Extension Protocol for Patients Previously Treated in Avapritinib Clinical Trials
Phase: PHASE4
Conditions: Gastrointestinal Stromal Tumors
Sponsor: Blueprint Medicines Corporation

Protocol BLU-285-1408 
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CLINICAL PROTOCOL 
DRUG:  
Avapritinib (also known as BLU-285) 
PROTOCOL NUMBER: 
BLU-285-1408 
PROTOCOL TITLE:   
Open-Label Extension Study to Evaluate the 
Safety of Long-Term Treatment with 
Avapritinib for Patients Previously Involved in 
an Avapritinib Study 
EudraCT NUMBER 
2020-005751-21 
SPONSOR:  
Blueprint Medicines  
45 Sidney Street  
Cambridge, MA 02139 
PROTOCOL DATE: 
07 April 2021 
VERSION NUMBER: 
Amendment 1  
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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APPROVAL PAGE 
 
Protocol Title: 
Extension Protocol for Patients Previously Treated in Avapritinib Clinical 
Trials 
Protocol No.:  
BLU-285-1408 
Original Protocol Date: 03 December 2020 
Protocol Version No.: 
Amendment 1 
Protocol Version Date: 07 April 2021 
This study protocol was subject to critical review and has been approved by Blueprint 
Medicines. The information contained in this protocol is consistent with the current risk-benefit 
evaluation of the investigational product. 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
 
 
 
Date 
 
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PROTOCOL SUMMARY  
 
 
Title:   
Extension Protocol for Patients Previously Treated in Avapritinib 
Clinical Trials 
Centers:  
Multiple study centers worldwide that were previously active on 
avapritinib clinical trials.   
Introduction and 
Rationale:   
Gastrointestinal stromal tumors (GIST) are the most common 
mesenchymal tumors occurring in the gastrointestinal (GI) tract, 
representing approximately 0.1–3.0% of all GI malignancies. 
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 
(PDGFRA) (10–15%), most commonly a substitution of valine for 
aspartic acid at amino acid 842 (D842V) in exon 18. On a 
molecular level, the most common sites for mutations in KIT at 
the time of diagnosis are exon 11 (60–70%) and exon 9 (5–15%) 
with exon 17 mutations being identified in approximately 1% of 
patients. Disease progression during treatment with a tyrosine 
kinase inhibitor (TKI) is associated with new mutations in KIT, 
with an increasing prevalence of mutations in exon 17.   
Avapritinib (also known as BLU-285) has demonstrated potent 
and selective activity against KIT exon 17 and PDGFRA exon 18 
mutants in pre-clinical studies. Avapritinib has been shown to be 
tolerable at active doses in toxicology and safety pharmacology 
studies. In the ongoing Phase 1 GIST trial, clinical activity was 
also observed in a broad range disease driving mutations.  
Avapritinib is now approved in the US for the treatment of adult 
patients with unresectable or metastatic GIST harboring a platelet-
derived growth factor receptor alpha (PDGFRA) exon 18 
mutation, including PDGFRA D842V mutations.  Avapritinib is 
also approved in the EU for the treatment of adult patients with 
unresectable or metastatic GIST harboring a platelet-derived 
growth factor receptor alpha (PDGFRA) D842V mutations. 
Number of  
Patients:  
Approximately 5 patients may be treated in this extension study. 
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Objectives:   
The objectives of the study are:  
 To provide long term safety data for GIST patients who are 
deriving clinical benefit from avapritinib on an existing 
avapritinib clinical trial To further characterize the rate of 
SAEs and AESIs of avapritinib. 
 
Study Design: 
This is an open-label extension study to provide long term safety 
data for GIST patients who are deriving clinical benefit from 
avapritinib upon the completion of avapritinib clinical trials. 
Duration of  
Patient  
Participation:   
The patient will remain on treatment and safety data will be 
collected as long as clinically appropriate according to the 
judgment of the Investigator. 
Duration of Study: The study is anticipated to last 24 months, or when the last patient 
discontinues from the study. 
Target  
Population: 
Patients who: 
 Have histologically confirmed metastatic or unresectable GIST 
 Have received prior treatment with avapritinib in a clinical 
trial and require continued therapy 
 Are free of disease progression since receiving avapritinib  
 Have adequate organ function 
 
Dosage and  
Administration: 
Avapritinib will be administered orally (PO) at the dose received 
by the patient on the prior avapritinib protocol in continuous 28-
day cycles. Dosing modifications for avapritinib-related toxicity is 
recommended; modification guidelines are provided in the 
protocol. 
Efficacy  
Evaluations: 
Disease responses as assessed by Investigator according to local 
standard of care. 
Safety  
Evaluations: 
General safety will be assessed by the monitoring and recording of 
all serious adverse events (SAEs), and adverse events of special 
interest (AESI) including cognitive effects and intracranial 
bleeding; regular monitoring of hematology and blood chemistry, 
regular measurement of vital signs and the performance of 
physical examinations and other safety assessments in accordance 
with standard of care. 
Safety  
Analysis: 
Serious Adverse events (SAEs) will be graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria 
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for Adverse Events (CTCAE) version 5. The proportion of patients 
who reported SAEs and AESIs will be collected and summarized 
for all patients who receive at least one dose of avapritinib. 
Summary of SAE and AESIs will also be provided by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ 
class (SOC) and preferred term (PT). Summary statistics will be 
provided for duration of avapritinib treatment. Dose 
discontinuation and reasons for dose discontinuation will also be 
reported. 
Efficacy Analysis: Investigators will monitor response to treatment according to local 
standard of care. Response to treatment will not be collected. 
 
 
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TABLE OF CONTENTS  
CLINICAL PROTOCOL ................................................................................................ 1 
Approval Page ................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................. 7 
LIST OF TABLES ............................................................................................................ 9 
LIST OF FIGURES .......................................................................................................... 9 
LIST OF ABBREVIATIONS ........................................................................................ 10 
1 
BACKGROUND AND RATIONALE .............................................................. 11 
1.1 
Background ......................................................................................................... 11 
1.1.1 Gastrointestinal Stromal Tumor ....................................................................... 11 
1.1.2 Avapritinib .......................................................................................................... 13 
1.1.3 Extension Study .................................................................................................. 14 
1.1.4 Extension Study Rationale ................................................................................. 14 
2 
STUDY OBJECTIVES ...................................................................................... 15 
3 
STUDY PLAN ..................................................................................................... 16 
3.1 
Study Design ........................................................................................................ 16 
4 
POPULATION .................................................................................................... 16 
4.1 
Number of Patients ............................................................................................. 16 
4.2 
Selection of Patients ............................................................................................ 16 
4.3 
Inclusion Criteria ................................................................................................ 16 
4.4 
Exclusion Criteria ............................................................................................... 17 
4.5 
Patient Identification and Registration ............................................................ 18 
4.6 
Patient Withdrawal Criteria .............................................................................. 18 
5 
STUDY CONDUCT ............................................................................................ 18 
5.1 
General Conduct ................................................................................................. 18 
5.2 
Early Study Termination ................................................................................... 22 
5.3 
Dose and Administration ................................................................................... 22 
5.3.1 Dose Reduction for Adverse Events .................................................................. 22 
5.4 
Prior and Concomitant Therapy ....................................................................... 23 
5.4.1 Prohibited Concomitant Therapy ..................................................................... 23 
5.4.2 Concomitant Therapy to be used with Caution ............................................... 24 
5.4.3 Permitted Concomitant Therapy ...................................................................... 24 
5.5 
Additional Precautions ....................................................................................... 24 
5.5.1 Contraception Requirements ............................................................................. 24 
5.5.2 Gamete and Embryo Banking ........................................................................... 26 
6 
DESCRIPTION OF STUDY PROCEDURES ................................................. 26 
6.1 
Assessment Prior to Initiating Treatment ........................................................ 26 
6.2 
Safety Assessments .............................................................................................. 26 
6.2.1 Physical Examination ......................................................................................... 26 
6.2.2 Eastern Cooperative Oncology Group Performance Status ........................... 26 
6.2.3 Vital Signs ............................................................................................................ 27 
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6.2.4 Clinical Laboratory Tests .................................................................................. 27 
6.2.5 Adverse Events and Concomitant Medications ............................................... 27 
6.3 
Assessment of Response ..................................................................................... 27 
6.4 
Patient Reported Outcome Instruments ........................................................... 28 
6.5 
Data Collection and Reporting .......................................................................... 28 
7 
STUDY DRUG MANAGEMENT ..................................................................... 28 
7.1 
Description ........................................................................................................... 28 
7.1.1 Avapritinib .......................................................................................................... 28 
7.2 
Accountability ..................................................................................................... 28 
7.3 
Compliance .......................................................................................................... 29 
8 
ADVERSE EVENTS .......................................................................................... 30 
8.1 
Definitions ............................................................................................................ 30 
9 
SERIOUS ADVERSE EVENTS ........................................................................ 30 
9.1 
Definition of Serious Adverse Event ................................................................. 30 
9.2 
Reporting Serious Adverse Events .................................................................... 31 
9.3 
Documenting Serious Adverse Events and Adverse Events of Special .......... 32 
Interest ................................................................................................................. 32 
9.4 
Assessment of Intensity ...................................................................................... 32 
9.5 
Assessment of Causality ..................................................................................... 33 
9.6 
Pregnancy Reporting .......................................................................................... 33 
9.7 
Overdose .............................................................................................................. 34 
10 
STATISTICS ....................................................................................................... 35 
11 
ETHICS AND RESPONSIBILITIES ............................................................... 35 
11.1 
Good Clinical Practice ........................................................................................ 35 
11.2 
Institutional Review Board ................................................................................ 35 
11.3 
Informed Consent ............................................................................................... 35 
11.4 
Records Management ......................................................................................... 36 
11.5 
Source Documentation ....................................................................................... 36 
11.6 
Study Files and Record Retention ..................................................................... 36 
11.7 
Liability and Insurance ...................................................................................... 36 
12 
AUDITING AND MONITORING .................................................................... 36 
13 
AMENDMENTS ................................................................................................. 38 
14 
STUDY REPORT AND PUBLICATIONS ...................................................... 39 
15 
STUDY DISCONTINUATION ......................................................................... 40 
16 
CONFIDENTIALITY ........................................................................................ 41 
17 
REFERENCES ................................................................................................... 42 
18 
APPENDICES ..................................................................................................... 45 
18.1 
Appendix 1: List of Prohibited Medications and Food ................................... 46 
18.2 
Appendix 2: List of Medications and Food to be Used with Caution ............ 46 
18.3 
Appendix 3: Eastern Cooperative Oncology Performance Group ................ 47 
Status .................................................................................................................... 47 
18.4 
Appendix 4: Investigator Signature Page ......................................................... 48 
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LIST OF TABLES  
Table 1:   
Schedule of Assessments ..........................................................................18  
Table 2:   
Dose Modification Guidelines for Avapritinib-related Toxicity ..........21  
  
LIST OF FIGURES  
Figure 1:  
Biochemical Activity of Avapritinib Against Disease-relevant KIT  
Mutants .....................................................................................................13  
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LIST OF ABBREVIATIONS  
Abbreviation  
Definition  
AE   
Adverse event  
AESI  
Adverse event of Special Interest  
CTCAE  
Common Terminology Criteria for Adverse Events  
CYP  
Cytochrome P450  
CRF  
CRO 
Case report form  
Clinical Research Organization 
GI  
Gastrointestinal  
GIST  
Gastrointestinal stromal tumor  
IB  
Investigator’s Brochure  
IEC  
Independent Ethics Committee  
KIT  
V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog 
NCI  
National Cancer Institute  
ORR  
Overall response rate  
PDGFRα  
Platelet-derived growth factor receptor alpha  
PFS  
Progression-free survival  
PO  
Orally  
PRO  
Patient reported outcome  
QD  
Once daily  
SAE  
Serious Adverse Event  
TKI  
Tyrosine kinase inhibitor  
 
 
 
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1 
BACKGROUND AND RATIONALE  
1.1 
Background   
1.1.1 
Gastrointestinal Stromal Tumor  
Gastrointestinal stromal tumors (GIST) is a rare sarcoma that arises 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% - 
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).   
Gastrointestinal stromal tumors 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.  
Molecular Pathology of GIST  
Approximately 90% of patients with newly diagnosed 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%) (Antonescu et al, 2005; Barnett and Heinrich, 
2012; Corless et al, 2005). A majority of mutations in PDGFRα occur at amino acid 842, 
with the most common mutation at this site being a substitution of valine for aspartic acid  
(D842V). The remaining cases, denoted as KIT and PDGFRα wild-type, are due to other 
abnormalities such as succinate dehydrogenase deficiency (Nannini et al, 2013).  
KIT-mutated GIST  
On a molecular level, the most common sites for mutations in KIT at the time of 
diagnosis are exon 11 (60-70%) and exon 9 (5-15%) with exon 17 mutations being 
identified in approximately 1% of patients (Debiec-Rychter et al, 2006; Heinrich et al, 
2008). Disease progression during treatment with a tyrosine kinase inhibitor (TKI) is 
most commonly due to the emergence of resistance mutations in KIT, including an 
increasing prevalence of those in exon 17, which are refractory to standard first and 
second line therapy, imatinib (Gleevec, 2016) and sunitinib (Sutent®, 2014). At the time 
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of progression on first-line TKI (imatinib) therapy, approximately 20-25% of patients had 
GIST harboring a mutation in exon 17 (Antonescu et al, 2005; Liegl et al, 2008; 
Wardelmann et al, 2006). No currently approved TKI selectively inhibits mutations in 
exon 17 of KIT.   
Although imatinib is effective in many patients with GIST as first-line therapy, some 
patients do not respond and subsequent lines of therapy for those who respond are 
significantly less effective. Therapeutic failure appears linked to acquired resistance 
mutations, particularly those involving the ATP binding pocket (exons 13 and 14) and 
activation loop (exons 17 and 18) of KIT (Heinrich et al, 2008). Post-imatinib,  
ATP-binding pocket mutations and activation-loop mutations occur at a rate of ~30% and 
~20%, respectively. Thirty-five percent of patients progress on imatinib without 
secondary mutations (mostly with KIT exon 9 mutations). The remainder of GIST  
patients who are unresponsive to imatinib harbor alterations in PDGFRα or succinate 
dehydrogenase (SDH). In KIT-mutant GIST, the response rate for patients with tumors 
bearing ATP-binding pocket mutations to sunitinib is low (ORR 11%) and responses 
rarely occur in the setting of activation-loop mutations (ORR 0%; Heinrich et al, 2008). 
Thus, patients failing imatinib due to either ATP-pocket or activation-loop mutations, 
represent an important medical need.   
PDGFRα-mutated GIST  
Gastrointestinal stromal tumors dependent on mutations in PDGFRα occur more 
frequently in the stomach, are more commonly resectable, have a somewhat more 
indolent clinical course than KIT-dependent GIST, and are less 2-deoxy-2-[fluorine-
18]fluoro-D-glucose positron emission tomography (18FDG-PET) avid compared to 
GIST dependent on a mutation in KIT (Matro et al, 2014). Despite the more indolent 
course while localized, once metastatic, patients with GIST harboring the PDGFRα 
D842V mutation have an extremely poor prognosis and respond poorly to imatinib and 
other TKIs (Cassier et al, 2012; Goodman et al, 2007; Heinrich et al, 2008; Yoo et al, 
2016).  
In a retrospective study, Cassier et al identified 44 patients with PDGFRα-mutant GIST 
who had advanced disease from databases at 12 European institutions  
(N = 3,510 genotyped GIST patients) and an additional 16 patients with advanced, 
PDGFRα-mutant GIST from the European Organisation for Research and Treatment of 
Cancer (EORTC) advanced GIST database (N = 465 genotyped GIST patients). Of 58 
patients evaluable for efficacy post-imatinib, 32 patients (55%) had the  
PDGFRα D842V mutation and the remainder had mutations in PDGFRα exon 4, 12, or 
18 (non-D842V). The non-D842V patients had an overall response rate (ORR) of 36% 
with imatinib and median PFS >1 year. In contrast, patients with the D842V-mutation 
had no response (ORR = 0%). Median PFS with second-line treatment was short (2.1 
months) and was not significantly different between imatinib, sunitinib, and other 
treatments. Similarly, in a small, retrospective Korean study (N=18) PDGFRα-mutant 
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GIST patients treated with imatinib reported a similar PDGFRα D842V prevalence (9/18; 
50%) and poor outcome (median PFS 3.8 months and ORR 0% [0/5 evaluable patients]). 
Patients with the D842V substitution treated with sunitinib as second-line therapy 
reported median PFS 1.9 months and ORR 0% (Yoo et al, 2016). A recent multicenter, 
retrospective study of adult patients with locally advanced, metastatic, or recurrent 
PDGFRα D842 mutant GIST diagnosed between Jan 2000 and Jul 2016 who were treated 
with at least one TKI showed a median PFS consistent with the findings of other studies 
that have shown a median PFS of 3–5 months. Twenty-two patients were identified at 3 
US academic institutions. One patient had a complete response to first-line imatinib 
following partial resection of the primary tumor and completed 1 year of treatment. No 
complete or partial responses were reported in patients receiving TKI treatment in the 
second-line or third-line setting. Median PFS across the first-, second- and third-line 
treatment groups was 5.6, 2.6, and 5.6 months, respectively (von Mehren et al, 2018).  
Avapritinib was first approved in the US on January 2020 for the treatment of adults with 
metastatic GIST harboring a PDGFRA exon 18 mutation and then received conditional 
approval in the EU in September 2020 as monotherapy for adult patients with 
unresectable or metastatic GIST harboring the PDGF D842V mutation. Avapritinib 
currently has an orphan drug designation in both the US and EU. 
1.1.2 
Avapritinib  
Avapritinib, 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-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.   
Avapritinib has demonstrated clinically important activity against GIST following 3 or 
more prior lines of therapy, and regardless of line of therapy in the setting of an exon 18 
mutation in PDGFRA in the ongoing NAVIGATOR clinical study (Heinrich et al, 2018).  
Please refer to the avapritinib Investigator’s Brochure (IB) for additional information.    
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Figure 1:  
Biochemical Activity of Avapritinib Against Disease-relevant KIT 
Mutants  
 
Source: Evans EK et al. Sci Transl Med. 2017;9(414):eaao1690  
1.1.3 
Extension Study   
This extension study is designed to provide long term safety data for GIST patients who 
are deriving clinical benefit from avapritinib on an existing avapritinib trial. GIST is a 
serious or immediately life-threatening condition, for which there are no standard 
treatment options available and continued treatment with avapritinib remains an effective 
treatment option.  
This study is sponsored by Blueprint Medicines.  
1.1.4 
Extension Study Rationale  
This extension study is designed to provide long term safety data for GIST patients who 
have been deriving clinical benefit from avapritinib treatment on an avapritinib trial that 
is has met its primary endpoints. 
This extension study is designed to provide ongoing safety data on patients previously 
enrolled on avapritinib safety and efficacy studies, that have completed their planned 
analyses.   
1.1.5 
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 
  
  
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metastatic and locally advanced, unresectable GIST. Sunitinib and regorafenib 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.  
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 al, 2015).  
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.   
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of avapritinib may be found in the avapritinib IB. 
2 
STUDY OBJECTIVES  
The objectives of the extension study are:  
 To provide long term safety data for GIST patients who are deriving clinical 
benefit from avapritinib on an existing avapritinib clinical trial  
 To further characterize the rate of SAEs and AESIs of avapritinib. 
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3 
STUDY PLAN  
3.1 
Study Design  
This is an open-label extension study to provide long term safety data for GIST patients 
who are deriving clinical benefit from avapritinib on an existing clinical trial. Avapritinib 
will be administered orally (PO) in adult patients with unresectable GIST until such time 
that avapritinib becomes available through other mechanisms or the Sponsor chooses to 
discontinue the Study.  Avapritinib will be administered once daily (QD) at the dose 
received by the patient on the prior avapritinib protocol in continuous 28-day cycles, with 
a maximum dose of 300 mg QD.   
All study visits are intended to be conducted on an outpatient basis but may be conducted 
on an inpatient basis as needed. After provision of written informed consent, patients will 
be evaluated for eligibility during the screening period before avapritinib administration 
on Cycle 1 Day 1 (C1D1). A treatment cycle is 28 days in duration.   
No minimum or maximum treatment duration has been set. Patients will be monitored at 
regular intervals for safety and for response to treatment, as per investigator assessed 
response. Patients may continue to receive avapritinib until precluded by toxicity, 
noncompliance, patient decision, physician decision, progressive disease, death, or 
closure of the study by the Sponsor.  
All patients will have an End of Study evaluation with reason for discontinuation 
recorded.   
4 
POPULATION  
4.1 
Number of Patients  
Approximately 5 patients may be enrolled in this extension study. 
4.2 
Selection of Patients  
Patients must meet the inclusion and exclusion criteria to be enrolled in the trial. The 
Sponsor will consider inclusion of patients who do not meet the inclusion and exclusion 
criteria on a case by case basis following receipt of supporting information and rationale 
from the Investigator. Such exceptions may also require approval by the Independent 
Ethics Committee (IEC), as appropriate.  
4.3 
Inclusion Criteria  
Patients meeting the following criteria will be eligible for participation in the Study:  
1. Patient has histologically confirmed metastatic or unresectable GIST as 
established by entry in a previous avapritinib clinical trial and has been receiving 
treatment with avapritinib on one of these trials.  
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2. Patient continues to receive clinical benefit from avapritinib treatment, as 
assessed by the investigator. 
3. Patient or legal guardian, if permitted by local regulatory authorities, provides 
informed consent. 
4.4 
Exclusion Criteria  
Patients meeting any of the following criteria will not be eligible for Study participation:  
1. Patient requires therapy with a concomitant medication that is a strong inhibitor 
or strong inducer of cytochrome P450 (CYP) 3A4 (see Section 5.4.1).  
2. Patient has a history of intracranial bleeding either prior to or during avapritinib 
treatment  
3. Patients who have poor organ function, defined as Adverse Events of NCI 
CTCAE version 5.0 Grade 3 or higher at the time of enrollment must delay start 
of treatment until symptoms return to Grade 2 or baseline, or the start of treatment 
has been approved by the Sponsor. 
4. Patients who have ongoing cognitive or mood effects Adverse Events of NCI 
CTCAE version 5.0 higher than Grade 1 must delay start of treatment until 
symptoms return to Grade 1 or baseline.  
5. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain 
from sexual intercourse or employ highly effective contraception from the time of 
enrollment and for at least 30 days after the last dose of avapritinib. Men who are 
unwilling, if not surgically sterile, to abstain from sexual intercourse or employ 
highly effective contraception from the time of first dose and for at least 90 days 
after the last dose of avapritinib. Refer to Section 5.5.1 for acceptable methods of 
contraception.  
6. 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 enrollment. 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.  
7. Women who are breast feeding.  
8. Patients with a known hypersensitivity to avapritinib or the excipients. 
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4.5 
Patient Identification and Registration  
Patients who are candidates for enrollment into this extension protocol will be evaluated 
for eligibility by the Investigator to ensure that the inclusion (see Section 4.3) and 
exclusion criteria (see Section 4.4) are met. Patients must be registered with the Sponsor 
(or Clinical Research Organization [CRO]) prior to approval for entry to the Study.   
4.6 
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, the primary reason(s) for discontinuation is to be 
recorded in the case report form (CRF). Following discontinuation of Study drug, all 
efforts will be made to complete and report the protocol-defined Study observations as 
completely as possible.  
If a patient discontinues treatment because of an adverse event (AE), protocol-specified 
safety follow-up is to be performed, and the patient should remain under the supervision 
of the Investigator or designee until the condition has returned to baseline or stabilized.   
5 
STUDY CONDUCT  
5.1 
General Conduct  
The schedule of assessments for the Study is provided in Table 1.   
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The end of the Study is defined as the time that the last patient completes his/her last 
visit.   
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 Table 1:  
Schedule of Assessments 
Study Activitiesa 
Screening 
Treatment 
EOTb 
Cycle 
 
C1 
Every 3 
months (+/- 
15 days) 
 
Program Day 
D0–28 
D1 
D1 
 
Informed consent 
X 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
Demographics 
X 
 
 
 
Physical examinationc 
X 
X 
X 
X 
Vital signsd 
X 
X 
X 
X 
ECOG statuse 
X 
 
 
 
Pregnancy (β-hCG) testf 
X 
 
X 
 
Hematologyg 
X 
X 
X 
X 
Serum chemistryh 
X 
X 
X 
X 
Efficacy assessmenti 
 
 
Per 
Investigator 
discretion 
 
Avapritinib administrationj 
 
X 
 
SAE and AESI monitoringk 
 
X 
Abbreviations:  AE = adverse event; AESI = adverse event of special interest; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated 
partial thromboplastin time; AST = aspartate aminotransferase; β-hCG = beta human chorionic gonadotropin; BUN = blood urea nitrogen; C = cycle, D = day, 
ECOG = Eastern Cooperative Oncology Group, EOT = end-of-treatment; GIST = gastrointestinal stromal tumor; Hgb = hemoglobin; INR = international 
normalized ratio; QD = once daily;SAE = serious adverse event; ULN = upper limit of normal. 
 
a Additional safety tests may be performed whenever clinically indicated, at the Investigator’s discretion. Whenever a test result is questionable, it should be 
repeated. Timing of procedures may be modified at Investigator discretion. 
b At EOT, the reason for EAP discontinuation and last day of dosing should be recorded. This can be done by telephone if necessary.  
c A complete physical examination including weight, evaluation of the skin, head and neck, lymph nodes, heart, lungs, breasts, abdomen, pelvis (if indicated 
based on symptoms), musculoskeletal system, neurologic system, and a basic assessment of mental status and mood will be performed at the Screening visit. 
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Subsequent physical examinations will focus on weight, signs of GIST, changes from previous physical examinations, neurologic, mental status, and mood 
examinations, and AEs.  
d Vital signs include temperature, pulse, systolic/diastolic blood pressure, and weight.  
e Refer to Appendix 3 for ECOG performance status scoring. 
f To be performed for women of child-bearing potential. A serum pregnancy test should be performed at baseline (within 7 days before the first dose of 
avapritinib). Serum or urine pregnancy test should be performed on D1 of every study visit, or more frequently if required by local requirements. 
g Hematology parameters to be measured include hemoglobin, white blood cell count with differential count, and platelet count. 
h Serum chemistry panel includes sodium, potassium, BUN or urea, bicarbonate (venous), creatinine, calcium, chloride, magnesium, phosphorus, albumin, AST, 
ALT, ALP, and total bilirubin (direct bilirubin if total bilirubin is > ULN).  
i Disease response assessments should be performed per standard of care.  
j Avapritinib will be administered QD in the morning at least 2 hours after and 1 hour before eating. 
k SAEs, AESIs and concomitant medications are to be collected from the date of the informed consent signature through end of treatment. See Section 9 for 
details of SAE/AESI. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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5.2 
Early Study 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.   
Circumstances that may warrant early termination include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to patients;  
• 
Other administrative reasons.  
Should the Study be terminated prematurely, all Study materials must be returned to the 
Sponsor or Sponsor’s designee.  
5.3 
Dose and Administration  
Avapritinib will be administered PO at the dose received by the patient on the prior 
avapritinib protocol in continuous 28-day cycles. Dosing will be continuous, with no 
inter-cycle rest periods unless warranted for individual safety reasons. Pre-specified dose 
modification recommendations for AEs related to avapritinib are described in Section 
5.3.1.   
Avapritinib should be administered with a glass of water (at least 8 ounces or 250 mL). 
The tablets should be taken on an empty stomach at least 1 hour before or least 2 hours 
after a meal. Each dose should be administered at approximately the same time each day. 
Do not make up for a missed dose within 8 hours of the next scheduled dose. If a patient 
vomits during or after taking avapritinib, the dose should not be replaced, and the next 
dose should be taken at the next scheduled dosing time.  
Patients should be instructed to swallow tablets whole and to not chew the tablets.  
Interruption in avapritinib dosing may be required for surgery or other procedure during 
the treatment period. At a minimum, avapritinib should be discontinued 48 hours before 
the procedure and resumed 48 hours after the procedure is completed.  
5.3.1 
Dose Reduction for Adverse Events  
Dosing modifications are recommended for patients experiencing avapritinib-related 
toxicity. Modification guidelines are summarized in Table 2.  
If a patient experiences a Grade 3 or worse (based on NCI CTCAE criteria) AE thought 
to be caused by avapritinib, avapritinib treatment should be interrupted until the AE 
improves to Grade 2 or to the patient’s baseline, or it is considered stable, and does not 
preclude continued therapy. At that time, avapritinib treatment may resume either at the 
same dose, or at reduced dose. Dose reductions should be in increments of 100 mg. If a 
Grade 3 or worse AE recurs, dosing should be interrupted as described above, and if 
dosing is resumed, the dose should be reduced by at least 100 mg.   
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Table 2:   
Dose Modification 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 1-4 
 
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. 
 
5.4 
Prior and Concomitant Therapy  
5.4.1 
Prohibited Concomitant Therapy  
Concomitant treatment with drugs that are strong CYP3A4 inhibitors are prohibited (refer 
to Appendix 1 for a list of strong CYP3A4 inhibitors).  
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Avapritinib should not be administered simultaneously with other antineoplastic therapy.  
If radiotherapy is required to treat local sites of disease, avapritinib treatment should be 
interrupted for 2 days prior to the first fraction of radiotherapy through 2 days after the 
last fraction.   
5.4.2 
Concomitant Therapy to be used with Caution  
Medications that are CYP2C9, CYP3A4, or BCRP substrates with a narrow therapeutic 
index should be used with caution (Refer to Appendix 2 for a list of these medications).  
In addition, medications that are known to increase the risk of seizures should be used 
with caution.  
5.4.3 
Permitted Concomitant Therapy  
Medications and treatments other than those specified in Section 5.4.1 and Section 5.4.2, 
including pallative and supportive care for disease-related symptoms are permitted.  
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. 
Prophylaxis for nausea, vomiting, and diarrhea may be given as needed.  
5.5 
Additional Precautions  
The light absorption characteristics of avapritinib suggest the possibility the avapritinib 
treatment will be associated with phototoxicity. Therefore, patients should use clothing 
and sunscreen to avoid direct sun exposure.   
Avapritinib treatment has been associated with seizures at high doses in toxicology 
studies in rats, and with intracranial bleeding in toxicology studies in dogs. There have 
been cases of intracranial bleeding in patients treated with avapritinib. Therefore, patients 
at increased risk of seizure, or increased risk of intracranial bleeding (such as those with a 
vascular aneurysm or a history of intracranial bleeding within the prior year) should only 
receive avapritinib if the potential benefits are anticipated to exceed the increased risk.  
5.5.1 
Contraception Requirements  
Women of childbearing potential must agree to use a highly effective method of 
contraception (CTFG, 2014) from the time of enrollment until at least 30 days after the 
last dose of avapritinib. Women are considered to be of childbearing potential after 
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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 their participation in the Study, and for 90 days after the last dose of 
avapritinib. 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);   
• 
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.   
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5.5.2 
Gamete and Embryo Banking  
Hypospermatogenesis was observed in the testis and epididymis of rats and dogs and did 
not recover after 2-week recovery. Patients should be reminded of the possibility of 
gamete and embryo banking.  
6 
DESCRIPTION OF STUDY PROCEDURES  
Upon entry into the Study, the following baseline procedures and laboratory tests are to 
be performed before treatment with avapritinib is initiated. Please refer to Table 1 for the 
Schedule of Assessments.  
6.1 
Assessment Prior to Initiating Treatment  
The following procedures will be performed at the Screening visit:  
• 
Obtain Informed Consent;  
• 
Obtain demographic data, including gender, date of birth/age, race, and ethnicity;  
• 
Complete physical examination, basic neurological assessment, and ECOG 
performance status;  
• 
Vital signs including height, weight, temperature, pulse, and systolic/diastolic blood 
pressure;  
• 
Clinical laboratory assessment (hematology, coagulation, serum chemistry);  
• 
Serum pregnancy test (for women of childbearing potential only);   
6.2 
Safety Assessments  
The schedule of safety assessments is detailed in Table 1. Additional safety assessments 
may be performed when clinically indicated, at the Investigator’s discretion.  
6.2.1 
Physical Examination  
A complete physical examination will be performed at the Screening visit. Subsequent 
physical examinations will be performed as outlined in Table 1, and will focus on 
symptoms and signs of GIST, changes from previous physical examinations, and AEs.   
6.2.2 
Eastern Cooperative Oncology Group Performance Status  
Determination of ECOG performance status will be performed at the time points outlined 
in Table 1. Refer to Appendix 3 for ECOG performance status scoring.  
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6.2.3 
Vital Signs  
Vital sign measurement will include temperature, systolic/diastolic blood pressure, and 
pulse, and will be performed at the time points outlined in Table 1.  
6.2.4 
Clinical Laboratory Tests  
Clinical laboratory evaluations will be performed at the local laboratory.  
Clinical laboratory evaluations will be conducted at the time points outlined in Table 1. 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 parameters are to be evaluated by the Investigator:  
Hematology:  
Hemoglobin (Hgb), white blood cell with differential count, platelet  
count   
Serum chemistry:  
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)  
Serum or Urine  
Pregnancya: 
β-hCG  
a For women of childbearing potential only, as defined in Section 9.6. A serum pregnancy test should be 
performed at baseline (within 7 days before the first dose of avapritinib). Serum or urine pregnancy test 
should be performed as required per local regulations and as outlined in Table 1.   
6.2.5 
Adverse Events and Concomitant Medications  
Each patient must be carefully monitored for the development of any AEs throughout the 
study from the start of avapritinib administration (or from the time of signing informed 
consent, for SAEs) to 30 days after the last administration.   In addition, SAEs that are 
assessed to be at least possibly related to Study treatment that occur > 30 days 
posttreatment are to be reported.  
Adverse events will be recorded locally, but only SAEs will be reported to the sponsor or 
its designee.  Complete details on AE and SAE monitoring are provided in Section 8 and 
Section 9, respectively.  
Concomitant medications will be recorded from the time of signing informed consent to 
30 days after the last dose.  
6.3 
Assessment of Response  
Investigator will perform assessment of response to treatment with avapritinib per local 
standard of care.   
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6.4 
Patient Reported Outcome Instruments  
No patient reported outcome instruments will be used in this study. 
6.5 
Data Collection and Reporting  
Limited data will be collected from this study as the primary analysis has been completed 
for the initial clinical trials conducted in this setting.  Nevertheless, adverse events will be 
reported and SAEs should be reported to the Sponsor, as required.  Treatment records 
including record of drug dispensation shall be maintained to ensure appropriate drug 
accountability.  
7 
STUDY DRUG MANAGEMENT  
7.1 
Description  
7.1.1 
Avapritinib  
7.1.1.1  
Formulation  
Avapritinib will be administered as an immediate release tablet for oral administration.  
The drug substance and drug product are manufactured and formulated following current 
Good Manufacturing Practices (GMP). Avapritinib tablets are prepared as 100 mg in 
strength.    
7.1.1.2  
Storage  
Avapritinib tablets must be stored at 15°C to 30°C (59°F to 86°F), in their original 
container, according to the package label. If the product has been exposed to 
temperatures outside of this range, advice must be sought from the Sponsor as to whether 
the product is still suitable for patient use.  
7.1.1.3  
Packaging and Shipment  
Avapritinib tablets will be supplied 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. Bottles will contain 30 tablets each.  
7.2 
Accountability  
Accountability for avapritinib at the clinical site is the responsibility of the Investigator.  
The Investigator will ensure that avapritinib 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 site, use by each patient, and return to 
the Sponsor or its designee (or disposal of the drug, if approved by the Sponsor). These 
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records will adequately document that the patients were provided the doses as specified 
in the protocol and should reconcile all avapritinib 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 site on an ongoing basis during monitoring visits.  
Avapritinib must not be used for any purpose other than this Study. Avapritinib 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.  
All used, unused, or expired avapritinib will be returned to the Sponsor or its designee, or 
if authorized, disposed of at the clinical site per the site’s Standard Operating Procedures 
and documented. All material containing avapritinib will be treated and disposed of as 
hazardous waste in accordance with governing regulations.  
7.3 
Compliance  
Patients will be dispensed the appropriate number of avapritinib bottles to allow for 
dosing until the next scheduled visit. Patients are to return all unused capsules and tablets 
(or the empty bottles) at the next scheduled visit. Compliance with the dosing regimen 
will be assessed based on return of unused drug (or empty bottles).  
 
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8 
ADVERSE EVENTS  
All patients will be monitored for adverse events throughout their participation in the 
Study.  Serious AEs and adverse events of special interest (AESIs) will be recorded in the 
CRF from the time of first dose of avapritinib through 30 days after the last avapritinib 
dose. In addition, serious adverse events (SAEs) and AESIs that are assessed as related to 
avapritinib treatment and that occur > 30 days posttreatment will also be reported. All 
related SAEs and AESIs should be monitored until they are resolved, stabilized, have 
returned to pre-exposure baseline, determined to be due to another illness, or until a 
subsequent therapy is initiated.   
8.1 
Definitions  
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (eg, an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality. An AE can arise from any use of the drug (eg, off-label use, 
use in combination with another drug) and from any route of administration, formulation, 
or dose, including an overdose. Overdose includes only clinically symptomatic doses that 
are at least twice the intended dose.  
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the Investigator to be clinically significant.  
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 
SERIOUS ADVERSE EVENTS  
9.1 
Definition of Serious Adverse Event  
A SAE is any event that meets any of the following criteria:  
• 
Death  
• 
Life-threatening  
A serious adverse event is life threatening if the patient was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a 
more serious form might have caused death. For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening 
even though drug induced hepatitis can be fatal.  
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• 
Inpatient hospitalization or prolongation of existing hospitalization  
Adverse events requiring hospitalization should be considered SAEs. Hospitalization for 
elective surgery or routine clinical procedures that are not the result of AE (e.g., elective 
surgery for a pre-existing condition that has not worsened) need not be considered AEs or 
SAEs. If anything, untoward is reported during the procedure, that occurrence must be 
reported as an AE, either 'serious' or 'non-serious' according to the usual criteria.  
In general, hospitalization signifies that the patient has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient 
setting. When in doubt as to whether 'hospitalization' occurred or was necessary, the AE 
should be considered serious.  
• 
Persistent or significant disability/incapacity  
An SAE 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.  
• 
Congenital anomaly/birth defect in the offspring of a subject who received 
avapritinib.  
• 
Other: 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 one of the outcomes listed in this definition.  
Examples of such events are:  
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 o 
Development of drug dependency or drug abuse  
9.2 
Reporting Serious Adverse Events  
All SAEs or serious pretreatment events 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, SAEs will be captured in the safety database only, 
they will not be captured in an CRF. 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. 
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 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 
 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. 
 
9.3 
Documenting Serious Adverse Events and Adverse Events of Special  
Interest  
Each patient must be carefully monitored for the development of any SAEs and AESIs,  
Adverse Events of Special Interest for avapritinib are, regardless of grade or causality:  
• 
cognitive effects which include the following terms: memory impairment, cognitive 
disorder, confusional state and encephalopathy.   
• 
intracranial bleeding including haemorrhage intracranial, cerebral haemorrhage , and 
subdural haematoma.   
This information should be obtained in the form of non-leading questions (eg, “How are 
you feeling?”) and from signs and symptoms detected during each examination, 
observations of study personnel, and spontaneous reports from patients.  
All SAEs and AESIs reported by the patient or revealed by observation, physical 
examination, laboratory testing or other diagnostic procedures will be recorded in the 
appropriate section of the CRF. When possible, signs and symptoms indicating a 
common underlying pathology should be noted as one comprehensive event.  
9.4 
Assessment of Intensity  
Intensity of all AEs, including clinically significant treatment-emergent laboratory 
abnormalities, will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse events not 
listed in the CTCAE will be graded as follows:  
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• 
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.  
9.5 
Assessment of Causality  
Relationship to avapritinib administration will be determined by the Investigator 
according to the following criteria:  
• 
Not Related: Exposure to avapritinib did not occur, or the occurrence of the AE is not 
reasonably related in time, or the AE is clearly caused by something other than 
avapritinib.  
• 
Related: The AE does not meet the criteria for “Not Related”.  
9.6 
Pregnancy Reporting  
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).  
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female patient or partner of a male patient occurring while the 
patient is being treated with avapritinib, or within 30 days of the patient’s last dose of 
avapritinib, are considered immediately reportable events. If a female partner of a male 
patient taking investigational product becomes pregnant, the male patient taking 
avapritinib should notify the Investigator, and the pregnant female partner should be 
advised to call her healthcare provider immediately. In pregnant female patients, 
avapritinibis to be discontinued immediately and the patient instructed to return any 
unused avapritinib to the Investigator. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported immediately using the Pregnancy Report Form. 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 or partner of a male 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.  
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All outcomes of pregnancy must be reported by the Investigator to the Sponsor or 
Medical Monitor on a Pregnancy Outcome Report form within 30 days after he/she has 
gained knowledge of the delivery or elective abortion.  
Any SAE that occurs during pregnancy 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 SAEs.  
9.7 
Overdose  
Overdose includes only clinically symptomatic doses that are at least twice the intended 
dose. Any instance of overdose (suspected or confirmed and irrespective of whether or 
not it involved avapritinib) must be communicated to Blueprint Medicines or a specified 
designee within 24 hours and be fully documented as an SAE. Details of any signs or 
symptoms and their management should be recorded including details of any antidote(s) 
administered.  
 
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10 STATISTICS  
Sample size estimation is not based on any hypothesis testing, rather an estimation of 
how many patients might roll over to avapritinib treatment after participation in an 
avapritinib clinical trial. Safety assessments in these patients from this protocol will be 
considered as continuum of these same patients while on other avapritinib studies when 
assessments of avapritinib safety in target populations are performed. 
The Safety Population is defined as all patients who enroll in and receive at least one 
dose of avapritinib on this Study. Reasons for treatment discontinuation will be reported. 
Duration of treatment will be summarized descriptively. SAE and AESIs will be 
summarized by Medical Dictionary for Regulatory Activities (MedDRA) system organ 
class (SOC) and preferred term (PT) in the Safety Population.    
11 ETHICS AND RESPONSIBILITIES  
11.1 Good Clinical Practice  
The Study will be conducted in accordance with the International Conference on  
Harmonization (ICH) for GCP and the appropriate regulatory requirement(s). The 
Investigator will be thoroughly familiar with the appropriate use of avapritinib 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 Ethics Committee  
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  
The Investigator must obtain 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 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 
clinical centers where IEC approval has been obtained. The protocol, IB, informed 
consent form, written information given to the patients, safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IEC. The 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 IEC according to local regulations and guidelines.  
11.3 Informed Consent  
Physicians are responsible for obtaining consent from each patient being treated with 
avapritinib as a part of the Study. The patient or the patient’s legal representative must 
give written consent prior to receiving treatment.   
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11.4 Records Management  
All data for the patients recruited for the Study will be entered onto the CRFs. Only 
authorized staff may enter data into the CRFs. If an entry error is made, the corrections to 
the CRFs will be made according to CRF guidelines by an authorized member of the site 
staff.  
11.5 Source Documentation  
Source documents/CRFs 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/CRF. The source document/CRF 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/CRF as soon as possible after information is collected, preferably on the same 
day that the 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/CRF to endorse the recorded data.   
The Investigator will retain all completed source documents  
11.6 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 for at least 2 years after the last 
marketing application approval 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.  
11.7 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 
phone or email routinely from a representative of the Sponsor (site monitor) and will 
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include questioning with regard to patient enrollment, status on treatment, data 
submission and clarification, drug disposition, and potential request for source 
documents, and clarification of administrative matters. All submitted documents should 
be redacted 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 avapritinib 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 IEC, and/or the Sponsor’s clinical quality assurance group or 
designee may request access to all source documents, CRFs, 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.   
 
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13 AMENDMENTS  
Protocol modifications, except those intended to reduce immediate risk to 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 
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 IEC and the Investigator must await 
approval before implementing the changes.   
If in the judgment of the IEC, the Investigator, and/or Blueprint Medicines, the 
amendment to the protocol substantially changes the design and/or increases the potential 
risk to the patient and/or has an impact on the patient's involvement as a 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 appropriate reports according to the applicable regulatory requirements.  
The publication policy of Blueprint Medicines is discussed in the Investigator's Clinical 
Research Agreement.  
 
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15 STUDY DISCONTINUATION  
Blueprint Medicines has initiated this Study to provide long-term safety data for patients 
who are deriving clinical benefit from avapritinib on an existing avapritinib clinical trial. 
Patients must meet strict inclusion criteria to be eligible for treatment with avapritinib. 
Blueprint Medicines will provide the drug used in this Study free of charge whenever 
possible but is not obligated to do so in all cases or after drug is commercially available 
in any market.   
Blueprint Medicines reserves the right to terminate the Study at any time; however, the 
intent is to continue until the drug is commercially available in any market, or other 
events dictate the need to close the Study and cease supply. In consideration of patients’ 
best interests, Blueprint Medicines intends to provide physicians and patients reasonable 
advance notice of discontinuation.   
Physicians and patients reserve the right to withdraw their consent to participate in the 
Study at any time for any reason.   
 
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16 CONFIDENTIALITY  
All information and data generated from treatment with avapritinib is considered 
confidential and must not be used or disclosed to any person or entity not directly 
involved unless prior written consent is gained from Blueprint Medicines. This 
information and data is owned by Blueprint Medicines.  
Authorized regulatory officials, IEC personnel, Blueprint Medicines and its authorized 
representatives are allowed access to the records.  
 
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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.  
Barnett CM, and Heinrich MC. Management of tyrosine kinase inhibitor-resistant 
gastrointestinal stromal tumors. Am Soc Clin Oncol Educ Book. 2012:663-8.  
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 2014  Recommendations related to contraception and pregnancy testing in 
clinical trials. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.  
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, 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. 2013;381(9863):295-302.  
FDA  2016  Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers.  
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginter 
actionslabeling/ucm093664.htm.  
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 
nationwide study. Eur J Cancer. 2005;41(18):2868-72.  
Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, et al. 
Approval summary: sunitinib for the treatment of imatinib refractory or intolerant 
gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res.  
2007;13(5):1367-73.  
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Heinrich M, Mehren Mv, Jones R, and al e. Avapritinib is highly active and welltolerated 
in patients (PTS) with advanced GIST driven by diverse variety of oncogenic mutations 
in KIT and PDGFRA. In Annual Meeting of the Connective Tissue Oncology Society. 
2018, Vol. 012 #3027631. Rome, Italy.  
Heinrich MC, Maki RG, Corless CL, Antonescu CR, Harlow A, Griffith D, et al. Primary 
and secondary kinase genotypes correlate with the biological and clinical activity of 
sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 
2008;26(33):5352-9.  
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.  
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.  
Matro JM, Yu JQ, Heinrich MC, Ramachandran A, Ku N, and Mehren Mv. Correlation 
of PET/CT and CT RECIST response in GIST patients with PDGFRA D842V gene 
mutations treated with crenolanib. Journal of Clinical Oncology. 
2014;32(15_suppl):10546-10546.  
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.  
Nannini M, Biasco G, Astolfi A, and Pantaleo MA. An overview on molecular biology of 
KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST). J Med Genet. 
2013;50(10):653-61.  
NCCN. National Comprehensive Cancer Network. Soft Tissue Sarcoma (Version 1.  
2015) [Online]. Available at:  
http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 22 April 
2015. 2015.  
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.  
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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®. [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals 
Inc.; 2017 [Online]. Available at: http://labeling.bayerhealthcare.com/html/products/pi/ 
Stivarga_PI.pdf. Accessed 31 August 2017. 2017.  
Sutent®. [Prescribing Information]. New York, NY: Pfizer Labs; 2014 [Online]. 
Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=607. Accessed 09 March 
2015. 2014.  
von Mehren M, M H, H S, P M, K M, A B, et al. A retrospective natural history study of 
patients with PDGFRα D842V mutant advanced gastrointestinal stromal tumor 
previously treated with a tyrosine kinase inhibitor. In American Society of Clinical 
Oncology Annual Meeting. 2018. Chicago, IL.  
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  
 
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18.1 Appendix 1: List of Prohibited Medications and Food  
EXCLUDED MEDICATIONS AND FOODS FOR PATIENTS RECEIVING  
AVAPRITINIB  
Strong CYP3A4 Inhibitors  
 
Boceprevir  
Strong CYP3A4 Inducers  
 
Carbamazepine  
Moderate CYP3A4 Inducers  
 
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.  
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. 
Source: (FDA, 2016)  
18.2 Appendix 2: List of Medications and Food to be Used with Caution  
MEDICATIONS TO BE USED WITH CAUTION WITH AVAPRITINIB  
 
CYP3A4 Substrates  
CYP2C9 Substrates  
BCRP Substrates  
Moderate CYP3A4 
Inhibitors  
 
Alfentanil  
Warfarin  
Rosuvastatin  
Erythromycin 
Cyclosporine  
Phenytoin  
Methotrexate  
Fluconazole  
Dihydroergotamine  
  
Lapatinib  
Crizotinib  
Ergotamine  
  
  
Dronedarone  
Fentanyl  
  
  
Imatinib  
Midazolam  
  
  
Diltiazem  
Pimozide  
  
  
  
Quinidine  
  
  
  
Simvastatin  
  
  
  
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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.  
Source: (FDA, 2016)  
18.3 Appendix 3: Eastern Cooperative Oncology Performance Group  
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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Protocol BLU-285-1408 
Confidential 
BLU-285  
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Blueprint Medicines Corporation 
07 April 2021 
18.4 Appendix 4: Investigator Signature Page 
Protocol BLU-285-1408 
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 participate in the 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 Conference on 
Harmonization guidelines.  
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  
DocuSign Envelope ID: 83BB163E-6249-439E-B947-D030B18B37E5