coagulation studies include prothrombin time, international normalized ratio and activated partial thromboplastin time. 
q The comprehensive serum chemistry panel includes sodium, potassium, blood urea nitrogen or urea, bicarbonate (venous), creatinine, calcium, chloride, 
magnesium, phosphorus, albumin, AST, ALT, alkaline phosphatase, and total bilirubin (direct bilirubin if total bilirubin is > ULN). 
r Only liver function tests (ALT, AST, alkaline phosphatase, total bilirubin (direct bilirubin if total is > ULN) are required. These should be performed locally 
and any clinically significant abnormalities should be reported as an Adverse Event, and the laboratory values supporting Adverse Event should be entered 
into unscheduled visit laboratory page on eCRF. 
s Liver function tests (ALT, AST, alkaline phosphatase, total bilirubin (direct bilirubin if total is > ULN) should be measured every 4 weeks. On even-
numbered cycles, when a study visit is not required, these tests should be done locally, and any clinically significant abnormalities should be entered as 
adverse events, and laboratory values should be entered in unscheduled laboratory eCRF. 
t 
Tumor imaging will be done at Screening and then every 8 weeks (± 1 week) from Cycle 1 Day 1 until disease progression and will be assessed by central 
radiology review. Disease response assessments using the Choi criteria will be performed centrally. Note that tumor imaging should occur every 8 weeks 
regardless of the scheduled treatment cycles ie, if study treatment is interrupted or discontinued for any reason, tumor imaging should continue according to 
an 8-week schedule until disease progression or death. Computed tomography (CT) with IV contrast of the chest and CT or MRI with IV contrast of the 
abdomen and pelvis will be performed. CT of the chest is not required after screening unless there were sites of disease in the chest. CT with IV contrast is the 
preferred imaging modality, unless a site of disease is better evaluated by MRI. If a patient is not tolerant of IV contrast, non-contrast scans may be 
performed. For each patient, the same method of tumor imaging used at baseline should be used throughout the study. 
u
Brain imaging should be performed at Screening, Week 12 (±1 week), and Week 24 (±1 week), and should be repeated as clinically indicated, ie, for
unexpected neurologic AE. Patients who have been on study for more than 12 weeks should have imaging performed at the next scheduled visit and 12 weeks
later (±1 week).
v The EORTC-QLQ-C30, 
 will be completed at scheduled clinical site visits up to 
EOT. The questionnaires are not required at the EOT visit or after cross-over. 
w Adverse events are to be recorded from the start of study drug administration through the Safety Follow-up Assessment. 
x Serious AEs and concomitant medications are to be recorded from the date of the informed consent signature through the Safety Follow-up Assessment. 


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6.6 
Additional Considerations 
6.6.1 
Precautions 
An in vitro phototoxicity study in 3T3 mouse fibroblasts as well as a phototoxicity study 
in pigmented rats demonstrated that avapritinib has a slight potential for phototoxicity.  
Therefore, prolonged exposure to sunlight should be avoided during treatment. In 
addition, patients should take other measures to avoid ultraviolet (UV) exposure such as 
wearing sunscreen and sunglasses, wearing protective clothing, and avoiding tanning 
beds. Refer to the avapritinib IB for details.  
Hypospermatogenesis was observed in the testis and epididymis of rats and dogs and did 
not recover after 2-week recovery. Patients should be informed of the possibility of 
gamete and embryo banking. 
Refer to the avapritinib Investigator Brochure for details. 
6.6.2 
Contraception Requirements 
Women of childbearing potential must agree to use a highly effective method of 
contraception (CTFG, 2014) from the time of randomization until at least 8 weeks after 
the last dose of study drug. Women are considered to be of childbearing potential after 
menarche until becoming postmenopausal (defined as no menses for at least 12 months 
without an alternative medical cause) unless permanently sterile. A high follicle 
stimulating hormone level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
follicle stimulating hormone measurement is insufficient. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy 
(CTFG, 2014). Because avapritinib and regorafenib are potential CYP3A4 inducers, 
women should use hormonal contraception with caution and supplement with other 
highly effective methods. 
Males with partners who are female of reproductive potential must agree that they will 
use condoms, and their partners will use a highly effective contraceptive method 
throughout the study, and for 90 days after the last dose of study treatment. 
Highly effective forms of contraception are defined as the following (CTFG, 2014): 
•
Combined (estrogen and progestogen containing) hormonal contraceptives that
inhibit ovulation, including oral, intravaginal and transdermal products.
•
Progestogen-only hormonal contraceptives that inhibit ovulation, including oral,
injectable, and implantable products.
•
Intrauterine devices (IUD) and intrauterine hormone-releasing system (IUS).


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•
Bilateral tubal occlusion (women).
•
Male partner vasectomy or other method of surgical sterilization provided that the
partner is the sole sexual partner of the trial participant and the vasectomized
partner has received medical assessment of the surgical success.
•
Sexual abstinence (men and women), when this is the preferred and usual lifestyle
of the patient. Periodic abstinence (such as calendar, symptothermal and
postovulation methods), withdrawal (coitus interruptus), and the lactational
amenorrhea method are not acceptable methods of contraception.
The following methods of contraception are not considered highly effective (CTFG, 
2014): 
•
Progesterone-only oral hormonal contraception that do not inhibit ovulation.
•
Barrier methods with or without spermicide, or spermicide alone.
7 DESCRIPTION OF STUDY PROCEDURES 
7.1 
Screening 
After informed consent, all patients will undergo screening procedures within 28 days 
before dosing on C1D1 to determine eligibility. Patients may be randomized in the 
system at any time but must be dosed within 28 days of signing of informed consent. 
The following procedures will be performed at the Screening visit: 
•
Obtain demographic data, including sex, date of birth/age, race, and ethnicity;
•
Complete medical history, including a history of GIST and/or other malignancies,
prior treatments, the response to each treatment if available, and concurrent illnesses;
•
Complete physical examination and a basic neurological assessment, including
ECOG PS;
•
Vital signs including weight, temperature, pulse, and systolic/diastolic blood pressure.
Height will also be measured at Screening;
•
12-lead ECG;
•
Obtain plasma sample for exploratory biomarkers and ctDNA mutation testing;
•
Clinical laboratory assessment (hematology, coagulation, serum chemistry, and
urinalysis);
•
Serum pregnancy test (women of childbearing potential only);


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• Tumor imaging by CT with IV contrast or MRI (CT is required for the chest and 
preferred for all body regions unless a site of disease is better imaged by MRI). If a 
patient is intolerant of IV contrast, CTs may be performed without IV contrast. 
• Brain imaging by MRI or CT (MRI is preferred, if available); 
• Recording of concomitant medications and SAEs. Concomitant medications and 
SAEs are to be collected from the date of the informed consent signature through the 
Safety Follow-up Assessment, while AEs are to be collected from start of study drug 
administration through the Safety Follow-up Assessment.  
7.2 
Safety Assessments 
The schedule of safety assessments is described in Table 2. All clinical and laboratory 
safety assessments will be assessed by the Investigator for clinical significance and 
clinically significant findings will be reported as AEs. Additional safety assessments may 
be performed if dictated by the local standard of care and when clinically indicated, at the 
Investigator’s discretion. 
7.2.1 
Physical Examination 
A complete physical examination including a basic neurological assessment will be 
performed at the Screening visit. Subsequent physical examinations will be performed as 
outlined in Table 2, and will focus on symptoms and signs of GIST, changes from 
previous physical examinations, and AEs. 
7.2.2 
Eastern Cooperative Oncology Group Performance Status 
Determination of ECOG PS will be performed at the time points outlined in Table 2. 
Refer to Appendix 5 for ECOG PS scoring. 
7.2.3 
Brain Imaging 
Brain imaging by MRI or CT (MRI is preferred) will be performed at the visits outlined 
in Table 2, and should be repeated as clinically indicated, ie, for unexpected neurologic 
AEs. Patients who have been on study for more than 12 weeks should have imaging 
performed at the next scheduled visit and 12 weeks later (±1 week). 
7.2.4 
Vital Signs 
Vital sign measurements will include temperature, systolic/diastolic blood pressure, 
pulse, and weight, and will be performed at the time points outlined in Table 2. Height 
will be measured at the Screening visit only. 
Blood pressure and pulse assessments should be conducted while the patient is seated or 
supine. 


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7.2.5 
ECGs 
Twelve-lead ECGs will be obtained for all patients at the time points outlined in Table 2. 
Twelve-lead ECGs are to be conducted after 5 minutes in recumbence or semi-
recumbency.  
7.2.6 
Clinical Laboratory Tests 
Clinical laboratory evaluations for safety will be performed at a central laboratory. 
Before starting the study, the Investigator will provide the Sponsor (or its designee) 
copies of all laboratory certifications and normal ranges for all laboratory assessments to 
be performed by that laboratory. Local laboratory assessments may be used to make 
treatment-related decisions.  
Clinical laboratory evaluations will be conducted at the time points outlined in Table 2. 
In addition, all clinically significant laboratory abnormalities noted on testing will be 
followed by repeat testing and further investigated according to the judgment of the 
Investigator.  
The following safety laboratory tests are to be evaluated by the Investigator:  
Hematology: 
Hemoglobin, red blood cell count (RBC), white blood cell 
count (WBC) with differential (including ANC), and 
platelet count 
Coagulation: 
Prothrombin time (PT), international normalized ratio 
(INR), and activated partial thromboplastin time (aPTT) 
Serum chemistry: 
Sodium, potassium, blood urea nitrogen (BUN) or urea, 
bicarbonate (venous), creatinine, calcium, chloride, 
magnesium, phosphorus, albumin, AST, ALT, alkaline 
phosphatase (ALP), total bilirubin (direct bilirubin if total 
> ULN) 
Urinalysis (dipstick): 
pH, specific gravity, bilirubin, blood, glucose, ketones, 
leukocyte esterase, nitrite, protein, and urobilinogen 
Serum or urine 
pregnancya: 
β-hCG 
a A serum pregnancy test should be performed for women of childbearing potential at Screening and at 
C1D1. A serum or urine pregnancy test should be performed every 4 weeks through 8 weeks after the last 
dose of study drug. 
7.2.7 
Adverse Events and Concomitant Medications 
Each patient must be carefully monitored for the development of any AEs throughout the 
study from C1D1 (or from the time of signing informed consent, for SAEs) to 30 days 


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after the last dose. In addition, SAEs that are assessed as related to study treatment that 
occur > 30 days after the last dose also are to be reported. 
Complete details on AE and SAE monitoring are provided in Section 9. 
Concomitant medications will be recorded from the time of signing informed consent to 
30 days after the last dose. 
7.3 
Pharmacokinetic Assessment 
Blood samples will be collected from patients in Arm A of the study (those receiving 
avapritinib) before and after study drug dosing to determine circulating plasma 
concentrations of avapritinib (including any relevant metabolites). There will be no PK 
samples collected from patients in Arm B of the study (those receiving regorafenib). 
Pharmacokinetic samples will be collected before dosing (ie, predose) on Day 1 of Cycles 
1, 2, 3, and 5. On C2D1, additional samples will be collected predose and at 1 hour 
(±10 minutes), 4 hours (±15 minutes), and 6-8 hours (±15 minutes) postdose in a total of 
25 patients at selected centers. On C3D1 and C5D1, in addition to the predose sample, 
samples will be collected at any 1 time point between 1-8 hours postdose. Note: The 
predose sample is to be collected before the day’s dose of avapritinib and should be taken 
as close as possible to 24 hours after the prior dose was taken. 
Additionally, Investigators may obtain blood samples for PK analysis at the time(s) that 
significant drug-related AEs and SAEs occur. 
7.4 
Blood Samples for Biomarker Assessment 
Blood samples will be collected for patients at the time points outlined in Table 2 to 
characterize the mutant allele fraction in plasma ctDNA at Baseline, each visit thereafter, 
and at end of treatment to measure changes from Baseline in the levels of KIT, PDGFRα, 
and other cancer-relevant mutant allele fractions. 
7.5 
Efficacy Assessments 
7.5.1 
Disease Response Assessment 
Blinded central radiology review of disease response or disease progression (per Choi 
criteria and per mRECIST, version 1.1) will be based on local imaging scans performed 
at the time points outlined in Table 2. Note that tumor imaging should occur every 
8 weeks (± 1 week) from Cycle 1 Day 1 regardless of the scheduled treatment cycles ie, if 
study treatment is interrupted or discontinued for any reason, tumor imaging should 
continue according to an 8-week schedule until disease progression or death. 
Computed tomography with IV contrast of the chest, CT or MRI with IV contrast of the 
abdomen and pelvis will be performed at Screening. At subsequent timepoints, the 
abdomen, pelvis, and all other body regions that contained sites of disease (target or non-
target) at Screening will be imaged. Computed tomography of the chest is not required if 


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there were no sites of disease in the chest at Screening. Computed tomography with IV 
contrast is the preferred imaging modality, unless a site of disease is better evaluated by 
MRI. If a patient is not tolerant of IV contrast, non-contrast scans may be performed. For 
each patient, the same method of tumor imaging used at Baseline should be used 
throughout the study. 
Computed tomography and MRI scans will be reviewed locally at the study center, 
ideally by the same individual for each patient at each time point, and disease response 
and progression will be assessed per mRECIST, version 1.1. Computed tomography and 
MRI scans will also be collected and reviewed centrally to provide a central assessment 
of response and progression, both per mRECIST, version 1.1 and per Choi criteria. 
Patients on either treatment arm considered by local assessment to have disease 
progression shall not discontinue treatment until progression (per mRECIST, version 1.1) 
has been confirmed by central radiology review. Patients may only cross over from 
regorafenib treatment to avapritinib treatment if disease progression has been confirmed 
by central radiology review. 
7.5.2 
Central Radiology Review 
A blinded central radiology review will be performed according to a prospectively 
established central imaging charter and conducted by an external imaging contract 
research organization. The central radiology review will be chartered to evaluate response 
assessment independently per mRECIST, version 1.1. (Appendix 6) and per Choi criteria 
(Appendix 7).   
A detailed study-specific Imaging Core Manual will be made available to sites regarding 
scan acquisition requirements. All radiological scans acquired at all scheduled time points 
and any additional (unscheduled) radiological scans must be sent to the external imaging 
contract research organization. 
7.5.3 
Quality-of-Life Instruments 
Patients will complete the EORTC-QLQ-C30 at scheduled clinical site visits up to 
the EOT visit, as outlined in Table 2. These assessments are provided in Appendix 8 
(EORTC-QLQ-C30). 
7.5.4 
 
 
 
 
 


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7.6 
Crossover From Regorafenib to Avapritinib 
Patients who experience disease progression while receiving regorafenib (Arm B), as 
confirmed by central radiology review, may be offered the opportunity to cross over to 
the avapritinib treatment arm (Arm A). 
Patients who cross over to avapritinib must complete a washout period of 7 to 28 days 
after their last dose of regorafenib and consent to cross over before starting treatment 
with avapritinib. At the first study visit after the washout period, cross over patients will 
complete the C1D1 assessment schedule except for the following tests, which are not 
required: PK blood sample and biomarker plasma sample. Otherwise patients who 
crossed over will follow the same schedule of assessments as on the main portion of the 
Protocol (except C1D15 or C2D15 visits, which are not required). After patients cross 
over to treatment with avapritinib, ECGs will be performed following the same schedule 
as prior to cross over and AEs will only be assessed for their relationship to avapritinib. 
7.7 
Continuing Avapritinib After Disease Progression 
Patients who experience disease progression while receiving avapritinib (Arm A), as 
confirmed by central radiology review, may be offered the opportunity to continue 
treatment with avapritinib if the following criteria are met: 
•
There are no symptoms or signs indicating clinical disease progression (including
worsening of laboratory values).
•
The patient is not experiencing rapid progression of disease or a progressive tumor
requiring urgent alternative medical intervention at critical anatomical sites (eg,
spinal cord compression).
•
There has been no decline in ECOG PS
Patients randomized to Arm A must consent to continue avapritinib treatment after 
disease progression. This consent must be obtained after disease progression has 
occurred. 
7.8 
End-of-Treatment, Safety Follow-up and Progression-Free Survival 
Follow-up 
All patients will attend an EOT visit approximately 14 days (± 7 days) after the last dose 
of study drug (see Table 2 for a description of EOT assessments). If an alternative 
antineoplastic treatment is started within 14 days of the last dose of study drug, the EOT 
visit should be conducted before the first dose of the alternative antineoplastic therapy. 
Tumor assessment for EOT procedures do not need to be repeated if they were performed 
within 7 days (or within 28 days for disease response assessments). 
A Safety Follow-up visit (clinic visit or a phone call) for resolution of any ongoing AE 
will be made 30 days (± 7 days) after the last dose of study drug, or at the time the patient 
initiates another antineoplastic therapy. 


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Thereafter, patients without documented PD will be followed approximately every 
8 weeks (±7 days) until disease progression, death, initiation of new anti-GIST therapy, 
withdrawal of consent, or closure of the study by the Sponsor. 
7.9 
Survival Follow-up 
After documentation of disease progression by central radiology review, patients or their 
designated care giver will be contacted by phone every 2 months until withdrawal of 
consent, death, or closure of the study by the Sponsor to collect the drug name of any 
new systemic antineoplastic therapy or the date of death. 
7.10 Sample Processing, Storage, and Shipment 
Instructions for the processing, storage, and shipment of all study samples for central 
analysis will be provided in a separate study manual. 
Samples will be stored until analysis and remaining samples will be retained until 
10 years after completion of the study, or until the research is discontinued, whichever 
occurs first. 
8 STUDY DRUG MANAGEMENT 
8.1 
Description 
Both the investigational drug, avapritinib and the control drug, regorafenib, will be 
administered during this study. 
8.1.1 
Avapritinib 
Avapritinib immediate release tablets will be supplied as 100 mg strength, round tablets 
composed of roller-compacted, aesthetically film-coated pharmacopeial excipients. 
Avapritinib is for investigational use only and should only be used within the context of 
this study.  
8.1.1.1 
Storage 
Avapritinib tablets must be stored at room temperature in their original container, 
according to the package label. Refer to the label or certificate of analysis for expiry. 
All study drug products must be stored in a secure, limited-access location and may be 
dispensed only by the Investigator or by a member of the staff specifically authorized by 
the Investigator. 


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8.1.1.2 
Packaging and Shipment 
Avapritinib tablets will be supplied to the study center, packaged in 60 cc Wide Mouth 
Round high-density polyethylene bottles. Each bottle will be induction-sealed and capped 
with a 33 mm child-resistant closure. 
Packaging will meet all regulatory requirements. See the pharmacy manual for additional 
details. 
8.1.2 
Regorafenib 
Regorafenib will be provided to the study center as 40 mg strength tablets, packaged in 
bottles, and will be labeled according to local regulations. In the US, locally obtained 
commercial supplies of regorafenib may be used and reimbursed by the Sponsor. 
Regorafenib is to be stored in the original bottle at 25°C (77°F); excursions are permitted 
from 15°C to 30°C (59°F to 86°F). See Appendix 1 for additional details. 
8.2 
Accountability 
Accountability for the study drug at the study center is the responsibility of the 
Investigator. The Investigator will 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. 
The Investigator or delegate will maintain accurate drug accountability records indicating 
the drug’s delivery date to the site, inventory at the study center, use by each patient, and 
return to the Sponsor or its designee (or disposal of the drug, if approved by the Sponsor). 
These records will adequately document that the patients were provided the doses as 
specified in the protocol and should reconcile all study drug received from the Sponsor. 
Accountability records will include dates, quantities, batch/serial numbers, expiration 
dates (if applicable), and patient numbers. The Sponsor or its designee will review drug 
accountability at the study center on an ongoing basis during monitoring visits. 
Study drug must not be used for any purpose other than the present study. Study drug that 
has been dispensed to a patient and returned unused must not be re-dispensed to a 
different patient. 
Patients will receive instructions for home administration of avapritinib or regorafenib. 
All used, unused, or expired study drug will be returned to the Sponsor or its designee, or 
if authorized, disposed of at the study center per the center’s Standard Operating 
Procedures and documented. All material containing avapritinib or regorafenib will be 
treated and disposed of as hazardous waste in accordance with governing regulations. 
8.3 
Compliance 
Patients will be dispensed the appropriate number of study drug bottles to allow for 
dosing for a full cycle, or until the next scheduled visit. Patients are to return all unused 


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tablets (or the empty bottles) on D1 of each treatment cycle or at the next scheduled visit. 
Compliance with the dosing regimen will be assessed based on return of unused drug (or 
empty bottles). 
8.4 
Overdose 
Overdose includes any dose higher than the intended dose. Any instance of overdose 
(suspected or confirmed), irrespective of whether or not it involves any signs or 
symptoms, must be reported to the Sponsor within 24 hours of awareness of the incident. 
Details of dose taken, any signs or symptoms and their management should be recorded, 
including details of any antidote(s) administered. 
If the overdose incident resulted in AEs, these must be reported in accordance with the 
instructions in Section 9 of this protocol. 
The highest dose of avapritinib studied clinically is 600 mg QD; there is no known 
antidote for avapritinib overdose. In the event of suspected overdose, hold avapritinib 
dosing, institute supportive care, and observe until clinical stabilization. 
The highest dose of regorafenib studied clinically is 220 mg QD. The most frequently 
observed adverse drug reactions at this dose were dermatological events, dysphonia, 
diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and 
fatigue. There is no known antidote for regorafenib overdose. In the event of suspected 
overdose, interrupt regorafenib, institute supportive care, and observe until clinical 
stabilization. 
9 ADVERSE EVENTS 
9.1 
Definitions 
9.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a study patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign, symptom, or disease (new, 
or exacerbated pre-existing condition). 
Adverse events include the following: 
• All AEs, whether or not considered related to the use of study drug; 
• All AEs occurring in association to any medication overdose, medication error, drug-
drug interaction, abuse, withdrawal, sensitivity, or toxicity; 


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• Any new illness, whether or not considered related to study drug, and any 
worsening/exacerbation of chronic or intermittent pre-existing conditions, including 
either an increase in frequency and/or intensity of the condition; 
• Any injuries or accidents; 
• Clinically significant abnormal results (new occurrence or worsening of previously 
known) from laboratory and physiological tests or physical examinations. 
9.1.2 
Adverse Event due to Protocol Procedures 
An untoward medical occurrence in a study patient which is associated by the 
Investigator with protocol procedures (nondrug study drugs) is considered an AE, even if 
the patient was not exposed to study drug. 
9.1.3 
Serious Adverse Event 
An AE is assessed as SAE if, in the view of either the Investigator or the Sponsor, it 
results in any of the following outcomes (seriousness criteria): 
• Death:  An AE that results in death. 
NOTE: For AEs that result in ‘death’ the adverse event term describing the medical 
occurrence causing death should be reported with the outcome and seriousness 
criteria recorded as ‘death’. Only if the cause of death is unknown and no other 
medical occurrence is suspected to have caused or contributed to ‘death’, ‘death’ 
should be used as adverse event term. 
• Life-threatening:  An AE is life-threatening.  
NOTE: The term ‘life-threatening’ refers to an event in which the study patient was at 
risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it was more severe.  
• Inpatient hospitalization or prolongation of existing hospitalization: All AEs 
requiring hospitalization (in-patient or emergency department treatment) for more 
than 24 hours should be considered SAEs.  
NOTE: Hospitalization for elective surgery or routine clinical procedures that are not 
the result of AE (eg, elective surgery for a pre-existing condition that has not 
worsened) should not be reported as AE or SAE. Any untoward medical occurrence 
in temporal relationship to the procedure, however, must be reported as an AE, either 
'serious' or ‘nonserious’ according to protocol definitions.  
• Persistent or significant disability/incapacity: An AE is incapacitating or disabling 
if the experience results in a substantial and/or permanent disruption of the patient's 
ability to carry out normal life functions. 


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• Congenital anomaly/birth defect: A fixed, permanent impairment in the offspring 
of a patient (or patient’s partner) who received study treatment. 
• Medically important events: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent 1 of the outcomes listed in this definition. 
Examples of such events are: 
o Intracranial bleeding events. All events of intracranial bleeding should be reported 
as SAEs. 
o Intensive treatment in an emergency room or at home for allergic bronchospasm. 
o Blood abnormalities or convulsions that do not result in inpatient hospitalization. 
• Development of drug dependency or drug abuse 
9.2 
Grading of Severity Using NCI CTCAE 
Intensity of all AEs, including clinically significant laboratory abnormalities, will be 
graded according to the NCI CTCAE, version 5.0. Adverse events not specifically 
defined will be graded as follows: 
• Grade 1: Mild, the event is noticeable to the patient but does not interfere with routine 
activity. 
• Grade 2: Moderate, the event interferes with routine activity but responds to 
symptomatic therapy or rest. 
• Grade 3: Severe, the event significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy. 
• Grade 4: Life-threatening, an event in which the patient was at risk of death at the 
time of the event. 
• Grade 5: Fatal, an event that results in the death of the patient. 
9.3 
Relationship to Study Drug (Causality Assessment) 
All AEs must have their causal relationship to study drug (study drug and/or protocol 
procedures) assessed by the Investigator using a binary system. Causality is either 
assessed as ‘related’ or ‘not related’: 
• Related: The AE is known to occur with the study drug, there is a reasonable 
possibility that the study drug caused the AE, or there is a temporal relationship 
between the study drug and event. Reasonable possibility means that there is evidence 
to suggest a causal relationship between the study drug and the AE. 


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• Not Related: Exposure to the study drug did not occur, or AE does not follow a 
reasonable temporal sequence from administration of the product and/or there is no 
reasonable possibility that the drug caused the AE. This assessment includes 
situations where an alternative etiology has been established (eg, the AE is related to 
other factors such as the patient’s clinical state, other therapeutic interventions, or 
concomitant drugs administered to the patient).  
9.4 
Adverse Event Monitoring Period 
Adverse events will be recorded in the eCRF from the first dose of a study drug dose 
through 30 days after the last dose of any study drug. Serious AEs and serious 
pretreatment events (see Section 9.9) will be recorded in the eCRF from the time of 
signing informed consent through 30 days after the last study drug dose. In addition, 
SAEs that are assessed as related to study treatment that occur > 30 days post-treatment 
will also be reported. All related AEs and AEs relating to cognitive function and 
intracranial bleeding should be monitored until they are resolved, are stabilized, have 
returned to pre-exposure baseline, are determined to be due to another illness, or until a 
subsequent antineoplastic therapy is initiated, even if > 30 days post last dose of study 
drug. For AEs considered not related to study drug, similar monitoring guidelines will 
only be required through 30 days after the last dose of study drug. 
9.5 
Eliciting Adverse Event Information 
The occurrence of an AE or SAE may come to the attention of study personnel during 
study visits and interviews of a study patient presenting for medical care (or, when 
appropriate, be reported by a caregiver, surrogate, or the patient's legally authorized 
representative), or upon review by a study monitor.  
The Investigator is responsible to report all directly observed AEs/SAEs, including all 
those spontaneously reported by the patient which came to the attention of site personnel.  
In addition, each study patient will be questioned about adverse events at each visit 
following the initiation of treatment.  
9.6 
Adverse Event Reporting Conventions and Principles 
9.6.1 
Laboratory Values 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or interruption of treatment, dose modification, therapeutic intervention, 
or is considered by the Investigator to be clinically significant. A laboratory value may 
also be considered a SAE when it meets any of the seriousness criteria (see 
Section 9.1.3).   
9.6.2 
Preexisting Conditions 
A pre-existing condition (ie, a disorder present before the AE reporting period started and 
noted on the pretreatment medical history/physical examination form) should not be 


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reported as an AE unless the condition worsens, or episodes increase in frequency or 
severity during the AE reporting period. 
9.6.3 
Pre-Planned Therapeutic Procedures 
Pre-planned therapeutic procedures not associated with a new medical condition or 
worsening pre-existing condition should not be reported as AEs. 
9.6.4 
Disease Progression 
In general, disease progression should not be reported as an AE (or an SAE), or cause of 
death in this study. Instead the AEs (or SAEs) considered as complications of disease 
progression should be reported. However, if no specific complications of disease 
progression can be identified that explain the clinical observations, “disease progression” 
may be reported as an AE, SAE, or cause of death. 
9.6.5 
Lack of Efficacy 
Lack of efficacy per se will not be reported as an AE or SAE. Such instances will be 
captured in the efficacy assessments. However, the signs, symptoms, and/or clinical 
sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the 
definition of an AE or SAE.  
9.6.6 
Adverse Events NCI CTCAE Grade 5 
All AEs with NCI CTCAE Grades 5 should be reported as SAE. 
9.6.7 
Second Malignancies 
The occurrence of a second malignancy should be reported as SAE. 
9.6.8 
Special Situations 
Certain safety events, called ‘Special Situations’, that occur in association with study 
drug(s) may require reporting. These Special Situations include, but are not limited to, the 
following: 
• Overdose of the study drug 
• Suspected abuse/misuse of the study drug 
• Inadvertent or accidental exposure to the study drug by anyone other than the patient 
• Medication error involving the study drug (with or without patient exposure to the 
Sponsor study drug, eg, name confusion) 
• Drug-drug interaction. 


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Special situations should be reported on the Special Situations CRF whether they result in 
an AE/SAE or not. Special situations with associated AE/SAE should also be reported on 
the corresponding AE/SAE forms, following applicable AE or SAE process. 
9.6.9 
Exposure in Utero and Pregnancy 
• A pregnancy in a female patient must be confirmed by a positive serum β human 
chorionic gonadotropin (β-HCG) test. 
• The study medication should be immediately discontinued once the pregnancy of a 
female study patient has been confirmed. 
• If any study patient or female partner of a male patient becomes or is found to be 
pregnant while receiving study drug or within 30 days of discontinuing the study 
medication, the pregnancy must be recorded on the Pregnancy Report Form/Exposure 
in Utero Form in the electronic data capture within 24 hours of awareness of the 
pregnancy. 
• If a female partner of a male patient becomes pregnant, the male patient should notify 
the Investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately. 
• The Investigator must follow up and document the course and outcome of all 
pregnancies even if the patient was discontinued from the study or if the study has 
finished. The female patient should receive any necessary counseling regarding the 
risks of continuing the pregnancy and the possible effects on the fetus. Monitoring 
should continue until conclusion of the pregnancy. 
• All outcomes of pregnancy must be reported by the Investigator to the Sponsor or 
Medical Monitor on a Pregnancy Outcome Report form within 24 hours after he/she 
has gained knowledge of the delivery or elective abortion.  
• All neonatal deaths that occur within 1 month after birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 1 month that the 
Investigator assesses as related to the in-utero exposure to the study medication 
should also be reported. 
• Pregnancy is neither an AE nor an SAE, unless a complication relating to the 
pregnancy occurs (eg, spontaneous abortion, which may qualify as an SAE). 
• Any SAE that occurs during the pregnancy of a study patient must be recorded on the 
SAE report form (eg, maternal serious complications, spontaneous or therapeutic 
abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, or birth 
defect) and reported within 24 hours in accordance with the procedure for reporting 
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9.7 
Adverse Event Collection and Reporting 
The Investigator or qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study drug or study 
procedures, or that caused the patient to discontinue study drug.  
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• All AEs/SAEs must be assessed by the Investigator for seriousness (see Section 9.1.3) 
and causality (see Section 9.3). 
• The Investigator will then record all relevant AE/SAE information in the CRF. Any 
laboratory assessments or other clinical findings considered an AE must be recorded 
on the AE page as well as the appropriate assessment page of the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the patient’s medical 
records in lieu of completion of the respective AE/SAE CRF pages. 
• There may be instances when copies of medical records for certain cases are 
requested. In this case, all patient identifiers, with the exception of the patient 
number, will be redacted on the copies of the medical records before submission to 
the requestor. 
• For SAEs, additional conventions apply as outlined in Section 9.9. 
9.8 
Adverse Event Electronic Data Capture 
All AEs, including SAEs, are to be accurately recorded on the AE page of the eCRF. 
Information to be recorded in the description of each AE (serious and non-serious) 
includes: 
• A medical diagnosis of the event (If a medical diagnosis cannot be determined, a 
description of each sign or symptom characterizing the event should be recorded.) 
• The date of onset of the event 
• The date of resolution of the event 
• Whether the event is serious or not 
• Intensity of the event (see Section 9.2) 
• Relationship of the event to study drug (see Section 9.3) 


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• Action taken: none; change in the study drug administration (eg, temporary 
interruption in intervention); drug treatment required; nondrug treatment required; 
hospitalization or prolongation of hospitalization required (complete SAE page); 
diagnostic procedure performed; patient discontinued from the study (complete End 
of Study visit) 
• Outcome: patient recovered without sequelae; patient recovered with sequelae; event 
ongoing; patient died. If this occurs, notify the Medical Monitor immediately. and 
complete the SAE form. 
9.8.1 
Follow-Up of Unresolved Events 
All related AEs and AEs relating to cognitive function and intracranial bleeding should 
be monitored until they are resolved, have stabilized, have returned to pre-exposure 
baseline, are determined to be due to another illness, or until a subsequent therapy is 
initiated even if > 30 days from last dose of study drug. For AEs considered not related to 
study drug, similar monitoring guidelines will only be required through 30 days after the 
last dose of study drug. If the patient withdraws from treatment because of an AE, every 
effort must be made to perform protocol-specified safety follow-up procedures, as 
outlined in Section 7.8. 
In the event a patient is withdrawn from study drug or the follow-up part of the study, the 
Medical Monitor must be informed. If there is a medical reason for withdrawal, the 
patient will remain under the supervision of the Investigator or designee until the 
condition has returned to baseline or stabilized. 
9.9 
Reporting Serious Adverse Events 
All SAEs or serious pretreatment events that occur during the AE monitoring period (see 
Section 9.4) must be reported by the Investigator to the Sponsor or its designee within 
24 hours from the point in time when the Investigator becomes aware of the SAE. In 
parallel, the eCRF pages for the AE should also be completed. The same 24-hour timeline 
applies for any follow-up information received by the Investigator. 
NOTE: Compliance with this time requirement is essential so that the Sponsor may 
comply with its regulatory obligations. 
All SAEs must be reported whether or not they are considered causally related to study 
treatment.  
SAE forms will be completed in English language and should contain, at a minimum: 
• Patient number/ID, sex, and age/year of birth 
• The date of the report 
• Name of the Investigator 


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•
Name of the suspected study drug
•
Assessment of event severity/intensity (and/or NCI CTCAE Grade)
•
Investigator causality assessment
•
A description of the event, including event term(s), seriousness criteria, and a clinical
summary of the event
•
SAEs with outcome ‘death’: cause of death, autopsy or death certificate, as applicable
and available
Refer to the study manual for reporting instructions. 
9.10 Regulatory and Institutional Reporting Responsibilities 
The Sponsor and/or its designee are responsible for reporting SAEs to all applicable 
regulatory agencies and the central ethics committees within the required timeline. 
The Investigators are responsible for submitting required safety information to their local 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) as per local 
regulations. This information includes, but is not limited to, any safety alert letter 
received from the Sponsor and any SAEs occurring at their investigative site. 
For patients who are screen failures (ie, sign informed consent, did not meet eligibility 
criteria, and therefore did not receive study drug), SAEs should be collected up to 
30 days after signing informed consent. 
10 STATISTICS 
10.1 General Procedures 
All tabular summaries will be presented by treatment arm. Continuous variables will be 
summarized using descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum). Categorical variables will be summarized showing the number and 
percentage (n, %) of patients within each category. Appropriate CIs will also be 
presented. All data will be provided in by-patient listings. 
Efficacy, safety, and PK will be assessed in the appropriate populations. 
10.2 Sample Size Estimation 
A total of approximately 460 patients will be needed for the study. Patients will be 
recruited from approximately 90 sites and it is expected that each site will enroll about 
3-10 patients.
The sample size calculation was based upon the assumption that the median PFS for 
regorafenib is approximately 5 months (Stivarga, 2017). Assuming avapritinib can reduce 


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the risk of PFS by 33%, ie, assuming the HR of 0.67 (avapritinib compared to 
regorafenib), a minimum of 264 PFS events are needed to provide 90% power at a 2-
sided alpha of 0.05 for the study. With an 18-month accrual period and a 6-month follow-
up period, the total sample size needed for the study is approximately 460 patients 
(230 patients per arm) in order to achieve 264 total PFS events. The sample size 
calculation has taken a 2% dropout rate into consideration and assumes accrual will 
follow a truncated exponential distribution with a scaled power parameter -9. 
The sample size calculated for the primary endpoint, PFS, is also sufficient for detecting 
a difference in ORR between the two arms. Assuming a null ORR of 5% and an 
alternative ORR of 15%, approximately 95% power is obtained using a test of two-
proportions. 
We assume the same effect size for OS as for PFS, hence the same number of 
events (264) is required to power the analysis. The timing of the OS analysis, however 
shall be later than the PFS analysis as it will be at such time that 264 deaths occur. 
Gate keeping sequential testing will be implemented to test PFS, then ORR, and then OS. 
10.3 Analysis Populations 
The following analysis populations will be used for presentation of the data: 
•
Intent-to-treat (ITT) Population: The ITT population includes all randomized patients,
independent of whether they received the study medication or not. All primary
efficacy analyses will be based on the ITT population. All patients in the ITT
population will be analyzed according to the treatment they were randomized to
receive and not according to what they actually received, if different.
•
Per-Protocol (PP) Population: The PP population includes all patients in the ITT
population who have no major violations of the inclusion/exclusion criteria. Patients
in this population will be analyzed according to the treatment to which they are
randomized. The analyses using data from the PP population are considered
supportive and sensitivity analyses.
•
Response-Evaluable (RE) Population: The response-evaluable population is defined
as all patients in the ITT population who received at least 1 dose of avapritinib or
regorafenib, have at least 1 target lesion per mRECIST, version 1.1, at Baseline and
have at least 1 postbaseline disease assessment by central radiology per mRECIST,
version 1.1. Selected efficacy analysis may be performed using the RE population.
•
Safety Population: The safety population is defined as all patients who received at
least 1 dose of study medication. The safety population will be analyzed according to
the treatment the patient actually received.
•
PK Population: The PK population is defined as all patients who have adequate PK
samples collected so that the PK parameters can be assessed and calculated.


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10.4 Randomization and Stratification 
Eligible patients will be randomized in a 1:1 ratio to receive avapritinib or regorafenib, 
stratified by line of therapy (third vs. fourth), geographic region (Asia vs. rest of the 
world), and mutation status measured in ctDNA or a tumor sample (PDGFRα D842V 
mutation present vs. absent). The randomization scheme will be generated by an 
independent statistical group. The randomization assignment will be implemented by an 
IWRS. 
10.5 Statistical Methods 
10.5.1 
Disposition 
A tabulation of the disposition of patients will be presented by treatment arm, including 
the number of patients randomized, patient distribution for each stratification factor, the 
number treated, the reasons for treatment discontinuation, and the reasons for study 
discontinuation. Entry criteria and protocol deviations will be listed. 
10.5.2 
Demographic and Baseline Characteristics 
Demographic and baseline disease characteristic data will be presented by treatment arm. 
Data to be tabulated will include sex, age, and race and ethnicity, as well as disease-
specific information. 
10.5.3 
Efficacy Analysis 
10.5.3.1 
Analysis of the Primary Efficacy Endpoint 
The primary endpoint of PFS is defined as the time from randomization to disease 
progression or death due to any cause, whichever occurs first. The primary analysis for 
PFS is based on the central radiological assessment of PD per mRECIST, version 1.1 in 
the ITT population.  
Patients without disease progression or death at the time of analysis will be censored at 
their last date of tumor evaluation. Patients who withdraw from the study and receive 
subsequent antineoplastic therapy without documented PD will be censored at the time of 
the last adequate (CT or MRI scan available) disease assessment. For PD documented 
between scheduled evaluations, the actual date of PD will be used, not the date of the 
next scheduled evaluation. For death or PD after no more than 1 missed evaluation, the 
date of the event will be the date of PD or death, whichever occurs first. For death or PD 
after more than 1 missed evaluation, the date of the event will be censored at the last 
adequate disease assessment. Detailed censoring methods will be described in the 
statistical analysis plan (SAP). 
The Kaplan-Meier method will be used to estimate the distribution of PFS for each 
treatment group. The primary treatment comparison is based on a stratified log-rank test 
in the ITT population. The HR, and its 95% CI, are to be estimated based on a stratified 
Cox’s model with treatment as the explanatory variable. Stratification factors include TKI 


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treatment (third vs. fourth), geographic region (Asia vs. rest of the world), and mutation 
status measured in ctDNA or a tumor sample (PDGFRα D842V mutation present vs. 
absent). 
Progression-free survival derived from the Investigator assessment per mRECIST, 
version 1.1 in the ITT population, and from central radiological assessment per Choi 
criteria in the ITT population will be evaluated and used as supportive evidence. The 
analysis of PFS based on the PP population will also be included as a sensitivity analysis. 
10.5.3.2 
Analyses of Secondary Efficacy Endpoints 
10.5.3.2.1 
Objective Response Rate 
Objective response rate is defined as the percentage of patients whose best response is 
CR or PR as assessed by central radiological assessment according to mRECIST, 
version 1.1. The ORR will be evaluated and analyzed for the ITT population. 
Objective response rate will be summarized for each treatment group. A stratified 
Cochran-Mantel-Haenszel (CMH) test will be performed to test treatment difference. A 
logistic regression model will be used to estimate the treatment effect measured in terms 
of odds ratios. The odds ratio and its 95% CI will be presented. 
A gate-keeping method will be implemented to control Type I error. The ORR will be 
analyzed when superiority is demonstrated for PFS.  
Additionally, response as assessed by investigator per mRECIST, version 1.1 and 
response based on central radiology per Choi criteria will be evaluated and analyzed for 
the ITT population as supportive analysis. All the proposed response assessments will be 
examined based on the response-evaluable population and/or per protocol population, as 
sensitivity analyses. 
10.5.3.2.2 
Overall Survival 
Overall survival is defined as the time from date of randomization to death due to any 
cause. The primary treatment comparison will be based on a rank preserving structural 
failure time (RPSFT) model to account for treatment crossover effects from regorafenib 
to avapritinib. The survival time gained/lost by receiving avapritinib after crossover in 
the regorafenib group will be estimated. Rank preserving structural failure time 
reconstructs the survival duration of patients as if they had never received avapritinib, 
assuming treatment is acting by multiplying survival time by a given factor once a patient 
starts receiving avapritinib (Korhonen et al, 2012). 
If the patient is alive or the vital status is unknown at the time of analysis, OS will be 
censored at the date the patient is last known to be alive. The Kaplan-Meier method will 
be used to estimate the distribution of OS for each treatment group. The HR and its 95% 
CI will be estimated based on Cox’s regression model with stratification factors as 
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In addition, the probability of survival by time after randomization based on Kaplan-
Meier estimates will be tabulated for each treatment group along with the standard errors 
estimated by the Greenwood formula. 
A gate-keeping method will be implemented to control Type I error. The OS will be 
analyzed when superiority is demonstrated for both PFS and ORR. The OS will also be 
analyzed at the follow-up when 264 events (deaths) occur. 
A sensitivity analysis will be conducted in the ITT population where treatment crossover 
is ignored. Other sensitivity analyses may be considered as appropriate. 
10.5.3.2.3 
Analyses of Health-Related Quality-of-Life 
The EORTC-QLQ-C30 questionnaire will be used to collect data on the patient’s 
functioning, disease-related symptoms, and health-related QoL. For all individual scores, 
eg, physical functioning, pain, role functioning, and appetite loss, etc, mean changes from 
baseline to Week 12 will be compared between treatment groups by a t-test. Post hoc 
analyses to explore thresholds for meaningful change using cumulative distribution 
function to determine clinical benefit will be outlined in the SAP. 
10.5.3.2.4 
Disease Control Rate 
Disease control is defined as rate of CR or PR of any duration, or SD lasting for at least 
16 weeks per mRECIST version 1.1 from the beginning of treatment. Disease control rate 
will be analyzed similarly as the ORR.  
10.5.3.2.5 
Duration of Response 
Duration of response (CR or PR) is calculated from the date of initial documentation of a 
response to the date of first documentation of PD or death due to any cause. Censoring 
rules for DOR will be similar to those for PFS. 
The Kaplan-Meier method will be used to descriptively summarize DOR. No inferential 
statistics will be performed. 
 
 
 
 
 
  
 
 
 


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10.5.4 
Exposure and Safety Analyses 
A summary of study drug exposure, including total dose, duration of treatment, dose 
intensity, and the proportion of patients with dose modifications will be summarized by 
treatment arm. Reasons for dose modifications will be listed by patient and summarized. 
Safety will be evaluated by the incidence of AEs, causality, intensity, seriousness, and 
type of AEs, and by the patient’s vital signs, ECOG PS scores, clinical laboratory test 
results, and ECG data. 
Concomitant medications will be listed by patient and will be summarized by treatment 
arm.  
All safety data will be summarized by treatment arm for the safety population. 
10.5.4.1 
Adverse Events 
Summary tables and listings for AEs will include TEAEs, where an AE is defined as any 
TEAE that occurred between the first dose of a study drug through 30 days after the last 
dose of any study drug. The incidence of TEAEs (new or worsening from Baseline) will 
be summarized according to the Medical Dictionary for Regulatory Activities (MedDRA) 
by system organ class and/or preferred term, intensity (based on NCI CTCAE version 5.0 
grading as assessed by the Investigator), seriousness, and relation to study treatment. The 
following summaries will be produced: 
•
All AEs
•
AEs leading to dose modifications
•
Treatment-related AEs
•
Grade 3 or higher AEs
•
Grade 3 or higher treatment-related AEs
•
Most commonly reported AEs (ie, those events reported by ≥ 10% of patients in
either treatment group)
•
SAEs
•
Treatment-related SAEs
•
Discontinuations due to AEs
By-patient listings will be provided for on-treatment deaths (on-treatment is defined as 
the period starting from the first dose to 30 days after the last dose), AEs, SAEs, and AEs 
leading to discontinuation of treatment. 


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10.5.4.2 
Laboratory Abnormalities 
For laboratory tests included in the NCI CTCAE version 5.0, laboratory data will be 
graded accordingly; a Grade 0 will be assigned for all non-missing values not graded as 1 
or higher. 
The following summaries will be generated separately for hematology, serum chemistry 
and coagulation studies, and urinalysis laboratory tests: 
•
Descriptive statistics for the actual values and/or change from Baseline of clinical
laboratory parameters over time.
•
Shift tables using NCI CTCAE grades to compare baseline to the worst on-treatment
value.
•
Listing of all laboratory data with values flagged to show the corresponding NCI
CTCAE grades.
In addition to the above-mentioned tables and listings, graphical displays of key safety 
parameters, such as scatter plots of actual values or change in laboratory test results over 
time or box plots may be specified in the SAP. 
10.5.4.3 
Other Safety Data 
Descriptive statistics for the actual values and/or the changes from Baseline of vital signs 
(including systolic and diastolic blood pressure, heart rate, and temperature) over time 
will be summarized.  
Descriptive statistics of ECOG PS over time will be summarized by frequency. 
Descriptive statistics for the actual values and changes from Baseline in ECG data over 
time will be summarized. In addition, a categorical analysis of QTcF intervals may be 
performed for each time point. Maximum QTcF intervals and maximum changes from 
Baseline may also be summarized similarly in a separate display. ECG abnormalities will 
be presented in a data listing. 
Additional safety analyses may be performed if deemed necessary. 
10.5.5 
Pharmacokinetics Analyses 
Avapritinib plasma concentration-time data for individual subjects in each cycle along 
with descriptive statistics will be summarized. 
Mean and individual subject predicted avapritinib exposure parameters (Cmax, AUC0-24, 
and Ctrough) from the PopPK model will be summarized, as appropriate. 


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10.5.6 
Analyses of the Exploratory Endpoints 
Baseline KIT, PDGFRα, and other cancer-relevant mutation status will be correlated with 
antineoplastic activity (PFS, ORR, DCR, OS) by analysis of ctDNA. 
Changes in KIT, PDGFRα and other cancer-relevant mutant allele fractions in ctDNA 
will be correlated with measures of antineoplastic activity (PFS, ORR, DCR, OS). 
For all other biomarker data, summary statistics and graphs will be provided as 
appropriate. Relationships between biomarker data and efficacy measures will be 
descriptively analyzed, as appropriate. 
11 ETHICS AND RESPONSIBILITIES 
11.1 Good Clinical Practice 
The study will be conducted in accordance with the International Council for 
Harmonisation (ICH) GCP guidelines and the appropriate regulatory requirement(s). The 
Investigator will be thoroughly familiar with the appropriate use of the study drug as 
described in the protocol and IB. Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. Master files 
should be established at the beginning of the study, maintained for the duration of the 
study, and retained according to the appropriate regulations. 
11.2 Independent Data Monitoring Committee 
A formal IDMC will be used for this study. The roles and responsibilities of the IDMC 
are listed below. Further details will be described separately in the IDMC charter. 
The IDMC is composed of 3 members, 2 oncologists with expertise in the treatment of 
patients with GIST, and a statistician with expertise in clinical trials. The members of the 
IDMC and their academic affiliation are the following: 
 
 
 
 
 
 
 
 
 
The aim of the committee is to safeguard the interests of trial participants, monitor the 
main outcome measures including safety and efficacy, and monitor the overall conduct of 
the trial. 


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The IDMC will receive and review information on the progress and accumulating data of 
this study and provide advice on the conduct of the study. 
The IDMC will make recommendations to the Blueprint Study Management Group and 
the Study Steering Committee regarding the following aspects of the study; as is relevant 
in regard to the study design: 
•
whether it is ethical to continue randomizing patients when there is compelling
evidence that the risk/benefit ratio favors one of the arms over the other or
conversely, where there is compelling evidence of futility (ie, that the study will
never lead to concluding against the null hypothesis) following protocol-defined
stopping rules.
•
whether the results of all or some of the study endpoints should be published or
presented publicly earlier than anticipated, ie, before study maturity.
•
whether a modification should be made to the study for safety reasons, for example, a
modification of the eligibility criteria when the risk/benefit ratio seems unfavorable in
specific subgroups of patients.
•
on early termination of a trial when the scientific value of the trial is insufficient,
either because of compelling external evidence regarding the hypothesis being tested
or because the trial will not be able to produce scientifically valid results due to lack
of accrual or lack of quality.
•
on modifications to the study sample size.
•
on actions needed to manage identified issues related to patient compliance or study
feasibility and/or quality.
The role of the IDMC is to perform interim reviews of the study’s progress including 
adherence to protocol, follow-up assessments, primary efficacy outcomes, and safety 
data. 
Specifically, this role includes: 
•
monitoring evidence for treatment harm (eg, toxicity, SAEs, deaths).
•
assessing the impact and relevance of external evidence.
•
deciding whether to recommend that the study continues to recruit participants or
whether recruitment should be terminated either for everyone or for some treatment
groups and/or some participant subgroups.
•
deciding whether study follow-up should be stopped earlier.
•
maintaining confidentiality of all study information that is not in the public domain.


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•
considering the ethical implications of any recommendations made by the IDMC.
•
monitoring planned sample size assumptions, preferably with regards to (i) a priori
assumptions about the control arm outcome and/or (ii) emerging differences in
clinically relevant subgroups, rather than on emerging, un-blinded differences
between treatment groups, overall.
•
suggesting additional data analyses if necessary.
•
advising on protocol modifications proposed by the Investigators or the Sponsor (eg,
to inclusion criteria, study endpoints, or sample size).
•
monitoring compliance with previous IDMC recommendations
11.3 Institutional Review Board/Independent Ethics Committee 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. 
The Investigator must obtain IRB/IEC approval for the investigation and must submit 
written documentation of the approval to the Sponsor before he or she can enroll any 
patient into the study. The IRB/IEC will review all appropriate study documentation in 
order to safeguard the rights, safety, and well-being of the patients. The study will only 
be conducted at study centers where IRB/IEC approval has been obtained. The protocol, 
IB, informed consent, advertisements (if applicable), written information given to the 
patients, safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC. The IRB/IEC is to be notified of any amendment to the 
protocol in accordance with local requirements. Progress reports and notifications of 
serious unexpected adverse drug reactions will be provided to the IRB/IEC according to 
local regulations and guidelines. 
11.4 Informed Consent 
The Investigator at each study center will ensure that the patient is given full and 
adequate oral and written information about the nature, purpose, possible risk, and benefit 
of the study. Patients must also be notified that they are free to discontinue from the study 
at any time. The patient should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
The patient’s signed and dated informed consent must be obtained before conducting any 
study-related procedures. The Investigator must maintain the original, signed consent 
form. A copy of the signed form must be given to the patient. 
The method of obtaining and documenting the informed consent and the contents of the 
consent will comply with ICH GCP and all applicable regulatory requirement(s). 


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11.5 Records Management 
All data for the patients recruited for the trial will be entered onto the eCRFs via an 
Electronic Data Capture system provided by the Sponsor or designee. Only authorized 
staff may enter data into the eCRFs. If an entry error is made, the corrections to the 
eCRFs will be made according to eCRF guidelines by an authorized member of the center 
staff. 
Electronic case report forms will be checked for correctness against source document 
data by the Sponsor’s monitor. If any entries into the eCRF are incorrect or incomplete, 
the monitor will ask the Investigator or the study center staff to make appropriate 
corrections, and the corrected eCRF will again be reviewed for completeness and 
consistency. Any discrepancies will be noted in the eCRF system by means of electronic 
data queries. Authorized study center staff will be asked to respond to all electronic 
queries according to the eCRF guidelines. 
11.6 Source Documentation 
Source documents/eCRFs will be completed for each study patient. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in 
the patient’s source document/eCRF. The source document/eCRF should indicate the 
patient’s participation in the study and should document the dates and details of study 
procedures, AEs, and patient status. 
The Investigator, or designated representative, should complete the source 
document/eCRF as soon as possible after information is collected, preferably on the same 
day that a study patient is seen for an examination, treatment, or any other study 
procedure. Any outstanding entries must be completed immediately after the final 
examination. An explanation should be given for all missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the source 
document/eCRF to endorse the recorded data.  
The Investigator will retain all completed source documents. 
11.7 Study Files and Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s). Records will be retained by the sponsor for at least 25 years 
after the last marketing application approval in major markets (ie, US, EU, Japan, 
Canada) or 2 years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirement(s). If the 
Investigator withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person willing to accept the responsibility. The Sponsor must be 
notified in writing if a custodial change occurs. 


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11.8 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. 
12 AUDITING AND MONITORING 
The study will be monitored by the Sponsor or its designee. Monitoring will be done by 
personal visits from a representative of the Sponsor (site monitor) and will include on-site 
review of the source documents/eCRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters. The review of medical 
records will be performed in a manner to ensure that patient confidentiality is maintained. 
The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent communications. 
All unused study drug and other study materials should be destroyed or returned to the 
Sponsor or designee after the study has been completed, as directed by the Sponsor. 
Regulatory authorities, the IRB/IEC, and/or the Sponsor’s clinical quality assurance 
group or designee may request access to all source documents, eCRFs, and other study 
documentation for an on-site audit or inspection. Direct access to these documents must 
be guaranteed by the Investigator, who must provide support at all times for these 
activities. 
13 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, 
may be made only by Blueprint Medicines. A protocol change intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the Investigator must await 
approval before implementing the changes. Blueprint Medicines will submit protocol 
amendments to the appropriate regulatory authorities for approval. 
If, in the judgment of the IRB/IEC, the Investigator, and/or Blueprint Medicines, the 
amendment to the protocol substantially changes the study design and/or increases the 
potential risk to the patient and/or has an impact on the patient’s involvement as a study 
participant, the currently approved written informed consent form will require similar 
modification. In such cases, informed consent will be renewed for patients enrolled in the 
study before continued participation. 


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14 STUDY REPORT AND PUBLICATIONS 
Blueprint Medicines is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication policy of Blueprint Medicines is discussed in the Investigator's Clinical 
Research Agreement. 
15 STUDY DISCONTINUATION  
Both Blueprint Medicines and the Investigator reserve the right to terminate the study at 
the Investigator’s site at any time. Should this be necessary, Blueprint Medicines or a 
specified designee will inform the appropriate regulatory authorities of the termination of 
the study and the reasons for its termination, and the Investigator will inform the 
IRB/IEC of the same. In terminating the study, Blueprint Medicines and the Principal 
Investigator will assure that adequate consideration is given to the protection of the 
patients’ interests. 
16 CONFIDENTIALITY 
All information generated in this study is considered confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Blueprint Medicines. However, authorized regulatory officials, 
IRB/IEC personnel and Blueprint Medicines and its authorized representatives are 
allowed full access to the records. 
Identification of patients and eCRFs shall be by initials (when permitted) and screening 
and treatment numbers only. 


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17 REFERENCES 
Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, et al. Acquired resistance to imatinib 
in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 
2005;11(11):4182-90. 
Cassier PA, Fumagalli E, Rutkowski P, Schoffski P, Van Glabbeke M, Debiec-Rychter M, et al. Outcome 
of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the 
tyrosine kinase inhibitor era. Clin Cancer Res. 2012;18(16):4458-64. 
Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, et al. PDGFRA mutations in 
gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 
2005;23(23):5357-64. 
CTFG. Recommendations related to contraception and pregnancy testing in clinical trials [Online]. 2014: 
Clinical Trial Facilitation Group. 
Dagher R, Cohen M, Williams G, Rothmann M, Gobburu J, Robbie G, et al. Approval summary: imatinib 
mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin 
Cancer Res. 2002;8(10):3034-8. 
Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, et al. KIT 
mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J 
Cancer. 2006;42(8):1093-103. 
Demetri GD, Benjamin R, Blanke CD, Choi H, Corless C, DeMatteo RP, et al. NCCN Task Force report: 
optimal management of patients with gastrointestinal stromal tumor (GIST)--expansion and update of 
NCCN clinical practice guidelines. J Natl Compr Canc Netw. 2004;2 Suppl 1:S-1-26; quiz 27-30. 
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of 
regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an 
international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013a;381(9863):295-302. 
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Supplement to: Demetri 
GD, Reichardt P, Kang Y-K, et al, on behalf of all GRID study investigators. Efficacy and safety of 
regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an 
international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 
2013b;381(9863):Webappendix material. 
Gleevec. Package Insert. 2016. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation. 
Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, and Hogendoorn PC. Incidence of 
gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer. 
2005;41(18):2868-72. 
Heinrich M, Jones R, von Mehren M, Schoffski P, Bauer S, Mir O, et al. GIST: imatinib and beyond 
Clinical activity of BLU-285 in advanced gastrointestinal stromal tumor (GIST). In American Society of 
Clinical Oncology Annual Meeting. 2017. 
Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations 
and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 
2003;21(23):4342-9. 
Kang YK, Ryu MH, Yoo C, Ryoo BY, Kim HJ, Lee JJ, et al. Resumption of imatinib to control metastatic 
or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a 
randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1175-82. 


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Korhonen P, Zuber E, Branson M, Hollaender N, Yateman N, Katiskalahti T, et al. Correcting overall 
survival for the impact of crossover via a rank-preserving structural failure time (RPSFT) model in the 
RECORD-1 trial of everolimus in metastatic renal-cell carcinoma. J Biopharm Stat. 2012;22(6):1258-71. 
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;216(1):64-74. 
Miettinen M, and Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, 
prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130(10):1466-78. 
Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, et al. Gastrointestinal 
stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate 
era--a population-based study in western Sweden. Cancer. 2005;103(4):821-9. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
Ozer-Stillman I, Strand L, Chang J, Mohamed AF, and Tranbarger-Freier KE. Meta-analysis for the 
association between overall survival and progression-free survival in gastrointestinal stromal tumor. Clin 
Cancer Res. 2015;21(2):295-302. 
Rammohan A, Sathyanesan J, Rajendran K, Pitchaimuthu A, Perumal SK, Srinivasan U, et al. A gist of 
gastrointestinal stromal tumors: A review. World J Gastrointest Oncol. 2013;5(6):102-12. 
Stivarga. Package Insert. 2017. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc. 
Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, et al. Polyclonal 
evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with 
imatinib mesylate. Clin Cancer Res. 2006;12(6):1743-9. 
Yoo C, Ryu MH, Jo J, Park I, Ryoo BY, and Kang YK. Efficacy of Imatinib in Patients with Platelet-
Derived Growth Factor Receptor Alpha-Mutated Gastrointestinal Stromal Tumors. Cancer Res Treat. 
2016;48(2):546-52. 


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18 APPENDICES 
18.1 Appendix 1 
REGORAFENIB LABELING INFORMATION 
US prescribing information for regorafenib is available at: 
http://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf. 
The Summary of Product Characteristics for regorafenib is available 
at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002573/WC500149164.pdf 
Canadian prescribing information for regorafenib is available 
at: https://omr.bayer.ca/omr/online/stivarga-pm-en.pdf. 


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18.2 Appendix 2 
PRESPECIFIED DOSE MODIFICATIONS FOR ADVERSE EVENTS 
RELATED TO REGORAFENIB 


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Prespecified dose modifications for adverse events related to study drug excluding hand–foot skin reaction, hypertension, and 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin increases 
National Cancer Institute Common 
Terminology Criteria for Adverse Events, 
version 5.0 (NCI-CTCAE v5.0) Grade 
Dose Interruption 
Dose Modificationa 
Dose for Subsequent Cycles 
Grade 0–2 
Treat on time 
No change 
No change 
Grade 3 
Delay until ≤ Grade 2b 
Reduce by 1 dose levelc 
If toxicity remains ≤ Grade 2, dose re-
escalation can be considered at the 
discretion of the treating investigator. If 
dose is re-escalated and toxicity (≥ Grade 3) 
recurs, institute permanent dose reduction 
Grade 4 
Delay until ≤ Grade 2b 
Reduce by 1 dose level. 
Permanent discontinuation can be considered at treating investigator’s discretion 
a Not for alopecia, non-refractory nausea/vomiting, non-refractory hypersensitivity, and asymptomatic laboratory abnormalities. 
b Patients requiring a delay of > 56 days should discontinue protocol therapy. 
c Dose level 0 = 160 mg, dose level –1 = 120 mg, dose level –2 = 80 mg. 
Source: (Demetri et al, 2013b) 


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Prespecified Dose Modifications for Treatment-related Hand–foot Skin Reaction 
Skin Toxicity Grade 
(according to NCI-CTCAE v5.0 “Palmar–
plantar erythrodysesthesia syndrome”) 
Occurrence 
Suggested dose modification (more liberal 
management is allowed if judged medically 
appropriate by the Investigator) 
Grade 1: Minimal skin changes or dermatitis (e.g., 
erythema, edema, or hyperkeratosis) without pain 
Any 
Maintain dose level and immediately institute 
supportive measures for symptomatic relief 
Grade 2: Skin changes (e.g., peeling,blisters, 
bleeding, fissures, edema, or hyperkeratosis) with 
pain; limiting instrumental activities of daily living 
1st occurrence 
Consider decreasing dose by 1 dose levela and 
immediately institute supportive measures. If there 
is no improvement, interrupt therapy for ≥ 7 days, 
until toxicity resolves to Grade 0–1b 
No improvement within 7 days or 2nd occurrence 
Interrupt therapy until toxicity resolves to 
Grade 0–1. Resume treatment at reduced dose 
levelb 
3rd occurrence 
Interrupt therapy until toxicity resolves to 
Grade 0–1. On resuming treatment, decrease dose 
by one additional dose levela,c 
4th occurrence 
Discontinue treatment 
Grade 3: Severe skin changes (e.g., peeling, 
blisters, bleeding, fissures, edema, 
orhyperkeratosis) with pain; limiting self-care 
activities of daily living  
1st occurrence 
Institute support measures immediately. Interrupt 
therapy for ≥ 7 days until toxicity resolves to 
Grade 0–1. On resuming treatment, decrease dose 
by one dose levela 
2nd occurrence 
Institute support measures immediately. Interrupt 
therapy for ≥ 7 days until toxicity resolves to 
Grade 0–1. On resuming treatment, decrease dose 
by one additional dose levela,c 
3rd occurrence 
Discontinue treatment permanently 
a Dose level 0 = 160 mg, dose level –1 = 120 mg, dose level –2 = 80 mg. 
b If toxicity returns to Grade 0–1 after dose reduction, re-escalation is permitted at the discretion of the investigator. 
c Patients requiring >2 dose level reductions (ie, a reduction that would result in a dose <80 mg) should discontinue protocol therapy. 
 


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Prespecified Dose Modifications for Treatment-related Hypertension 
NCI-CTCAE 
v5.0 
Grade 
Definition 
Antihypertensive therapy 
Study drug dosing 
Grade 1 
Systolic blood pressure (BP) 120– 139 
mmHg or diastolic BP 80-89 mmHg 
None 
Continue study drug 
Consider increased blood pressure monitoring 
Grade 2 
Systolic BP 140–159 mmHg or diastolic 
BP 90–99 mmHg if previously within 
normal limits; change in baseline medical 
intervention indicated; recurrent or 
persistent (≥ 24 h);  
or 
Symptomatic increase by > 20 mmHg 
(diastolic) or to > 140/90 mmHg; 
monotherapy indicated initiated 
Treat to achieve diastolic BP ≤ 90 mmHg 
If BP previously within normal limits, 
start antihypertensive monotherapy 
If patient already on antihypertensive 
medication, titrate dose up 
Continue study drug 
If symptomatic, hold study drug until 
symptoms resolve and diastolic BP 
≤ 90 mmHga 
On resuming study drug, continue at same 
dose level 
Grade 3 
Systolic BP ≥ 160 mmHg or diastolic BP 
≥ 100 mmHg; 
Medical intervention indicated; 
More than one drug or more intensive 
therapy than previously used indicated 
Treat to achieve diastolic BP ≤ 90 mmHg 
— 
Start antihypertensive medication 
and/or 
— 
Increase current antihypertensive 
medication 
and/or 
— 
Add additional antihypertensive 
medications 
Hold study drug until diastolic BP ≤ 90 mmHg 
and, if symptomatic, symptoms resolvea On 
resuming study drug, continue at same dose 
level  
If BP is not controlled with addition of new or 
more intensive therapy, reduce study drug by 
one dose levelb,c  
If Grade 3 hypertension recurs despite study 
drug dose reduction and antihypertensive 
therapy, reduce study drug by one additional 
dose levelb,d 
Grade 4 
Life-threatening consequences (e.g., 
malignant hypertension, transient or 
permanent neurological deficit, 
hypertensive crisis) 
Urgent intervention indicated 
 
Discontinue treatment 
a Patients requiring a delay of > 4 weeks should discontinue protocol therapy. 
b Dose level 0 = 160 mg, dose level –1 = 120 mg, dose level –2 = 80 mg. 
c If blood pressure remains controlled for at least one full cycle, study drug dose re-escalation is permitted at the investigator’s discretion. 
d Patients requiring >2 study drug dose level reductions (ie, a reduction that would result in a study drug dose < 80 mg) should discontinue protocol therapy 


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Prespecified Dose Modifications for Treatment-related Increases in ALT and/or AST and/or Bilirubin 
NCI-CTCAE v5.0 Grade 
1st occurrence 
Restart 
Reoccurrence 
Baseline Grade 0→Grade 1 
or Baseline Grade 1→Grade 2 
Give study drug on time 
Check AST, ALT and bilirubin twice 
weekly for 2 weeks then weekly for at 
least 4 weeks 
 
Give study drug on time 
Check AST, ALT and bilirubin twice 
weekly for 2 weeks then weekly for at 
least 4 weeks 
Baseline Grade 0→Grade 2 
Delay study drug until ≤ Grade 1 
Check AST, ALT, and bilirubin twice 
weekly 
Reduce study drug by 1 dose levela 
Check AST, ALT, and bilirubin twice 
weekly for 2 weeks then weekly for at 
least 4 weeksb 
Discontinue study drugc 
Baseline any Grade→Grade 3 
Delay study drug until ≤ Grade 1 if 
baseline was Grade 0 or 1 or until 
Grade 2 if baseline was Grade 2 
Check AST, ALT, and bilirubin twice 
weekly 
If ALT or AST >8× upper limit of 
normal, with concomitant rise in 
bilirubin (of any degree) versus 
previous bilirubin values, consider 
permanent discontinuation of study 
drug at first occurrencec 
Reduce study drug by 1 dose levela 
Check AST, ALT, and bilirubin twice 
weekly for 2 weeks then weekly for at 
least 4 weeksb 
Discontinue treatmentc 
Baseline any Grade→Grade 4 
Discontinue treatmentc 
 
 
a Dose level 0 = 160 mg, dose level –1 = 120 mg, dose level –2 = 80 mg. 
b If all values remain stable for two full cycles, study drug dose re-escalation may be considered at the discretion of the investigator. After re-escalation AST, ALT, bilirubin should 
be checked twice weekly for 2 weeks then weekly for at least 4 weeks. 
c In case of discontinuation, check AST, ALT, and bilirubin twice weekly for 2 weeks then weekly until recovery to baseline. 
 


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18.3 Appendix 3 
EXCLUDED MEDICATIONS AND FOODS FOR PATIENTS 
RECEIVING AVAPRITINIB 
Strong CYP3A4 Inhibitors 
Strong CYP3A4 Inducers 
Moderate CYP3A4 Inducers 
Boceprevir 
Carbamazepine 
Bosentan 
Clarithromycin 
Phenytoin 
Efavirenz 
Cobicistat 
Rifampin 
Etravirine 
Conivaptan 
St. John’s Wort 
Modafinil 
Grapefruit, grapefruit juice 
Phenobarbital 
Dabrafenib 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprevir 
Telithromycin 
Voriconazole 
Abbreviations:  CYP3A4 = cytochrome P450 3A4. 
CBD Oil is not considered to be a CYP3A4 inhibitor or inducer and is therefore permitted while 
on treatment. 
This list is not intended to be exhaustive. A similar restriction will apply to other drugs that are known to 
strongly modulate CYP3A4 via inhibition or induction or are moderate CYP3A4 inducers; appropriate 
medical judgement is required. Please contact Blueprint Medicines with any queries you have on this issue. 


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EXCLUDED MEDICATIONS AND FOODS FOR PATIENTS 
RECEIVING REGORAFENIB 
Strong CYP3A4 Inhibitors 
Strong CYP3A4 Inducers 
Strong UGT1A9 Inhibitors 
Boceprevir 
Carbamazepine 
Mefenamic acid 
Clarithromycin 
Phenytoin 
diflunisal 
Cobicistat 
Rifampin 
Niflumic acid 
Conivaptan 
St. John’s Wort 
 
Grapefruit, grapefruit juice 
Phenobarbital 
 
Indinavir 
 
 
Itraconazole 
 
 
Ketoconazole 
 
 
Lopinavir 
 
 
Nefazodone 
 
 
Nelfinavir 
 
 
Posaconazole 
 
 
Ritonavir 
 
 
Saquinavir 
 
 
Telaprevir 
 
 
Telithromycin 
 
 
Voriconazole 
 
 
Abbreviations:  CYP3A4 = cytochrome P450 3A4. 
This list is not intended to be exhaustive. A similar restriction will apply to other drugs that are known to 
strongly modulate CYP3A4 via inhibition or induction or are strong inhibitors of UGT1A9; appropriate 
medical judgement is required. Please contact Blueprint Medicines with any queries you have on this issue. 


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18.4 Appendix 4 
MEDICATIONS TO BE USED WITH CAUTION WITH AVAPRITINIB 
CYP3A4 Substrates 
CYP2C9 Substrates 
BCRP Substrates 
Moderate CYP3A4 
Inhibitors 
Alfentanil 
Warfarin 
Rosuvastatin 
Erythromycin 
Cyclosporine 
Methotrexate 
Fluconazole 
Dihydroergotamine 
Lapatinib 
Crizotinib 
Ergotamine 
Dronedarone 
Fentanyl 
Imatinib 
Midazolam 
Diltiazem 
Pimozide 
Quinidine 
Simvastatin 
Sirolimus 
Tacrolimus 
Terfenadine 
Abbreviations: BCRP = Breast Cancer Resistance Protein; CYP3A4 = Cytochrome P450 3A4; CYP2C9 = 
cytochrome P450 2C9 
This list is not intended to be exhaustive. A similar restriction will apply to other drugs that are sensitive 
substrates of CYP3A4, CYP2C9, or BCRP, and moderate inhibitors of CYP3A4; appropriate medical 
judgement is required. Please contact Blueprint Medicines with any queries you have on this issue. 


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MEDICATIONS TO BE USED WITH CAUTION WITH 
REGORAFENIB 
BCRP Substrates 
Methotrexate 
Fluvastatin 
Atorvastatin 
Abbreviations: BCRP = Breast Cancer Resistance Protein. 


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18.5 Appendix 5 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS 
Grade 
Symptomatology 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair 
5 
Dead 
Source: (Oken et al, 1982). 


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18.6 Appendix 6 
MODIFICATIONS TO RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS VERSION 1.1 (MRECIST 1.1), FOR PATIENTS 
WITH GIST 
1. No lymph nodes to be chosen as target lesions. Enlarged lymph nodes are to be
followed up as non-target lesions.
2. No bone lesions to be chosen as target lesions.
3.
18Fluorodeoxyglucose positron emission tomography (18FDG-PET) is not acceptable
for radiological assessment.
4. A progressively growing new tumor nodule within a pre-existing tumor mass must
meet the following criteria in order to be regarded as unequivocal evidence of
progressive disease:
a.
The lesion must be ≥ 2 cm in size and definitely be a new active GIST lesions
(eg, enhanced with contrast or other criteria to rule out artifact); or
b. The lesion must be expanding on at least 2 sequential imaging studies.
Source:  (Demetri et al, 2013a) 


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18.7 Appendix 7 
 
 
 
 


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18.8 Appendix 8 
 


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18.9 
 
 
 
 
 
 
 
 
 
  
 


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18.10 Appendix 10 


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18.11 Appendix 11 


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18.12 Appendix 12 


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18.13 Appendix 13 


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18.14 Appendix 14 
BLU-285-1303 
An International, Multicenter Open-label Randomized Phase 3 Study of 
BLU-285 vs Regorafenib in Patients with Locally Advanced Unresectable or 
Metastatic Gastrointestinal Stromal Tumor (GIST) 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to 
avapritinib are the confidential and proprietary information of Blueprint Medicines, and 
except as may be required by federal, state or local laws or regulation, may not be 
disclosed to others without prior written permission of Blueprint Medicines. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
Federal Code of Regulations for Good Clinical Practices and International Council for 
Harmonisation guidelines, and will make a reasonable effort to complete the study within 
the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Blueprint Medicines or specified 
designees. I will discuss the material with them to ensure that they are fully informed 
about avapritinib and the study. 
______________________________ 
______________________________ 
Principal Investigator Name (printed) 
Signature 
___________ 
Date 
 

SAP_001.pdf: 
Statistical Analysis Plan BLU-285-1303  
Avapritinib 
 
ClinicalTrials.gov Document Cover Page 
 
Statistical Analysis Plan 
 
Study BLU-285-1303 
 
Study Title: An International, Multicenter, Open-label, Randomized, Phase 3 Study of BLU-285 vs 
Regorafenib in Patients With Locally Advanced Unresectable or Metastatic Gastrointestinal Stromal 
Tumor (GIST) 
 
Document Date: 01 February 2020 
 
NCT Number: NCT03465722 




Avapritinib 
Statistical Analysis Plan Study BLU-285-1303 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .....................................................................................1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...........................................7 
1. INTRODUCTION ................................................................................................................9 
1.1 Study Design .................................................................................................................10 
1.2 Study Objectives ...........................................................................................................12 
 Primary Objectives ................................................................................................12 
 Secondary Objectives ............................................................................................12 
 Exploratory Objectives ..........................................................................................12 
1.3 Sample Size Justification ..............................................................................................13 
1.4 Endpoints ......................................................................................................................13 
 Primary Efficacy Endpoint ....................................................................................13 
 Secondary Efficacy Endpoints ...............................................................................13 
 Exploratory Endpoints ...........................................................................................14 
2. POPULATIONS FOR ANALYSIS ...................................................................................15 
2.1 Intent-to-Treat (ITT) Population ..................................................................................15 
2.2 Safety Population ..........................................................................................................15 
2.3 Per Protocol (PP) Population ........................................................................................15 
2.4 Response-Evaluable (RE) Population ..........................................................................15 
3. GENERAL STATISTICAL CONSIDERATIONS ............................................................16 
3.1 Randomization, Stratification, and Blinding ................................................................16 
3.2 Data Analysis General Information and Definition ......................................................16 
 Study Drug .............................................................................................................16 
 Day 1 and Other Days ............................................................................................17 
 Calculations Using Dates .......................................................................................17 
 Duration Derivation ...............................................................................................18 
 Baseline and Rebaseline Values ............................................................................18 
 Last Contact ...........................................................................................................18 
 Table Headings ......................................................................................................18 
3.3 Methods for Handling Missing Data ............................................................................19 
3.4 Windowing of Visits .....................................................................................................19 
3.5 Withdrawals, Dropouts, Lost to Follow-Up .................................................................20 
3.6 Protocol Deviations ......................................................................................................20 
4. STATISTICAL METHODOLOGY ...................................................................................21 
4.1 Analysis Populations ....................................................................................................21 
4.2 Patient Disposition ........................................................................................................21 
4.3 Demographics and Baseline Disease Characteristics ...................................................22 


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 Demographics ........................................................................................................22 
 Baseline Disease Characteristics ...........................................................................23 
 Medical History .....................................................................................................23 
4.4 Prior and Concomitant Medications and Prior Therapies ............................................24 
 Prior and Concomitant Medications ......................................................................24 
 Prior Therapies and Surgery Procedures for the Underlying Malignancy .............24 
4.5 Study Treatments and Extent of Exposure ...................................................................25 
 Treatment Duration ................................................................................................25 
 Cumulative Dose....................................................................................................26 
 Average Daily Dose ...............................................................................................26 
 Dose Intensity ........................................................................................................26 
 Relative Dose Intensity ..........................................................................................26 
 Dose Modification .................................................................................................26 
 Treatment Compliance ...........................................................................................27 
4.6 Efficacy Analyses .........................................................................................................27 
 Multiplicity ............................................................................................................27 
 Analysis of Primary Efficacy Endpoint .................................................................27 
 Analysis of Secondary Efficacy Endpoints ...........................................................30 
 Analysis of Exploratory Efficacy Endpoints .........................................................33 
 Subgroup Analysis .................................................................................................35 
4.7 Safety Analyses ............................................................................................................35 
 Adverse Events ......................................................................................................36 
 Adverse Events of Special Interest ........................................................................37 
 Dementia Adverse Events ......................................................................................38 
 Deaths ....................................................................................................................41 
 Clinical Laboratory Evaluations ............................................................................41 
4.8 Vital Signs ....................................................................................................................41 
4.9 Electrocardiograms .......................................................................................................42 
4.10 Physical Examination .................................................................................................42 
4.11 Basic Neurological Assessment ..................................................................................42 
4.12 ECOG Performance Status .........................................................................................42 
5. INTERIM ANALYSES ......................................................................................................43 
6. CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL ..............................44 
7. APPENDICES ....................................................................................................................45 
7.1 Data Imputation Guidelines ..........................................................................................45 
 Adverse Event Date Imputation .............................................................................45 
 Concomitant Medication Date Imputation ............................................................46 
 Prior Therapies Date Imputation............................................................................46 


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 Death Date Imputation ...........................................................................................47 
 Post-Therapies Date Imputation ............................................................................47 
 Other Imputations ..................................................................................................47 
7.2 Table, Listing, and Figure Format ................................................................................48 
7.3 Conventions ..................................................................................................................48 
7.4 Implementing the Rank-Preserving Structural Failure Time Model ............................50 
8. REFERENCES ...................................................................................................................51 
 


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LIST OF TABLES 
Table 1: 
Visit Windows .................................................................................................... 20 
Table 2:  
Progression Free Survival Censoring Rules ....................................................... 29 
Table 3:  
Scoring the QLQ-C30 version 3.0 ...................................................................... 32 
Table 4: 
Summary of Adverse Event Tables: ................................................................... 39 
 


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LIST OF FIGURES 
Figure 1: 
Study Schematic ................................................................................................. 11 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANC 
Absolute neutrophil count 
ATC 
Anatomical therapeutic chemical 
β-hCG 
Beta human chorionic gonadotropin 
BMI 
Body mass index 
BP 
Blood pressure 
BSC 
Best supportive care 
C3D1 
Cycle 3 Day 1 
CBR 
Clinical benefit rate 
CI 
Confidence interval  
CR 
Complete response 
CS 
Clinically significant 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CXDX 
Cycle X Day X 
D842V 
Aspartic acid to valine at amino acid 842 
DCR 
Disease control rate 
DE 
Dose escalation 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EORTC-QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of 
Life 
EQ-5D-5L 
EuroQol 5 Dimension 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOT 
End-of-treatment 
FDA 
Food and Drug Administration 
GIST 
Gastrointestinal stromal tumors 
IDMC  
Independent Data Monitoring Committee 
ITT 
Intent-to-Treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
KIT 
V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog 
KM 
Kaplan-Meier 
MAF 
Mutant allele fractions 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 


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Abbreviation 
Term 
mRECIST 1.1 
Modified Response Evaluation Criteria in Solid Tumors version 1.1 
NCI 
National Cancer Institute 
NCS 
Not clinically significant 
NE 
Not evaluable 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive Disease 
PFS 
Progression free survival 
PDGFRA 
Platelet-derived growth factor receptor alpha 
PK 
Pharmacokinetic 
PR 
Partial response 
PRO 
Patient reported outcome 
PT 
Preferred term 
QD 
Once daily 
QoL 
Quality of life 
QTcF 
QT interval corrected using Fridericia's formula 
RDI 
Relative dose intensity 
RE 
Response-evaluable 
R/R 
Relapsed or refractory  
RPSFT 
Rank preserving structural failure time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
System organ class 
StdDev 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitor 
TNM 
Tumor/lymph nodes/metastasis 
TTR 
Time to response 
ULN 
Upper limit of normal 
US 
United States (of America) 
VAS 
Visual analog scale 
WHO 
World Health Organization 
 
 
 
 
 
 


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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analyses and data presentations 
to be performed for Blueprint Medicines, Protocol No. BLU-285-1303 (amendment 3 dated 
20 JUN 2019) ‘An International, Multicenter, Open-label, Randomized, Phase 3 Study of 
Avapritinib (BLU-285) vs Regorafenib in Patients with Locally Advanced Unresectable or 
Metastatic Gastrointestinal Stromal Tumor (GIST)’. It contains definitions of analysis 
populations, derived variables, and statistical methods for the analysis of efficacy and safety. 
It is to ensure that the data listings, summary tables, and figures which will be produced, and 
the statistical methodologies that will be used, are complete and appropriate to allow valid 
conclusions regarding the study objectives. 
The SAP will be finalized and approved prior to the clinical database lock for the final 
analysis, when approximately 264 progression free survival (PFS) events are reached. The 
analyses of safety, efficacy and pharmacokinetics will include all data collected in the 
database through the data cutoff date. 
A follow-up analysis for overall survival will be conducted when approximately 264 deaths 
have been observed. Additional data collected after the database lock from the primary 
analysis of the study will be prepared as an addendum to the study report per regulatory or 
scientific need.  
Selected analyses from this SAP will be performed for the Independent Data Monitoring 
Committee (IDMC) to review accumulated data from the study. Further details are described 
separately in the IDMC Charter. 
Analysis of pharmacokinetics (PK) is outside the scope of this SAP and will be addressed 
separately.  
 
 


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1.1 
Study Design 
This is an open-label, randomized, Phase 3 study in patients with locally advanced 
unresectable or metastatic GIST previously treated with imatinib and 1 or 2 other tyrosine 
kinase inhibitors (TKIs).  
All study visits are intended to be conducted on an outpatient basis. After provision of 
written informed consent, patients will be evaluated for study eligibility during the screening 
period within 4 weeks (28 days) before study drug administration on Cycle 1 Day 1 (C1D1). 
During the screening period, eligibility will be confirmed; management of baseline 
concomitant conditions will be recorded and stabilized; baseline symptoms will be assessed; 
hematology, blood chemistry, mutation status, brain imaging (computed tomography (CT) 
scan or magnetic resonance imaging (MRI)), and baseline tumor assessments (CT scan or 
MRI) will be performed.  
Approximately 460 patients are to be randomly assigned, in a 1:1 ratio, to 1 of 2 treatment 
arms: Arm A (avapritinib) or Arm B (regorafenib) stratified by TKI treatment (third versus 
fourth), geographic region (Asia versus rest of the world), and PDGFRA D842V mutation 
status measured in ctDNA or a tumor sample (PDGFRA D842V mutation present versus 
absent). PDGFRA D842V mutation present is defined if a PDGFRA D842V mutation is 
detected per local or/and central testing. At least 70% of the patients enrolled should be 
receiving the study drug as their third TKI treatment for GIST. 
Patients randomized to Arm A will receive avapritinib 300 mg orally (PO) once daily (QD) 
with the option to escalate to 400 mg PO QD at the Investigator’s discretion (the escalation 
option was removed in protocol amendment 3), if specific criteria are met as described in the 
protocol. Patients randomized to Arm B will receive regorafenib 160 mg PO QD for 
3 weeks out of every 4 week (28 days) cycle (i.e., 3 weeks on/1 week off). 
Patients who experience disease progression on avapritinib as determined by central 
radiology may be offered the opportunity to continue treatment with avapritinib if there is no 
clinical evidence of disease progression or laboratory abnormalities attributable to disease 
progression, no rapid progression of disease or a progressive tumor requiring urgent 
alternative medical intervention at critical anatomical sites, and no decline in Eastern 
Cooperative Oncology Group Performance Status (ECOG PS). Patients who experience 
disease progression on regorafenib, as determined by central radiology, may be offered the 
opportunity to cross over to avapritinib.  
 


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Figure 1: 
Study Schematic 
 
Abbreviations:  GIST = gastrointestinal stromal tumor; N = number of patients; R = randomized; 
TKI = tyrosine kinase inhibitor. 
 
 
 
 
 


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1.2 
Study Objectives 
 
Primary Objectives 
The primary objective is to demonstrate the efficacy of avapritinib based on PFS as 
determined by central radiological assessment per mRECIST 1.1 in patients with advanced 
GIST following 2 or 3 prior TKI therapies, including imatinib, compared to patients treated 
with regorafenib. 
 
Secondary Objectives 
The key secondary objectives are: 
• To evaluate objective response rate (ORR) as determined by central radiological 
assessment per mRECIST 1.1 in patients with advanced GIST treated with avapritinib 
compared to patients treated with regorafenib. 
• To evaluate overall survival (OS) in patients with advanced GIST treated with 
avapritinib compared to patients treated with regorafenib. 
Additional secondary objectives are: 
• To evaluate the European Organisation for Research and Treatment of Cancer Quality of 
Life (EORTC-QLQ-C30) individual scores in patients with advanced GIST treated with 
avapritinib compared to patients treated with regorafenib. 
• To evaluate the safety and tolerability of avapritinib compared to regorafenib. 
• To evaluate objective response rate as assessed by the Investigator per mRECIST 1.1 in 
patients with advanced GIST treated with avapritinib compared to patients treated with 
regorafenib. 
• To evaluate objective response rate as determined by central radiological assessment per 
Choi criteria in patients with advanced GIST treated with avapritinib compared to 
patients treated with regorafenib. 
• To evaluate disease control rate (DCR) per mRECIST 1.1 in patients with advanced 
GIST treated with avapritinib compared to patients treated with regorafenib.  
• To evaluate duration of response (DOR) per mRECIST 1.1 in patients with advanced 
GIST treated with avapritinib compared to patients treated with regorafenib.  
• To determine steady state systemic exposure of avapritinib (out of scope for this SAP). 
• To assess the patient-reported perception of abdominal pain. 
 
Exploratory Objectives 


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1.3 
Sample Size Justification 
The sample size calculation was based upon the assumption that the median PFS for 
regorafenib is approximately 5 months (Demetri 2013). Assuming avapritinib can reduce the 
risk of PFS events by 33%, i.e., a hazard ratio (HR) of 0.67 (avapritinib compared to 
regorafenib), a minimum of 264 PFS events are needed to provide 90% power at a 2-sided 
alpha of 0.05 for the study. With an 18-month accrual period and a 6-month follow-up 
period, the total sample size needed for the study is approximately 460 patients (230 patients 
per arm). This sample size takes a 2% dropout rate into consideration and assumes accrual 
will follow a truncated exponential distribution with a scaled power parameter of -9. 
The sample size calculated for the primary endpoint, PFS, is also sufficient to detect a 
difference in ORR between the two arms. Assuming a null ORR of 5% and an alternative 
ORR of 15%, a sample size of 460 patients provides approximately 95% power to detect a 
difference in ORR using a test of two-proportions at a 2-sided alpha of 0.05. 
Assuming the same effect size for OS as PFS (HR = 0.67), the same number of events (264) 
is required to power the OS analysis. The timing of the OS analysis will occur later than the 
PFS analysis as it will be at such time when 264 deaths occur. 
1.4 
Endpoints 
    Primary Efficacy Endpoint 
The primary endpoint is PFS, based on central radiological assessment per mRECIST 1.1, in 
patients with advanced GIST. Progression-free survival is defined as time from 
randomization to the earlier of disease progression or death due to any cause. 
    Secondary Efficacy Endpoints 
The key secondary endpoints are: 
• ORR defined as the percentage of patients whose best response is complete response 
(CR) or partial response (PR) as assessed by central radiology using mRECIST 1.1. 
• OS defined as the time from date of randomization to death due to any cause. 
Additional secondary endpoints include: 


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• All individual EORTC-QLQ-C30 scores, including symptom and function scales, 
and the global health status score. 
• ORR as assessed by Investigator per mRECIST 1.1. 
• ORR as assessed by central radiology per Choi criteria. 
• DCR is defined as the rate of CR or PR of any duration or stable disease (SD) lasting 
at least 16 weeks from the date of randomization. 
• Duration of response defined as the time from first documentation of tumor response 
to disease progression or death due to any cause. 
• 
Adverse events, serious AEs (SAEs), and changes in safety laboratory parameters, 
12-lead ECG evaluations, and ECOG PS. The intensity of AEs will be assessed by 
the NCI CTCAE, version 4.03 or 5.0. 
• Abdominal pain as measured by a numeric rating scale (0-10). 
    Exploratory Endpoints 
 
 


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2. POPULATIONS FOR ANALYSIS 
2.1 
Intent-to-Treat (ITT) Population  
The ITT Population includes all randomized patients, independent of whether they received 
the study medication or not. All primary efficacy analyses will be based on the ITT 
Population. All patients in the ITT Population will be analyzed according to the treatment 
they were randomized to receive.  
2.2 
Safety Population 
The Safety Population includes all patients who have received at least 1 dose of study drug. 
All patients in the Safety Population will be analyzed according to the treatment actually 
received.  
2.3 
Per Protocol (PP) Population  
The PP Population includes all patients in the ITT Population who have no major violations 
of the inclusion/exclusion criteria or other major deviations as specified in the “Protocol 
Deviations and Non-Compliance Management Plan”. Patients who actually receive 
incorrect treatment compared to what they were randomized to receive will be excluded 
from the PP Population. The PP Population will be used for selected efficacy analyses as 
supportive analyses. 
2.4 
Response-Evaluable (RE) Population 
The RE Population is defined as all patients in the ITT Population who received at least 1 
dose of avapritinib or regorafenib, have at least 1 target lesion at baseline as determined by 
central radiology per mRECIST 1.1, and have at least 1 post-baseline disease assessment by 
central radiology per mRECIST 1.1. Selected efficacy analysis will be performed using the 
RE Population. Results in this population will be analyzed according to the treatment to 
which patients were randomized to receive. 
 
 


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3. GENERAL STATISTICAL CONSIDERATIONS 
3.1 
Randomization, Stratification, and Blinding 
Patients who meet all study eligibility criteria will be randomized by an interactive web 
response system (IWRS). 
The randomization will be stratified by the following 3 variables (stratification factors): 
• TKI treatment (third versus fourth) 
• Geographic region (Asia versus rest of the world) 
• PDGFRA D842V mutation (present versus absent). 
If a patient is randomized using incorrect baseline information from the stratification factors, 
that randomization will be accepted but the analysis will be based on the correct baseline 
information.  
If fewer than 5 patients are in a stratification group of all three factors, that group will be 
combined with another stratification group. If the PDGFRA D842V is present in fewer than 
24 patients overall (i.e., on average, each combination of the other two stratification under 
each treatment arm contains fewer than 3 patients), then all stratified analyses in this SAP 
will be based only on TKI treatment and geographic region stratification factors. 
To control bias during the study conduct and analyses, and to ensure proper type I error 
control, patient treatment assignments are blinded to pre-defined study team members (refer 
to “Plan for Providing Blinded Data to Biostatistics” for details).  An unblinded team will 
conduct analyses by treatment, e.g., IDMC until the final database lock, upon which the 
study team will be unblinded to conduct the primary analysis.  
3.2 
Data Analysis General Information and Definition 
Summary statistics for continuous variables will include n (non-missing observations), 
mean, standard deviation (StdDev), minimum, median, and maximum. Summary statistics 
for categorical variables will be presented in terms of frequencies and percentages. Time to 
event data will be summarized using the Kaplan-Meier (KM) method, which will include the 
estimated median with 95% confidence interval (CI) and the 25th and 75th percentiles. All 
relevant patient data will be included in listings.  
 
Study Drug 
Study drug or study treatment refers to avapritinib or regorafenib. 


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Day 1 and Other Days  
Date of first dose of study drug (or Day 1) is defined as the day of the first administration 
of study drug after enrollment. First dose refers to first dose in study unless otherwise 
specified. 
Date of first dose of study drug during extended study treatment period (or CC1D1) is 
defined as the day of the first administration of study drug after cross-over or continuation 
post disease progression per central radiology.  
Date of last dose of study drug is defined as the date of last administration of study drug 
(last dose) in the study. For patients who have not ended treatment and whose last dose date 
is missing, the cutoff date will be used. The date of last dose of study drug will be calculated 
separately for the main study treatment period, the extended study treatment period, and 
both periods combined. 
The extended study treatment period (or extended study) is defined as any time on or after 
CC1D1 in the study.  
The main study treatment period (or main study) is defined as any time before CC1D1 in 
the study. 
Day -1 is defined as the day before the first administration of study drug in the study (Day 
1). 
 
Calculations Using Dates 
Calculations using dates will adhere to the following conventions: 
Study day for a date of interest (TARGET DATE) is calculated as 
STUDY DAY = TARGET DATE – Day 1 + 1 if TARGET DATE is on or after Day 1; 
STUDY DAY = TARGET DATE – Day 1 otherwise. 
Note that negative study days are reflective of observations obtained during the screening 
period.   
Age (in days) is calculated as 
AGE = CONSENT DATE – BIRTH DATE (DOB) + 1.  
Age (in years) is calculated as 
Age (in years) = (year of consent) - (year of DOB) if the day of consent ≥ birthday;  
Age (in years) = (year of consent) - (year of DOB) - 1 otherwise. 
This is equivalent to the following:  
[(year of consent) - (year of DOB)] – [(month of consent) ≤ (month of DOB)] + [(month of 
consent) = (month of DOB) and (day of consent) ≥ (day of DOB)] 


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Duration Derivation 
Unless otherwise specified for a specific panel or variable, duration variables will be derived 
according to the following rules: 
Duration (in days) = [end date – start date +1] 
Duration (in weeks) = [end date – start date +1] / 7  
Duration (in months) = [end date – start date +1] / 30.4375  
Duration (in years) = [end date – start date +1] / 365.25. 
Duration variables expressed in units greater than day will be rounded to 1 decimal place. 
 
Baseline and Rebaseline Values 
Baseline is defined as the last observation prior to first dose of study drug, i.e., the Day 1 
pre-dose value or the last available (including unscheduled) value before Day 1 if a Day 1 
pre-dose value is unavailable. For summaries using the ITT Population, patients who were 
randomized but did not receive study drug will be baselined at their last available 
observation.  
 
Rebaseline is defined as the last observation prior to first dose of avapritinib in the extended 
study treatment period. For summaries using the ITT Population, patients who signed 
informed consent to crossover to avapritinib post-disease progression but did not 
subsequently receive study drug will be re-baselined at their last available observation. 
Patients who are initially randomized to avapritinib will not be rebaselined for continuation 
to avapritinib post-disease progression. 
 
Last Contact 
Last contact or last date known alive is defined as the last non-imputed date of any patient 
record prior to or on the data cutoff date in the clinical database.  
 
Table Headings 
All analyses will be tabulated by treatment group and include a total if appropriate. The treatment 
groups are defined as below:  
• avapritinib (“ava”) – Data collected during the main study treatment period only from 
patients randomized* to avapritinib. 
• Regorafenib (“rego”) – Data collected during the main study treatment period only from 
patients randomized* to regorafenib. 
• avapritinib overall (“ava overall”) – Data collected during both the main and extended 
study treatment periods from patients randomized* to avapritinib. 


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• regorafenib to avapritinib (“rego to ava”) – Data collected during the extended study 
treatment period only from patients randomized* to regorafenib. During this period, 
patients are treated with avapritinib after crossing over from regorafenib.  
*For analyses using the Safety Population, patients will be grouped based on the study drug 
actually received during the main study treatment period rather than the study drug they were 
randomized to. 
Safety, laboratory, exposure, compliance, dose modification, concomitant medications, and major 
protocol deviation analyses will be presented using the 4 groups above. 
Efficacy analyses will be presented using 2 groups (avapritinib, regorafenib). 
Analysis populations, patient dispositions, baseline or demographic characteristics, patients by 
country by site, medical history, and prior therapies for the underlying malignancy will be 
presented using 3 groups (avapritinib, regorafenib, total). 
3.3 
Methods for Handling Missing Data  
Refer to Section 7.1 for detailed date imputation guidelines.  
3.4 
Windowing of Visits 
Data will be summarized by visit following the visit windows in Table 1 when appropriate 
(e.g., lab parameters). If multiple assessments occur within a visit window, the assessment 
closest to the target day will be used. In case of ties, with equal number of days on either 
side of target day, the value from the day before target day shall be used. 
The extended study treatment period will be windowed similarly. The extended study 
treatment period visits will have a prefix “C”, e.g., C Week 4 (CC2D1).   


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Table 1: 
Visit Windows  
Visit  
Start day 
Target Day 
End day 
Week 4 (C2D1) 
2 
29 ± 2 
43 
Week 8 (C3D1) 
44 
57 ± 3 
71 
Week 12 (C4D1) 
72 
85 ± 3 
99 
Week 16 (C5D1) 
100 
113 ± 3 
127 
Week 20 (C6D1) 
128 
141 ± 3 
155 
Week 24 (C7D1) 
156 
169 ± 7 
183 
Week 28 (C8D1) 
184 
197 ± 7 
211 
Week 4*X (C(X+1)D1) 
28*X–12  
28*X+1 ± 7 
28*X+15 
Note: Visit window for Week 4 will not include Day 1 if the Day 1 observation is marked as baseline; X can be 
4, 5, 6… until all visit windows are covered. CXDX in parentheses are for calculation purposes and will not be 
presented in outputs. 
3.5 
Withdrawals, Dropouts, Lost to Follow-Up 
Patients may withdraw or be withdrawn from study treatments at any time for any of the 
following reasons:  
• Withdrawal of consent 
• Adverse event (AE) 
• Disease progression 
• Death 
• Investigator decision 
• Protocol deviation 
• Pregnancy 
• Lost to follow-up. 
3.6 
Protocol Deviations 
All protocol deviations will be entered into the RAVE database by site staff, and their 
classifications will be entered by designated CRO or sponsor study team members. Details 
on reporting of protocol deviations can be found in the Protocol Deviations and Non-
Compliance Management Plan. 
Prior to database lock, protocol deviations will be reviewed and categorized as major or 
minor for summarization. 
All major protocol deviations will be tabulated for the ITT Population by treatment. 


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A listing of patients with protocol deviations will be provided. A separate listing of patients 
with major protocol deviations that lead to exclusion from the PP population or any analysis 
will be provided. 
4. STATISTICAL METHODOLOGY 
4.1 
Analysis Populations  
A summary of analysis populations by treatment will be presented along with percentages 
relative to the ITT Population. Derived stratification factors will be tabulated for each factor 
and all combinations. 
• Prior Lines of TKI (2, 3)  
• PDGFRA D842V (present, absent) 
• Region (Asia, Rest of World) 
4.2 
Patient Disposition 
The number and percent of patients will be tabulated for the ITT, Safety, PP, and RE 
Populations, respectively, for the following categories: 
• Patients in the population 
• Patients who receive study treatment  
• Patients who end main study treatment without continuation or cross-over to 
avapritinib 
• Patients who continue or cross-over to avapritinib 
• Patients who end treatment after continuation or cross-over to avapritinib 
• Patients who receive subsequent anti-cancer therapy 
Reasons for treatment discontinuation will be summarized with the following categories 
collected on the electronic case report form (eCRF): 
• Patient refuses treatment 
• Withdrawal of consent 
• Pregnancy 
• Adverse event and related adverse event 
• Disease progression (confirmed by Central Review) 
• Clinical progression 
• Protocol deviation 


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• Investigator decision 
• Lost to follow-up 
• Administrative/Other 
• Sponsor decision 
Listings will be provided for patients who discontinue treatment with the reason for treatment 
discontinuation. 
Reasons for treatment discontinuation after continuation or cross-over to avapritinib will be 
similarly summarized. 
Reasons for study discontinuation will be summarized with the following categories: 
• Withdrawal of consent 
• Death 
• Lost to follow-up 
• Administrative/Other 
• Sponsor decision 
Listings will be provided for patients who discontinue from study with the reason for study 
discontinuation. 
4.3 
Demographics and Baseline Disease Characteristics  
Demographic and baseline disease characteristic data will be summarized for the ITT, 
Safety, PP, and RE Populations. Medical history data will be summarized for the ITT 
Population. 
 
Demographics 
The number and percentage of patients in each of the following categories will be presented: 
• Age group (<65 years or ≥65 years) 
• Sex  
• Region 
• Ethnicity 
• Race. 
Patients’ age (years), height (cm), weight (kg), body mass index (BMI) (kg/m2), and other 
continuous demographic variables will be summarized descriptively.  
BMI will be calculated as: BMI (kg/m2) = (weight in kg) / (height in m)2. 


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Baseline Disease Characteristics 
The number and percentage of patients in each of the following categories will be presented: 
• Mutation Status 
o KIT V654A or T670I (Present, Absent) 
o KIT mutation status in KIT V654A and T670I mutation absent patients 
(Exon 17 mutation detected, KIT mutation other than exon 17 detected, no KIT 
mutation detected) 
o Specific Exon 17 mutations (D816X, D820X, N822X, Y823X) in KIT V654A 
and T670I mutation absent patients 
o PDGFRA D842V  
o PDGFRA non-D842V  
• The Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, 2) 
• Metastatic disease (Yes, No) 
• Largest target lesion size (≤5 cm, >5 to ≤10 cm, >10 cm) by central radiology 
assessment 
• Patient staged at screening by tumor/lymph nodes/metastasis (TNM) system (Yes, 
No) 
• Current stage at screening by TNM 
• Prior imatinib (Yes, No) 
• Prior sunitinib (Yes, No) 
• Primary tumor site of GIST at the time of diagnosis 
• Site(s) of metastatic disease 
• Prior surgical resection (Yes, No), and type of resection (total, partial, other). 
Continuous baseline disease characteristics will be summarized using descriptive statistics.  
 
Medical History 
Ongoing medical history data will be summarized by system organ class (SOC) and 
preferred term (PT) per Medical Dictionary for Regulatory Activities (MedDRA) version 
18.1. Patients with multiple events coded to the same system organ class or preferred term 
will only be counted once in the summary for that category. 
All medical history data will be listed. 


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4.4 
Prior and Concomitant Medications and Prior Therapies 
Prior and concomitant medications and prior therapies will be summarized for the ITT 
population.  
 
Prior and Concomitant Medications 
Prior medications are all medications which started and stopped before exposure to study 
drug. Concomitant medications are all medications taken at any time from the first dose date 
of study drug to last dose date of study drug + 30 days.  
When summarizing data collected only from the main study treatment period, concomitant 
medications include medications taken at any time from the first dose date of study drug to 
the earlier of the last dose date of study drug + 30 days or the first dose date of study drug 
during the extended study treatment period. 
When summarizing data collected only from the extended study treatment period, 
concomitant medications include medications taken at any time from the first dose date of 
avapritinib during the extended study treatment period to the last dose date of avapritinib + 
30 days. 
If the last dose date of study drug is not available, then the cutoff date is used in place of the 
last dose date.  
The number and percentage of patients taking concomitant medications and significant non-
drug therapies will be summarized and listed by therapeutic area (ATCText3) and preferred 
drug name. A patient taking the same medication multiple times is counted only once under 
that preferred drug name. 
Prior (with clear flag) and concomitant medications will be listed. 
Medications are coded using the World Health Organization Drug dictionary B3 enhanced, 
version Mar 2019. 
 
Prior Therapies and Surgery Procedures for the Underlying Malignancy 
Prior therapy is defined as all treatment that started and ended on or before first dose date of 
study drug.  
The number and percentage of patients for each category below will be summarized by PT: 
• Prior non-TKI Therapy (Yes, No) 
• Prior radiation therapy (Yes, No; type (external, brachytherapy or IORT)) 
• Prior lines of TKIs (2 lines, >2 lines) 
• Prior cancer related surgery-procedures (Yes, No) 
• Best response to any prior TKI (CR, PR, SD, progressive disease, NE) 


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• Best response to last prior TKI (CR, PR, SD, progressive disease, NE) 
• Type of prior surgery procedure (total resection, partial resection or other), and the 
site of the procedure.  
Continuous variables to be summarized include: 
• Time between diagnosis and randomization date 
• Time between the end of last prior line of anticancer therapy and randomization date  
• Duration of previous exposure to TKI 
The duration of previous exposure to TKI will be the sum of exposure from each prior TKI 
therapy, which is number of days from start date to end date captured on the prior cancer 
therapy eCRF page. 
No overlap between the exposure to prior therapies and avapritinib will be allowed and any 
overlap of exposure will be queried at the data review stage. The end date of the last prior 
therapy will be imputed as ‘Day 1 – 15’ if the imputation of partial dates is within 14 days of 
Day 1. However, if Day 1 of study drug is within the first half of the month, and last prior 
therapy ended on the same month as study drug start, the day component of last prior 
therapy end date will be imputed as 1.  
4.5 
Study Treatments and Extent of Exposure 
Study drug exposure, including the number of doses administered, cumulative dose, dose 
intensity, relative dose intensity (RDI), duration of treatment, and the proportion of patients 
with dose modifications will be summarized descriptively by time (every 4 weeks and the 
overall duration of the data collection period) for the Safety Population. 
Day 1 + 28*(X–1) is the start date of each 4 week period. Day 28 + 28*(X–1) is the end date 
of each 4 week period. The end date of last 4 week period is the date of last dose of study 
drug.  
 
Treatment Duration 
Duration of treatment (days) = (treatment end date – treatment start date + 1).  
Duration of treatment (weeks) = (treatment end date – treatment start date + 1) / 7.  
The treatment start date is the first dose date of study drug.  
For patients receiving avapritinib, the treatment end date is the last dose date of study drug.  
For patients receiving regorafenib, the treatment end date is the earliest of the last dose date 
of study drug + 7 days, the data cutoff date, or the death date, to account for the dosing 
schedule of regorafenib. 
For patients with last dose date missing, the earlier of the data cutoff date or the death date 
will be used. 


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Descriptive statistics will be provided for the duration of treatment in weeks. 
 
Cumulative Dose  
Cumulative dose (mg) is defined as sum of all doses taken. The dosage will be counted as 0 
for days when the study drug is not taken. 
 
Average Daily Dose  
Average daily dose (mg) is defined as the cumulative dose divided by the number of days 
dosed.  
 
Dose Intensity  
Dose intensity (mg/day) is defined as the cumulative dose divided by the duration of 
treatment (in days).  
 
Relative Dose Intensity 
Relative dose intensity is defined as the ratio: dose intensity / planned dose intensity. 
Planned dose intensity is based on initial assigned daily dose.  
Relative dose intensity will be summarized both descriptively as a continuous variable and 
categorically in the following groups:  <75%, 75% to <90%, 90% to 120%, and ≥120%. 
 
Dose Modification 
The number and percentage of patients with the following dose modifications will be 
summarized:  
• Dose reduction due to AE (0, 1, 2, or >2) 
• Dose interruption/missing due to AE (0, 1, 2, or >2) 
• Dose discontinuation due to AE  
• Dose reduction (0, 1, 2, or >2) 
• Dose interruption/missing (0, 1, 2, or >2) 
• Dose discontinuation  
• Dose increase (Yes, No) 
Time to first dose reduction among patients with at least one dose reduction is the time 
elapsed, in weeks, from the date of first dose of study drug to the date when the first dose 
reduction occurred. Time to first dose reduction will be summarized as a continuous 
variable. 
Details of dose modifications will be provided in listings. 


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Treatment Compliance 
The number of pills dispensed, returned, and taken (defined as the difference between the 
number of pills dispensed and returned), and compliance (defined as the percentage of pills 
taken relative to pills dispensed) will be summarized descriptively for the Safety Population.  
4.6 
Efficacy Analyses 
All efficacy analyses will be conducted by treatment for the ITT Population. Selected 
analyses may be conducted in the PP and RE Populations. Endpoints involving response 
assessment will be based on central radiology per mRECIST 1.1. Investigator assessment 
per mRECIST 1.1, or central radiology assessment per Choi criteria will only be used 
supportively.  
 
Multiplicity 
A gate-keeping method will be implemented to control Type I error. This strategy will apply 
to the primary and key secondary efficacy endpoints: PFS, ORR, and OS. 
PFS will be analyzed first when approximately 264 events are reached. In line with the gate 
keeping strategy, ORR will only be assessed for superiority should PFS have demonstrated 
superiority.  
A formal OS interim analysis will be performed at the time of the final analysis of PFS and 
ORR for which superiority is demonstrated. The alpha for the interim analysis of the OS will 
follow the O’Brien-Fleming boundary method. The amount of alpha spent on OS at the time 
of the final PFS analysis will be specified according to the actual proportion of deaths 
observed at the time of the database lock regardless of whether the exact targeted number of 
PFS events has occurred at the lock. The exact amount of alpha spending at the interim 
analysis will be calculated using the alpha spending function developed by Lan and DeMet. 
OS will be analyzed when superiority is demonstrated for both PFS and ORR. The OS will 
also be analyzed at the follow-up when 264 events (deaths) occur, using the remaining 
unspent alpha.  
 
Analysis of Primary Efficacy Endpoint 
The primary endpoint of PFS is defined as the time from the date of randomization to the 
earlier of the date of first documented disease progression or death due to any cause. 
The primary analysis for PFS is based on the central radiological assessment of PD per 
mRECIST 1.1.  
Patients who are still in response at time of data cutoff will be censored at their last valid 
assessment. Complete censoring rules (both European Medicines Agency [EMA] and United 
States [US] Food and Drug Administration [FDA]) are specified in Table 2. The analysis 
will be primarily based on FDA Guidance for Cancer Trial Endpoints (FDA, 2007). The 


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censoring rules based on the EMA Guideline on the evaluation of anticancer medicinal 
products in man will be used as a sensitivity analysis (EMA, 2017).  
The Kaplan-Meier (KM) method will be used to estimate the survival distribution function. 
The median PFS and its two-sided 95% CI and the 25th and 75th percentiles will be 
estimated. In addition, the event rates (or event-free) at specific time-points (e.g., 3-, 6-, and 
12-month, etc.) will be computed, along with their standard errors using Greenwood’s 
formula (Klein, 2003). Plots of survival curves by treatment using the KM method will be 
presented. Additional survival plots will be provided by treatment for each of the three 
stratification factors (defined in Section 3.1). 
The primary treatment comparison is based on a stratified log-rank test.  
The hazard ratio (HR) and its 95% CI will be estimated based on a stratified Cox model with 
treatment as the explanatory variable and strata for the stratification factors.  
If patients were randomized based on incorrect strata, then the corrected strata will be used 
for stratified analyses rather than the incorrect strata recorded at randomization. 
As a sensitivity analysis, the stratified analyses of PFS based on the central radiological 
assessment of PD per mRECIST 1.1 will be repeated for the PP Population. Unstratified 
analyses based on the ITT population may also be conducted.  
PFS derived from the Investigator’s assessment per mRECIST 1.1 will be used as a 
supportive analysis of the primary endpoint. 
 


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Table 2:  
Progression Free Survival Censoring Rules 
Situation 
Date of Progression or 
Censoring 
FDA Censoring 
Rules 
EMA Censoring 
Rules 
No baseline assessments and 
alive after 2 scheduled 
assessments (defined by 
130 days) 
Date of randomization 
Censored 
Censored 
Progression documented 
between scheduled visits 
Date of radiological 
assessment showing new 
lesions or an increase in 
measured lesions 
Event 
Event 
No progression 
Date of last radiological 
assessment with evidence of 
no progression (or 
randomization date if no 
assessment) 
Censored 
Censored 
New anticancer/ non-protocol 
treatment started prior to 
progression 
Date of last radiological 
assessment with evidence of 
no progression prior to the 
start of new anticancer 
treatment 
Censored 
Event at date of 
disease 
progression/death 
Death before the second 
scheduled post-baseline 
assessment (defined by within 
130 days of date of 
randomization) 
Date of death 
Event 
Event 
Death between scheduled 
assessments  
Date of death 
Event 
Event 
Death or progression 
immediately after an extended 
lost to follow-up time (2 more 
missed scheduled assessments 
defined by at least x1 days) 
Date of last radiological 
assessment with evidence of 
no progression 
(randomization date if first 2 
scheduled assessments are 
missing) 
Censored 
Event at date of 
disease 
progression/death 
1 x = 130 days if the death or progression date is ≤336 days from first dose date; x = 210 days if the death or 
progression date is ≥337 days from randomization date. 
 


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Analysis of Secondary Efficacy Endpoints 
 Objective Response Rate 
The ORR is defined as the proportion of patients with a best response of CR or PR. The 
primary analysis of ORR will be assessed by central radiology per mRECIST 1.1 for the ITT 
population.  
The ORR and its two-sided 95% CI will be estimated using the exact binomial distribution 
(Clopper-Pearson).  
Additionally, the best overall response following the hierarchical order of CR, PR, SD, PD,  
and not evaluable (NE) will be tabulated. Non-CR/Non-PD will be treated as SD. 
A Cochran-Mantel-Haenszel (CMH) test will be performed to test for treatment difference. 
Stratification will be by the randomization stratification factors. An unstratified CMH test 
will be performed as a sensitivity analysis. 
The following additional sensitivity analyses will be conducted to assess the robustness of 
the primary analysis: 
• ORR assessed by central radiology per mRECIST 1.1 in the PP and RE Populations.  
• 
ORR assessed by central radiology per mRECIST 1.1 in the ITT Population by each 
stratification factor. 
• 
ORR as assessed by the Investigator in the ITT Population will be summarized for 
best overall response.  
 Overall Survival  
Overall survival is defined as the time from randomization to the date of death. Patients who 
die before or on the data cutoff date will be considered to have had an OS event. All patients 
who do not have a death record prior to or on the cutoff date will be censored at the last date 
known alive.  
The primary treatment comparison will be based on a stratified log-rank test using the ITT 
Population. The HR and its 95% CI will be estimated using a stratified Cox model with 
treatment as the explanatory variable and strata as the stratification factors. An unstratified 
log-rank test will be performed as a sensitivity analysis. 
A rank preserving structural failure time (RPSFT) model will be applied as a supportive 
analysis to account for treatment crossover effects from regorafenib to avapritinib. The 
survival time gained/lost by receiving avapritinib after crossover in the regorafenib group 
will be estimated. The RPSFT reconstructs the survival duration of crossover patients as if 
they had never received avapritinib, assuming treatment acts by multiplying survival time by 
a given factor once a patient starts receiving avapritinib (Korhonen et al, 2012). See 
Appendix 2 (Section 7.4) for further details of implementing this method. 


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Kaplan-Meier plots will be presented for overall survival for both the primary and sensitivity 
analyses. 
 Duration of Response  
Duration of response is defined as the time from first documented response (CR/PR) to 
earlier of the date of first documented disease progression or death due to any cause. 
Patients without CR or PR will be excluded from this analysis. Patients who are still in 
response at time of data cutoff will be censored at their last valid assessment. Complete 
censoring rules (both European Medicines Agency [EMA] and United States [US] Food and 
Drug Administration [FDA]) are specified in Table 2. The analysis will be primarily based 
on FDA Guidance for Cancer Trial Endpoints (FDA, 2007). The censoring rules based on 
the EMA Guideline on the evaluation of anticancer medicinal products in man will be used 
as a sensitivity analysis (EMA, 2017).  
Duration of response will be analyzed for the responders (CR/PR) in the ITT Population 
using KM methods and will include the estimated median with two-sided 95% CI and the 
25th and 75th percentiles. DOR at specific time-points (e.g., 3-, 6-, and 12-month, etc.) will 
be computed with respective standard errors using Greenwood’s formula (Klein, 2003).  
Sensitivity analyses will be conducted for DOR based on Investigator assessment per 
mRECIST 1.1. Both FDA and EMA censoring rules will be applied. 
 Disease Control Rate 
Disease control rate (DCR) is defined as the proportion of patients with a CR/PR of any 
duration, or SD lasting for 16 weeks from date of randomization. The response will be 
assessed per mRECIST 1.1. DCR and its two-sided 95% CI will be estimated for the ITT 
Population using the exact binomial distribution (Clopper-Pearson).  
 Response Rate by Choi Criteria 
The ORR per Choi response criteria (Weng, 2013) and its two-sided 95% CI will be 
estimated for the ITT Population using the exact binomial distribution (Clopper-Pearson).  
The best overall response per Choi criteria following the hierarchical order of CR, PR, SD, 
PD, and NE will be tabulated. 
 EORTC-QLQ-C30 
All questionnaire analyses will be based on the ITT population, and only includes those 
patients with baseline assessments for each instrument.  
The EORTC QLQ-C30 (version 3.0) is a 30-item questionnaire used to evaluate QoL, and 
includes five functional domains (physical (PF), cognitive (CF), role (RF), emotional (EF), 
and social (SF)), three symptom scales (fatigue (FA), nausea and vomiting (NV), and pain 
(PA)), a global health status / QoL scale (QL), and six single items (dyspnea (DY), insomnia 
(SL), appetite loss (AP), constipation (CO), diarrhea (DI), and financial difficulties (FI)).  


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All of the scales and single-item measures range in score from 0 to 100. A high score for a 
functional scale represents a high/healthy level of functioning, a high score for the global 
health status represents a high QoL, but a high score for a symptom scale / item represents a 
high level of symptomatology / problems. The scoring method is outlined in Table 3.  
Table 3:  
Scoring the QLQ-C30 version 3.0 
 
Scale 
Number 
Item 
Version 
Function 
Global health Status /QoL 
QL 
2 
6 
29, 30 
 
Functional Scales 
Physical functioning 
PF 
5 
3 
1 to 5 
F 
Role functioning 
RF 
2 
3 
6,7 
F 
Emotional functioning 
EF 
4 
3 
21 to 24 
F 
Cognitive functioning 
CF 
2 
3 
20, 25 
F 
Social function 
SF 
2 
3 
26, 27 
F 
Symptom scales/items 
Fatigue 
FA 
3 
3 
10, 12, 18 
 
Nausea and vomiting 
NV 
2 
3 
14,15 
 
Pain 
PA 
2 
3 
9, 19 
 
Dyspnea 
DY 
1 
3 
8 
 
Insomnia 
SL 
1 
3 
11 
 
Appetite loss 
AP 
1 
3 
13 
 
Constipation 
CO 
1 
3 
16 
 
Diarrhea 
DI 
1 
3 
17 
 
Financial difficulties 
FI 
1 
3 
28 
 
*Item range is the difference between the possible maximum and the minimum response to individual items. 
Raw score (RS) is calculated as the average of item score when at least half of the items are 
not missing. A linear transformation to 0-100 will then be applied to get the score (S) use 
ranges provided in Table 3. 
For functional scales S = (1 – (RS – 1) / range) x 100 
For symptom scales / items and global health status S= ((RS – 1) / range) x 100 
Calculated scale scores will be descriptively summarized at baseline and Day 1 of each 
assessed cycle. Change and percentage change from baseline will also be summarized for 
post-baseline assessments. 
Box plots of the change from baseline will be presented.  
As a sensitivity analysis, cumulative density function (CDF) plots of QoL will be produced 
at Day 1 of each assessed cycle: the horizontal axis displays the absolute score change from 
baseline, and the vertical axis shows the proportion of patients whose absolute score change 
from baseline is less than or equal to the value indicated on the x-axis. Similar CDF plots 
will be produced for all 6 functional scales at Day 1 of each assessed cycle.  


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For physical functioning, pain, role functioning and appetite loss, the mean change from 
baseline to Week 12 will be compared between treatment groups using a t-test.  
 Abdominal Pain 
Abdominal pain is measured as a numeric rating scale (0-10). 
For each scheduled assessment a summary will be given of the observed data. In addition, 
for post-baseline assessments, the change and percentage change from baseline will also be 
summarized. 
 
Analysis of Exploratory Efficacy Endpoints 
 


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Subgroup Analysis 
For ORR, DOR, and PFS as assessed by central radiology, and OS, the following subgroup 
analyses will be conducted. Corresponding forest plots will be provided based on the odds 
ratio or hazard ratio by treatment for each subgroup. Analyses will only be performed if the 
subgroup contains ≥ 5 patients. 
• Age (<65 years, ≥65 years) 
• Gender (Male, Female) 
• Region (US, Europe, Asia, Other) 
*Australia to be combined with Europe 
• Race (White, Asian, Other) 
• Largest target lesion (≤10 cm, >10 cm) 
• ECOG Performance Score at Baseline (0, 1) 
• V654A or T670I Mutation Status (Present, Absent) 
• PDGFRA D842V Mutation Status (Present, Absent) 
• Stratification factors (Respective stratification levels). 
• The following subgroup analyses will be performed in patients who are V654A 
mutation negative and T670I mutation negative: 
o D816X Mutation Status (Present, Absent) 
o D820X Mutation Status (Present, Absent) 
o N822X Mutation Status (Present, Absent) 
o Y823X Mutation Status (Present, Absent) 
4.7 
Safety Analyses 
Safety will be evaluated by the incidence of AEs, causality, intensity, seriousness, and 
outcome of AEs, the patient’s vital signs, ECOG PS, clinical laboratory test results, and 
ECG data. 
All safety data will be summarized by treatment group for the Safety Population. 


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Adverse Events 
Adverse Events will be analyzed using treatment-emergent adverse events (TEAEs). The 
TEAE definition is dependent on the study period (e.g., main study treatment period) 
reported. An AE is considered a TEAE for a specified study period if the AE occurs during 
or after administration of the first dose of study drug from the same study period through up 
to the earlier of the last dose of study drug in that period + 30 days or the day before the start 
of crossover/extended treatment. 
Adverse Event refers to TEAEs unless otherwise specified throughout this document. All 
AEs will be coded using MedDRA version 18.1. The severity will be graded using the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.03 (patients enrolled before protocol amendment 2) and 5.0. 
 A patient experiencing multiple AEs under the same PT or SOC will be counted only once 
for that PT or SOC by maximum severity. If a patient experiences the same AE more than 
once with more than one causal relationship to study drug, the strongest causal relationship 
to study drug will be given precedence. Any missing severity, causality, or outcome will not 
be imputed and classified as ‘Missing’. Detailed imputation rules for missing AE dates are 
in Section 7.1. 
The number of patients with at least one AE will be summarized (Table 4). The following 
tables summarize incidences of various aspects of AEs and serious adverse events (SAEs): 
1. AE Summary (including all subsequent items) 
2. AE by PT 
3. AE by SOC and PT 
4. AE related to study drug by PT 
5. AE related to study drug by SOC and PT 
6. SAE by PT 
7. SAE by SOC and PT 
8. SAE related to study drug by PT 
9. SAE related to study drug by SOC and PT 
10. Grade 3/4/5 AE by PT 
11. Grade 3/4/5 AE by SOC and PT 
12. Grade 3/4/5 AE related to study drug by PT 
13. Grade 3/4/5 AE related to study drug by SOC and PT 
14. AE by PT and NCI CTCAE Grade 
15. AE by SOC, PT, and NCI CTCAE Grade 


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16. AE related to study drug by PT and NCI CTCAE Grade 
17. AE related to study drug by SOC, PT, and NCI CTCAE Grade 
18. SAE by PT and NCI CTCAE Grade 
19. SAE by SOC, PT, and NCI CTCAE Grade 
20. SAE related to study drug by PT and NCI CTCAE Grade 
21. AE leading to interruption of study drug by SOC and PT 
22. AE leading to interruption of study drug by PT 
23. AE leading to dose reduction of study drug by SOC and PT 
24. AE leading to dose reduction of study drug by PT 
25. AE leading to permanent discontinuation of study drug by SOC and PT 
26. AE leading to permanent discontinuation of study drug by PT 
27. AE related to study drug leading to interruption of study drug by PT 
28. AE related to study drug leading to dose reduction of study drug by PT 
29. AE related to study drug leading to permanent discontinuation of study drug by PT 
All AEs will be listed by patient.  
Subgroup analyses will be conducted for items 1 – 13 above (details in Table 4) in the 
Safety Population. 
 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) will be summarized by category (cognitive effects 
and intracranial bleeding) and relevant PTs.  
• Cognitive effects consisting of 4 PTs: cognitive disorder, memory impairment, 
confusional state, encephalopathy 
• Intracranial bleeding consisting of 3 PTs: haemorrhage intracranial, cerebral 
haemorrhage, subdural haematoma. 
The general rules for summarizing AE specified in Section 4.7.1 apply for AESIs for 
avapritinib. The following AESI tables will be presented: 
• AESI by AESI category and PT 
• AESI related to study drug by AESI category and PT 
• Serious AESI by AESI category and PT 
• Serious AESI related to study drug by AESI category and PT 
• Grade 3/4/5 AESI by AESI category and PT 


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• Grade 3/4/5 AESI related to study drug by AESI category and PT 
• AESI by AESI category, PT, and NCI CTCAE Grade 
• AESI leading to permanent discontinuation of study drug by PT 
• AESI related to study drug leading to permanent discontinuation of study drug by PT 
 
Dementia Adverse Events 
Dementia adverse events will be summarized using MedDRA Dementia SMQ PTs. The 
general rules for summarizing AE specified in Section 4.7.1 apply for dementia AE for 
avapritinib. The following dementia AE tables will be presented: 
• Dementia AE by PT 
• Dementia AE related to study drug by PT 
• Serious Dementia AE by PT 
• Serious Dementia AE related to study drug by PT 
• Grade 3/4/5 Dementia AE by PT 
• Grade 3/4/5 Dementia AE related to study drug by PT 
• Dementia AE by PT and NCI CTCAE Grade 
• Dementia AE related to study drug by PT and NCI CTCAE Grade 
• Serious Dementia AE by PT and NCI CTCAE Grade 
• Serious Dementia AE related to study drug by PT and NCI CTCAE Grade 
 


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Table 4: 
Summary of Adverse Event Tables: 
Safety Endpoint 
Main 
Table 
by PT 
by SOC, PT 
by PT, 
CTCAE 
by SOC, 
PT, 
CTCAE 
Overall Subgroup 
Overall Subgroup 
Overall 
Overall 
Summary Table (each item below one row) 
X 
 
 
 
 
 
 
AE 
 
X 
X 
X 
X 
X 
X 
SAE 
 
X 
X 
X 
X 
X 
X 
Grade 3+ AE 
 
X 
X 
X 
X 
 
 
Related AE 
 
X 
X 
X 
X 
X 
X 
Related SAE 
 
X 
X 
X 
X 
X 
 
Related Grade 3+ AE 
 
X 
X 
X 
X 
 
 
AE Leading to Permanent Study Discontinuation 
 
X 
 
X 
 
 
 
Related AE Leading to Permanent Study Discontinuation 
 
X 
 
 
 
 
 
AE Leading to Dose Interruption  
 
X 
 
X 
 
 
 
Related AE Leading to Dose Interruption 
 
X 
 
 
 
 
 
AE Leading to Dose Reduction  
 
X 
 
X 
 
 
 
Related AE Leading to Dose Reduction 
 
X 
 
 
 
 
 
Listing (Death, Discontinuation, SAE) 
X 
 
 
 
 
 
 
AESI by Category and  
 
X 
 
 
 
X 
 
Related AESI by Category and 
 
X 
 
 
 
 
 
Serious AESI by Category and 
 
X 
 
 
 
 
 
Related Serious AESI by Category and 
 
X 
 
 
 
 
 
Grade 3+ AESI by Category and 
 
X 
 
 
 
 
 
Related Grade 3+ AESI by Category and  
 
X 
 
 
 
 
 
AESI Leading to Permanent Study Discontinuation 
 
X 
 
 
 
 
 
Related AESI Leading to Permanent Study Discontinuation 
 
X 
 
 
 
X 
 
Dementia AE 
 
X 
 
 
 
X 
 
Related Dementia AE 
 
X 
 
 
 
X 
 


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Serious Dementia AE 
 
X 
 
 
 
X 
 
Related Serious Dementia AE 
 
X 
 
 
 
X 
 
Grade 3+ Dementia AE 
 
X 
 
 
 
 
 
Related Grade 3+ Dementia AE 
 
X 
 
 
 
 
 
 
 


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Deaths 
On treatment deaths will be summarized by treatment group by SOC and PT.  
A listing of patients who died will be provided specifying the date of death, the cause of 
death, and the date of last dose of study drug. On treatment deaths, defined as deaths which 
occur between the first dose date of study drug to last dose date of study drug during the 
relevant study treatment period + 30 days, will be clearly marked. 
 
Clinical Laboratory Evaluations 
The central laboratory parameters with both baseline and post-baseline assessments will be 
summarized by treatment group and scheduled visit for the Safety Population. If there are 
multiple values recorded for a specific visit, then the last reported value will be used for that 
visit. Baseline is defined as the last assessment prior to start of study treatment. Data will be 
presented in Standard International units. 
Clinical laboratory values will be graded according to NCI CTCAE version 4.03 or 5.0 for 
applicable parameters. Shift tables of laboratory data from baseline to worst grade during 
treatment, including unscheduled visits, will be presented. For laboratory parameters 
(including hemoglobin, glucose, sodium, potassium, magnesium, glucose, bilirubin, and 
phosphate), shift tables in maximum CTCAE grades of worst high and worst low assessment 
will be presented separately. 
Overall summary and changes from baseline will be presented for hematology and serum 
chemistry (including coagulation) laboratory values.  
Listings will be provided for each laboratory parameter. All results outside predefined 
normal ranges and CTCAE grade will be flagged in the data listings. 
Urinalysis will be presented in listing only. 
Boxplots of selected lab tests (including leukocytes, neutrophils, platelets, hemoglobin, 
alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, 
and phosphate) values will be presented by visit.  
Local laboratory tests will be listed only, with the exception of the shift tables, which will 
include both central and local results when deriving the worst grade. 
4.8 
Vital Signs 
Vital signs (weight, systolic blood pressure, diastolic blood pressure, heart rate, and 
temperature) will be summarized at each scheduled assessment for the Safety Population. 
The change and percentage change from baseline will also be summarized for post-baseline 
assessments. 
 


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4.9 
Electrocardiograms  
Electrocardiogram overall interpretations (normal, abnormal not clinically significant 
[NCS], abnormal clinically significant [CS], and NE) and changes from baseline [expressed 
as improvement, no change, and deterioration] will be summarized by treatment group and 
scheduled visit for the Safety Population.  
• Improvement = abnormal CS to abnormal NCS or normal, abnormal NCS to normal  
• Deterioration = normal to abnormal NCS or CS, abnormal NCS to abnormal CS  
• No change = normal to normal, abnormal NCS to abnormal NCS, abnormal CS to 
abnormal CS. 
If an interpretation is missing for any patient, then an ‘Unknown’ category will be presented. 
ECG parameters (heart rate, PR interval, QT interval, QRS interval, and QTcF) will be 
descriptively summarized by scheduled visit. The change and percentage change from 
baseline will be summarized for post-baseline assessments. 
The proportion of patients with a QT interval and QTcF interval >450, >480 and >500 msec 
will be summarized. In addition, the proportion of patients with a change from baseline in 
QT interval and QTcF interval >30 and >60 msec will also be summarized. 
Note, ECGs are not assessed following either continuation or crossover of treatment to 
avapritinib, following disease progression based on central review. 
4.10 
Physical Examination  
Any abnormal, clinically significant physical examination results captured at screening will 
be treated as either medical history or adverse event data, as appropriate. Data will be listed 
for patients who have physical examinations performed. 
4.11   
Basic Neurological Assessment 
Basic neurological assessment results at screening will be summarized.  
4.12 
ECOG Performance Status 
ECOG PS will be summarized by scheduled visit. The number and percentage of patients 
with each response will be summarized. 
Note, ECOG PS is also scheduled to be captured following either continuation or crossover 
of treatment to avapritinib, following disease progression based on central radiological 
assessment. These scheduled assessments will also be summarized. 


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5. INTERIM ANALYSES 
No interim analysis is planned for the primary endpoint of this study.  An interim analysis of 
OS is planned at the time of final analysis when superiority of the PFS and ORR are 
established. 
The OS interim analysis will be performed at the time of the final analysis of PFS and ORR 
for which superiority is demonstrated. The alpha for the interim analysis of the OS will 
follow the O’Brien-Fleming boundary method. The amount of alpha spent on OS at the time 
of the final PFS analysis will be specified according to the actual proportion of deaths 
observed at the time of the database lock regardless of whether the exact targeted number of 
PFS events has occurred at the lock. The exact amount of alpha spending at the interim 
analysis will be calculated using the alpha spending function developed by Lan and DeMet. 
OS will be analyzed when superiority is demonstrated for both PFS and ORR. The OS will 
also be analyzed at the follow-up when 264 events (deaths) occur, using the remaining 
unspent alpha.  
 
 
 


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6. CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL 
There is no change to planned analyses from the protocol.  
 
 


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7. APPENDICES 
7.1 Data Imputation Guidelines 
No imputation will be made for completely missing date unless otherwise specified. General 
imputation rules mentioned below apply to partially missing or impossible dates:  
• If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date 
• If the start date is not missing, and the imputed stop date is before the start date, then 
the imputed stop date will be equal to the start date 
• Any imputed dates need to be logical. For example, last dose date should not be later 
than death date. 
When imputation rules in subsequent sections contradicts the general rule, always follow the 
general rule. 
 Adverse Event Date Imputation 
Follow the general rule specified in Section 7.1. 
Incomplete Start Date: 
Missing day, month, and year 
• No imputation will be made; the corresponding AE will be included. 
Missing day and month 
• If the year is the same as the year of the first dose date, then impute day and month 
as the day and month of the first dose date 
• If the year is prior to the year of the first dose date, then impute day and month as 
31 Dec 
• If the year is after the year of the first dose date, then impute day and month as 
01 Jan. 
Missing day only 
• If the month and year are the same as those of the first dose date, then impute day as 
the day of the first dose date 
• If either the year of partial date is before the year of the first dose date, or the years 
are the same, but the month of partial date is before the month of the first dose date, 
then impute day as last day of the month 
• If either the year of partial date is after the year of the first dose date, or the years are 
the same, but the month of partial date is after the month of the first dose date, then 
impute day as first day of the month. 


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Incomplete Stop Date: 
Missing day, month, and year 
• No imputation will be made. 
Missing day and month 
• If the year is the same as the year of the last dose date, then impute day and month as 
the day and month of the last dose date 
• If the year is prior to the year of the last dose date, then impute day and month as 
31 Dec 
• If the year is after the year of the last dose date, then impute day and month as 
01 Jan. 
Missing day only 
• If the month and year are the same as those of the last dose date, then impute day as 
the day of the last dose date; 
• If either the year of partial date is not the same as the year of the last dose date, or 
the years are the same, but the month of partial date is not the same as the month of 
the last dose date, then impute day as last day of the month. 
 Concomitant Medication Date Imputation 
Follow the general rules specified in Section 7.1 and rules in Section 7.1.1. 
 Prior Therapies Date Imputation 
Follow the general rule specified in Section 7.1. 
For start date partial as month and year are available, then impute day as ‘01’. E.g. impute 
partial date of ‘DEC2013’ as ‘01DEC2013’. 
For start date partial as year only is available, then impute day and month as ‘01JAN’. E.g. 
impute partial date of ‘2013’ as ‘01JAN2013’. 
For end date partial as month and year are available, then impute day as last day of the 
month. E.g. impute partial date of ‘JUN2013’ as ‘30JUN2013’. 
For end date partial as year only is available, then impute day and month as the last day of 
the year. E.g. impute partial date of ‘2013’ as ‘31DEC2013’. 
If the imputed starting date is earlier than initial diagnosis date, it should be set as the initial 
diagnosis date. No overlap between the exposure to prior therapies and study drug will be 
allowed and any overlap of exposure will be queried at data review stage. The end date of 
prior therapies will be imputed to first dose date of study drug – 15 if there is overlap due to 
imputation of partial dates. When there are multiple lines of prior therapies, the end date of 


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prior therapies will be imputed to first dose date of the subsequent line of therapy -1 if there 
is overlap due to imputation of partial dates. If the end year for one prior therapy is the same 
as the start year for the next prior therapy, impute Jun 30 and Jul 1 of that year for the end 
and start days if missing months and days. If the end year and month for one prior therapy is 
the same as the start year and month for the next prior therapy, impute 15th and 16th of that 
year and month for the end and start days if missing days.  
 Death Date Imputation 
• If death date is completely missing, will use latest alive date + 1 
• If both month and day are missing, then use the first date (01 JAN) of the year, or 
latest alive date + 1, whichever is later 
• If only day is missing, then use the first day of the month, or latest alive date + 1, 
whichever is later. 
 Post-Therapies Date Imputation 
Follow the general rule specified in Section 7.1. 
 Other Imputations 
Follow the general rule specified in Section 7.1. 
 
 


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7.2 Table, Listing, and Figure Format  
In the top left portion of each table/listing, a table/listing number followed by the title of the 
table/listing will be presented. After the title line, optional sub-title or population 
information can be presented. Horizontal lines will appear before and after the column 
heading of the table/listing. Footnotes will be put under the main body of text at the bottom 
of the page.  
The sponsor name, protocol number, programmer user identification, status of the 
table/listing (i.e. draft or final) and SAS program name will appear bottom left in a string 
and the page number will appear on the bottom right corner of each table/listing. The date 
and time of creation of table/listing will appear bottom left under the sponsor name. The 
source listing number will appear bottom left.  
A landscape layout is for both table and listing presentations for post-text tables. A portrait 
layout is for in text table. 
The left and right margins of all tables and listings will be a minimum of 2.1 cm from the 
left and 1.9 cm from the right. The top and bottom margins will be a minimum 2.92 cm. 
Header and footer will be both 1.27 cm. 
There is no special requirement of font type and size, but an 8-point font size for tables and 
7or 8-point for listings is proposed using Courier New font. A maximum SAS line size = 
141 and page size = 44 for 8-point font size, and line size = 161 and page size = 50 for 7-
point will be used to fit on both United Kingdom and US paper sizes. 
In a listing, in the case that a patient’s record has been continued to the next page, an 
appropriate identification (e.g. the patient identification number) must be presented at the 
beginning of that page. 
7.3 Conventions 
Continuous variables will be summarized using the number of observations (n), mean, 
standard deviation (Std Dev), median, minimum, and maximum. The same number of 
decimal places as in the raw data will be presented when reporting minimum and maximum, 
1 more decimal place than in the raw data will be presented when reporting mean and 
median, and 2 more decimal places than in the raw data will be presented when reporting 
standard deviation. 
Time to event variables will be summarized using Kaplan-Meier (KM) method, which will 
include the estimated median with 95% CIs and 25th and 75th percentiles. 
Unless otherwise specified frequency tabulations will be presented by number and 
percentage, where the percentage is presented in brackets to 1 decimal place (XX.X%). 
P-values, if applicable, will be presented to 3 decimal places. If a p-value is less than 0.05 
but is greater than or equal to 0.01, then an asterisk (*) will be added next to this value. If a 
p-value is less than 0.01 but is greater than or equal to 0.001, then two asterisks (**) will be 


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added next to this value. Finally, if the p-value is less than 0.001 then three asterisks (***) 
will be added next to this value and it will be presented as <0.001. If the rounded result is a 
value of 1.000, it will be displayed as >0.999.  
Any date information in the listing will use the date9. format, for example, 07MAY2002. In 
the listing, a unit associated with a variable will be presented only once within parentheses 
either below or next to that variable in the heading portion. If a parameter has multiple units, 
each unit will be displayed only once, as applicable. 
All tables will have their source listing referenced in a footnote. Listings should be sorted by 
analysis group, patient and visit and have the source data received by data management 
referenced in a footnote. All tables and listings will be converted into Microsoft Word 
documents and collated into two complete documents.  
An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more patients.  
Unless otherwise specified, the estimated mean and median for a set of values are printed 
out to 1 more significant digit than the original values, and standard deviations are printed 
out to 2 more significant digits than the original values. The minimum and maximum should 
report the same significant digits as the original values. For example, for systolic blood 
pressure: 
N 
XX 
Mean (Std Dev) 
XXX.X (X.XX) 
Median 
XXX.X 
Min, Max 
XXX, XXX 
Tabular display of data for medical history, prior/concomitant medications, and all tabular 
displays of adverse event data are presented by the body system, treatment class, or SOC 
with the highest occurrence in the avapritinib treatment group in decreasing order, assuming 
all terms are coded. Within the body system, drug class and SOC, medical history (by 
preferred term), drugs (by ATC1 code), and adverse events (by preferred term) are displayed 
in decreasing order. If incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated are 
reported as “-”. 
The percentage of patients is normally calculated as a proportion of the number of patients 
assessed in the relevant treatment group (or overall) for the analysis set presented.  
For categorical summaries (number and percentage of patients) where a patient can be 
included in more than one category, describe in a footnote or programming note if the 
patient is included in the summary statistics for all relevant categories or just 1 category and 
the criteria for selecting the criteria. 
 
 


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7.4 Implementing the Rank-Preserving Structural Failure Time Model 
A conventional analysis of overall survival, taking into account only the randomized 
treatment arm, does not account for the crossover from regorafenib to avapritinib, and the 
analysis can be biased and treatment effect underestimated. The rank-preserving structural 
failure time (RPSFT) model attempts to minimize this bias.  
The model assumes that once a patient has switched from regorafenib to avapritinib, the 
overall survival that would have been seen, had the patient not switched, is multiplied by a 
given factor once the patient has switched. The observed survival for a patient who has 
switched is then transformed as if they had never received avapritinib and had continued on 
regorafenib.  
The overall survival for a given patient, can be written as the sum of the time they were off 
avapritinib + the time they were on avapritinib. Here the time they were off avapritinib is 
when they were on regorafenib: 
Ti = Toffi + Toni 
The above formulation is also valid for patients randomized to avapritinib (Toffi = 0) and 
those randomized to regorafenib who do not switch (Toni = 0). 
The aim of the RPSFT model is to estimate for patients who do switch treatment, the 
survival time that would have been seen if they had not switched treatment. This adjusted 
survival time, Ui, is derived as: 
Ui = Toffi + Toni(exp(ψ))   [1] 
exp(ψ), the acceleration factor, is the factor by which the time on avapritinib is multiplied in 
order to estimate the time that would have been seen if the patient had not switched. 
In applying the model, the first step is to estimate ψ. This is done by applying formular [1] 
to all patients. At the correct value of ψ, an analysis of Ui by randomized treatment should 
result in a test statistic of 0. The log rank test will be used for this analysis, and the correct 
value of ψ is derived iteratively by running through a search grid in order to find the 
optimum value. 
Once ψ has been derived, the survival times for patients who switch treatment are then 
transformed according to [1] above. Note, censoring needs to be applied as appropriate for 
transformed times that extend further than the data cutoff/end of study. 
Once the transformation has been done, the data is then analyzed as usual by an appropriate 
method. 
Further details of the method, and specifically the implementation in SAS, can be found in 
the PharmaSUG 2018 – Paper EP-04, Implementing the Rank-Preserving Structural Failure 
Time Model in SAS and R, Bradford J Danner and Indrani Sarkar. 
 
 


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