A Phase 1/2 Study of ARQ 087 in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations, Including Intrahepatic Cholangiocarcinoma With FGFR2 Gene Fusion
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Basilea Pharmaceutica

NCT01752920

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SYNOPSIS 
Study Title: 
A Phase 1/2 Study of ARQ 087 in Adult Subjects with Advanced Solid Tumors with 
FGFR Genetic Alterations, Including Intrahepatic Cholangiocarcinoma with FGFR2 
Gene Fusion 
Study Number: 
ARQ 087-101 
Study Phase:  
1/2 
Primary Objective:  To assess the safety and tolerability of ARQ 087 in subjects with advanced solid 
tumors (Part 1; Dose Escalation/Food-effect Cohorts) or with advanced solid tumors 
with FGFR genetic alterations, including intrahepatic cholangiocarcinoma (iCCA) 
with FGFR2 gene fusion (Part 2; Expanded Cohort, signal finding). 
Secondary 
Objectives: 
 
 
To assess the pharmacokinetic profile of ARQ 087 in subjects enrolled in Part 1 
(Dose Escalation/Food-effect Cohorts) of the study  
 
To assess the pharmacodynamic activity of ARQ 087 in blood and tumor biopsy 
specimens obtained from subjects with advanced solid tumors 
 
To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 
dose (RP2D) of ARQ 087 (Part 1) 
 
To further evaluate the RP2D of ARQ 087 in subjects with FGFR genetic 
alterations, including subjects with iCCA with FGFR2 gene fusion (Part 2; 
Expanded Cohort, signal finding) 
 
To generate preliminary evidence of anti-tumor activity  
 
To generate preliminary biomarker evidence of target inhibition 
 
To identify specific target subject (patient) population, e.g., subjects with iCCA 
with FGFR2 gene fusion or with other solid tumors with FGFR genetic 
alterations 
Exploratory 
Objectives: 
 
To validate and assess FGFR family members (specifically, FGFR2 and 
potentially those harboring activating mutations) as predictive biomarkers 
 
To evaluate the association between known markers of the FGF signaling 
pathway, toxicity, and clinical activity  
Study Design: 
 
This is an open-label, Phase 1/2, dose escalation and signal finding study of 
ARQ 087 administered to subjects with advanced solid tumors.  The study is 
designed to explore the safety, tolerability, pharmacokinetics, pharmacodynamics, 
and preliminary efficacy of ARQ 087 and to define a RP2D of ARQ 087.  
To assess the safety of ARQ 087, a minimum of three subjects will be enrolled in 
each cohort. To assess pharmacodynamic changes, archival and/or fresh tumor tissue 
biopsy samples and blood samples will be collected. Pharmacokinetic assessments 
will be performed for a single dose (Cohorts 1-4) and continuous dosing (all Cohorts) 
with ARQ 087. Radiographic evaluation of potential anti-tumor activity of ARQ 087 
(CT scan, MRI, or PET scan) will be performed at Baseline, and every eight weeks 
(e.g., every two cycles or Week 8, Week 16, etc.) thereafter or as otherwise clinically 
indicated. 
Initially, treatment will consist of two treatment periods (Cohorts 1-4): Treatment 
Period 1 (single dose administration for 72-hour PK assessment) and Treatment 
Period 2 (continuous dosing), and starting with Cohort 5, a single treatment period of 
continuous dosing, including a Food-effect Cohort will be implemented. Dose 

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escalation will continue until MTD or RP2D is determined (see Sections 4.1, 4.3, and 
5.3). 
Treatment will be initiated at a dose level of 25 mg/qod (every other day). All 
cycles/cohorts of therapy will consist of the oral administration of ARQ 087 at dose 
levels and administration schedules specified for their respective dose cohorts; the 
drug should be taken one hour prior to or two hours after the meal.  
Dose escalation will be performed after three or six subjects are evaluated in each 
cohort. In the first four cohorts, the dose may be doubled, and in the next cohorts, the 
dose escalation will follow a modified Fibonacci scheme (increase by 50%, 30%, and 
25%) until RP2D or MTD is determined. The Food-effect Cohort will enroll at least 
six subjects with luminal breast A or B, endometrial, urothelial, gastric, or lung 
cancer with known and/or confirmed FGFR1-3 amplification, mutation or gene 
rearrangement (fusion, translocation), or with adrenocortical carcinoma, 
cholangiocarcinoma, or sarcomas, independent from FGFR1-3 status. All subjects 
enrolled in the Food-effect Cohort should agree to and be eligible for paired biopsy. 
Once the MTD/RP2D level is determined, the Expanded Cohort (Part 2) will enroll 
approximately 50-60 subjects with advanced solid tumors with documented 
(known/confirmed) FGFR genetic alterations, including iCCA with FGFR2 gene 
fusion. The tumor type eligibility should be confirmed by the Sponsor’s Medical 
Monitor or designee prior to enrollment. 
The RP2D has been defined as 300 mg qd under fasting conditions. 
Study Population:  
 
Adult subjects with advanced solid tumors whose cancer has progressed following 
standard therapy, or who have been unable to tolerate standard therapy, and/or for 
whom no standard treatment is available will be enrolled. Subject accrual will occur 
over a period of time dependent upon the number of cohorts enrolled. 
The exact number of subjects estimated for this study is dependent on the number of 
subject cohorts investigated based on the toxicity encountered (Part 1).  It is expected 
that approximately 60-120 subjects at five to fifteen sites in the United States and 
Italy will be enrolled in this study. Once the MTD/RP2D level is determined, an 
Expanded Cohort (Part 2) will be enrolled. The Expanded Cohort (Part 2) of 
approximately 50-60 subjects with advanced solid tumors with FGFR genetic 
alterations, including iCCA with FGFR2 gene fusion will be enrolled. 
Inclusion Criteria  
1. Signed written informed consent granted prior to initiation of any study-
specific procedures 
2. Male or female subjects of ≥ 18 years of age 
3. Histologically or cytologically confirmed locally advanced, inoperable, or 
metastatic solid tumors. All subjects eligible for enrollment in the Expanded 
Cohort must have documented and/or confirmed FGFR genetic alterations, 
including iCCA with FGFR2 gene fusion. 
4. Failure to respond to standard therapy, or for whom standard therapy does not 
exist. 
 
Subjects enrolled in the Expanded Cohort should have no more than two 
prior systemic regimens with confirmed disease progression. 
 
If the subject is refractory or has disease progression within 6 months of 
adjuvant treatment, then the previous treatment should be considered as a 
line of treatment rather than adjuvant therapy. 
 
Subjects who did not receive prior systemic therapy for locally advanced 
and/or metastatic iCCA with confirmed FGFR2 gene fusion and for 

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whom, in the opinion of the Investigator, treatment with ARQ 087 is 
appropriate may be enrolled 
5. Evaluable or measurable disease  
6. Archival and/or fresh biopsy tissue samples must be available prior to the first 
dose of the study drug.  
 
All subjects eligible for enrollment in the Expanded Cohort (Part 2) must 
have known (documented and/or confirmed) FGFR genetic alterations. 
 
Archival tumor samples should be collected for all subjects enrolled in the 
Expanded Cohort. Paired fresh tumor biopsy is optional for subjects 
enrolled in the Expanded Cohort.  Both archival and pre-treatment fresh 
tumor samples (optional) should be collected prior to the first dose of the 
study drug. 
 
All subjects eligible for enrollment in the Food-effect Cohort must have 
the following tumor types: luminal breast A or B, endometrial, urothelial, 
gastric, or lung cancer with known and/or confirmed FGFR1-3 high level 
amplification, mutation or gene rearrangement (fusion, translocation), or 
adrenocortical carcinoma, cholangiocarcinoma, or sarcomas, independent 
from FGFR1-3 mutation status 
 
All subjects eligible for enrollment in the Food-effect Cohort should agree 
to and be eligible for paired biopsy 
7. Life expectancy  12 weeks 
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 
(Appendix 2) 
9. Hemoglobin (Hgb) ≥ 9.0 g/dL 
10. Absolute neutrophil count (ANC)  1.5 x 109/L 
11. Platelet count ≥ 100 x 109/L 
12. Total bilirubin  1.5 x upper limit of normal (ULN) (≤ 2 ULN for subjects with 
cholangiocarcinoma) 
13. Aspartate transaminase (AST) and alanine transaminase (ALT)  3 ULN ( 5 x 
ULN for subjects with liver metastases) 
14. Serum creatinine  1.5 x ULN or creatinine clearance > 60 mL/min/1.73 m2 for 
subjects with creatinine levels above institutional normal 
15. Albumin  2.8 g/dL 
16. INR 0.8 to ULN or  3 for subjects receiving anticoagulant therapy such as 
Coumadin or heparin 
17. Male or female subjects of child-producing potential must agree to use double-
barrier contraceptive measures, oral contraception, or avoidance of intercourse 
during the study and for 90 days after the last dose of ARQ 087 
18. Women of childbearing potential must have a negative serum pregnancy test 
during Screening Period and within 48 hours of the first dose of ARQ 087. 
“Women of childbearing potential” is defined as sexually mature women who 
have not undergone a hysterectomy or who have not been naturally 
postmenopausal for at least 12 consecutive months prior to the first dose of 
ARQ 087. 
Exclusion Criteria 
1. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal, 
targeted therapy, or investigational agents within four weeks or five times of 
the drug half-life, whichever is LONGER, of the first dose of ARQ 087  

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2. Major surgery or radiation therapy within four weeks of the first dose of 
ARQ 087 
3. Previous treatment with FGFR inhibitors (e.g., ponatinib, dovitinib, nintedanib, 
AZD4547, NVP-BGJ398, LY2784455, BAY1163877) 
4. History of allergic reactions attributed to compounds of similar chemical or 
biologic composition as ARQ 087 
5. Unable or unwilling to swallow the complete daily dose of ARQ 087 
6. Clinically unstable central nervous system metastasis (to be eligible, subjects 
must have stable disease  3 months, confirmed by MRI or CT scan, and/or 
have CNS metastases well controlled by low-dose steroids, anti-epileptics, or 
other symptom-relieving medications) 
7. History of myocardial infarction (MI) or congestive heart failure defined as 
Class II to IV per the New York Heart Association (NYHA) classification 
within 6 months of the first dose of ARQ 087 (MI that occurred > 6 months 
prior to the first dose of ARQ 087 will be permitted)  
8. Significant gastrointestinal disorder(s) that could, in the opinion of the 
Investigator, interfere with the absorption, metabolism, or excretion of 
ARQ 087 (e.g., Crohn’s disease, ulcerative colitis, extensive gastric resection) 
9. History and/or current evidence of clinically relevant ectopic 
mineralization/calcification including but not limited to the soft tissue, kidneys, 
intestine, myocardium, and lung with the exception of calcified lymph nodes, 
asymptomatic nephrolithiasis, and asymptomatic coronary calcification (If 
indicated, standard CT or MRI may be used to assess ectopic mineralization/ 
calcification.) 
10. Previous malignancy within 2 years of the first dose of ARQ 087, except 
curatively treated non-melanoma skin cancer, carcinoma in-situ of the breast or 
cervix, superficial bladder tumors 
11. Known human immunodeficiency virus (HIV) infection 
12. Concurrent uncontrolled illness not related to cancer, including but not limited 
to: 
 
Psychiatric illness/substance abuse/social situation that would limit 
compliance with study requirements 
 
Uncontrolled diabetes mellitus  
13. Blood transfusion within 5 days of the blood draw being used to confirm 
eligibility 
14. Pregnant or breastfeeding  

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Test Product, Dose, 
and Mode of 
Administration:  
 
Part 1: Subjects in Cohorts 1-4 of this study will receive ARQ 087 orally, as a single 
dose (Treatment Period 1) or on a continuous schedule (Treatment Period 2) at dose 
levels and administration schedules specified for their respective dose cohorts. 
Starting with Cohort 5, treatment will consist of a single treatment period of 
continuous dosing that will cease at the subject’s discontinuation from the study. 
ARQ 087 should be taken one hour prior to or two hours after the meal, except by 
subjects enrolled in the Food-effect cohort, who will be required to take ARQ 087 
with their morning meals. Dosing will begin at 25 mg/qod (first cohort) and escalate 
until the RP2D or MTD is determined. Based on the drug safety profile and Food-
effect Cohort PK data, 300 mg qd has been defined as a RP2D and is recommended 
for further evaluation in the Expanded Cohort (Part 2).  
During Treatment Period 2 (Cohorts 1-4) and in all cohorts starting with Cohort 5, 
including the Expanded Cohort, cycles will be repeated in four-week (28-day) 
intervals until progression of disease, unacceptable toxicity, or another 
discontinuation criterion is met.  In the case of toxicity, dose adjustment will be 
permitted.  
Criteria for Dose 
Escalation (Part 1): 
Enrollment at the next dose level and/or additional subjects into the ongoing cohort 
will occur according to the following criteria: 
 
If zero of three initially treated subjects experience a dose-limiting toxicity 
(DLT) by Day 29 of continuous dosing, then dose escalation will occur 
 
If one of three initially treated subjects experiences a DLT by Day 29 of 
continuous dosing, then an additional three subjects will be enrolled for a total 
of six subjects treated at the same dose level. Escalation will occur if no 
additional DLTs are seen in that cohort. 
 
If two or more treated subjects at a dose level experience a DLT by Day 29 of 
continuous dosing, dose escalation will stop and the prior dose level will be 
considered the MTD. If the first dose results in MTD, subsequent subjects will 
be enrolled at a lower dose or at a less frequent drug administration schedule 
(e.g., 25 mg twice a week). 
The MTD is defined as the dose level at which no more than one out of six subjects 
has an observable DLT. 
If a subject withdraws from study treatment for any reason other than a DLT during 
the first cycle (28 days), that subject will be replaced. During the dose escalation 
phase, if a subject experiences a DLT, such subject should be permanently 
discontinued from the treatment. 
Duration of 
Treatment:  
For an individual subject, treatment with ARQ 087 will continue until disease 
progression (clinical or radiological), unacceptable toxicity, or another 
discontinuation criterion is met.  It is expected that most subjects will receive 
between one and six cycles of ARQ 087 for a treatment period of four to 24 weeks.  
Pharmacokinetic 
and 
Pharmacodynamic 
Variables: 
Part 1 only: Pharmacokinetic variables will include Cmax, AUC, and half-life.  In 
Cohorts 1-4, for each dose level, blood samples for PK determination will be drawn 
during Treatment Period 1 (single dose, Days 1-4) and Treatment Period 2 
(continuous dosing) on Day 8, Day 15, Day 22, and Day 23 of Cycle 1 of ARQ 087 
administration. (Except for subjects enrolled in Cohort 1 [25 mg every other day], for 
these subjects Cycle 1 Week 4 visits should be scheduled on the day of ARQ 087 
administration and the next consecutive day, when drug is not taken, e.g., Cycle 1 
Day 21 and Day 22 or Cycle 1 Day 23 and Day 24.) Starting with Cohort 5, PK 
samples will be collected on Day 1, Day 2, Day 8, Day 15, Day 22, Day 23 of 

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Cycle 1, on Day 1 and Day 15 of each subsequent cycle, and at the End of Treatment 
visit.  
In Part 2, the Expanded Cohort, collection of PK samples will be optional; the 
recommended timepoints should be as follows: Day 1, Day 8, Day 15, Day 22, 
Day 23 of Cycle 1, on Day 1 and Day 15 of each subsequent cycle, and at the End of 
Treatment visit. 
Part 1. In Cohorts 1-4, blood samples will be collected during Treatment Period 1 
(single dose, Days 1-4) and Treatment Period 2 (continuous dosing) on Day 8, 
Day 15, and Day 22 of Cycle 1, and on Day 1 of every subsequent cycle for 
evaluations of pharmacodynamic changes of factors including phosphate, glucose, 
FGF 7, 19, 21, and/or 23 utilizing standard blood chemistry methodologies and 
ELISA-based assays. Starting with Cohort 5 and in all subsequent Cohorts, blood 
samples for evaluation of pharmacodynamic changes of factors including phosphate, 
glucose, FGF 19, 21 and 23 will be collected on Day 1, Day 8, Day 15, Day 22 of 
Cycle 1, and on Day 1 of Cycles 2-5. 
Information on the tumor‘s genomic characteristics, such as FGFR protein 
expression, gene copy number and mRNA amplification, and/or mutational/gene re-
arrangement (fusion, translocation) status, is required for this study. All baseline 
samples (archival or newly acquired) will be evaluated by immunohistochemistry 
(IHC), FISH (gene copy number), ISH or qNPA (mRNA amplification), and/or DNA 
sequencing (mutational/gene re-arrangement [fusion, translocation] status 
assessment).  
Pathology specimens (pre- and post-treatment tumor biopsies) will be evaluated for 
changes in total FGFR1, total FGFR2, pFGFR, pFRS2α, and/or pERK status by IHC, 
mesoscale, or immunoprecipitation/Western blot analysis.   
Part 2 (Expanded Cohort): Blood samples for evaluation of pharmacodynamic 
changes in FGF 19, 21, and 23 will be collected on Day 1 of Cycles 1-6. 
Criteria for 
Determination of 
Dose-Limiting 
Toxicity (Part 1): 
 
Dose-limiting toxicities will be determined during the first cycle (four weeks/ 
28 days) of treatment. A DLT is defined by the occurrence of any of the following 
toxicities related to ARQ 087 within the first cycle of treatment and graded according 
to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03:  
 
Grade 4 anemia  
 
Grade 4 neutropenia  
 
Grade 4 thrombocytopenia  
 
Grade 3 neutropenia with fever (≥ 38°C/100.4°F)  
 
Grade 3 neutropenia lasting longer than 7 days despite optimal treatment 
 
Grade 3 thrombocytopenia in the presence of bleeding  
 
≥ Grade 3 hyperglycemia (fasting blood glucose > 250 mg/dL or non-fasting 
> 500 mg/dL) requiring insulin (uncontrolled with metformin) 
 
≥ Grade 3 non-hematological toxicity of any duration, except for the following: 
o 
Nausea, vomiting, or diarrhea responding to optimal medical management 
within 48 hours 
o 
Alopecia  
 
Any other toxicity that in the view of the Investigator represents a clinically 
significant hazard to the subject 

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Statistical 
Methods:  
 
All subjects receiving at least one daily dose of ARQ 087 will be considered 
evaluable for safety analyses.  In addition to the evaluation and categorization of 
adverse events, listings of laboratory test results collected at baseline and during the 
study will be generated.  Descriptive statistics summarizing the changes in those 
laboratory tests over time will be presented. 
Subjects who have received at least one cycle of ARQ 087 and have had at least one 
disease assessment following the initiation of therapy will be considered evaluable 
for response.  The anti-tumor activity will be evaluated on an exploratory basis and 
will be summarized using descriptive statistics or graphics. 
For the Expanded Cohort (Part 2), for the iCCA sub-cohort, statistical analysis will 
include interim monitoring for futility.  After response data from 10 subjects with 
iCCA are available, the response rate will be assessed. If the objective response is 
observed in ≤ 30% of enrolled subjects, the enrollment will be stopped for lack of 
efficacy. 

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TABLE OF CONTENTS 
SYNOPSIS 
2 
TABLE OF CONTENTS 
9 
LIST OF TABLES 
13 
LIST OF FIGURES 
14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
15 
1 
INTRODUCTION 
20 
1.1 
Background and Rationale 
20 
1.2 
Preclinical Data 
22 
1.3 
In Vitro Pharmacology 
22 
1.3.1 
Biochemistry: Inhibition of FGFR Kinase Activity by ARQ 087 
22 
1.3.2 
Cell Biology: Anti-Proliferative Effect and FGFR Pathway Inhibition by 
ARQ 087 in Human Cancer Cell Lines 
24 
1.4 
In Vivo Pharmacology 
29 
1.4.1 
Evaluation of ARQ 087 in Human and Murine Xenografts of Various 
Histological Types in Athymic Mice 
29 
1.5 
Pharmacodynamic Biomarkers 
34 
1.5.1 
In Vivo Pharmacodynamics 
34 
1.5.2 
Pharmacokinetic Characteristics 
35 
1.6 
Nonclinical Toxicology 
35 
1.7 
Clinical Experience 
39 
2 
STUDY OBJECTIVES 
40 
2.1 
Primary Objective 
40 
2.2 
Secondary and Exploratory Objectives 
40 
3 
SELECTION OF STUDY POPULATION 
41 
3.1 
Inclusion Criteria 
41 
3.2 
Exclusion Criteria 
43 
3.3 
Number of Subjects 
44 
4 
INVESTIGATIONAL PLAN 
45 
4.1 
Overall Study Design 
45 
4.1.1 
Part 1: Dose Escalation Cohorts 
45 
4.1.2 
Part 2: Expanded Cohort 
48 
4.2 
Rationale for Study Design 
48 
4.2.1 
Part 1: Dose Escalation/Food-effect Cohorts 
48 
4.2.2 
Part 2: Expanded Cohort 
49 
4.3 
Selection of Initial Dose 
49 
4.4 
Criteria for Dose Escalation and Determination of Dose-Limiting Toxicity 
49 
4.5 
Dose-Limiting Toxicity 
50 

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4.6 
Study Duration 
51 
5 
STUDY VISITS 
52 
5.1 
Informed Consent 
52 
5.2 
Pre-Study Evaluations (Baseline) (Within 21 Days Prior to the First Dose of 
ARQ 087) 
52 
5.3 
Treatment Period 1 (PK): Single-Dose Administration of ARQ 087; Cohorts 1-4 
53 
5.3.1 
Day 1 (Day of the Single Dose of ARQ 087 Administration) 
53 
5.3.2 
Day 2 (24 Hours; ± 2 Hours, Post-Dose on Day 1) 
54 
5.3.3 
Day 3 (48 Hours; ± 2 Hours, Post-Dose on Day 1) 
54 
5.3.4 
Day 4 (72 Hours; ± 2 Hours, Post-Dose on Day 1) 
54 
5.4 
Continuous Administration of ARQ 087: Dose Escalation/Food-effect Cohorts 
and Expanded Cohort 
55 
5.4.1 
Cycle 1, Weekly Evaluations 
55 
5.4.2 
Week 2 (Day 8; ± 3 Days) 
55 
5.4.3 
Week 3 (Day 15; ± 3 Days) 
56 
5.4.4 
Week 4 (Day 22; ± 3 Days) 
56 
5.4.5 
Week 4 (Day 23; except Expanded Cohort) 
56 
5.5 
Cycle 2 and Following Cycles, Bi-weekly Evaluations 
57 
5.5.1 
Week 1 (Day 1; ± 3 Days) 
57 
5.5.2 
Week 3 (Day 15; ± 3 Days) 
57 
5.6 
End of Treatment Visit (7 [+3] Days after the Last Dose of ARQ 087) 
58 
5.7 
30-day (± 3 Days) Safety Follow-Up Visit 
58 
5.8 
Discontinuation from the Treatment/Study 
59 
5.9 
Study Discontinuation 
59 
6 
STUDY PROCEDURES 
60 
6.1 
Medical History 
60 
6.2 
Physical Examination 
60 
6.3 
12-Lead ECG, Echocardiography, and MUGA Scan 
60 
6.4 
Clinical Laboratory Tests 
60 
6.5 
Pharmacokinetic Assessments 
61 
6.6 
Pharmacodynamic Assessments 
62 
6.7 
Tumor Evaluation 
63 
6.8 
Tumor Biopsy 
63 
7 
TREATMENT 
65 
7.1 
ARQ 087 
65 
7.1.1 
Investigational Product Accountability 
65 
7.1.2 
Storage and Handling 
65 
7.1.3 
ARQ 087 Administration 
65 
7.2 
Missed or Vomited Doses 
66 

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7.3 
Dose Modifications 
66 
7.4 
Treatment Compliance 
67 
7.5 
Blinding 
67 
7.6 
Prior Treatment 
67 
7.7 
Concomitant Treatments 
67 
7.7.1 
Permitted Treatment 
67 
7.7.2 
Prohibited Treatment/Treatment to Be Avoided or Used with Caution 
68 
7.8 
Potential Risks for Study Subjects 
68 
8 
SAFETY ASSESSMENTS 
70 
8.1 
Definitions 
70 
8.1.1 
Adverse Event 
70 
8.1.2 
Serious Adverse Event 
70 
8.1.3 
Unexpected Adverse Event or Serious Adverse Event 
70 
8.1.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
70 
8.1.5 
Inpatient Hospitalization 
70 
8.1.6 
Study Drug-related Adverse Event or Serious Adverse Event 
71 
8.1.7 
Further Adverse Event and Serious Adverse Event Defining 
71 
8.2 
Responsibilities and Procedures 
71 
8.3 
Adverse Event and Serious Adverse Event Assessment Criteria 
72 
8.4 
Serious Adverse Event Reporting 
72 
8.5 
Post-Treatment Safety Follow-up 
73 
8.6 
Grading of Severity 
73 
8.7 
Assessment of Causality 
73 
8.7.1 
Related Adverse Events 
73 
8.7.2 
Not Related Adverse Events 
74 
9 
QUALITY CONTROL AND ASSURANCE 
75 
10 PLANNED STATISTICAL METHODS 
76 
10.1 
Determination of Sample Size 
76 
10.2 
Analysis Variables 
76 
10.2.1 
Demographics and Baseline Characteristics 
76 
10.2.2 
Safety 
76 
10.2.3 
Efficacy 
76 
10.2.4 
Pharmacokinetics 
76 
10.3 
Statistical Methods 
77 
10.3.1 
Demographic and Baseline Characteristics 
77 
10.3.2 
Extent of Treatment Exposure 
77 
10.3.3 
Analyses of Safety Variables 
77 
10.3.4 
Analysis of Efficacy Variables 
78 

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10.3.5 
Pharmacokinetics and Pharmacodynamics 
78 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICE AND ETHICAL 
CONSIDERATIONS 
79 
11.1 
Institutional Review Board or Independent Ethics Committee Approval 
79 
11.2 
Compliance with Good Clinical Practice and Ethical Considerations 
79 
11.3 
Subject Information and Consent 
79 
12 STUDY MANAGEMENT AND MATERIALS 
81 
12.1 
Monitoring, Verification of Data, Audit, and Inspection 
81 
12.2 
Data Recording and Retention of Study Data 
81 
12.3 
Electronic Case Report Forms 
81 
12.4 
Confidentiality, Publication and Disclosure Policy 
82 
13 REFERENCES 
83 
APPENDIX 1: SCHEDULE OF ASSESSMENTS 
85 
APPENDIX 2: PERFORMANCE STATUS 
91 
APPENDIX 3: PHARMACOKINETIC AND PHARMACODYNAMIC SAMPLING 
SCHEDULES 
92 
APPENDIX 4: EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS AND 
INDUCERS FOR SPECIFIC CYP ENZYMES FOR STUDY 
97 
APPENDIX 5: EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS AND 
INDUCERS OF P-GLYCOPROTEIN 
100 
APPENDIX 6: ASSESSMENT OF ANTI-TUMOR ACTIVITY 
101 
SPONSOR SIGNATURE 
109 
INVESTIGATOR’S SIGNATURE 
110 
 
 
 
 
 

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LIST OF TABLES 
Table 1.1. Biochemical Activity of ARQ 087 Against FGFR1, FGFR2, FGFR2 (N549H), 
FGFR3, and FGFR4 
Table 1.2 Biochemical Activity of ARQ 087 Against a Panel of Kinases Using the MSA 
Assay 
Table 1.3 Approximate EC50 values for ARQ 087 
Table 4.1 Dosing Guidelines 
Table 7.1 Dose Delays/Reductions for Drug-Related Toxicity 
Table 7.2 ARQ 087 Dose Reduction Schema 
22 
23 
25 
47 
66 
67 
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LIST OF FIGURES 
Figure 1.1. Schematic Diagram of Intracellular Signaling Cascade Mediated by 
FGF/FGFRs12 
21 
Figure 1.2 ARQ 087 Inhibits Ectopically Expressed FGFR1, 2, and 3 in COS-1 Cells 
24 
Figure 1.3 Kato III and SNU-16 Cells Dependent on FGFR2 Signaling for Proliferation 
27 
Figure 1.4 Inhibition of FGFR2 Pathway by ARQ 087 
28 
Figure 1.5 Inhibition of SNU-16 Human Gastric Tumor Xenograft Growth by ARQ 087 
30 
Figure 1.6 Inhibition of BaF3/FGFR2 Tumor Xenograft Growth by ARQ 087 
31 
Figure 1.7 Inhibition of AN3CA Tumor Xenograft Growth by ARQ 087 
32 
Figure 1.8 Inhibition of Tumor Progression in ST413 and ST328 Endometrial Patient-
derived Xenograft Models 
33 
Figure 1.9 Inhibition of FGFR2 Pathway in SNU-16 Gastric Carcinoma Xenograft 
Tumors by ARQ 087 
34 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AR 
accumulation ratio 
ASCO 
American Society of Clinical Oncologists 
AST 
aspartate transaminase 
AUC 
area under the concentration–time curve 
AUC0-10 
area under the concentration–time curve from time 0 to 10 hours 
AUC0-24 
area under the concentration–time curve from time 0 to 24 hours after 
dose administration 
AUC0-inf 
area under the concentration–time curve from hour 0 to infinity  
AUC0-t 
area under the concentration–time curve from time 0 up to the last 
measurable sampling time 
BID 
twice a day 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL/F 
apparent clearance, calculated as Dose/AUC(0-inf) 
Cmax 
maximum plasma concentration 
CR 
complete regression 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DAG 
data analysis group 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EGFR (EGFR) 
epidermal growth factor receptor (gene) 
ELISA 
enzyme-linked immunosorbent assay 

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ABBREVIATION 
DEFINITION 
ERK1, 2 
Extracellular extracellular signal-regulated kinase 1, 2 
ESA 
erythropoiesis stimulating agent 
FAK 
focal adhesion kinase 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 
FGFR (FGFR) 
fibroblast growth factor receptor 
FIH 
first-in-human 
FISH 
fluorescence in situ hybridization 
FNA 
fine-needle aspiration 
g 
microgram 
Gab-1 
growth factor receptor-bound protein 2-associated-binding protein 1 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma-glutamyl transpeptidase 
GI50 
concentration required for 50% inhibition of cell growth 
GLP 
Good Laboratory Practice 
Grb-2 
growth factor receptor-bound protein 2 
h 
hour 
HbA1c 
glycated hemoglobin 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
Hct 
hematocrit 
HERG 
human ether-à-go-go–related gene 
Hgb 
hemoglobin 
HGF/SF 
hepatocyte growth factor/scatter factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
IC50 
inhibitor concentration required for 50% inhibition 
iCCA 
intrahepatic cholangiocarcinoma 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IHC 
immunohistochemistry 
INR 
international normalized ratio 
IP 
intraperitoneal 
IRB 
institutional review board 
ITT 
intent to treat 
IV 
intravenous(ly) 
kg 
kilogram 

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ABBREVIATION 
DEFINITION 
L 
liter 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI 
myocardial infarction 
min 
minutes 
mL 
milliliter 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
MTS 
colorimetric cell proliferation assay 
MUGA 
multi gated acquisition scan 
NCI 
National Cancer Institute  
ng 
nanogram 
nm 
nanometer 
nM 
nanomolar 
µM 
micromolar 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
pERK 
phosphorylated extracellular signal-regulated kinase 
PET 
positron emission tomography 
pFAK 
phosphorylated focal adhesion kinase 
pFGFR 
phosphorylated fibroblast growth factor receptor 
pFRS2 
phosphorylated fibroblast growth factor receptor substrate  
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI3K 
phosphatidylinositol 3-kinase 
PK 
pharmacokinetics 
PKC 
protein kinase C 
PLC 
phospholipase C gamma 
PO 
per os (by mouth) 
PopPK 
population pharmacokinetics 

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ABBREVIATION 
DEFINITION 
PR 
partial response 
PROs 
patient reported outcomes 
PS 
performance status 
PSI 
pulmonary symptoms index 
PT 
prothrombin time 
PTK2B, PYK2PYK2 
proline tyrosine kinase 2 beta (gene), proline tyrosine kinase 
(protein)proline-rich tyrosine kinase 2 
PTT 
partial thromboplastin time 
QD 
once daily 
qNPA 
quantitative nuclease protection assay 
QOD 
Q2D 
every other day 
QTc 
heart rate-corrected QT interval   
RBC 
red blood cell (count) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
s 
second(s) 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
small cell lung cancer 
SD 
stable disease 
standard deviation 
SF 
scatter factor 
Shc 
Src homology 2 domain-containing transforming protein  
SOC 
system organ class 
STAT 
signal transducer and activator of transcription  
STD 
severely toxic dose 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
elimination half-life 
t1/2Z 
apparent plasma terminal phase half-life; = (ln2)/ Z 
TEAE 
treatment-emergent AE 
TGI 
tumor growth inhibition 
TKIs 
tyrosine kinase inhibitors 
Tmax 
time to maximum observed concentration 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution, calculated as Dose/AUC(0-inf)/Z 

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ABBREVIATION 
DEFINITION 
WBC 
white blood cell (count) 
WT 
wild type 

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1 
INTRODUCTION 
1.1 
Background and Rationale 
Fibroblast growth factors (FGFs) and their receptors (FGFRs) play important roles in cell 
proliferation, cell differentiation, cell migration, cell survival, protein synthesis, and 
angiogenesis.  The FGFR family consists of four genes encoding tyrosine kinase receptors 
(FGFR1, FGFR2, FGFR3, and FGFR4).  Dysregulation of FGFR signaling has been 
implicated in a number of developmental syndromes as well as cancers, e.g., squamous non-
small cell lung cancer (NSCLC), small cell lung cancer (SCLC), gastric, liver, breast, 
ovarian, endometrial, and bladder carcinomas, fueling significant interest in FGFRs as targets 
for therapeutic intervention. In human cancers, FGFRs have been found to be dysregulated 
by multiple mechanisms, including aberrant expression, mutations, chromosomal 
rearrangements, and amplifications.1,2,3,4 A growing body of evidence establishes the role of 
FGFR signaling including FGFR2 gene fusion in the development of intrahepatic 
cholangiocarcinoma (iCCA).5,6,7,8 Intrahepatic cholangiocarcinoma is a rare disease 
(incidence rate in the US is 0.9 per 100,000) with a very poor prognosis and limited treatment 
options for advanced, inoperable tumors.9,10,11 
FGFRs like other receptor tyrosine kinases are activated by tyrosine phosphorylation and 
signal through multiple signal transduction pathways including mitogen-activated protein 
kinases (MAPK), phosphatidylinositol 3-kinase (PI3K) phospholipase Cγ (PLCγ), protein 
kinase C (PKC) and signal transducer and activator of transcription (STAT). Activation leads 
to a series of cellular signaling events including increased cell proliferation, differentiation 
and migration (Figure 1.1).  

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Figure 1.1. Schematic Diagram of Intracellular Signaling Cascade Mediated by 
FGF/FGFRs12 
 
ArQule, Inc. (ArQule) has discovered a novel class of FGFR inhibitors from which ARQ 087 
emerged as the lead candidate for advancement into clinical development. Nonclinical 
studies were conducted in order to characterize the biological activity of ARQ 087.  These 
studies included in vitro and in vivo assessments of the activity of ARQ 087 against isolated 
kinases, anti-proliferative effects in cell culture, in vitro and in vivo pharmacodynamic 
effects, and growth inhibitory effects in human tumor xenograft models in mice. 
ARQ 087 is a potent multi-kinase inhibitor with pan-FGFR activity against FGFR1, FGFR2, 
mutant FGFR2 (N549H), FGFR3, and FGFR4 kinases, all exhibiting IC50 values in the low 
nanomolar range in biochemical assays. In cell-based systems, ARQ 087 inhibited 
endogenously expressed FGFR2 and ectopically expressed FGFR1, 2, and 3 in COS-1 cells 
(a fibroblast-like cell line derived from monkey kidney tissue).  ARQ 087 displayed potent 
inhibition of FGFR2 phosphorylation in Kato III and SNU-16 human gastric carcinoma cells 
with comparable antiproliferative potencies in the MTS assay. Concentration-dependent 
inhibition of phosphorylation of downstream FGFR pathway signals (FRS2α, MEK, ERK, 
and AKT) was evident in response to ARQ 087 treatment in both in vitro and in vivo 
pharmacodynamic assays.  Cell proliferation studies suggested a correlation of FGFR2 
mRNA amplification in gastric and other cancers with associated sensitivity to treatment with 
ARQ 087. Correspondingly, ARQ 087 induced regressions in FGFR2-driven xenograft 
models (SNU-16 and BaF3/FGFR2) and inhibited tumor progression in a model harboring a 
FGFR2-activating mutation (AN3CA). 

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ARQ 087 has been formulated as a capsule filled with a powder blend of ARQ 087 and 
suitable excipients for use in a Phase 1 study to be conducted in adult subjects with locally 
advanced or metastatic malignant tumors.  
1.2 
Preclinical Data 
1.3 
In Vitro Pharmacology 
Dysregulation in the FGFR tyrosine kinase family has been implicated in a number of human 
cancers, including gastric, breast, lung, endometrial, and bladder carcinomas fueling 
significant interest in FGFRs as targets for therapeutic intervention.1,2,3,4 A novel class of 
pan-FGFR inhibitors has been discovered and developed at ArQule. From this class, 
ARQ 087 emerged as the candidate for advancement into full pre-clinical development for 
potential clinical evaluation. 
1.3.1 
 
Biochemistry: Inhibition of FGFR Kinase Activity by ARQ 087 
FGFR kinase biochemical assays were developed by ArQule. FGFR2 (N549H) mutant 
protein was used throughout the lead optimization process due to higher enzymatic activity 
when compared to wild-type protein.  Lead compound selectivity against all four FGFR 
isoforms were assayed using a PYK2-derived biotinylated peptide substrate (biotin-
AGAGSIESDIYAEIPDETC-NH2) and the AlphaScreen™ (Amplified Luminescent 
Proximity Homogeneous Assay) technology.  
ARQ 087, the lead candidate for clinical development, inhibits FGFR1, FGFR2, and FGFR3 
with biochemical IC50 values in the 1.8-14 nM range and FGFR4 with somewhat lower 
potency (IC50 value = 34.3-37 nM) (Table 1.1.)13.  The biochemical potency of ARQ 087 
against FGFR1, FGFR2, FGFR3 and FGFR4 was determined in-house using an 
AlphaScreen™ assay and also using a mobility shift assay (MSA) at Carna Biosciences 
(Table 1.1). ARQ 087 was most potent against FGFR2 in the MSA assay with an IC50 value 
of 1.8 nM.  Together the data suggest that the potencies against FGFR kinases determined 
using the in-house FGFR AlphaScreen™ assay were comparable (within 10-fold) to the 
Carna Biosciences FGFR MSA.13 
 
Table 1.1. Biochemical Activity of ARQ 087 Against FGFR1, FGFR2, FGFR2 (N549H), 
FGFR3, and FGFR4 
ARQ 087 
FGFR1 
(nM) 
FGFR2 
(nM) 
FGFR2 (N549H) 
(nM) 
FGFR3 
(nM) 
FGFR4 
(nM) 
AlphaScreen™ 
6 ± 1 
14 ± 4 
22 ± 8 
8 ± 2 
37 ± 23 
MSA (Carna Biosciences) 
4.5 
1.8 
NT 
4.5 
34.3 
Table 1.1: Diluted ARQ 087 and enzyme were added to each well of a reaction plate and were pre-incubated 
together for 20 minutes.  The final concentration for FGFR1, FGFR2, FGFR2 (N549H), FGFR3, and FGFR4 
were 6 nM, 6 nM, 1 nM, 13 nM, and 13 nM, respectively.  After pre-incubation, the kinase reaction was 
initiated by the addition of a PYK2/ATP mixture.  The final concentrations of PYK2 were 69 nM for FGFR1, 
FGFR2, FGFR2 (N549H), and FGFR3, and 227 nM for FGFR4. The final concentrations for ATP were 30 µM 
for FGFR1, FGFR2, FGFR2 (N549H), and FGFR3, and 150 µM for FGFR4. The plates were incubated for 
1 hour and the reaction was stopped by the addition of stop/detection reagent (10 mM EDTA and 500 ng/well of 

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both AlphaScreen™ streptavidin and phospho-tyrosine beads [PerkinElmer]). The assay plates were then 
incubated for an additional 1 hour.  Fluorescence (excitation λ: 680 nm, emission λ: 570 nm) to determine 
PYK2 substrate phosphorylation was measured on the Envision® Multilabel Reader (PerkinElmer) and IC50 
values were calculated using XLFit™ (IDBS Limited).  The MSA data was generated by Carna Biosciences 
using the Caliper microfluidics platform. 
NT = not tested.  
Note AlphaScreen™ data are reported as the mean ± SD (standard deviation).  The MSA data are reported as 
the average of two values. 
To determine the kinase selectivity of ARQ 087, the compound was tested against a panel of 
298 kinases at a concentration of 0.1 M. Among 298 kinases assayed, ~50 kinases 
(including FGFR1, FGFR2, FGFR3, and FGFR4) were inhibited greater than 50% by 
ARQ 087 at 0.1 M.13 In this subset of kinases, examination of IC50 values revealed that 
ARQ 087 inhibited (within a 3-fold range of the IC50 value for FGFR2) five other kinases 
(RET, DDR2, PDGFRβ, FMS, and mutant KIT [V560G]) which are outside of the FGFR 
family. Overall, of ~50 kinases assayed, 25, with the exception of FGFR4, exhibited 
sensitivities to ARQ 087 within a 3- to 10-fold range of the IC50 value for FGFR2 (Table 
1.2). Together the data confirmed that ARQ 087 is highly potent against the FGFR family 
kinases, and also showed that it is a moderately selective kinase inhibitor. 
Table 1.2 Biochemical Activity of ARQ 087 Against a Panel of Kinases Using the MSA 
Assay 
Kinase 
Average IC50 (nM) 
FGFR2 
1.8 
RET 
3.0 
DDR2 
3.6 
FMS 
3.8 
PDGFR 
4.1 
FGFR3 
4.5 
FGFR1 
4.5 
KIT (V560G) 
5.2 
LCK 
6.2 
RET (M918T) 
7.4 
YES 
7.6 
ARG 
7.9 
KIT 
8.2 
FGFR3 (K650E) 
9.2 
PDGFR 
9.5 
QIK 
9.7 
PDGFRα (V561D) 
10.5 
FLT1 
10.7 
SRC 
11.1 
FGFR3 (K650M) 
11.3 
ABL 
13.7 

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Kinase 
Average IC50 (nM) 
EPHA1 
14.7 
FGR 
17.0 
CSK 
17.4 
FGFR4 
34.3 
Table 1.2: Biochemical Activity of ARQ 087 against a Panel of Kinases Using the MSA Assay.  FGFR family 
members are highlighted.  Kinase assays were conducted as described (www.carnabio.com) and ARQ 087 was 
tested in duplicate at concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, and 0.0003 µM. Data reported 
is the average of two determinations. 
 
1.3.2 
 
Cell Biology: Anti-Proliferative Effect and FGFR Pathway Inhibition by 
ARQ 087 in Human Cancer Cell Lines 
To determine whether ARQ 087 inhibits FGFR1, FGFR2, FGFR3, and FGFR4 in cells, we 
ectopically expressed full-length FGFR1, FGFR2, FGFR3, and FGFR4 in COS-1 cells and 
found that ARQ 087 inhibited the phosphorylation of FGFR1, FGFR2, and FGFR3 but not 
FGFR4 in this system (Figure 1.2).  The IC50 values for inhibition of FGFR phosphorylation 
for FGFR1-, FGFR2-, FGFR3-, and FGFR4-overexpressing cells were < 0.123 µM, 
0.185 µM, 0.463 µM, and > 10 µM, respectively. These data indicate that ARQ 087 is able to 
inhibit FGFR1, FGFR2 and FGFR3 in cells.14   
Figure 1.2 ARQ 087 Inhibits Ectopically Expressed FGFR1, 2, and 3 in COS-1 Cells  
 
Figure 1.2: COS-1 cells were transfected with mammalian expression vectors encoding full-length FGFR1, 
FGFR2, FGFR3, or FGFR4.  Forty-eight hours post-transfection cells were treated with indicated 
concentrations of ARQ 087 for 2 hours followed by stimulation with a mixture of FGF1, FGF2, and FGF7 for 
15 minutes.  Cell lysates were subjected to Western blot analysis to determine the expression of FGFR2, 
phospho-FGFR2, and ß-actin.14 
ARQ 087 was active in several tumor cell lines over-expressing wild type or mutant FGFRs.  
From a panel of ~50 cell lines, in general, those that overexpressed FGFR2 were the most 
sensitive to ARQ 087 in the MTS cell proliferation assays.14 These included the gastric 
carcinoma cell lines SNU-16 and Kato III, the breast carcinoma cell line MFM-223, the 
colorectal adenocarcinoma cell line NCI-H716, and the endometrial carcinoma cell line 
MFE-280 (possesses an activating mutant form of FGFR2). In addition, the FGFR2-

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Figure 1.3 Kato III and SNU-16 Cells Dependent on FGFR2 Signaling for Proliferation 
A. 
 
 
 
 
 
 
B. 
 
Figure 1.3: Dependency of Kato III and SNU-16 cells on FGFR2 signaling for proliferation.  
(A) Kato III and SNU-16 cells were treated with the indicated siRNA for 24, 48, or 72 hrs.  Cell growth was 
assessed by MTS assay.   
(B) Kato III and SNU-16 cells were treated with the indicated siRNA for 48 hrs followed by stimulation with 
100 pM of FGF7 for 15 min.   
Cell lysates were subjected to Western blot analysis to determine expression levels of FGFR2, phospho-FGFR2 
(these cell lines predominantly express FGFR2, thus phospho-FGFR indicates phospho-FGFR2), phospho-
MEK, phospho-AKT, and -actin. (The membranes were then scanned using the Odyssey infrared scanner 
(LiCor). These methods were developed in our laboratory and are described in detail elsewhere.22  
 
The ability of ARQ 087 to inhibit the FGFR2 pathway was assessed in Kato III and SNU-16 
cells.  ARQ 087 inhibited the phosphorylation of FGFR2, and the phosphorylation of its 
immediate downstream substrate FRS2α, as well as the phosphorylation of further 
downstream components MEK, ERK, and AKT (Figure 1.4).  The IC50 values for inhibition 
of FGFR2 phosphorylation were 92 ± 25 nM (Mean ± SD) and 52 ± 15 nM (Mean ± SD) for 
Kato III 
20
40
60
80
100
120
% Growth
FGFR1
siRNA
FGFR2
siRNA
FGFR3
siRNA
FGFR4
siRNA
Control
siRNA
24 hrs
48 hrs
72 hrs
% Growth
FGFR1
siRNA
FGFR2
siRNA
FGFR3
siRNA
FGFR4
siRNA
Control
siRNA
24 hrs
24 hrs
48 hrs
48 hrs
72 hrs
72 hrs
0
20
40
60
80
100
120
% Growth
FGFR1
siRNA
FGFR2
siRNA
FGFR3
siRNA
FGFR4
siRNA
Control
siRNA
24 hrs
48 hrs
72 hrs
% Growth
FGFR1
siRNA
FGFR2
siRNA
FGFR3
siRNA
FGFR4
siRNA
Control
siRNA
24 hrs
24 hrs
48 hrs
48 hrs
72 hrs
72 hrs
0
0
20
40
60
80
100
120
Control
siRNA
FGFR1
siRNA
FGFR2
siRNA
FGFR3
siRNA
FGFR4
siRNA
% Growth
24hrs%
48hrs %
72 hrs%
SNU-16 

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Kato III and SNU-16, respectively.  Based on these results, it was concluded that ARQ 087 
inhibited the FGFR2 pathway in FGFR2-dependent cancer cells. 
Figure 1.4 Inhibition of FGFR2 Pathway by ARQ 087 
 
Figure 1.4: Inhibition of FGFR2 Pathway by ARQ 087 
Kato III and SNU-16 cells were treated with indicated concentrations of ARQ 087 for 2 hrs followed by 
stimulation with 100 pM of KGF for 15 min.  Cell lysates were subjected to Western blot analysis with the 
indicated antibodies as described in  
 

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Figure 1.3. 
1.4 
In Vivo Pharmacology 
1.4.1 
 
Evaluation of ARQ 087 in Human and Murine Xenografts of Various 
Histological Types in Athymic Mice 
ARQ 087 is a pan-FGFR inhibitor which demonstrated potent inhibition of cell proliferation 
in cancer cells with FGFR2 amplification (e.g. Kato-III and SNU-16) or in cells possessing 
an FGFR2 activating mutation (AN3CA).  
The in vivo anti-tumor efficacy of ARQ 087 was assessed in athymic mice harboring human 
gastric (SNU-16)23,24, endometrial (AN3CA)25 carcinomas, or a murine B cell lymphoma 
(BaF3)26 stably transfected with FGFR2.  ARQ 087 was formulated in DMA: Cremophor EL: 
propylene glycol: 0.2M acetate buffer, pH 5 (10:10:30:50) for all in vivo experiments and 
administered orally.  Robust in vivo activity for ARQ 087 is illustrated in Figure 1.5 through 
Figure 1.7.  Two SNU-16 xenograft studies were conducted for ARQ 087.  In the first 
SNU-16 xenograft study (Figure 1.5), drug treatment was initiated with a mean tumor size 
range of ~150 mg.  In this study, 75 mg/kg and 50 mg/kg groups achieved 80% and 64% 
tumor growth inhibition (TGI), respectively.  Partial regressions were observed in both of 
these dose groups. Additionally, at 75 mg/kg, one complete regression (CR) was observed.  
In the second SNU-16 xenograft study, drug treatment was initiated with mean tumor size 
range ~400 mg.  Tumor regression in the second study was observed in the 75 mg/kg group 
while minimal tumor growth inhibition was observed in both the 25 mg/kg (30% TGI) and 
50 mg/kg (28% TGI) groups.  Additionally, ARQ 087 demonstrated significant tumor 
shrinkage in the BaF3/FGFR2 model (Figure 1.6).  The 100 mg/kg group resulted in 94% 
TGI accompanied by 3 CRs (complete regressions) and the 50 mg/kg group had 63% TGI.  
The mean net body weight loss on Day 14 was 3.9% and on Day 19 was 10.4%.  There was 
no body weight loss or complete/partial regressions in the 50 mg/kg dose level group.  
Adverse body weight loss was observed at the highest dose of 150 mg/kg, resulting in dosing 
suspension on Day 7.  ARQ 087 did not slow tumor progression in a BaF3/INSR (insulin 
receptor) model, demonstrating selectivity of this compound towards FGFR2. Fifty four 
percent TGI was observed in the AN3CA xenograft model on a daily (QD) schedule at 
75 mg/kg and on an every other day (Q2D) schedule at 150 mg/kg (Figure 1.7).  All doses of 
ARQ 087 were well tolerated with no evidence of body weight loss.  
 

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Figure 1.5 Inhibition of SNU-16 Human Gastric Tumor Xenograft Growth by ARQ 087 
 
Figure 1.5: ARQ 087 Inhibits Tumor Growth in the SNU-16 Xenograft Model. 
Treatment with ARQ 087 was initiated with mean tumor size range ~150 mg.  Partial (7) and complete 
regressions (1) were observed in the 75 mg/kg dose group. ARQ 312 is a first generation pan-FGFR inhibitor 
previously identified at ArQule.  
Error bars represent SD. 
0
100
200
300
400
500
600
9
11
13
15
17
19
21
23
25
Mean Tumor Weight (mg)
Days Post Implantation
FGFR2-39 - Evaluation of ARQ 087 in the SNU-16
Control
ARQ 312 250mg/kg Q1Dx12, 2 deaths, (5PR, 1CR)
ARQ 087 0mg/kg Q1Dx14
ARQ 087 50mg/kg Q1Dx14, (3PR)
ARQ 087 25mg/kg Q1Dx14
ARQ 087 75mg/kg Q1Dx14, (2PR, 1CR)
Dosing Period
92%
80%
64%

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Figure 1.6 Inhibition of BaF3/FGFR2 Tumor Xenograft Growth by ARQ 087 
 
Figure 1.6: ARQ 087 Inhibits Tumor Growth in the BaF3/FGFR2 Xenograft Model. 
Treatment with ARQ 087 was initiated with mean tumor size range ~150 mg. ARQ 087 demonstrated 
significant tumor shrinkage in the BaF3/FGFR2 model.  ARQ 312 is a first generation pan-FGFR inhibitor 
previously identified at ArQule.  
Error bars represent SD. 
 
 
 
 
0
200
400
600
800
1000
1200
1400
1600
1800
5
7
9
11
13
15
17
Mean Tumor Weight (mg)
Days Post Implantation
FGFR2-37 - Evaluation of ARQ 087 in the BaF3/FGFR2 Tumor Model
ARQ 087 0mg/kg Q1DX9
ARQ 312 250mg/kg Q1DX9
ARQ 087 150mg/kg Q1DX7, Toxic, 1 death 2 CR's
ARQ 087 50mg/kg Q1Dx9
ARQ 087 100mg/kg Q1DX9, 1 death , 3 CR's
63%
74%
92%
94%
note: dosing began SD+1
ARQ 087

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Figure 1.7 Inhibition of AN3CA Tumor Xenograft Growth by ARQ 087 
 
Figure 1.7: ARQ 087 Inhibits Tumor Growth in the AN3CA Xenograft Model. 
Treatment with ARQ 087 was initiated with mean tumor size range ~200 mg. ARQ 087 administered orally at 
150 mg/kg on a Q2Dx5 schedule and ARQ 087 administered orally at 75 mg/kg on a Q1Dx10 schedule resulted 
in significant inhibition of tumor progression. 
Vinblastine=Positive control 
 
 
0
500
1000
1500
2000
2500
11
13
15
17
19
21
23
Mean Tumor Weight (mg)
FGFR2-41: Evaluation of ARQ087 on AN3CA Tumor Model
ARQ 087 0mg/kg Q1D x 10
ARQ 087 60mg/kg Q1D x 10
ARQ 087 40mg/kg Q1D x 10
Vinblastine 10mg/kg Q5Dx2 IV (SD+1)
ARQ 087 75mg/kg Q1D x 10
ARQ 087 150mg/kg Q2Dx5
TGI = 99%
TGI = 54%
TGI = 34%
Days Post Implantation
Dosing Period 
Q1Dx10
ARQ 087 Structure
Q2Dx5
Q5Dx2

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A patient derived xenograft screen was conducted with ARQ 087 in 23 endometrial tumor 
models.27  Animals were dosed with 75 mg/kg ARQ 087 po: Q1Dx14 and the mean tumor 
volume was measured.  Figure 1.8 shows two models where there was an effect on tumor 
growth following the 14 day ARQ 087 treatment.   
 
Figure 1.8 Inhibition of Tumor Progression in ST413 and ST328 Endometrial Patient-
derived Xenograft Models 
 
Figure 1.8: ARQ 087 Inhibits Tumor Progression in the ST413 and the ST328 Patient-derived Xenograft 
Models. 
ARQ 087 was administered orally at 75 mg/kg on a Q1Dx14 schedule.  The effect of ARQ 087 on tumor 
volume for ST413(A) and ST328(C) are shown along with the historical control data for the models (B and D). 
 
In summary, ARQ 087 demonstrated biological activity in several in vivo xenograft models. 
PRs and CRs were observed in two models dependent upon FGFR2 signaling (the human 
gastric [SNU-16] and murine transfected cell line [BaF3/FGFR2]) (Figure 1.5 and Figure 
1.6). In addition, data obtained using patient-derived endometrial cancer xenograft models 
has demonstrated that ARQ 087 slowed tumor progression during the 14-day treatment 
period. 
0
500
1000
0
14
28
42
Cubic Millimeters
Day
ST413 Tumor Volume (Mean)
ARQ 087 
75mg/kg;po:qdx14
A 
B 
0
500
1000
0
7
14
21
28
Cubic Millimeters
Day
ST328 Tumor Volume (Mean)
ARQ 087  
75mg/kg;po:qdx14 
C 
D 

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1.5 
Pharmacodynamic Biomarkers 
1.5.1 
 
In Vivo Pharmacodynamics 
Evidence of ARQ 087 target engagement can be detected by measuring the inhibition of 
phosphorylation of ARQ 087 target receptor tyrosine kinase (RTKs) as well as key 
downstream signaling proteins. The pharmacodynamic effects of ARQ 087 on the FGFR 
pathway were confirmed both in vitro and in vivo.  The effects were most evident in FGFR2-
overexpressing cell lines such as the gastric carcinoma cell lines SNU-16 and Kato III. In 
preclinical xenograft tumor models, inhibition of phosphorylation of FGFR, FRS2, and 
ERK was observed using IHC on SNU-16 tumors at the efficacious dose of 75 mg/kg (Figure 
1.9)28. By Western blotting analysis, MEK and ERK phosphorylation levels were reduced by 
68% and 82%, respectively. This dose resulted in plasma levels of ARQ 087 of 4.9 ± 2.3 
µM.28 
 
Figure 1.9 Inhibition of FGFR2 Pathway in SNU-16 Gastric Carcinoma Xenograft 
Tumors by ARQ 087  
 
Figure 1.9: Target engagement study for ARQ 087 in SNU-16 tumor xenograft model (mean tumor size of 
~400 mg at drug treatment initiation). Female NCr nu/nu mice with established subcutaneous SNU-16 tumors 
were treated with indicated doses of ARQ 087 or vehicle control.  Tumor samples were collected 4 hrs after the 
last dose. Mice in the group dosed with 75 mg/kg were sacrificed on Day 9 after treatment initiation in order to 

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obtain sufficient quantities of tumor tissue.  The remaining groups were sacrificed at Day 21.  IHC staining of 
pFGFR, total FGFR2, pFRS2α, and pERK were performed on tumor tissues. Representative photomicrographs 
are shown.28  
Changes in plasma levels of FGF19, FGF21, and FGF23 as well as soluble FGFR, collagen 
IV, phosphate, glucose, and calcium either have been observed with other FGFR inhibitors or 
represent viable blood-based biomarkers to assess pharmacodynamic action of ARQ 087. In 
cell-based systems, ARQ 087 inhibited endogenously expressed FGFR2 and ectopically 
expressed FGFR1, 2, and 3 in COS-1 cells.  ARQ 087 demonstrated potent inhibition of 
FGFR2 phosphorylation in Kato III and SNU-16 human gastric carcinoma cells with 
comparable antiproliferative potencies in the MTS assay. Cell proliferation studies suggested 
a correlation of FGFR2 mRNA amplification in gastric and other cancers with associated 
sensitivity to treatment with ARQ 087. Concentration-dependent inhibition of 
phosphorylation of downstream FGFR pathway signals (FRS2α, MEK, ERK, and AKT) was 
evident in response to ARQ 087 treatment in both in vitro and in vivo pharmacodynamic 
assays.  Correspondingly, ARQ 087 induced regressions in FGFR2-driven xenograft models 
(SNU-16 and BaF3/FGFR2) and inhibited tumor progression in a model harboring a FGFR2-
activating mutation (AN3CA).   
1.5.2 
 
Pharmacokinetic Characteristics  
The oral bioavailability of ARQ 087 in rats was 37%, and in dogs ranged from 38 to 46% 
(solution or powder filled capsule, respectively), and indicated that ARQ 087 may have 
slightly higher bioavailability in dogs. 
Cross-species NADPH-dependent metabolism studies revealed that ARQ 087 was highly 
stable in mouse, rat, dog, monkey, and human liver microsomes with half-life values 
≥ 56 min.  Consistent with these data, half-life values for all individual CYP450 human 
isoforms tested were ≥ 53 min.  In human liver microsomes, ARQ 087 showed no significant 
liability against 3A4, 2C8, 2C9, and 2C19.  However, ARQ 087 showed potential to inhibit 
CYP 1A2 with an IC50 of 12.1 µM, and 2D6 with an IC50 of 18.6 µM.  ARQ 087 did not 
significantly induce CYP3A and CYP1A2 activity in fresh human hepatocytes.  In one of 
four independent donors, ARQ 087 induced CYP2B6 activity >40% of control at 5 µM.  
Caco-2 studies conducted with ARQ 087 showed high permeability and no significant efflux, 
suggesting ARQ 087 is not a P-gp substrate.  However, data from in vitro ATPase assays in 
human P-gp and human mutant (Thr482) BCRP membranes suggested that ARQ 087 may be 
a potential substrate and/or inhibitor of P-gp and mutant (Thr482) BCRP.  Protein binding in 
rat, dog, and human plasma was > 99.0%.  ARQ 087 was stable in human, rat, dog, and 
mouse whole blood and plasma for at least 2 hours at room temperature.  Additionally, 
ARQ 087 was stable (> 80% remaining) for at least 240 minutes at 37°C. 
1.6 
Nonclinical Toxicology 
Studies were conducted in rats to evaluate the toxicokinetics after oral gavage of ARQ 087. 
The results indicate that exposure to ARQ 087 generally increased as the dose was increased 
from 5 to 50 mg/kg/day. After reaching Cmax, ARQ 087 concentrations readily declined with 
t1/2 values ranging from 5.56 to 8.84 hours on Day 1 and 5.61 to 9.32 hours on Day 28, 
although determination of t1/2 was limited due to the lack of a distinct elimination phase in 
some groups. Values for Cmax and AUC0-24 were generally higher on Day 28 than on Day 1 

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indicating accumulation of ARQ 087 after multiple dosing at 5 and 15 mg/kg/day.  The 
accumulation ratio for AUC0-24 ranged from 1.64 to 2.94.  Sex differences were less than 
2-fold in ARQ 087 Cmax and AUC0-24 values, although females generally had higher 
exposures than males.  Values for CL/F and Vz/F generally appeared dose independent. 
Studies were also conducted in dogs to evaluate the toxicokinetics after oral capsule dosing 
of ARQ 087.  The results show that exposure to ARQ 087 increased as the ARQ 087 dose 
level increased from 3 to 30 mg/kg/day.  After reaching Cmax, ARQ 087 concentrations 
readily declined with the mean t1/2 values ranging from 4.80 to 7.43 hours on Day 1 and from 
6.41 to 10.8 hours on Day 28, although determination of t1/2 was limited due to the lack of a 
distinct elimination phase in some animals.  Values for mean Cmax and AUC0-24 were 
generally higher after multiple dosing on Day 7 and 28 than on Day 1, indicating 
accumulation of ARQ 087 in dogs.  The mean accumulation ratio (AR) for AUC0-24 ranged 
from 2.79 to 3.46 on Day 7 at the 30 mg/kg/day dose level and from 2.04 to 3.59 on Day 28 
for the 3 and 10 mg/kg/day dose levels.  Sex differences were less than 2-fold in ARQ 087 
mean Cmax and AUC0-24 values.  Values for CL/F and Vz/F generally appeared to be dose 
independent. 
Studies were conducted in dogs to evaluate the effects of different formulations (solution and 
solid) on the oral bioavailability of ARQ 087 relative to IV administration. Capsule 
formulations, dosed with ARQ 087 at a dose of 50 mg/kg, resulted in AUC0-24 values for 
ARQ 087 ranging from 14524 to 18659 h•ng/mL, Cmax values ranging from 1050 to 
1324 ng/mL, and %F values ranging from 38 to 46. A separate study evaluating capsule 
formulations dosed at 25 mg ARQ 087/kg resulted in AUC0-inf values for ARQ 087 ranging 
from 3388 to 6666 h•ng/mL, Cmax values ranging from 166 to 296 ng/mL.  
ARQ 087 was reasonably well tolerated over the course of the 28-day GLP toxicity studies 
with a NOAEL dose of 20 mg/kg/day (18 days)i in dog and a non-severely toxic dose in rats 
of 15 mg/kg/day.  The severely toxic dose in rats was determined to be 50 mg/kg/day. 
The toxicity profile of orally administered ARQ 087 in rat and dog studies was characterized 
principally by decreases in body weight and/or body weight gain, an effect generally 
correlated to a decrease in food consumption. Trends in reversibility during the recovery 
phase were observed for decreases in body weight and/or body weight gain and decreased 
food consumption in dogs but not in rats. Target organ toxicities based on the results of the 
28-day rat and dog studies were associated to those involving gastrointestinal (rat, dog), 
hematological (rat, dog), liver (rat, dog), bone (rat), and lung (rat) function. 
In the 28-day rat study, all control, low, and mid dose (0, 5, and 15 mg/kg) animals survived 
to the scheduled terminal necropsy.  All high dose (50 mg/kg) animals, excluding those 
designated for recovery, were sacrificed and/or necropsied between Days 12 and 14 of the 
dosing phase.  ARQ 087-related clinical observations were limited to animals given 
50 mg/kg/day, which made necessary the suspension of further dosing and an unscheduled 
terminal necropsy.  These clinical observations, along with decreases in body weight/body 
weight gain and food consumption included hunched appearance and swelling of the 
                                                 
i Animals in the 30/20 mg/kg/day group were dosed on Days 1 through 7 at 30 mg/kg/day at which point this 
dose level was not tolerated and they were put on dosing holiday on Days 8 through 11. Dosing was resumed on 
Day 12 at 20 mg/kg/day. 

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abdomen (noted in one female), thinness, nasal and oral discharge, fecal abnormalities (few 
and nonformed), squinting of the eyes, and pelage/skin abnormalities.  Clinical observations 
associated with thinness and decreases in body weight/body weight gain that did not resolve 
following the 2-week recovery phase were noted for animals given 50 mg/kg/day of 
ARQ 087. 
Additionally, in the 28-day rat study, ARQ 087 administration was associated with several 
effects on clinical pathology test results.  The most toxicologically important effects included 
reduced erythropoiesis at ≥ 15 mg/kg/day, suspected lymphoid tissue injury at 50 mg/kg/day 
(females), and liver injury at ≥ 15 mg/kg/day.  Specifically, reduced erythropoiesis was 
associated with decreased red cell mass and absolute reticulocyte counts as well as changes 
in erythrocytic indices.  Decreased lymphocyte counts were observed in females given 
50 mg/kg/day.  Increased alanine aminotransferase (ALT) activity was first observed in 
males given 5 mg/kg/day, followed by increased ALT and alkaline phosphatase (ALP) 
activity in animals given 15 mg/kg/day.  At dose levels of 50 mg/kg/day, increased ALT, 
aspartate aminotransferase (AST), ALP, and gamma glutamyltransferase (GGT) activities 
were observed.  A few less specific test article-related effects, especially changes in 
electrolyte values, were observed during the recovery phase in animals given 50 mg/kg/day.  
These changes may have been associated with mild dehydration.  No macroscopic findings 
were attributed to the test article at the terminal or recovery necropsy.  In animals sacrificed 
in moribund condition or at the terminal sacrifice, test article-related microscopic findings 
were observed in the femur and sternum bone and marrow, alimentary canal (tongue, 
esophagus, nonglandular stomach, duodenum, ileum, and jejunum), spleen, and lung.  Most 
findings were limited to the 50 mg/kg/day dose level.  Exceptions were the lung and spleen, 
where findings were also observed at 15 mg/kg/day.  All test article-related microscopic 
findings observed at the terminal necropsy and in animals sacrificed at an unscheduled 
interval were reversed at the recovery necropsy, excluding femur and sternum physeal 
hypertrophy, increased splenic extramedullary hematopoiesis, and lung vacuolated 
macrophage infiltrates.  Tongue and esophageal ulcers observed at 50 mg/kg/day were 
considered severely toxic. 
In shorter duration 7-day repeat dose toxicity studies, minimally longer prothrombin time and 
activated partial thromboplastin time was observed in male rats dosed at 150 mg/kg/day. 
In the 28-day dog study, oral capsule administration of ARQ 087 was tolerated in dogs at 
3 and 10 mg/kg/day for 29 days and at 20 mg/kg/day for 18 days; however, it was not 
tolerated at 30 mg/kg/day for 7 days.  Animals given 30 mg/kg/day had vomitus, abnormal 
feces, body weight loss, and/or markedly reduced food consumption during the first week of 
dosing.  One male given 30 mg/kg/day was sacrificed on Day 6 of the dosing phase in 
moribund condition that included clinical observations of vomitus, limited use of the hind 
quarters, ataxia, rigid stance, hypoactivity, dilated and minimally responsive pupils, 
excessive salivation, occasional tonic front limbs, and postictal and close to seizure 
threshold.  The male had clinical pathology findings consistent with inflammation/stress, 
dehydration, and lower serum potassium and chloride that likely resulted from vomiting.  
Potentially adverse, test article-related microscopic findings of acute inflammation and 
ulceration of the esophagus were also noted, and the moribund condition of the male is 
partially attributed to these microscopic findings.  All other animals survived to their 
scheduled sacrifices.  Due to adverse findings observed at 30 mg/kg/day, dosing was 

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suspended on Day 8 and resumed on Day 12 of the dosing phase at 20 mg/kg/day.  Abnormal 
feces observed for most animals given 20 mg/kg/day was not adverse because it did not 
impact the health of the animals.  Animals given 30/20 mg/kg/day had white discolored 
haircoat of the entire head during the dosing and recovery phases; however, this observation 
was not adverse, and no corresponding microscopic finding was present.  No test article-
related changes in ECG parameters or ophthalmic examinations were observed.  No test 
article-related clinical pathology effects were observed at 3 or 10 mg/kg/day.  A few minor, 
potentially test article-related findings in animals given 30/20 mg/kg/day were minor and not 
considered adverse or toxicologically important.  Potentially adverse, test article-related 
microscopic findings of acute inflammation and ulceration of the esophagus occurred in one 
male given 30/20 mg/kg/day.  Test article-related microscopic findings noted during the 
dosing phase were not present in recovery animals. 
The hERG IC50 for ARQ 087 was greater than 3 µM.  No effect on QT was observed in dogs 
in the cardiovascular study (60 mg/kg) or in the ECG in the 28-day toxicity study (up to 
30/20 mg/kg). 
Additionally, the hemodynamic and electrocardiographic effects of ARQ 087 were examined 
in telemeterized dogs.  A slight, transient increase in mean arterial pressure and its 
components (~15% compared to vehicle) was observed 40 to 120 minutes after dosing with 
60 mg/kg ARQ 087. A concomitant increase in heart rate was also noted, and was on average 
~20% higher compared to heart rates observed after vehicle dosing within this timeframe.  
There were no notable effects of ARQ 087 on pulse pressure, PR interval, QRS duration, 
QTcVDW interval, or arrhythmogenesis. 
ARQ 087 was found to have phototoxic potential in the 3T3 Neutral Red Uptake 
Phototoxicity Test. 
Transient effects on clinical chemistry such as increased glucose levels and phosphorous 
levels were observed in rats and/or dogs in shorter duration 7-Day repeat dose toxicity 
studies and may be characteristic of FGFR kinase inhibitors.31,32,33  
Based on the findings from the 4-week toxicity studies, the rat is considered as the more 
sensitive of the two species and will be evaluated for purposes of estimating a safe starting 
dose for a First in Human (FIH) study conducted in subjects with advanced malignancies. As 
described in the ICH guidance document: S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals, a safe human starting dose based on assessment of toxicity in rodent 
species is 1/10 of the severely toxic dose in 10% of the animals (STD 10).  The STD 10 for 
ARQ 087 was determined to be 50 mg/kg/day, however, due to the need to sacrifice the 
50 mg/kg/day animals between Days 12 and 14 of the dosing phase (except those designated 
for recovery), the 15 mg/kg dose was used to select the safe starting dose in humans.  From 
this dose, the Phase 1 starting dose is calculated to be 9 mg/m2/day or 15.3 mg/day (BSA 
1.7). For the purpose of this FIH study the starting dose is suggested to be 25 mg every other 
day (QOD) to conform to available capsule dosage strengths (25 and 100 mg) and minimize 
capsule consumption burden for subjects. 
In summary, the pre-clinical data support that ARQ 087 has the potential to exert significant 
anti-tumor effects on human tumors driven by oncogenic FGFR with an acceptable 
therapeutic window. 

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1.7 
Clinical Experience 
The initial safety and tolerability of ARQ 087 have been established in the open-label, Dose 
Escalation part (Part 1) of the ongoing ARQ 087-101 study in adult subjects with advanced 
solid tumors. A total of 61 subjects with different types of solid tumors have been enrolled 
and treated with ARQ 087.  
As of 31-Mar-2015, in the Dose Escalation/Food-effect Cohorts, in two out of three subjects 
with iCCA, a significant reduction in tumor burden (assessed per RECIST v. 1.1) has been 
observed. Both subjects have confirmed FGFR2 fusion (BICC1 and KIAA1217, 
respectively), one subject has had a partial response (PR) (with 35% tumor reduction after 
8 weeks of treatment; the subject completed 24 weeks of treatment) and another subject has 
demonstrated a durable stable disease (SD) (with maximum 26% tumor reduction; currently, 
the subject is at Week 34 of treatment). The subject with the durable SD received four 
regimens of prior chemotherapy including gemcitabine plus cisplatin. The subject with the 
PR did not receive any prior systemic therapy. The third subject with unknown FGFR status 
was discontinued from the treatment after 8 weeks due to lack of clinical benefit. 
Overall, the drug has demonstrated a favorable safety profile with manageable toxicities. The 
most common (≥ 5%) drug-related adverse events (AE) reported to date include fatigue 
(50.0%), nausea (46.7%), aspartate aminotransferase increased (30.0 %,), diarrhoea (25.0%), 
vomiting (21.7%), constipation, decreased appetite (20.0%, each), dysgeusia (15.0%), 
alanine aminotransferase increased (11.7%), anaemia, dyspepsia, blood creatinine increased, 
dry skin (8.3%, each), dry mouth, blood alkaline phosphatase increased (6.7%, each), and 
gastrooesophageal reflux disease, rash maculo-papular (5.0%, each). 
The RP2D has been defined as 300 mg qd under fasting conditions. 
Based on the non-clinical and clinical literature data, early efficacy results observed in the 
Dose Escalation part of this study, and known unmet need for new, effective treatments for 
iCCA patients, it seems reasonable to further evaluate ARQ 087 in subjects with iCCA with 
FGFR2 fusion. 
Detailed non-clinical and clinical data can be found in the ARQ 087 Investigator’s Brochure 
(IB).

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this first-in-human (FIH) study is to assess the safety and 
tolerability of ARQ 087 in subjects with advanced solid tumors (Part 1; Dose 
Escalation/Food-effect Cohorts) or with advanced solid tumors with FGFR genetic 
alterations, including iCCA with FGFR2 gene fusion (Part 2; Expanded Cohort, signal 
finding). 
2.2 
Secondary and Exploratory Objectives 
The secondary objectives of this study are: 
 
To assess the pharmacokinetic profile of ARQ 087 in subjects enrolled in Part 1 (Dose 
Escalation/Food-effect Cohorts) of the study  
 
To assess the pharmacodynamic activity of ARQ 087 in blood and tumor biopsy 
specimens obtained from subjects with advanced solid tumors 
 
To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose 
(RP2D) of ARQ 087 (Part 1) 
 
To further evaluate the RP2D of ARQ 087 in subjects with FGFR genetic alterations, 
including subjects with iCCA with FGFR2 gene fusion (Part 2; Expanded Cohort, signal 
finding) 
 
To generate preliminary evidence of anti-tumor activity  
 
To generate preliminary biomarker evidence of target inhibition 
 
To identify specific target subject (patient) population, e.g., subjects with iCCA with 
FGFR2 gene fusion or with other solid tumors with FGFR genetic alterations 
The exploratory objectives of this study are: 
 
To validate and assess FGFR family members (specifically FGFR2 and potentially those 
harboring activating mutations) as predictive biomarkers 
 
To evaluate the association between known markers of the FGF signaling pathway, 
toxicity, and clinical activity  
 
 

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3 
SELECTION OF STUDY POPULATION  
Adult subjects with advanced solid tumors whose cancer has progressed following standard 
therapy, or who have been unable to tolerate standard therapy, and/or for whom no standard 
treatment is available will be enrolled. 
The exact number of subjects estimated for this study is dependent on the number of subject 
cohorts investigated based on the toxicity encountered.  It is expected that approximately 
60-120 subjects at five to fifteen sites in the United States and Italy will be enrolled in this 
study. Once the MTD/RP2D level is determined, an Expanded Cohort will be enrolled. 
Subject accrual will occur over a period of time dependent upon the number of cohorts 
enrolled.  
The Food-effect Cohort (Part 1) will enroll at least six subjects with luminal breast A or B, 
endometrial, urothelial, gastric, or lung cancer with known and/or confirmed FGFR1-3 high 
level amplification, mutation or gene rearrangement (fusion, translocation), or with 
adrenocortical carcinoma, cholangiocarcinoma, or sarcomas, independent from FGFR1-3 
status. All subjects enrolled in the Food-effect Cohort should agree to and be eligible for 
paired biopsy. 
The Expanded Cohort (Part 2) of approximately 50-60 subjects with advanced solid tumors 
with FGFR genetic alterations, including iCCA with FGFR2 gene fusion will be enrolled. 
The tumor type eligibility should be confirmed by the Sponsor’s Medical Monitor or 
designee prior to enrollment. If at the time of the first restaging (C3D1), in two out of the 
first five enrolled subjects with the same tumor type, objective response (significant, ≥ 15%, 
reduction in tumor size) is not achieved, such tumor sub-cohort may be closed for further 
enrollment.  If the objective response in the first 10 subjects with iCCA is observed in ≤30% 
of the enrolled subjects, the enrollment will be stopped for lack of efficacy. 
3.1 
Inclusion Criteria 
Each prospective subject must meet ALL of the following inclusion criteria in order to be 
eligible for this study: 
1. Signed written informed consent granted prior to initiation of any study-specific 
procedures 
2. Male or female subjects of ≥ 18 years of age 
3. Histologically or cytologically confirmed locally advanced, inoperable, or metastatic 
solid tumors. All subjects eligible for enrollment in the Expanded Cohort must have 
documented and/or confirmed FGFR genetic alterations, including iCCA with FGFR2 
gene fusion. 
4. Failure to respond to standard therapy, or for whom standard therapy does not exist. 
 Subjects enrolled in the Expanded Cohort should have no more than two prior 
systemic regimens with confirmed disease progression. 
 If the subject is refractory or has disease progression within 6 months of adjuvant 
treatment, then the previous treatment should be considered as a line of treatment 
rather than adjuvant therapy. 

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 Subjects who did not receive prior systemic therapy for locally advanced and/or 
metastatic iCCA with confirmed FGFR2 gene fusion and for whom, in the opinion 
of the Investigator, treatment with ARQ 087 is appropriate may be enrolled 
5. Evaluable or measurable disease  
6. Archival and/or fresh biopsy tissue samples must be available prior to the first dose of 
the study drug.  
 All subjects eligible for enrollment in the Expanded Cohort (Part 2) must have 
known (documented and/or confirmed) FGFR genetic alterations.  
 Archival tumor samples should be collected for all subjects enrolled in the 
Expanded Cohort. Paired fresh tumor biopsy is optional for subjects enrolled in the 
Expanded Cohort.  Both archival and pre-treatment fresh tumor samples (optional) 
should be collected prior to the first dose of the study drug 
 All subjects eligible for enrollment in the Food-effect Cohort must have the 
following tumor types: luminal breast A or B, endometrial, urothelial, gastric, or 
lung cancer with known and/or confirmed FGFR1-3 high level amplification, 
mutation or gene rearrangement (fusion, translocation), or adrenocortical 
carcinoma, cholangiocarcinoma, or sarcomas, independent from FGFR1-3 mutation 
status 
 All subjects eligible for enrollment in the Food-effect Cohort should agree to and be 
eligible for paired biopsy 
7. Life expectancy  12 weeks 
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 
(Appendix 2) 
9. Hemoglobin (Hgb) ≥ 9.0 g/dL 
10.  Absolute neutrophil count (ANC)  1.5 x 109/L 
11. Platelet count ≥ 100 x 109/L 
12. Total bilirubin  1.5 x upper limit of normal (ULN) (≤ 2 ULN for subjects with 
cholangiocarcinoma) 
13. Aspartate transaminase (AST) and alanine transaminase (ALT)  3 ULN ( 5 x ULN for 
subjects with liver metastases) 
14. Serum creatinine  1.5 x ULN or creatinine clearance > 60 mL/min/1.73 m2 for subjects 
with creatinine levels above institutional normal 
15. Albumin  2.8 g/dL 
16. INR 0.8 to ULN or  3 for subjects receiving anticoagulant therapy such as Coumadin 
or heparin 
17. Male or female subjects of child-producing potential must agree to use double-barrier 
contraceptive measures, oral contraception, or avoidance of intercourse during the study 
and for 90 days after the last dose of ARQ 087 
18. Women of childbearing potential must have a negative serum pregnancy test during 
Screening Period and within 48 hours of the first dose of ARQ 087. “Women of 
childbearing potential” is defined as sexually mature women who have not undergone a 

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hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive 
months prior to the first dose of ARQ 087. 
3.2 
Exclusion Criteria 
Prospective Subjects who meet ANY of the following criteria will not be eligible for 
enrollment into this study: 
1. Anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal, targeted 
therapy, or investigational agents within four weeks or five times of the drug half-life, 
whichever is LONGER, of the first dose of ARQ 087  
2. Major surgery or radiation therapy within four weeks of the first dose of ARQ 087 
3. Previous treatment with FGFR inhibitors (e.g., ponatinib, dovitinib, nintedanib, 
AZD4547, NVP-BGJ398, LY2784455, BAY1163877) 
4. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition as ARQ 087 
5. Unable or unwilling to swallow the complete daily dose of ARQ 087 
6. Clinically unstable central nervous system metastasis (to be eligible, subjects must have 
stable disease  3 months, confirmed by MRI or CT scan, and/or have CNS metastases 
well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving 
medications) 
7. History of myocardial infarction (MI) or congestive heart failure defined as Class II to 
IV per the New York Heart Association (NYHA) classification within 6 months of the 
first dose of ARQ 087 (MI that occurred > 6 months prior to the first dose of ARQ 087 
will be permitted)  
8. Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, 
interfere with the absorption, metabolism, or excretion of ARQ 087 (e.g., Crohn’s 
disease, ulcerative colitis, extensive gastric resection)    
9. History and/or current evidence of clinically relevant ectopic 
mineralization/calcification including but not limited to the soft tissue, kidneys, 
intestine, myocardium, and lung with the exception of calcified lymph nodes, 
asymptomatic nephrolithiasis, and asymptomatic coronary calcification (If indicated, 
standard CT or MRI may be used to assess ectopic mineralization/calcification.) 
10. Previous malignancy within 2 years of the first dose of ARQ 087, except curatively 
treated non-melanoma skin cancer, carcinoma in-situ of the breast or cervix, superficial 
bladder tumors 
11. Known human immunodeficiency virus (HIV) infection 
12. Concurrent uncontrolled illness not related to cancer, including but not limited to: 
 
Psychiatric illness/substance abuse/social situation that would limit compliance 
with study requirements 
 
Uncontrolled diabetes mellitus  
13. Blood transfusion within 5 days of the blood draw being used to confirm eligibility 
14. Pregnant or breastfeeding  

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3.3 
Number of Subjects 
The exact number of subjects estimated for this study is dependent on the number of subject 
cohorts investigated based on the toxicity encountered.  It is expected that approximately 
60 to 120 subjects will be enrolled in the Dose Escalation/Food-effect Cohorts (Part 1) and 
the Expanded Cohort (Part 2). 
 
 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is an open-label, Phase 1/2, dose escalation and signal finding study of ARQ 087 
administered to subjects with advanced solid tumors.  The study is designed to explore the 
safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of 
ARQ 087 and to define a RP2D of ARQ 087.  
4.1.1 
 
Part 1: Dose Escalation Cohorts 
Treatment will be initiated at a dose level of 25 mg/qod (every other day). All cycles/cohorts 
of therapy will consist of the oral administration of ARQ 087 at dose levels and 
administration schedules specified for their respective dose cohorts; the drug should be taken 
one hour prior to or two hours after the meal.  In Cohorts 1-4, treatment will consist of two 
treatment periods: Treatment Period 1 (single dose administration for 72-hour PK 
assessment) and Treatment Period 2 (continuous dosing that will cease at the subject’s 
discontinuation from the study).  
To assess safety of ARQ 087, a minimum of three subjects will be enrolled in each cohort. 
To assess pharmacodynamic changes, enrollment of additional subjects from whom paired 
(pre- and post-treatment) biopsies may be obtained will be allowed in each cohort. Each dose 
escalation cohort may enroll up to six subjects. 
Cohorts 1 – 4 (Part 1) 
 
SCREENING PERIOD: 
-21 – 0 days 
TREATMENT PERIOD 1 (PK): 
Single-dose administration on D1 
PK samples: 0-72 hrs post dose (D1 – D4) 
(Washout period between Treatment Period 1 Day 1 
and Treatment Period 2, C1D1 should be ≥ 72 hrs) 
TREATMENT PERIOD 2: 
Continuous dosing, C1D1+ until the 
subject’s discontinuation from the study 

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Given the long half-life (~ 1 week) of ARQ 087 in human subjects and hence the length of 
time (~35 days) to reach steady state, it was determined that it was reasonable to eliminate 
the single dose phase. Hence, starting with Cohort 5, treatment will consist of a single 
treatment period of continuous dosing that will cease at the subject’s discontinuation from 
the study.  
 
Cohort 5 and all Subsequent Dose Escalation/Food-effect Cohorts (Part 1) 
 
Tumor assessments (CT scan, MRI, or PET scan) will be performed at Baseline, and every 
eight weeks during Treatment Period 2 (e.g., on Day 1 of every odd cycle, Cycle 3 Day 1, 
Cycle 5 Day 1, or Week 8, Week 16, etc.) or as otherwise clinically indicated.  
Dose escalation will be performed after three or six subjects are evaluated in each cohort (see 
Table 4.1). If a DLT is observed in one of the three subjects in a cohort in the first 28 days of 
therapy, the additional three subjects will be enrolled in the cohort sequentially. 
If no DLT is seen in the first three evaluable subjects in the first 28 days of therapy, dose 
escalation will occur and another three subjects will be enrolled and treated at the next 
ARQ 087 dose level.  If two or more subjects experience a DLT at Dose Level 1, subsequent 
subjects will be enrolled at a lower dose or at a less frequent drug administration schedule 
(e.g., 25 mg twice a week). If a subject withdraws from study treatment for any reason other 
than a DLT during the first 28 days (first cycle), that subject will be replaced.  
The MTD is defined as the dose level at which no more than one subject with a DLT is 
observed among six subjects.  Once the MTD is determined, up to six additional subjects 
may be treated at this dose level of ARQ 087. If the MTD is not reached, dose escalation will 
proceed with the purpose of determining a RP2D of ARQ 087.  
In the first four cohorts, the dose may be doubled, and in the next cohorts, the dose escalation 
will follow a modified Fibonacci scheme (increase by 50%, 30%, and 25%) until RP2D or 
MTD is determined.  
SCREENING PERIOD: 
-21 – 0 days 
TREATMENT PERIOD 
Continuous dosing, C1D1+ until the 
subject’s discontinuation from the study 
FOOD-EFFECT COHORT 
(At least 6 subjects with pre-defined 
tumor types) 
Continuous dosing, C1D1+ until the 
subject’s discontinuation from the study 

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Subjects enrolled in the Food-effect Cohort will be asked to take ARQ 087 (400 mg qd) with 
or immediately after their morning meals (moderate-fat meal) and to keep a food diary 
(breakfast). The moderate-fat breakfast should contain approximately 550 kcal, with 
approximately 25% of the calories from fat. The Food-effect Cohort will enroll at least six 
subjects with luminal breast A or B, endometrial, urothelial, gastric, or lung cancer with 
known and/or confirmed FGFR1-3 amplification, mutation or gene rearrangement (fusion, 
translocation), or with adrenocortical carcinoma, cholangiocarcinoma, or sarcomas, 
independent from FGFR1-3 status. All subjects enrolled in the Food-effect Cohort should 
agree to and be eligible for paired biopsy. Once the MTD/RP2D level is determined, the 
Expanded Cohort (Part 2) will enroll approximately 50-60 subjects with advanced solid 
tumors with documented (known/confirmed) FGFR genetic alterations, including iCCA with 
FGFR2 gene fusion.  
Based on the drug safety profile and the Food-effect Cohort PK data, 300 mg qd under fasted 
condition (1 hour prior or 2 hours after the meal) has been defined as a RP2D and is 
recommended for further evaluation in the Expanded Cohort. Also, in two out of three 
subjects with iCCA enrolled in the Food-effect cohort, an objective response (assessed per 
RECIST) was observed. Both subjects had confirmed FGFR2 gene fusion, one subject had 
PR (with 34% tumor reduction) after 8 weeks of treatment and another subject demonstrated 
a durable SD after 28 weeks on treatment (with maximum 26% tumor reduction). 
Table 4.1 Dosing Guidelines 
Cohort 
Total Daily Dosea 
Dose per Administration 
Number of Subjects 
Dose Escalation Cohorts: Part 1 
 
25 mg 
1 cap x 25 mg x twice a week 
3-6b 
1a 
25 mg 
1 cap x 25 mg x qod 
3-6b 
2 
25 mg 
1 cap x 25 mg x qd 
3-6b 
3 
50 mg 
2 caps x 25 mg x qd 
3-6b 
4 
100 mg 
1 caps x 100 mg x qd 
3-6 b 
5* 
150 mg 
2 caps x 25 mg & 1cap x 
100 mg x qd 
3-6b 
6 
200 mg 
2 caps x 100 mg x qd 
3-6b 
7 
250 mg 
2 caps x 25 mg & 2 caps x 
100 mg x qd 
3-6b 
8 
325 mg 
1 cap x 25 mg & 3 caps x 
100 mg x qd 
3-6b 
9 
425 mg 
1 cap x 25 mg & 4 caps x 
100 mg x qd 
3-6b 
10 
550 mg 
2 caps x 25 mg & 5 caps x 
100 mg x qd 
3-6b 
Food-effecta 
400 mg 
4 caps x 100 mg qd 
at least 6 
Expanded Cohort: Part 2 
Expandedc 
300 mg  
3 caps x 100 mg x qd  
under fasting conditions 
approx. 50-60 
*Starting from Cohort 5, the dose escalation will follow a modified Fibonacci scheme (increase by 50%, 

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30%, and 25%) 
To avoid potential non-compliance due to capsule burden, the dose escalation may be stopped at the dose 
level of 550 mg/daily 
aTotal daily dose must be administered one hour prior to or two hours after the meal [Exceptions: 1) Cohort 1 
is dosed every other day and 2) Food-effect Cohort] 
bIf a DLT is seen in one of three treated subjects, an additional three subjects will be treated at the same dose 
level 
cBased on the safety profile and PK results of the Food-effect cohort, the dose of 300 mg qd under fasting 
conditions has been defined as MTD/RP2D and should be further evaluated in the Expanded Cohort 
Preliminary PK results reported in subjects enrolled in Cohorts 1-3, have shown that 
ARQ 087 has a long half-life (~ 1 week) and accumulates with continuous dosing in human 
subjects (~4 to 14 fold across all cohorts, 4 to 8 fold in cohorts dosed at ≥ 100 mg qd). 
Additionally, preliminary PK results showed that Day 22 exposure (AUC and Cmax) remained 
essentially the same when increasing the dose from 250 to 425 mg qd, suggesting that drug 
exposure has reached a plateau at dose levels above 250 mg qd. The ArQule Medical 
Monitor and Investigator(s) will review all significant ARQ 087-related toxicities and PK 
data to determine if the dose escalation schedule requires modification.  Intermediate doses 
or different drug administration schedules (e.g., 2 weeks on/1 week off) may be investigated 
after agreement between ArQule’s Medical Monitor and the Investigator(s). 
4.1.2 
 
Part 2: Expanded Cohort 
 
Approximately 50-60 subjects with advanced solid tumors with FGFR genetic alterations, 
including iCCA with FGFR2 gene fusion will be enrolled. The tumor type eligibility should 
be confirmed by the Sponsor’s Medical Monitor or designee prior to enrollment. If, at the 
time of the first restaging (C3D1), in two out of the first five enrolled subjects  with the same 
tumor type, an objective response (significant, ≥ 15%, reduction in tumor size) is not 
achieved, such tumor sub-cohort may be closed for further enrollment.   
Interim monitoring for futility will be incorporated after response data from 10 subjects with 
iCCA are available. If objective response is observed in ≥ 30% of enrolled subjects, up to 
20 additional subjects with iCCA with FGFR2 fusion will be enrolled. 
4.2 
Rationale for Study Design 
4.2.1 
 
Part 1: Dose Escalation/Food-effect Cohorts 
This is the FIH, open-label clinical study with ARQ 087.  This study will be conducted to 
evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetics of ARQ 087 in 
subjects with advanced solid tumors. 
SCREENING PERIOD 
-21 – 0 days 
EXPANDED COHORT 
(Approximately 50-60 subjects with FGFR genetic 
alterations, including iCCA with FGFR2 gene fusion) 
Continuous dosing, C1D1+ until the subject’s 
discontinuation from the study  

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The principal objective of Phase 1 studies is the assessment of the safety, tolerability, 
pharmacokinetics, and pharmacodynamics as well as determination of the RP2D of a new 
drug. For traditional chemotherapeutic agents that show limited selectivity for cancer cells 
over normal cells, RP2D is generally set at the MTD.  However, for targeted agents, such as 
ARQ 087, the RP2D range may be below the MTD.  For such therapies, it is important to 
collect pharmacokinetic and pharmacodynamic data to establish the dosing regimen that 
achieves the desired plasma concentration required for the intended pharmacologic effect.  
Although pharmacokinetic and pharmacodynamic results may ultimately lead to selection of 
a lower dose, it is considered important to establish the clinical toxicity, including DLT as 
part of a thorough clinical evaluation of anticancer drugs.  Therefore, in the current study 
dosing may be escalated beyond what is expected to produce therapeutic levels.  
4.2.2 
 
Part 2: Expanded Cohort 
Once the MTD/RP2D is determined, subjects with advanced solid tumors with FGFR genetic 
alterations, including iCCA with FGFR2 gene fusion, will be enrolled in Part 2, the signal 
finding Expanded Cohort. 
4.3 
Selection of Initial Dose  
Based on the findings from the 4-week toxicity studies, the rat is considered as the more 
sensitive of the two species and will be evaluated for purposes of estimating a safe starting 
dose for a First in Human (FIH) study conducted in subjects with advanced malignancies. As 
described in the ICH guidance document: S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals, a safe human starting dose based on assessment of toxicity in rodent 
species is 1/10 of the severely toxic dose in 10% of the animals (STD 10).  The STD 10 for 
ARQ 087 was determined to be 50 mg/kg/day, however, due to the need to sacrifice the 
50 mg/kg/day animals between Days 12 and 14 of the dosing phase (except those designated 
for recovery), the 15 mg/kg dose was used to select the safe starting dose in humans.  From 
this dose, the Phase 1 starting dose is calculated be 9 mg/m2/day or 15.3 mg/day (BSA 1.7). 
For the purpose of this FIH study the starting dose is suggested to be 25 mg every other day 
(QOD) to conform to available capsule dosage strengths (25 and 100 mg) and minimize 
capsule consumption burden for subjects. 
4.4 
Criteria for Dose Escalation and Determination of Dose-Limiting 
Toxicity  
Evaluable subjects are defined as having been exposed to at least 28 days of continuous 
administration of ARQ 087 (e.g., qod, qd, 2 weeks on/1 week off, etc.). Based on the 
tolerability and safety of ARQ 087 evaluable subjects, enrollment at the next dose level 
and/or additional subjects into the ongoing cohort will occur according to the following:  
 
If zero of three initially treated subjects experience a DLT by Day 29 of continuous 
dosing, then dose escalation will occur 
 
If one of three initially treated subjects experiences a DLT by Day 29 of continuous 
dosing, then an additional three subjects will be enrolled for a total of six subjects treated 

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at the same dose level.  Escalation will occur if no additional DLTs are seen in that 
cohort. 
 
If two or more of three initially treated subjects at a dose level experience a DLT by 
Day 29 of continuous dosing, dose escalation will stop and the prior dose level will be 
considered the MTD. If the first dose results in MTD, subsequent subjects will be 
enrolled at a lower dose or at a less frequent drug administration schedule (e.g., 
25 mg/twice a week). 
The MTD is defined as the dose level at which no more than one out of six subjects has an 
observable DLT. 
Preliminary PK results reported in subjects enrolled in Cohorts 1-10 and the Food-effect 
Cohort have shown that ARQ 087 has a long half-life (~ 1 week) and accumulates (~4 to 
14 fold across all cohorts, 4 to 8 fold in cohorts dosed at ≥ 100 mg qd) with continuous 
dosing.  To determine MTD or RP2D and drug administration schedules, clinical PK 
parameters will be continuously monitored and assessed throughout the study.   
Based on the drug safety profile and preliminary Food-effect Cohort PK data, 300 mg qd 
under fasting conditions has been defined as the RP2D and is recommended for further 
evaluation in the Expanded Cohort. 
4.5 
Dose-Limiting Toxicity 
Dose-limiting toxicities will be determined during the first four weeks/28 days (first cycle) of 
Treatment Period 2 (Cohorts 1-4) or during Cycle 1 (Cohort 5 and all subsequent cohorts). A 
DLT is defined by the occurrence of any of the following toxicities related to ARQ 087 
within the first 28 days of continuous treatment (Treatment Period 2 or Cycle 1 of 
Continuous Dosing) and graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03:  
 
Grade 4 anemia  
 
Grade 4 neutropenia  
 
Grade 4 thrombocytopenia  
 
Grade 3 neutropenia with fever (≥ 38°C/100.4°F )  
 
Grade 3 neutropenia lasting longer than 7 days despite optimal treatment 
 
Grade 3 thrombocytopenia in the presence of bleeding  
 
≥ Grade 3 hyperglycemia (fasting blood glucose > 250 mg/dL or non-fasting 
> 500 mg/dL) requiring insulin (uncontrolled with metformin) 
 
≥ Grade 3 non-hematological toxicity of any duration, except for the following: 
o Nausea, vomiting, or diarrhea responding to optimal medical management within 
48 hours 
o Alopecia  
 
Any other toxicity that in the view of the Investigator represents a clinically significant 
hazard to the subject 

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Note: During the dose escalation phase, if the subject experienced a DLT, such subject 
should be permanently discontinued from the treatment. 
4.6 
Study Duration  
Subjects will receive treatment with ARQ 087 until progression of disease (clinical or 
radiological), unacceptable toxicity, or another of the discontinuation criterion is met (see 
Section 5.8).  It is expected that most subjects will receive between one and six cycles of 
ARQ 087 for a treatment period of four to 24 weeks.  
 

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5 
STUDY VISITS 
Before the start of any study required procedures, the Investigator or designee must obtain a 
signed written informed consent form (ICF) for the study from each prospective study 
subject or his/her legal representative.  
Study visits will consist of Pre-study Visit(s), during which the subject’s eligibility for the 
study and baseline disease state will be evaluated; four Daily Visits during Treatment 
Period 1 (Cohorts 1-4); four Weekly Visits during Cycle 1; and Bi-weekly Visits thereafter 
(Cycle 2+) during which the subject will be evaluated. Additionally, an End of Treatment 
Visit(s) and 30-day Safety Follow-up(s) Visit will be performed (see Appendix 1 for the 
Schedule of Assessments).  
Following the Pre-study evaluation and a determination by the Investigator and ArQule’s 
Medical Monitor that the subject meets all inclusion/exclusion criteria, the subject will be 
considered entered into the study.   
5.1 
Informed Consent 
A sample ICF with core information will be provided to each study site. Prior to study 
initiation at a given study site, each site/Investigator must obtain a written approval/favorable 
opinion from its respective IRB/IEC for the ICF and any other written information to be 
provided to subjects.  All ICFs must be compliant with International Conference on 
Harmonization (ICH) GCP guidelines, and local regulations and must be approved by the 
Sponsor prior to submission to IRB/IEC. The written approval of the IRB/IEC, together with 
the approved subject information/ICF, must be maintained in the study master files. 
Written informed consent must be obtained from a prospective subject before any study-
specific procedures are performed on that individual. Subjects who agree to participate in the 
study will sign the most recently approved ICF and will be provided with a copy of the fully 
executed document. The original, executed ICF will be maintained in the respective subject’s 
clinical study file.  
5.2 
Pre-Study Evaluations (Baseline) (Within 21 Days Prior to the First 
Dose of ARQ 087) 
After written informed consent is obtained, the subject’s eligibility for the study and baseline 
disease state will be assessed.  
The following will be evaluated and documented within 21 days prior to the first dose of 
ARQ 087 (Day -21 – Day 0): 
 
Obtain written informed consent from the subject or subject’s legal representative 
 
Medical history (see Section 6.1) 
 
Physical examination, including mucous membranes and skin (see Section 6.2) 
 
ECOG PS (see Appendix 2) 
 
Vital signs (height, weight, temperature, blood pressure, respiration rate, and pulse) 
 
Fasting clinical blood tests (see Section 6.4)* 

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 
Urinalysis (see Section 6.4)  
 
Serum pregnancy test, if applicable (see Section 6.4) 
 
12-lead electrocardiogram (ECG) (see Section 6.3) 
 
Echocardiography or Multiple Gated Acquisition (MUGA) scan, if applicable (see 
Section 6.3) 
 
Blood samples for tumor markers, if applicable (to be tested at study site) 
 
Collect archival and/or fresh tissue biopsy samples (see Section 6.8) 
o For subjects enrolled in the Expanded Cohort, archival samples should be 
collected for all enrolled subjects, paired biopsy is optional. Both archival and 
pre-treatment fresh tumor samples should be collected prior to the first dose of 
the study drug 
o For subjects enrolled in the Food-effect Cohort, both archival and paired biopsy 
should be collected. If archival tissue is not available, paired fresh tumor biopsy 
should be performed to confirm the subjects’ FGFR1-3 or KIT/PDGFR status.  
 
Record prior and concomitant medications (medications used within 30 days prior to the 
first dose of ARQ 087) 
 
Tumor measurement and staging [e.g., computed tomography (CT) scan, magnetic 
resonance imaging (MRI) or positron emission tomography (PET)] (see Section 6.7, 
Appendix 6) Note: CT, PET, and MRI scans can be used as a Baseline assessment if 
they were performed within four weeks (28 days) prior to the first dose of ARQ 087.   
* Fasting clinical blood tests obtained during the Pre-study Visit can be used for Day 1 if they are performed 
within 72 hours prior to the first dose of the study drug (Cycle 1, Day 1 visit). 
Subjects who satisfy all inclusion and exclusion criteria may be enrolled in the study. 
5.3 
Treatment Period 1 (PK): Single-Dose Administration of ARQ 087; 
Cohorts 1-4 
The approximate duration of Treatment Period 1 will be 4 days. 
5.3.1 
 
Day 1 (Day of the Single Dose of ARQ 087 Administration) 
The following assessments will be made during this visit: 
 
Physical examination, including mucous membranes and skin 
 
ECOG PS 
 
Vital signs (temperature, blood pressure, respiration rate, and pulse) 
 
Fasting clinical blood tests (see Section 6.4)* 
 
Blood sample for pharmacokinetics (see Section 6.5; blood samples will be collected 
immediately prior to the first dose of ARQ 087 and will continue through 72 hours after 
study drug administration.)   
 
Blood samples for pharmacodynamics (see Section 6.6) 

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 
Tumor biopsy (if applicable, see Section 6.8) 
 
Record concomitant medications 
 
Administer a single dose of ARQ 087  
 
Assess adverse events (AE; after study drug administration) 
* If Baseline fasting clinical blood tests are obtained more than 72 hours prior to the first dose of ARQ 087, 
then Day 1 fasting clinical blood tests should be repeated, however, they may be obtained within 24 hours 
prior to the first dose of study drug. 
5.3.2 
 
Day 2 (24 Hours; ± 2 Hours, Post-Dose on Day 1)  
The following assessments will be made during this visit: 
 
Vital signs (temperature, blood pressure, respiration rate, and pulse) 
 
Blood sample for pharmacokinetics (see Section 6.5) 
 
Blood samples for pharmacodynamics (see Section 6.6) 
 
Assess AEs  
 
Record concomitant medications 
5.3.3 
 
Day 3 (48 Hours; ± 2 Hours, Post-Dose on Day 1)  
The following assessments will be made during this visit: 
 
Vital signs (temperature, blood pressure, respiration rate, and pulse) 
 
Blood sample for pharmacokinetics (see Section 6.5) 
 
Blood samples for pharmacodynamics (see Section 6.6) 
 
Assess AEs  
 
Record concomitant medications 
5.3.4 
 
Day 4 (72 Hours; ± 2 Hours, Post-Dose on Day 1)  
The following assessments will be made during this visit: 
 
Vital signs (temperature, blood pressure, respiration rate, and pulse) 
 
Blood sample for pharmacokinetics (see Section 6.5) 
 
Blood samples for pharmacodynamics (see Section 6.6) 
 
Assess AEs  
 
Record concomitant medications 
The washout time between Treatment Period 1 and Treatment Period 2 should be at least 
72 hours. If the subject continues to be eligible, the treatment with ARQ 087 per the 
Treatment Period 2 schedule may be initiated immediately after the 72-hour PK sample is 
drawn. 

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5.4 
Continuous Administration of ARQ 087: Dose Escalation/Food-
effect Cohorts and Expanded Cohort 
After completion of the Treatment Period 1 Day 4 (Cohorts 1-4) assessments or if the subject 
is enrolled in the Dose Escalation/Food-effect and Expanded cohorts, the subject will 
continue treatment according to the schedule of visits and assessments described below. 
5.4.1 
 
Cycle 1, Weekly Evaluations 
5.4.1.1 
 Week 1 (Day 1) 
The following assessments will be made during this visit: 
 
Physical examination, including mucous membranes and skin 
 
ECOG PS 
 
Vital signs (weight, temperature, blood pressure, respiration rate and pulse) 
 
Fasting clinical blood tests (see Section 6.4)* 
 
Urinalysis (see Section 6.4) 
 
Blood sample for pharmacokinetics (except Expanded Cohort, see Section 6.5)   
 
Blood samples for pharmacodynamics (see Section 6.6) 
 
Blood samples for tumor marker(s), if applicable (to be tested at the study site) 
 
12-lead ECG (see Section 6.3) 
 
Record concomitant medications 
 
Dispense ARQ 087  
 
Assess AEs (after study drug administration) 
* Fasting clinical blood tests may be obtained within 24 hours of the visit.  
5.4.2 
 
Week 2 (Day 8; ± 3 Days) 
The following assessments will be made during this visit: 
 
Physical examination, including mucous membranes and skin 
 
ECOG PS 
 
Vital signs (temperature, blood pressure, respiration rate and pulse) 
 
Fasting clinical blood tests (see Section 6.4)* 
 
Blood sample for pharmacokinetics (except Expanded Cohort, see Section 6.5) 
 
Blood sample for pharmacodynamics (except Expanded Cohort, see Section 6.6) 
 
Assess AEs  
 
Record concomitant medications 
 
Dispense ARQ 087 

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* Fasting clinical blood tests may be obtained within 24 hours of the visit.  
5.4.3 
 
Week 3 (Day 15; ± 3 Days) 
The following assessments will be made during this visit: 
 
Physical examination, including mucous membranes and skin  
 
ECOG PS  
 
Vital signs (weight, temperature, blood pressure, respiration rate and pulse) 
 
Fasting clinical blood tests (see Section 6.4)* 
 
Urinalysis (see Section 6.4) 
 
12-lead ECG (see Section 6.3) 
 
Blood sample for pharmacokinetics (except Expanded Cohort, see Section 6.5) 
 
Blood sample for pharmacodynamics (except Expanded Cohort, see Section 6.6) 
 
Assess AEs  
 
Record concomitant medications  
 
Dispense ARQ 087 
* Fasting clinical blood tests may be obtained within 24 hours of the visit.  
5.4.4 
 
Week 4 (Day 22; ± 3 Days) 
The following assessments will be made during this visit: 
 
Physical examination, including mucous membranes and skin  
 
ECOG PS  
 
Vital signs (temperature, blood pressure, respiration rate and pulse) 
 
Fasting clinical blood tests (see Section 6.4)* 
 
Blood samples for pharmacokinetics (except Expanded Cohort, see Section 6.5) 
 
Blood sample for pharmacodynamics (except Expanded Cohort, see Section 6.6) 
 
Tumor biopsy if applicable (see Section 6.8) 
 
Assess AEs  
 
Record concomitant medications 
 
Dispense ARQ 087 
* Fasting clinical blood tests may be obtained within 24 hours of the visit.  
5.4.5 
 
Week 4 (Day 23; except Expanded Cohort) 
The following assessments will be made during this visit: 
 
Vital signs (temperature, blood pressure, respiration rate and pulse) 
 
Blood sample for pharmacokinetics (see Section 6.5) 

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 
Assess AEs  
 
Record concomitant medications 
Note: Because the Cycle 1 Day 22 and Day 23 visits are days when the full PK is performed, 
subjects enrolled in Cohort 1 (25 mg every other day) Cycle 1 Week 4 visits should be 
scheduled on the day of ARQ 087 administration and the next consecutive day, when drug is 
not taken, e.g., Cycle 1 Day 21 and Day 22 or Cycle 1 Day 23 and Day 24.  
5.5 
Cycle 2 and Following Cycles, Bi-weekly Evaluations  
5.5.1 
 
Week 1 (Day 1; ± 3 Days) 
The following assessments will be made during this visit: 
 
Physical examination, including mucous membranes and skin 
 
ECOG PS 
 
Vital signs (weight, temperature, blood pressure, respiration rate and pulse) 
 
Fasting clinical blood tests (see Section 6.4)* 
 
Blood samples for tumor marker(s), if applicable (to be tested at study site) 
 
Blood samples for pharmacokinetics (except Expanded Cohort, see Section 6.5) 
 
Blood samples for pharmacodynamics (see Section 6.6) 
 
Urinalysis (see Section 6.4) 
 
Tumor measurement and staging (see Section 6.7, Day 1 of every odd cycle or every 
8 weeks, e.g. C3D1, C5D1, etc.) 
 
12-lead ECG (see Section 6.3) 
 
Echocardiography or MUGA scan to measure LVEF, if applicable and clinically 
indicated (see Section 6.3) 
 
Assess AEs  
 
Record concomitant medications 
 
Dispense ARQ 087 
* Fasting clinical blood tests may be obtained within 24 hours of the visit.  
5.5.2 
 
Week 3 (Day 15; ± 3 Days) 
The following assessments will be made during this visit: 
 
Physical examination, including mucous membranes and skin  
 
ECOG PS  
 
Vital signs (temperature, blood pressure, respiration rate and pulse) 
 
Fasting clinical blood tests (see Section 6.4)* 
 
Blood samples for pharmacokinetics (except Expanded Cohort, see Section 6.5) 

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 
Assess AEs  
 
Record concomitant medications  
 
Dispense ARQ 087 
* Fasting clinical blood tests may be obtained within 24 hours of the visit.  
Note: Subjects who do not experience Grade 3/4 toxicity after four cycles (16 weeks) at the 
same dose level can be evaluated every four weeks (monthly) upon agreement between the 
Investigator and the ArQule Medical Monitor. The schedule of assessment should follow the 
Cycle 2 Week 1 schedule. 
5.6 
End of Treatment Visit (7 [+3] Days after the Last Dose of ARQ 087) 
If possible, the End of Treatment Visit should be performed 7 [+3] days after the last dose of 
ARQ 087. The following assessments will be made during the End of Treatment Visit: 
 
Physical examination, including mucous membranes and skin 
 
ECOG PS  
 
Vital signs (weight, temperature, blood pressure, respiration rate, and pulse) 
 
Fasting clinical blood tests (see Section 6.4) 
 
Urinalysis (see Section 6.4) 
 
Serum pregnancy test, if applicable (see Section 6.4) 
 
12-lead ECG (see Section 6.3) 
 
Echocardiography or MUGA scan to measure LVEF, if applicable (see Section 6.3) 
 
Blood samples for tumor marker(s), if applicable (to be tested at study site) 
 
Blood samples for pharmacokinetics (except Expanded Cohort, see Section 6.5) 
 
Tumor measurement and staging if not done within four weeks (28 days) prior to the end 
of treatment visit (see Section 6.7) 
 
AEs assessment 
 
Record concomitant medications 
5.7 
30-day (± 3 Days) Safety Follow-Up Visit  
All subjects will be followed for a minimum of 30 days after the last dose of ARQ 087.  If a 
subject is removed from the study treatment due to drug-related AEs, the subject will be 
followed until drug-related AEs occurring during the study or within 30 days after the last 
dose of ARQ 087 have resolved to baseline, CTCAE Grade 1, stabilized, or are deemed 
irreversible.  If a subject receives other anticancer therapy within the 30-day follow-up 
period, the follow-up for AEs will cease, beginning the first day of the new therapy.  
Note: The visit can be done either as an office visit or over the telephone. 

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5.8 
Discontinuation from the Treatment/Study 
Subjects will be removed from the study treatment at any time if they meet any of the 
following criteria: 
 
Documented radiographic or clinical progression of disease* 
 
Noncompliance with any part of the study, as evaluated by the Investigator and Medical 
Monitor 
 
Clinically unacceptable toxicities despite optimal treatment or dose reduction 
 
Withdrawal of consent 
 
Investigator’s decision (in agreement with the Sponsor/Medical Monitor or designee) 
 
Lost to Follow-up 
 
Death 
* Subjects may remain on treatment if, in the opinion of the Investigator and with the agreement of 
ArQule’s Medical Monitor, they continue to derive benefit from the treatment. 
Subjects will be removed from the study if they meet any of the following criteria: 
 
Safety follow-up visit is completed per protocol and drug-related AEs have resolved to 
baseline, CTCAE Grade 1, stabilized, or are deemed irreversible. 
 
Withdrawal of consent 
 
Lost to Follow-up 
 
Death 
5.9 
Study Discontinuation  
The Sponsor reserves the right to temporarily or permanently discontinue the study at any 
site and at any time. Reasons for study discontinuation may include, but are not limited to, 
the following: 
 
Safety concerns 
 
Poor enrollment 
 
Non-compliance with the protocol, Good Clinical Practice (GCP) guidelines, or other 
regulatory requirements by the Investigator(s) 
 
Request to discontinue the trial by a regulatory or health authority 
 
Discontinuation of product development 
 
Manufacturing difficulties/concerns 
The Sponsor and/or designee will promptly inform all Investigators and the appropriate 
regulatory authorities if the study is suspended or terminated for safety reasons. In the case of 
such termination, the Investigator will notify the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). 
 

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6 
STUDY PROCEDURES  
6.1 
Medical History 
Medical history will include but not be limited to the following: 
 
Demography: date of birth, sex, ethnic origin, height, and weight 
 
Clinically significant prior diagnoses, surgeries, and current medications 
o Medications used within 30 days prior to the first dose of ARQ 087 should be 
reported 
 
Prior cancer history, current cancer diagnosis, tumor stage at time of diagnosis and 
screening, previous anti-cancer therapy, including dates, duration and outcome of 
treatment, previous radiation therapy, including anatomic site, dose and dates of 
treatment, previous cancer-related surgical procedures, including type of the procedure 
and dates 
6.2 
Physical Examination 
Complete physical examination of the major body systems, including mucous membranes, 
skin, height (Baseline visit only), weight (Baseline visit, Cycle 1 Day 1 and Day 15, on 
Day 1 of all subsequent cycles, and End of Treatment visit), vital signs (blood pressure, heart 
rate, respiratory rate, temperature [oral, axillary, or tympanic]), and ECOG PS (Appendix 2). 
6.3 
12-Lead ECG, Echocardiography, and MUGA Scan  
Twelve-lead ECG should be conducted at the Baseline Visit, on Day 1 and Day 15 of 
Cycle 1, on Day 1 of all subsequent cycles (e.g., Cycle 2, Cycle 3, etc.), and at the End of 
Treatment Visit. Additional ECG(s) may be conducted if clinically indicated.  
For subjects previously treated with anthracyclines (e.g., epirubicin [Ellence, 
Pharmorubicin]; idarubicin [Idamycin]; doxorubicin [Adriamycin, Rubex]; and daunorubicin 
[Cerubidine]), an echocardiography or MUGA scan to measure LVEF should be performed 
at Baseline, and, if clinically indicated, every eight/twelve weeks (e.g., Day 1 Cycle 3, Day 1 
Cycle 6, Day 1 Cycle 9, Day 1 Cycle 12, etc.), and at the End of Treatment Visit.  
For the individual subject, the same method of measuring LVEF should be used throughout 
the study. 
6.4 
Clinical Laboratory Tests 
Safety laboratory determinations will include hematology, blood chemistry, liver function 
tests, coagulation tests, and urinalyses.  All laboratory tests required during the study must be 
obtained at a local laboratory designated by the Investigator.  Fasting clinical blood tests 
obtained during the Pre-study Visit can be used for Day 1 if they are performed within 
72 hours prior to the first dose of the study drug (Treatment Period 1, Day 1 in Cohorts 1-4 or 
Cycle 1 Day 1 visit in Cohort 5 and all subsequent cohorts). During Treatment Period 2 
(Cohorts 1-4) or the Continuous Treatment Administration (Cohort 5 and all subsequent 
cohorts), clinical blood tests can be obtained within 24 hours prior to the scheduled visit. 

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Chemistry samples should be taken in a fasting state (fasting at least 8 hours) prior to 
administration of the morning dose of ARQ 087*.  
 
Hematology: complete blood count (CBC) including hemoglobin, hematocrit, white 
blood cell count (WBC) with 5-part differential, red blood cell (RBC), platelet, and 
reticulocyte count 
 
Blood chemistry: albumin, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, 
creatinine, glucose, glycated hemoglobin (HbA1c)**, magnesium, phosphate, potassium, 
total protein, sodium, uric acid 
 
Liver function tests (LFT): alanine transaminase (ALT), aspartate transaminase (AST), 
alkaline phosphatase (ALP), total and direct bilirubin, lactate dehydrogenase (LDH) 
 
Thyroid function tests (at Baseline and End of Treatment, and if clinically indicated): 
thyroid stimulating hormone (TSH), triiodothyronine (total T3), thyroxine (free T4) 
 
Coagulation tests (at Baseline and End of Treatment, and if clinically indicated): 
prothrombin time (PT), international normalized ratio (INR), and partial prothrombin 
time (PTT)  
 
Routine urinalysis: dipstick and microscopy (only if clinically indicated or dipstick is not 
done) including protein, specific gravity, glucose and blood 
o To assess ARQ 087 metabolism, the Sponsor may request collection of 24-hour 
urine samples  
 
Serum pregnancy test (at Baseline and End of Treatment only): for female subjects of 
childbearing potential  
*ARQ 087 should be administered in the fasted state, except to subjects enrolled in the Food-effect Cohort.  
**HbA1c should be done at Baseline and End of Treatment, and if clinically indicated 
6.5 
Pharmacokinetic Assessments  
Pharmacokinetic variables will include Cmax, AUC, and half-life.  To assess single dose PK, 
blood samples will be collected for four consecutive days during Treatment Period 1 
(Cohorts 1-4), on Day 1 (full assessment), Day 2 (24 hrs post-dose), Day 3 (48 hrs post-
dose), and Day 4 (72 hrs post-dose).  The washout period between Treatment Period 1, Day 1 
and Treatment Period 2, Day 1 Cycle 1 should be at least 72 hours. During Treatment 
Period 2 (continuous administration of ARQ 087), PK samples will be collected on Day 8, 
Day 15, Day 22 (full assessment), and Day 23 (24 hrs post-dose on Day 22) of Cycle 1 (see 
Appendix 3). However, for subjects enrolled in Cohort 1 (25 mg every other day), Cycle 1 
Week 4 visits should be scheduled on the day of ARQ 087 administration and the next 
consecutive day, when drug is not taken, e.g., Cycle 1 Day 21 and Day 22 or Cycle 1 Day 23 
and Day 24.  Also, a Cycle 1 Day 1 pre-dose sample should be collected if the Cycle 1 Day 1 
visit differs from the Treatment Period 1, Day 4 visit (72 hours). 
During continuous administration of ARQ 087 (Cohort 5 and all subsequent cohorts, 
including ALL subjects enrolled in the Food-effect Cohort, and for up to 10 subjects enrolled 
in the Expanded Cohort at selected sites), PK samples will be collected on Day 1 (full 
assessment), Day 2, Day 8 (pre-dose), Day 15 (pre-dose), Day 22 (full assessment), and 

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Day 23 (pre-dose) of Cycle 1; and on Day 1 and Day 15 of all subsequent cycles (pre-dose), 
and End of Treatment (see Appendix 3). 
The blood sampling date and time and the time of the last dose of ARQ 087 administration 
prior to PK blood draw should be recorded on the eCRF. 
Detailed instructions for collection and shipment of plasma PK samples will be provided in 
the laboratory manual. 
6.6 
Pharmacodynamic Assessments  
The goal of the proposed biomarker study is to evaluate the tumoral and serum- or plasma-
based pharmacodynamic response in subjects treated with ARQ 087.   
Information on tumor FGFR protein expression, gene copy number and mRNA 
amplification, and/or mutational/gene re-arrangement (fusion, translocation) status is 
required for this study. If these are not known, tumor biopsy should be done to assess these 
parameters prior to the first dose of ARQ 087. All baseline samples (archival or newly 
acquired) will be evaluated by immunohistochemistry (IHC), FISH (gene copy number), ISH 
or qNPA (mRNA amplification), and/or DNA sequencing (mutational/gene re-arrangement 
[fusion, translocation] status assessment).  
Pathology specimens (pre- and post-treatment tumor biopsies) will be evaluated for changes 
in total FGFR1, total FGFR2, pFGFR, pFRS2 and/or pERK status by either IHC, 
mesoscale, or immunoprecipitation/Western blot analysis. A post-treatment tumor biopsy 
should be collected between Cycle 1 Day 22 and Cycle 2 Day 1 at least 1 hour post-dose. In 
subjects who have been on treatment ≥8 weeks and with the subject’s agreement, additional 
post-treatment biopsies may be collected. 
Blood samples (pre-dose) will be collected during Treatment Period 1 on Day 1, Day 2, 
Day 3, and Day 4 (Cohorts 1-4), and during Treatment Period 2 Cycle 1 (Cohort 5 and all 
subsequent Dose Escalation cohorts) on Day 1, Day 8, Day 15, and Day 22, and on Day 1 of 
Cycles 2-5 for evaluations of pharmacodynamic changes of factors including phosphate, 
glucose, FGF 19, 21, and/or 23 utilizing standard blood chemistry methodologies and 
ELISA-based assays.  
For subjects enrolled in the Expanded Cohort, blood samples for evaluations of 
pharmacodynamic changes of FGF 19, 21, and 23 will be collected on Day 1 of the first six 
cycles. 
Samples for pharmacokinetic and pharmacodynamic assessments will be labeled by 
personnel from the institution with subjects’ study ID; subjects’ identity will not be made 
known to employees from the Sponsor, additional collaborators, or other investigators. 
Samples will only be used for the purposes of the protocol and will only be used by ArQule’s 
personnel or by an external laboratory chosen by ArQule to outsource the analyses according 
to internal guidelines. Samples will be kept until all protocol-related analyses are completed, 
for a period not exceeding 10 years or as required by local law. 
Detailed instructions for collection, testing, and shipment of tissue, plasma, or serum 
pharmacodynamic samples will be provided in the laboratory manual. 

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6.7 
Tumor Evaluation  
Tumor assessments (CT scan, PET scan, or MRI) will be performed at Baseline, and every 
eight weeks (e.g., on Day 1 of every odd cycle, Day 1 Cycle 3, Day 1 Cycle 5, or Week 8, 
Week 16, etc.) or as otherwise clinically indicated.  
For subjects who do not experience disease progression and continue to benefit from the 
treatment after 11 cycles, tumor evaluation may be performed every 3 months (e.g., Day 1 of 
Cycle 14, Day 1 of Cycle 17, Day 1 of Cycle 20, etc.) upon agreement between the 
Investigator and ArQule’s Medical Monitor. 
Standard imaging studies should be performed according to institutional procedures and/or 
standard of care.  Tumor response will be evaluated using relevant guidelines (see 
Appendix 6 for RECIST 1.1 guidelines).   
6.8 
Tumor Biopsy 
All enrolled subjects should agree to provide archival tissue and to have a fresh tumor 
biopsy.  
 
For ALL subjects, archival tissue biopsy samples should be collected  
 
For subjects enrolled into the Expanded Cohort, samples will be tested for genetic 
alterations, that may include FGFR genetic alterations, FGFR gene fusions, and 
KIT/PDGFR mutations 
 
For subjects enrolled in the Dose Escalation and Food-effect Cohorts, samples will be 
tested to assess protein expression levels of FGFR family members (FGFR1 and FGFR2) 
and/or to confirm the tumor's genomic profile, e.g., KIT/PDGFR mutation or FGFR1-3 
amplification, mutations/gene rearrangement (fusion, translocation) status 
 
If archival samples are not available, a fresh core needle biopsy or fine needle aspiration 
(FNA) may be collected during the Screening Period. Core needle biopsy samples 
collected within 30 days prior to the first dose of ARQ 087 are considered fresh. 
 
If allocated slots are available, for subjects eligible for enrollment in the Dose Escalation 
cohorts, paired (pre- and post-treatment) tumor biopsy is optional. The paired tumor 
biopsy will be done only if, in the Investigator’s opinion, a minimally invasive biopsy 
may be performed.  
 
For all subjects enrolled in the Food-effect Cohort, a paired tumor biopsy is mandatory.  
 
In Cohorts 1-4, tumor samples will be collected at Baseline/archival and 4-6 hours after 
ARQ 087 administration on Day 1 of Treatment Period 1 or on Day 1 of Cycle 1 of 
Treatment Period 2. Starting with Cohort 5, a post-treatment tumor biopsy should be 
collected between Cycle 1 Day 22 and Cycle 2 Day 1 at least 1 hour post-dose. 
(Additionally, optional post-treatment biopsies may be collected at any time during 
treatment at least 1 hour post-dose.)  
 
For subjects enrolled in the Expanded Cohort pre- and post-treatment (paired) biopsy is 
optional. If a paired biopsy is deemed safe and with the subject’s consent, the biopsy 
may be performed at Baseline, at any time point between Cycle 1 Day 22 and Cycle 2 

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Day 1 visits, and an additional optional biopsy may be performed at any time during the 
treatment including the End of Treatment Visit. 
Prior to a subject’s enrollment, the Investigator should establish availability of suitable 
pathology specimens and/or evaluate the subject’s eligibility for tumor biopsy.  
The testing may include assessment of FGFR1 and FGFR2 protein levels, pFGFR, pFRS2α, 
and pERK expression levels. 
Fresh tumor biopsy samples must be frozen immediately after the samples are obtained. 
Detailed instructions for collection, shipment, and testing of tissue samples will be provided 
in the laboratory manual. 
 
 
 

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7 
TREATMENT 
7.1 
ARQ 087 
ARQ 087 capsules (multiple strengths of 25 mg and 100 mg) will be supplied to the research 
pharmacy at the clinical site. Study drug will be labeled as an investigational agent according 
to relevant Federal laws and regulatory guidelines. 
7.1.1 
 
Investigational Product Accountability 
ArQule will provide study drug and drug accountability documentation required for 
completion of this study.  The recipient will acknowledge receipt of the drug indicating 
shipment content and condition.  Damaged supplies will be replaced.   
Drug Accountability Records (logs) will be maintained.  These records should record 
quantities of study drug received and quantities dispensed to subjects, including lot number, 
date dispensed, subject identifier number, subject initials, protocol number, dose, quantity 
returned, balance remaining, and the initials of the person dispensing the drug.  Accurate 
records of all study drug dispensed from and returned to the study site are to be maintained. 
The study site must supply a copy of their drug destruction policy to ArQule before 
authorization for destruction will be granted. Product accountability will be monitored 
throughout the study. Upon completion or termination of the study, and after inventory by an 
ArQule monitor or designated representative, all unopened drug is to be returned to ArQule 
or designee in the original containers.  
7.1.2 
 
Storage and Handling 
At a study site, ARQ 087 should be stored refrigerated (2°-8°C; 35°-46°F) or at controlled 
room temperature (15°-30°C; 59°-86°F) depending on the storage instructions provided on 
the label of the container in which the capsules are shipped to the site and dispensed to the 
subject. Until dispensed to the subject, the study drug should be stored in a secure locked 
area accessible to authorized personnel only. 
7.1.3 
 
ARQ 087 Administration 
ARQ 087 will be administered once a day, orally. ARQ 087 must be administered in the 
fasted state, except for subjects who are enrolled in the Food-effect Cohort. Subjects in the 
Food-effect Cohort will be asked to take ARQ 087 with their morning meals and to keep a 
food diary (breakfast). 
For administrative reasons, during continuous dosing, the treatment period is divided into 
4-week cycles (28 days). 
The dose of ARQ 087 to be administered depends on the dose level cohort to which the 
subject is enrolled, with the initial dose level of 25 mg qod, see Section 4.1 for details. 
For individual subjects, treatment will continue until unacceptable toxicity, disease 
progression (clinical or radiological), or other discontinuation criterion is met.  It is expected 
that most subjects will receive ARQ 087 for one to six treatment cycles (4 to 24 weeks). 

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7.2 
Missed or Vomited Doses 
A missed or vomited dose should not be replaced. The subject should be instructed to take 
the next scheduled dose at the regularly scheduled time. If the subject vomited the very first 
dose of study drug, the subject may be re-challenged per discretion of the Investigator. 
7.3 
Dose Modifications 
In general, once the dose of ARQ 087 has been modified for a subject, all subsequent cycles 
should be administered to that subject at the modified dose. The modified dose will be 
considered the maximum dose for all subsequent cycles for that subject.  
When a drug-related toxicity is observed, dose delays and/or reductions in ARQ 087 
administration are allowed.  If dose reduction is indicated, a subject should be assigned to the 
previous (lower) cohort dose (dose re-escalation is not permitted). In the event of a dose 
modification, the dose change(s) must be captured in the electronic data capture (EDC) 
system. If questions or considerations regarding dose modification arise or a specific dose 
modification is needed, ArQule’s Medical Monitor or designee should be consulted. 
If the subject experienced a DLT, such subject should be permanently discontinued from the 
treatment. During the dose escalation period, intra-subject dose escalation is not allowed. 
Once the MTD/RP2D is reached, intra-subject dose escalation may be considered to optimize 
the dose level taking into consideration the available dosage strengths. A maximum of one 
intra-subject dose escalation per subject may be considered. 
 
Table 7.1 Dose Delays/Reductions for Drug-Related Toxicity 
Event Grade 
Action 
Grade 1 or 2, including 
significant increase in LFTs (as 
assessed by the Investigator) 
and alopecia 
Continue current dose level, unless dose 
interruption/modification may be clinically indicated, e.g., due 
to significant increase in LFTs 
Grade 3-4 nausea, vomiting or 
diarrhea lasting < 24 hours 
Withhold ARQ 087 until recovery to Grade 1 or baseline. If 
recovery occurs within 24 hours, restart ARQ 087 at the 
current dose level.  
Grade 3-4 toxicity, including 
nausea, vomiting or diarrhea 
lasting ≥ 24 hours 
Withhold ARQ 087 until recovery to Grade 1 or baseline.  
- If recovery occurs within 14 days, restart ARQ 087 at the 
dose and schedule of the previous cohort for all subsequent 
cycles, unless further dose reduction is required.  
- If recovery occurs within 21 days of the drug hold, ARQ 087 
may be restarted upon agreement between the Investigator and 
the Sponsor’s Medical Monitor. Treatment should be restarted 
at the dose and schedule of the previous cohort for all 
subsequent cycles, unless further dose reduction is required.  
- If recovery occurs after more than 21 days of the drug hold, 
ARQ 087 should be permanently discontinued 

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Table 7.2 ARQ 087 Dose Reduction Schema  
Current Dose 
Dose after Reduction 
Dose Level 1: 3 capsules qd (300 mg daily) 
Dose Level 2: 2 capsules qd (200 mg daily) 
Dose Level 2: 2 capsules qd (200 mg daily) 
Dose Level 3: 1 capsule qd (100 mg daily) 
Dose Level 3: 1 capsule qd (100 mg daily) 
 
7.4 
Treatment Compliance 
A subject is considered compliant with the study protocol when study medication is 
administered at a compliance level of ≥ 80%.  In order to evaluate the safety of ARQ 087, 
replacement of non-compliant subjects will be allowed during Cycle 1 of Treatment 
Period 2/Continuous Dosing. 
Compliance will be calculated using the following equation: 
(Number of capsules actually ingested / number of capsules that should have been ingested 
per dose level) x 100 = % compliance 
7.5 
Blinding 
This is an open-label study.  Neither the subject nor the Investigator and site staff will be 
blinded to the treatment administered. 
7.6 
Prior Treatment 
Reasonable efforts will be made to determine all relevant prior treatments received by the 
subject within 30 days prior to the first ARQ 087 dose.  All relevant information must be 
recorded on the appropriate subject's electronic case report form (eCRF).  All surgical 
procedure history, prior chemotherapy, and radiation therapy must be recorded on the 
appropriate eCRF. 
7.7 
Concomitant Treatments 
All information regarding concomitant treatments (medications or procedures) must be 
recorded on the subject’s eCRF (including the name of the medication or procedure and 
duration of treatment). Complete information of analgesic consumption should be obtained 
and recorded.  
7.7.1 
 
Permitted Treatment 
Palliative and supportive care for disease-related symptoms will be offered to all subjects.  
In addition, the following treatments are allowed:  
 
Standard therapies for concurrent medical conditions  
o If active hepatitis B virus (HBV) replication is discovered, the subject must be 
immediately treated with conventional anti-viral therapy (excluding interferon) 
per standard of care 

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 
Erythropoietin Stimulating Agents (ESA): Please follow the American Society of 
Clinical Oncology (ASCO), the American Society of Hematology, MEDICARE 
guidelines for the use of epoetin in subjects with cancer and FDA alerts dates 09 March 
2007, 08 November 2007, 12 March 2008, 31 July 2008, and 02 December 2008.  
 
Hematopoietic growth factors, including filgrastim (Neupogen®), or other granulocyte 
colony stimulating factors (G-CSF). Please follow ASCO guidelines for the use of white 
blood cell growth factors. http://jco.ascopubs.org/content/24/19/3187.full  
 
Prophylactic antiemetics may be administered according to standard practice  
 
Megestrol acetate (Megace®) 
 
Use of topical corticosteroids, topical and systemic antibiotics according to SOC or 
institutional guidelines 
7.7.2 
 
Prohibited Treatment/Treatment to Be Avoided or Used with Caution 
The following treatments are not allowed during the study:  
 
Any concurrent anti-cancer therapy including chemotherapy, radiotherapy, hormonal, 
targeted therapy, or immunotherapy  
o Palliative radiotherapy for local pain-control may be allowed, provided the 
subject does not meet criteria of progressive disease and treated lesions will not 
be included in the target/non-target lesion assessment  
 
Other investigational agents  
 
Immunosuppressive therapies, including systemic corticosteroids (except up to a 
25 mg/day prednisone-equivalent dose or when used intermittently in an antiemetic 
regimen, for CNS metastases management or as premedication for imaging studies)  
The following treatments should be avoided, if possible or used with caution during the 
study: 
 
ARQ 087 may inhibit CYP1A2 or CYP2D6 metabolism, hence co-administration of 
ARQ 087 with drugs known to be substrates of CYP1A2 or CYP2D6 should be avoided 
or used with caution (see Appendix 4) 
 
ARQ 087 may be a substrate and inhibitor of human P-glycoprotein (P-gp), therefore co-
administration of ARQ 087 with drugs known to be P-gp substrates with narrow 
therapeutic index should be avoided or used with caution (see Appendix 5) 
 
Drugs with known liver toxicity, e.g., clotrimazole, should be avoided or used with 
caution; if such drugs need to be administered, LFT should be done every 4-5 days 
during the drugs’ co-administration 
7.8 
Potential Risks for Study Subjects 
Based on pre-clinical data it has been suggested that ARQ 087 may cause a phototoxic 
reaction in some subjects exposed to the sunlight while being treated with the drug. The 
amount of ARQ 087 that may be required to cause such reaction is unknown. All subjects 
should be instructed to avoid sunlight exposure, to use sunscreen to protect exposed areas of 

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the body (e.g., forehead, nose, lips, and hands), and to immediately report symptoms that 
may be associated with phototoxic reaction (redness, pruritus, swelling, blister formation). 
 
 

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8 
SAFETY ASSESSMENTS 
8.1 
Definitions 
8.1.1 
 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject or clinical investigational 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with study-drug treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
8.1.2 
 
Serious Adverse Event 
An SAE is any adverse experience occurring at any dose that results in any of the following 
outcomes: 
 
Death 
 
Life-threatening  
 
Requires new inpatient hospitalization defined as a hospital admission lasting > 24 hours 
(not including emergency room visit without hospital admission), or prolongation of 
existing hospitalization  
 
Persistent or significant disability/incapacity 
 
Congenital anomaly/birth defect 
 
Other important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above.  An important medical event may be 
considered an SAE based upon appropriate medical judgment.   
8.1.3 
 
Unexpected Adverse Event or Serious Adverse Event 
An unexpected AE or SAE is one for which the nature or severity of the event is not 
consistent with the applicable product information, as summarized in the Investigator’s 
Brochure. 
8.1.4 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
All adverse events that are determined by the Investigator or by the Sponsor as having a 
reasonable suspected causal relationship to a study drug and that are both unexpected and 
serious are considered to be SUSARs and are subject to expedited regulatory reporting. 
8.1.5 
 
Inpatient Hospitalization 
An inpatient hospitalization is a hospital admission that lasts more than 24 hours. 

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8.1.6 
 
Study Drug-related Adverse Event or Serious Adverse Event 
Study drug-related AE or SAE is defined as an AE or SAE that is related to the treatment 
with ARQ 087 
8.1.7 
 
Further Adverse Event and Serious Adverse Event Defining  
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified.  However, if an observed or reported sign or symptom is not 
considered a component of a specific disease or syndrome by the Investigator, it should be 
recorded as a separate AE. 
Laboratory data are to be collected as stipulated in this protocol.  Clinical syndromes 
associated with laboratory abnormalities are to be recorded as appropriate (e.g., diabetes 
mellitus instead of hyperglycemia). 
Scheduled hospitalizations or elective surgical procedures will not be considered as AEs or 
SAEs.   
Prolongation of a scheduled hospitalization can be considered an SAE.   
Complications associated with scheduled procedures are considered AEs or SAEs. 
Progression of disease is considered an efficacy outcome parameter and should not be 
captured as an AE or a SAE unless its outcome is death.   
Adverse events including SAEs that occur following the execution of the ICF but prior to 
dosing will not be recorded as AEs or SAEs.  
Adverse events including SAEs that occur after subjects receive any anticancer therapy other 
than the study-defined treatments will not be recorded as AEs or SAEs.  
8.2 
Responsibilities and Procedures 
The responsibility for the safety of an individual subject lies in all cases with the Investigator.  
This includes the timely review of all safety data obtained during the course of the study. 
An Investigator must instruct his/her subjects to report any AE and SAE they experience.   
Investigators capture, evaluate, and document all AEs and SAEs occurring during a subject’s 
enrollment in the trial, commencing with the first day of treatment and including the 
protocol-defined 30-day post-treatment follow-up period (Code of Federal Regulations 
[CFR] 21 §312.64[b]) as source documents and on designated eCRF pages. These AEs/SAEs 
must be recorded in the EDC system of this study.  
Investigators should assess AEs at each scheduled and non-scheduled visit, by the use of 
open-ended questioning, physical examination, and review of laboratory results.  
Note: It is important to record all AEs and SAEs that result in temporary and permanent 
discontinuation of study drug, regardless of severity.  
Investigators must report all SAEs, whether or not they are considered study-drug related, to 
the Sponsor or designee within 24 hours from knowledge of the event (see Section 8.4).   

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In cases of SUSARs, Investigators are responsible for reporting to their local IRBs/IECs; and 
the Sponsor or designee(s) is responsible for notifying regulatory authorities and all relevant 
Investigators of SUSARs.  
8.3 
Adverse Event and Serious Adverse Event Assessment Criteria 
Adverse events and SAEs are evaluated and graded using NCI CTCAE guidelines, 
version 4.03. 
8.4 
Serious Adverse Event Reporting 
The Investigators are obligated to immediately report to Global Safety Surveillance, Inc. 
(Telerx Healthcare ConneXions), the drug safety designee of the Sponsor, each SAE that 
occurs during this investigation, within 24 hours from knowledge of the event, whether or not 
it is considered study-drug related. All requested supplementary documents (e.g., discharge 
letter, autopsy report, etc.); relevant data (e.g., electrocardiograms, lab tests, discharge 
summaries, post mortem results, etc.) must be faxed or e-mail within 24 hours after available. 
If any questions or considerations regarding an SAE arise, the ArQule Medical Monitor or 
designee should be consulted.  
Healthcare ConneXions SAE Fax number for US reports: 888-314-7557 
ArQule Medical Monitor 
Julia Kazakin, M.D. 
Telephone: (781) 994-0478 
e-mail: jkazakin@arqule.com 
The information provided in a SAE report should be as complete as possible but contain a 
minimum of:  
 
A short description of the AE (diagnosis) and the reason why the AE was categorized as 
serious  
 
Subject identification and treatment (if applicable)  
 
Investigator’s name and phone number (if applicable)  
 
Name of the suspect medicinal product and dates of administration  
 
Assessment of causality  
If all information about the SAE is not yet known, the Investigator will be required to report 
any additional information within 24 hours as it becomes available. 
All SAEs will be evaluated by the Sponsor’s Medical Monitor or designee.  In the case of a 
SUSAR, the Sponsor or designee will report the event to all pertinent regulatory authorities 
having jurisdiction over ongoing ARQ 087 trials in an expedited manner (within 7 days or 
15 days of knowledge) and to all Investigators involved in ARQ 087 clinical trials. 
The Investigators must in turn notify their governing IRB/IEC. 

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8.5 
Post-Treatment Safety Follow-up 
In this study, the post-treatment safety follow-up period is defined as 30 days after the last 
dose of assigned treatment. All AEs occurring during the study period from the time of the 
first dose of study drug administration to the last day of the 30-day post-treatment follow-up 
period will be captured.  
All subjects will be followed for a minimum of 30 days after discontinuation of the study 
drug. All subjects should be instructed to reported AEs or SAEs occurring during the 30-day 
post-treatment safety follow-up period.   
Unresolved study drug related (see Section 8.1.6 for definition) AEs and SAEs at the time of 
treatment discontinuation or new study drug related AEs and SAEs that occur during the 
30-day safety follow-up period will be followed until they have, in opinion of the 
Investigator, resolved to baseline, have stabilized, or are deemed to be irreversible.  
If a subject receives other anticancer therapy within the 30-day follow-up period, the follow-
up for AEs will cease, beginning the first day of the new therapy.  
8.6 
Grading of Severity 
Each AE or SAE will be graded for severity according to NCI CTCAE (version 4.03).  The 
criteria can be found at http://ctep.cancer.gov/reporting/ctc.html.  
For AEs not listed in the NCI CTCAE version 4.03, a similar grading system should be used 
as follows: 
 
Grade 1 Mild AE 
 
Grade 2 Moderate AE 
 
Grade 3 Severe AE 
 
Grade 4 Life-threatening or disabling AE 
 
Grade 5 Death  
For AEs that can be described by the NCI CTCAE guidelines, the NCI CTCAE Grade 4 
(life-threatening or disabling AE) is assessed based on unique clinical descriptions of severity 
for each AE, and these criteria may be different from those used for the assessment of AE 
seriousness.  An AE assessed as Grade 4 based on the NCI CTCAE grades may or may not 
be assessed as serious based on the seriousness criteria. 
8.7 
Assessment of Causality 
The relationship between an adverse event and the study product (ARQ 087) will be 
determined by the Investigator on the basis of his/her clinical judgment and the following 
definitions. 
8.7.1 
 
Related Adverse Events 
 
The AE follows a reasonable temporal sequence from study drug administration, and 
cannot be reasonably explained by the subject’s clinical state or other factors (e.g., 
disease under study, concomitant diseases, concomitant medications) 

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 
The AE follows a reasonable temporal sequence from study drug administration, and is a 
known reaction to the drug under study or its chemical group, or is predicted by known 
pharmacology, a known reaction to agent, or chemical group. 
8.7.2 
 
Not Related Adverse Events 
 
The AE does not follow a reasonable temporal sequence from study product 
administration, or can be reasonably explained by the subject’s clinical state or other 
factors (e.g., disease under study, concurrent diseases, and concomitant medications). 

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9 
QUALITY CONTROL AND ASSURANCE 
The study will be initiated and conducted under the Sponsorship of ArQule.  Study drug 
ARQ 087, clinical supplies, and eCRFs will be supplied by ArQule or its representative.  
Representatives of ArQule will monitor the study to verify study data, medical records, and 
eCRFs in accordance with current ICH GCPs and other applicable regulations and 
guidelines. 
 
 

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10 PLANNED STATISTICAL METHODS 
The material presented in this section will serve as the basis for the statistical analysis plan.  
This plan may be revised during the study to accommodate protocol amendments.  Because 
of the nature of this study, no formal statistical analysis is planned.  Evaluation of the data 
will consist primarily of summary displays (e.g., descriptive statistics and graphs).   
In addition, for the iCCA sub-cohort of the Expanded Cohort (Part 2), statistical analysis will 
include interim monitoring for futility.  After response data from 10 subjects with iCCA are 
available, the response rate will be assessed. If the objective response is observed in ≤ 30% 
of enrolled subjects, the enrollment will be stopped for lack of efficacy. 
10.1 Determination of Sample Size 
The exact number of subjects estimated for this study is dependent on the number of subject 
cohorts investigated based on the toxicity encountered.  It is expected that approximately 
60-120 subjects at five to fifteen sites in the United States and Italy will be enrolled in this 
study. 
10.2 Analysis Variables 
10.2.1 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will include: 
 
Demographics  
 
Baseline disease characteristics  
 
Clinically significant medical history, including surgeries 
 
Prior therapies 
 
Baseline concomitant medications and treatments 
10.2.2 
Safety  
Safety variables include the reported AEs, laboratory tests, vital signs, ECOG performance 
status, and physical examination. 
10.2.3 
Efficacy  
Response rate/disease control rate and progression free survival will be used to determine 
preliminary evidence of activity. 
Progression Free Survival (PFS) is defined as time from first dose until documented 
radiographic disease progression or death, whichever occurs first. 
10.2.4 
Pharmacokinetics  
Pharmacokinetics parameters include Cmax, AUC, and half-life. 

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10.3 Statistical Methods 
All subjects receiving at least one daily dose of ARQ 087 will be considered evaluable for 
safety analyses.  Subjects who have received at least one cycle of ARQ 087 and have had at 
least one disease assessment following the initiation of therapy will be considered evaluable 
for response. 
10.3.1 
Demographic and Baseline Characteristics 
All demographic and baseline characteristics will be descriptively summarized.  Categorical 
variables will be summarized as the number and percentage of subjects in each category.  
Continuous variables will be summarized as mean, standard deviation, median, minimum, 
and maximum. 
10.3.2 
Extent of Treatment Exposure  
Duration of exposure is defined as the total number of days of study drug administration, 
ignoring any temporary drug discontinuation.  If the date of last administration is unknown, 
the date until which the dispensed drug would have lasted without counting the extra drug 
provided should be used. 
10.3.3 
Analyses of Safety Variables 
10.3.3.1 
 
Adverse Events 
Adverse events will be evaluated for severity using NCI CTCAE, version 4.03.  Adverse 
Event summaries will include the incidence of TEAEs.  All TEAEs will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA®) and summaries will present data 
by system organ class and preferred term.  Separate TEAE summaries will be generated for 
the following: 
 
All TEAEs 
 
Severe TEAEs (Grade 3 or higher) 
 
SAEs 
 
TEAEs leading to treatment discontinuation 
 
TEAEs resulting in death 
 
TEAEs listed according to maximum severity 
10.3.3.2 
 
Laboratory Test 
Summary statistics for baseline, each post-baseline measurement, and change from baseline 
for each post-baseline measurement will be presented for each hematology, serum chemistry, 
liver function test, electrolyte, and urinalysis parameter.  
10.3.3.3 
 
Vital Signs 
Summary statistics for baseline, each post-baseline measurement, and change from baseline 
for each post-baseline measurement will be presented for each vital sign parameter. 

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10.3.3.4 
 
ECOG Performance Status  
Number and percent of subjects having each ECOG performance status level will be 
presented for baseline and each post-baseline measurement. 
10.3.3.5 
 
Physical Exams  
Data from physical exams will be presented in the data listings.   
10.3.4 
Analysis of Efficacy Variables 
10.3.4.1 
 
Progression Free Survival  
Progression Free Survival (PFS) will be estimated based on a Kaplan-Meier estimate.  
Median PFS time and the 95% confidence interval will be estimated. 
10.3.4.2 
 
Response Rate  
Analyses on the ORR will be performed in evaluable subject population. The 95% 
confidence interval will be estimated.   
The 95% confidence interval for percent of subjects in each RECIST response category (e.g., 
CR, PR, SD, and PD) and disease control rate will also be estimated. 
10.3.5 
Pharmacokinetics and Pharmacodynamics 
10.3.5.1 
 
Pharmacokinetics 
Pharmacokinetics parameters include Cmax, AUC, and half-life; summary statistics will be 
performed. 
10.3.5.2 
 
Pharmacodynamics  
Summary statistics including mean, standard deviation, median, coefficient of variation, 
minimum and maximum for baseline, each post-baseline measurement, and change from 
baseline will be performed on the specified tumoral biomarkers (FGFR1-2 protein, pFGFR, 
pFRS2 and pERK levels) and blood biomarkers (e.g., phosphate, glucose, FGF 19, 21, 
and/or 23 utilizing standard blood chemistry methodologies and ELISA-based assays). 
To explore the association of blood concentration with clinical outcome, the above 
descriptive statistics will also be presented separately for each response category (CR, PR, 
and SD combined vs. PD).  Logistic regression will also be utilized if appropriate.  

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11 COMPLIANCE WITH GOOD CLINICAL PRACTICE AND ETHICAL 
CONSIDERATIONS  
11.1 Institutional Review Board or Independent Ethics Committee 
Approval 
The protocol, any protocol modifications, the ICF, and, if applicable, permission to use 
private health information must be approved by the Investigator’s IRB/IEC in compliance 
with Federal regulations 21 CFR §56 prior to study initiation.  Documentation of this 
approval must be provided to ArQule or its designee, and made available during an 
inspection by the FDA or other regulatory agency inspectors.  The Investigator will also 
provide ArQule with the General Assurance Number documenting that the IRB/IEC is duly 
constituted, as well as a list of the names, occupations, and affiliations of the members of the 
IRB/IEC when available.  
Before initiating a trial, the Investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC and where applicable, competent 
authorities/regulatory bodies for the trial protocol/amendment(s), written ICF subject 
recruitment procedures (e.g., advertisements) and written information to be provided to 
subjects. 
11.2 Compliance with Good Clinical Practice and Ethical 
Considerations 
This study must be conducted in compliance with IRB/IEC informed consent regulation and 
the ICH GCP Guidelines.  In addition, all local regulatory requirements will be adhered to, in 
particular those affording greater protection to the safety of the trial participants. 
This study will also be conducted according to the current revision of the Declaration of 
Helsinki Revised Edinburgh, Scotland, 2000, with all subsequent revisions and with local 
laws and regulations relevant to the use of new therapeutic agents in the country of conduct. 
Changes to the protocol will require written IRB/IEC and, where applicable, competent 
authorities/regulatory bodies approval/favorable opinion prior to implementation, except 
when the modification is needed to eliminate an immediate hazard(s) to subjects. 
11.3 Subject Information and Consent 
The Investigator, or designee, is responsible for the content of the ICF, but the original and 
any updated versions must be approved by ArQule prior to submission to the IRB/IEC.  The 
ICF should also include any additional information required by local laws relating to 
institutional review. 
Before any study-related procedures are undertaken, the Investigator or authorized designee 
must obtain written, informed consent from each study participant (or his/her legal 
representative) in accordance with US federal regulations (21 CFR §50) and the ICH 
document “Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance.”  
Informed consent will be obtained by discussing with the subject the purpose of the study, 
the risks and benefits, the study procedures, and any other information relevant to the subject.  

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The Investigator or designee must explain to the subject that for purposes of evaluating the 
study results, that subject’s private health information obtained during the study may be 
shared with the study Sponsor, regulatory agencies, and IRBs/IECs, before enrolling that 
subject into the study.  It is the Investigator’s (or designee’s) responsibility to obtain 
permission to use private health information per the Health Information Portability and 
Accountability Act (HIPAA) from each subject, or if appropriate, the subject’s legal 
representative. 
The subject or his/her legal representative will document his/her informed consent by signing 
the current version of the written, IRB-approved ICF in the presence of a witness. The person 
who conducted the informed consent discussion with the subject and/or subject’s legal 
representative must also sign the ICF.  The subject is given a fully executed copy of the ICF 
bearing all appropriate signatures, and the original must be maintained in the clinical master 
files at the site. 
All active subjects participating on the protocol must be re-consented each time the ICF is 
updated and re-approved by the IRB/IEC.   
 
 

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12 STUDY MANAGEMENT AND MATERIALS 
12.1 Monitoring, Verification of Data, Audit, and Inspection 
An ArQule monitor or designee will periodically visit each clinical study site to discuss the 
progress of the clinical trial and to review eCRFs and original source documents for accuracy 
of data recording, study drug accountability, and correspondence.  The extent and frequency 
of monitoring visits will be determined by the Sponsor or designee based on the status of the 
trial and the performance of the site. When requested, the Investigator must be available to 
the study monitor for personal, one-to-one consultation.   
Periodically, some or all of the facilities used in the trial may be reviewed or inspected by the 
IRB/IEC and/or regulatory authorities. An audit or inspection may include, for example, a 
review of all source documents, drug records, and original clinical medical notes. 
The Investigator is to ensure that the trial participants are aware of and consent to the review 
of personal information during the data verification process, as part of the 
monitoring/auditing process conducted by properly authorized agents of ArQule, or be 
subject to inspection by regulatory authorities.  In addition, participation and personal 
information is treated as strictly confidential to the extent of applicable law and is not 
publicly available.   
12.2 Data Recording and Retention of Study Data 
In compliance with GCP, the medical records/medical notes, and other study-related 
materials should be clearly marked and permit easy identification of participation by an 
individual in a specified clinical trial. 
The Investigator is to record all data with respect to protocol procedures, drug administration, 
laboratory data, safety data, and efficacy ratings on the eCRFs. 
If the Investigator relocates or retires, or otherwise withdraws his/her responsibility for 
maintenance and retention of the master clinical study records, ArQule must be notified in 
writing so that adequate provision can be made with regard to the trial documents. 
Trial documents should be retained for at least two years after the approval of a marketing 
application in an ICH region and until there are no pending or planned marketing 
applications in an ICH region, or at least two years have elapsed since the formal 
discontinuation of clinical development of ARQ 087 by ArQule.  The documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with ArQule that it will inform the Investigator, in writing, as to when the 
retention of these documents are no longer necessary. 
12.3 Electronic Case Report Forms 
An EDC system will be used to collect the data in this study.  The EDC system provides 
functionality for the clinical sites to enter the data directly into the eCRFs and respond to data 
discrepancies.  Once the data are entered, the information is encrypted and transmitted over 
the Internet to a clinical trial server where it is electronically reviewed.  Any resulting data 
queries are immediately sent back to the site for resolution.  The system automatically keeps 

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a full audit trail of all data changes that occur.  The clinical team will undertake additional 
manual review of the data, but all resulting data queries or clarifications will be entered into 
the EDC system for resolution.  All eCRFs will be completed according to instructions 
provided in the eCRF Completion Guidelines and ICH/GCP guidelines. 
12.4 Confidentiality, Publication and Disclosure Policy  
The Investigator understands that ArQule will use the information developed in the clinical 
study in connection with the development of ARQ 087.  This information may be disclosed 
to other clinical Investigators, the FDA, and other government agencies. 
All information disclosed to the Investigator by ArQule for the purpose of having the 
Investigator conduct the clinical trial described in this protocol, or information generated by 
the Investigator as results in the clinical trial shall be treated by the Investigator as strictly 
confidential.  The Investigator shall not use such information other than for the purpose of 
conducting the clinical trial and may not disclose such information to others, except when 
such disclosure is made to colleagues and/or employees who reasonably require the 
information in order to assist in carrying out the clinical trial and who are bound by like-
obligations of confidentiality.  Notwithstanding, the Investigator may use or disclose to 
others any information which: (i) was known to the Investigator prior to the date of its 
disclosure; (ii) is now, or becomes in the future, publicly available; or (iii) is lawfully 
disclosed to the Investigator on a non-confidential basis by a third party who is not obligated 
to ArQule or any other party to retain such information in confidence. 
ArQule acknowledges that the Investigator has certain professional responsibilities to report 
to the scientific community on findings made in the clinical investigations they conduct.  The 
Investigator shall have the right to publish the results of research performed under this 
protocol, provided that such publication does not disclose any Confidential Information or 
trade secrets of ArQule (other than the Data).  If the study is conducted as part of a multi-
center protocol, the Investigator agrees not to independently publish the findings except as 
part of an overall multi-center publication, unless specifically approved in writing by ArQule 
or unless more than 12 months have elapsed since the last subject in the study has completed 
his/her study designed treatment. 
 
 

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Vivo Study FGFR2-47. ArQule Technical Report: TR-087-034 R01;07 September 2012. 
25. Bresciano K, Bull C, Wang Y, Waghorne C, Chen CR. Overall Summary Report for 
ARQ 087 In Vivo Study FGFR2-41. ArQule Technical Report: TR-087-019 R00;02 May 
2011. 
26. Bresciano K, Bull C, Wang Y, Waghorne C. Overall Summary Report for ARQ 087 In 
Vivo Study FGFR2-37. ArQule Technical Report: TR-087-015 R00;29 March 2011. 
27. START Discovery (South Texas Accelerated Research Therapeutics). San Antonio, TX; 
data on file. 
28. Chang E, Waghorne C. IHC Biomarker Report of FGFR2-47; ARQ 087 Target 
Engagement Study in SNU-16 Xenograft Model. ArQule Technical Report: TR-087-047 
R00;25 April 2011. 
29. Bresciano K, Bull C, Wang Y, Waghorne C, Chen CR. Overall Summary Report for 
ARQ 087 In Vivo Study FGFR2-40. ArQule Technical Report: TR-087-018 R00;29 
March 2011. 
30. Bresciano K, Bull C, Wang Y, Waghorne C, Chen, CR. Overall Summary Report for 
ARQ 087 In Vivo Study FGFR2-38. ArQule Technical Report: TR-087-016 R01;05 Sep 
2012. 
31. Cuevas-Ramos D, Almeda-Valdes P, Aguilar-Salinas CA, et al. The Role of Fibroblast 
Growth Factor 21 (FGF21) on Energy Balance, Glucose, and Lipid Metabolism. Curr 
Diabetes Rev. 2009;5:216-20. 
32. Kharitonenkov A, Larsen P. FGF21 Reloaded: Challenges of a Rapidly Growing Field. 
Trends in Endocrinol and Metab. 2011;22(3):81-6. 
33. Brown A, Courtney CL, King LM, Groom SC, Graziano MJ. Cartilage Dysplasia and 
Tissue Mineralization in the Rat Following Administration of a FGF Receptor Tyrosine 
Kinase Inhibitor. Toxicol Pathol. 2005;33:449-55. 
34. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.

ArQule, Inc. 
 
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APPENDIX 1: SCHEDULE OF ASSESSMENTS 
Part 1: Cohorts 1-4 
Tests & Procedures 
Pre-
Study 
Visit(s) 
Treatment Period 1: 
Single-dose (PK)1 
Treatment Period 2: Continuous Dosing 
Weekly Visits1 
End of 
Treatment Visit 
30-day Safety 
Follow-up 
 
Baseline 
 
 
Cycle 1 
Cycle 2+ 
 
 
Week 
 
0 
0 
1 
2 
3 
4 
1 
3 
7 days after the 
last dose of 
ARQ 087 
30 days after 
the last dose of 
ARQ 087 
Day 
0 
Day 1 
Day 2, 3, 4 
1 
8 
15 
22 
1 
15 
 
 
Window 
-21 – 0 
0 
0 
0 
± 3 days 
 
 
± 3 days 
+3 days 
± 3 days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS  
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs, Weight3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology4 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry4 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Liver Function Tests4 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation tests4 
X 
 
 
 
 
 
 
 
 
X 
 
Thyroid function tests4 
X 
 
 
 
 
 
 
 
 
X 
 
Urinalysis4 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Serum Pregnancy Test4 
X 
 
 
 
 
 
 
 
 
X 
 
Tumor Markers, if 
applicable 
X 
 
 
X 
 
 
 
X 
 
X 
 
12-Lead ECG5 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Echocardiography or 
MUGA, if applicable5 
X 
 
 
 
 
 
 
X 
 
X 
 
Pharmacokinetics6 
 
X 
X 
 
X 
X 
X 
 
 
 
 

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Part 1: Cohorts 1-4 
Tests & Procedures 
Pre-
Study 
Visit(s) 
Treatment Period 1: 
Single-dose (PK)1 
Treatment Period 2: Continuous Dosing 
Weekly Visits1 
End of 
Treatment Visit 
30-day Safety 
Follow-up 
 
Baseline 
 
 
Cycle 1 
Cycle 2+ 
 
 
Week 
 
0 
0 
1 
2 
3 
4 
1 
3 
7 days after the 
last dose of 
ARQ 087 
30 days after 
the last dose of 
ARQ 087 
Day 
0 
Day 1 
Day 2, 3, 4 
1 
8 
15 
22 
1 
15 
 
 
Window 
-21 – 0 
0 
0 
0 
± 3 days 
 
 
± 3 days 
+3 days 
± 3 days 
Pharmacodynamics6 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Archival and/or Fresh 
Tumor Biopsy7 
X 
X 
 
X 
 
 
 
 
 
 
 
FGFR mutation, if 
unknown, Expanded 
Cohort only7  
X 
 
 
 
 
 
 
 
 
 
 
Tumor Measurement and 
Staging8 
X9 
 
 
 
 
 
 
X 
 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ARQ 087 Dispensation 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
1. 
Washout period between Treatment Period 1 Day 1 and Treatment Period 2 Cycle 1 Day 1 should be at least 72 hrs 
2. 
Physical examination, including mucous membrane and skin 
3. 
Weight at Baseline visit, on Day 1 and Day 15 of Cycle 1, on Day 1 of each subsequent cycle, and End of Treatment visit. 
4. 
Refer to Section 6.4 for description of laboratory assessments 
5. 
Refer to Section 6.3 for detailed description of assessments (Echocardiography or MUGA should be performed at Baseline, C3D1, C5D1, etc., and End of Treatment) 
6. 
Refer to Sections 6.5 and 6.6.for pharmacokinetic and pharmacodynamic blood samples collection schedules. Note: Because Cycle 1 Day 22 and Day 23 visits are days when 
the full PK is performed, subjects enrolled in Cohort 1 (25 mg every other day) Cycle 1 Week 4 visits should be scheduled on the day of ARQ 087 administration and next 
consecutive day, when drug is not taken, e.g., Cycle 1 Day 21 and Day 22 or Cycle 1 Day 23 and Day 24.  
7. 
Refer to Section 6.8 for detailed description of tumor tissue samples collection. If archival tissue is not available, baseline tumor biopsy will be performed to confirm FGFR 
mutation (the Expanded Cohort only).  
8. 
Refer to Sections 6.7 and Appendix 6 for tumor evaluation description (Baseline, C3D1, C5D1, etc., and End of Treatment) 
9. 
Unless tumor evaluation/measurement has been performed within 28 days prior to the first dose of ARQ 087 
 

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Appendix 1: Schedule of Assessments continued 
Part 1: Cohorts 5-10 and Food-effect Cohort 
Tests & Procedures 
Pre-
Study 
Visit(s) 
Continuous Dosing Weekly Visits 
End of 
Treatment Visit 
30-day Safety 
Follow-up 
 
Baseline 
Cycle 1 
Cycle 2+ 
 
 
Week 
 
1 
2 
3 
4 
1 
3 
~7 days after 
the last dose of 
ARQ 087 
~30 days after 
the last dose of 
ARQ 087 
Day 
0 
1 
2 
8 
15 
22 
23 
1 
15 
 
 
Window 
-21 – 0 
0 
 
± 3 days 
 
 
 
± 3 days 
+3 days 
±3 days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination1 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
ECOG PS  
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Vital Signs, Weight2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology3 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Blood Chemistry3 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Liver Function Tests3 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Coagulation tests3 
X 
 
 
 
 
 
 
 
 
X 
 
Thyroid function tests3 
X 
 
 
 
 
 
 
 
 
X 
 
Urinalysis3 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Serum Pregnancy Test3 
X 
 
 
 
 
 
 
 
 
X 
 
Tumor Markers, if 
applicable 
X 
X 
 
 
 
 
 
X 
 
X 
 
12-Lead ECG4 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Echocardiography or 
MUGA, if applicable4 
X 
 
 
 
 
 
 
X 
 
X 
 
Pharmacokinetics5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Part 1: Cohorts 5-10 and Food-effect Cohort 
Tests & Procedures 
Pre-
Study 
Visit(s) 
Continuous Dosing Weekly Visits 
End of 
Treatment Visit 
30-day Safety 
Follow-up 
 
Baseline 
Cycle 1 
Cycle 2+ 
 
 
Week 
 
1 
2 
3 
4 
1 
3 
~7 days after 
the last dose of 
ARQ 087 
~30 days after 
the last dose of 
ARQ 087 
Day 
0 
1 
2 
8 
15 
22 
23 
1 
15 
 
 
Window 
-21 – 0 
0 
 
± 3 days 
 
 
 
± 3 days 
+3 days 
±3 days 
Pharmacodynamics5 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Archival and/or Fresh 
Tumor Biopsy6 
X 
 
 
 
 
X 
 
 
 
 
 
Tumor’s genomic status, if 
unknown, Food-effect & 
Expanded Cohorts6 
X 
 
 
 
 
 
 
 
 
 
 
Tumor Measurement and 
Staging7 
X8 
 
 
 
 
 
 
X 
 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ARQ 087 Dispensation 
 
X 
 
X 
X 
X 
 
X 
X 
 
 
1. 
Physical examination, including mucous membrane and skin 
2. 
Weight at Baseline visit, on Day 1 and Day 15 of Cycle 1, on Day 1 of each subsequent cycle, and End of Treatment visit. 
3. 
Refer to Section 6.4 for description of laboratory assessments 
4. 
Refer to Section 6.3 for detailed description of assessments (Echocardiography or MUGA should be performed at Baseline, C3D1, C6D1, C9D1, etc., and End of Treatment) 
5. 
Refer to Sections 6.5 and 6.6.for pharmacokinetic and pharmacodynamic blood samples collection schedules.  
6. 
Refer to Section 6.8 for detailed description of tumor tissue samples collection. If archival tissue is not available, baseline tumor biopsy should be performed. Paired biopsy is 
mandatory for subjects enrolled in the Expanded and Food-effect Cohorts. 
7. 
Refer to Sections 6.7 and Appendix 6 for tumor evaluation description (Baseline, C3D1, C5D1, etc., and End of Treatment) 
8. 
Unless tumor evaluation/measurement has been performed within 28 days prior to the first dose of ARQ 087 
 
 

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Appendix 1: Schedule of Assessments continued 
Part 2: Expanded Cohort 
Tests & Procedures 
Pre-
Study 
Visit(s) 
Weekly Visits 
End of 
Treatment Visit 
30-day Safety 
Follow-up 
 
Baseline 
Cycle 1 
Cycle 2+ 
 
 
Week 
 
1 
2 
3 
4 
1 
3 
~7 days after 
the last dose of 
ARQ 087 
~30 days after 
the last dose of 
ARQ 087 
Day 
0 
1 
8 
15 
22 
1 
15 
 
 
Window 
-21 – 0 
0 
± 3 days 
 
 
± 3 days 
+3 days 
±3 days 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Examination1 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS  
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs, Weight2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology3 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry3 
X 
X 
X 
X 
X 
X 
X 
X 
 
Liver Function Tests3 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation tests3 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
Urinalysis3 
X 
X 
 
X 
 
X 
 
X 
 
Serum Pregnancy Test3 
X 
 
 
 
 
 
 
X 
 
Tumor Markers, if 
applicable 
X 
X 
 
 
 
X 
 
X 
 
12-Lead ECG4 
X 
X 
 
X 
 
X 
 
X 
 
Echocardiography or 
MUGA, if applicable4 
X 
 
 
 
 
X 
 
X 
 
Pharmacodynamics5 
 
X 
X 
X 
X 
X 
 
X 
 

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10 Apr 2015 
 
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Part 2: Expanded Cohort 
Tests & Procedures 
Pre-
Study 
Visit(s) 
Weekly Visits 
End of 
Treatment Visit 
30-day Safety 
Follow-up 
 
Baseline 
Cycle 1 
Cycle 2+ 
 
 
Week 
 
1 
2 
3 
4 
1 
3 
~7 days after 
the last dose of 
ARQ 087 
~30 days after 
the last dose of 
ARQ 087 
Day 
0 
1 
8 
15 
22 
1 
15 
 
 
Window 
-21 – 0 
0 
± 3 days 
 
 
± 3 days 
+3 days 
±3 days 
Archival and/or Fresh 
Tumor Biopsy(optional)6 
X 
 
 
 
X 
 
 
 
 
Tumor’s genomic status, if 
unknown6 
X 
 
 
 
 
 
 
 
 
Tumor Measurement and 
Staging7 
X8 
 
 
 
 
X 
 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
ARQ 087 Dispensation 
 
X 
X 
X 
X 
X 
X 
 
 
1. 
Physical examination, including mucous membrane and skin 
2. 
Weight at Baseline visit, on Day 1 and Day 15 of Cycle 1, on Day 1 of each subsequent cycle, and End of Treatment visit. 
3. 
Refer to Section 6.4 for description of laboratory assessments 
4. 
Refer to Section 6.3 for detailed description of assessments (if applicable, Echocardiography or MUGA should be performed at Baseline and End of Treatment. If clinically 
indicated the test may be done at any time during the study treatment.) 
5. 
Refer to Sections 6.6 for pharmacodynamic blood samples collection schedules. 
6. 
Refer to Section 6.8 for detailed description of tumor tissue samples collection. If archival tissue is not available, baseline tumor biopsy should be performed. Paired biopsy is 
optional for subjects enrolled in the Expanded Cohort. 
7. 
Refer to Sections 6.7 and Appendix 6 for tumor evaluation description (Baseline, C3D1, C5D1, etc., and End of Treatment) 
8. 
Unless tumor evaluation/measurement has been performed within 28 days prior to the first dose of ARQ 087 
 

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APPENDIX 2: PERFORMANCE STATUS 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
In bed <50% of the time.  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 
In bed >50% of the time.  Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 

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APPENDIX 3: PHARMACOKINETIC AND PHARMACODYNAMIC 
SAMPLING SCHEDULES 
Blood Collection Schedule for Pharmacokinetic Assessment: Cohorts 1-4 
DAY 
Procedure 
Sample 
Desired Time 
TREATMENT PERIOD 1: DAY 1 (single dose administration) 
1 
Draw blood sample 
PK 
0 hour (prior to ARQ 087 administration ) 
1 
Draw blood sample 
PK 
1 (±10 min) hour 
1 
Draw blood sample 
PK 
2 (±15 min) hours 
1 
Draw blood sample 
PK 
4 (±15 min) hours 
1 
Draw blood sample 
PK 
6 (±15 min) hours 
1 
Draw blood sample 
PK 
8 (±15 min) hours 
1 
Draw blood sample 
PK 
10 (±15 min) hours 
1 
Draw blood sample 
PK 
12 (±15 min) hours 
TREATMENT PERIOD 1: DAY 2 (single dose administration) 
2 
Draw blood sample 
PK 
24 hours (±2 hrs) (post ARQ 087 administration) 
TREATMENT PERIOD 1: DAY 3 (single dose administration) 
3 
Draw blood sample 
PK 
48 hours (±2 hrs) (post ARQ 087 administration) 
TREATMENT PERIOD 1: DAY 4 (single dose administration) 
4 
Draw blood sample 
PK 
72 hours (±2 hrs) (post ARQ 087 administration) 
TREATMENT PERIOD 2: CYCLE 1 DAY 8 (continuous dosing) 
8 
Draw blood sample 
PK 
Prior to ARQ 087 administration on Day 8 
TREATMENT PERIOD 2: CYCLE 1 DAY 15 (continuous dosing) 
15 
Draw blood sample 
PK 
Prior to  ARQ 087 administration on Day 15 
TREATMENT PERIOD 2: CYCLE 1 DAY 22* (continuous dosing) 
22 
Draw blood sample 
PK 
0 hour (prior to ARQ 087 administration) 
22 
Draw blood sample 
PK 
1 (±10 min) hour 
22 
Draw blood sample 
PK 
2 (±15 min) hours 
22 
Draw blood sample 
PK 
4 (±15 min) hours 
22 
Draw blood sample 
PK 
6 (±15 min) hours 
22 
Draw blood sample 
PK 
8 (±15 min) hours 
22 
Draw blood sample 
PK 
10 (±15 min) hours 
22 
Draw blood sample 
PK 
12 (±15 min) hours 
TREATMENT PERIOD 2: CYCLE 1 DAY 23* (continuous dosing) 
23 
Draw blood sample 
PK 
24 hours (±2 hrs) 
(post ARQ 087 administration on Day 22 and 
prior to ARQ 087 administration on Day 23) 
* Because Cycle 1 Day 22 and Day 23 visits are days when the full PK is performed, subjects enrolled in 
Cohort 1 (25 mg every other day), Cycle 1 Week 4 visits should be scheduled on the day of ARQ 087 
administration and next consecutive day, when drug is not taken, e.g., Cycle 1 Day 21 and Day 22 or Cycle 1 
Day 23 and Day 24.  

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Blood Collection Schedule for Pharmacokinetic Assessment:  
Cohorts 5-10 and Food-effect Cohort* 
CxDx 
Procedure 
Sample 
Desired Time 
CYCLE 1 DAY 1  
C1D1 
Draw blood sample 
PK 
0 hour (prior to ARQ 087 administration ) 
C1D1 
Draw blood sample 
PK 
1 (±10 min) hour 
C1D1 
Draw blood sample 
PK 
2 (±15 min) hours 
C1D1 
Draw blood sample 
PK 
4 (±15 min) hours 
C1D1 
Draw blood sample 
PK 
6 (±15 min) hours 
C1D1 
Draw blood sample 
PK 
8 (±15 min) hours 
C1D1 
Draw blood sample 
PK 
10 (±15 min) hours 
collect up through Food-effect Cohort then 
optional for Expanded Cohort 
C1D1 
Draw blood sample 
PK 
12 (±15 min) hours 
collect up through Food-effect Cohort then omit 
for Expanded Cohort 
CYCLE 1 DAY 2  
C1D2 
Draw blood sample 
PK 
24 hours (±2 hrs)  
(post ARQ 087 administration on Day 1 and 
prior to ARQ 087 administration on Day 2) 
collect up through Food-effect Cohort then omit 
for Expanded Cohort 
CYCLE 1 DAY 8  
C1D8 
Draw blood sample 
PK 
Prior to ARQ 087 administration on Day 8 
CYCLE 1 DAY 15  
C1D15 
Draw blood sample 
PK 
Prior to ARQ 087 administration on Day 15 
CYCLE 1 DAY 22  
C1D22 
Draw blood sample 
PK 
0 hour (prior to ARQ 087 administration) 
C1D22 
Draw blood sample 
PK 
1 (±10 min) hour 
C1D22 
Draw blood sample 
PK 
2 (±15 min) hours 
C1D22 
Draw blood sample 
PK 
4 (±15 min) hours 
C1D22 
Draw blood sample 
PK 
6 (±15 min) hours 
C1D22 
Draw blood sample 
PK 
8 (±15 min) hours 
C1D22 
Draw blood sample 
PK 
10 (±15 min) hours 
collect up through Food Effect cohort then 
optional for Expanded cohort 
C1D22 
Draw blood sample 
PK 
12 (±15 min) hours 
collect up through Food-effect Cohort then omit 
for Expanded Cohort 

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Blood Collection Schedule for Pharmacokinetic Assessment:  
Cohorts 5-10 and Food-effect Cohort* 
CxDx 
Procedure 
Sample 
Desired Time 
CYCLE 1 DAY 23 
C1D23 
Draw blood sample 
PK 
24 hours (±2 hrs) 
(post ARQ 087 administration on Day 22 and 
prior to ARQ 087 administration on Day 23) 
CYCLE 2 DAY 1 (and all subsequent cycles) 
CxD1 
Draw blood sample 
PK 
Prior to ARQ 087 administration on Day 1 
CYCLE 2 DAY 15 (and all subsequent cycles) 
CxD15 
Draw blood sample 
PK 
Prior to ARQ 087 administration on Day 15 
END OF TREATMENT  
EOT 
Draw blood sample 
PK 
 
* 1. Subjects enrolled in the Food-effect Cohort should take ARQ 087 with their morning meal 
   2. PK samples may be collected from up to 10 subjects enrolled in the Expanded Cohort 
 

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TUMOR TISSUE BIOPSY AND BLOOD COLLECTION SCHEDULES FOR 
PART 1: DOSE ESCALATION 
Tumor Tissue Biopsy Schedule for Pharmacodynamic Assessment: Cohorts 1-4 
Day 
Procedure 
Sample 
Desired Time 
BASELINE 
-21 – 0 days 
Tumor 
biopsy 
TB-01 
0 
(prior to ARQ 087 administration) 
TREATMENT PERIOD 1 DAY 1 or TREATMENT PERIOD 2, CYCLE 1 DAY 1 
Tx Period 1, Day 1 or 
Tx Period 2, Cycle 1 Day 1 
Tumor 
biopsy 
TB-02 
Tx Period 1, Day 1 or Tx Period 2, Cycle 1 Day 1 
(4-6 hrs after ARQ 087 administration) 
 
Tumor Tissue Biopsy Schedule for Pharmacodynamic Assessment: Cohorts 5-10 and 
Food-effect Cohort 
Day 
Procedure 
Sample 
Desired Time 
BASELINE 
-21 – 0 days 
Tumor 
biopsy 
TB-01 
0 
(Prior to ARQ 087 administration) 
CYCLE 1 DAY 22 – CYCLE 2 DAY 1 
C1D22-C2D1 
(post-treatment biopsy) 
Tumor 
biopsy 
TB-02 
At least 1 hr after ARQ 087 administration 
Optional (additional) Biopsies 
>C3D1 
(post-treatment biopsy) 
Tumor 
biopsy 
TB-03 
At least 1 hr after ARQ 087 administration 
 
Blood Collection Schedule for Pharmacodynamic Assessment: Cohorts 5-10 and 
Food-effect Cohort 
CxDx 
Procedure 
Sample 
Desired Time 
CYCLE 1 DAY 1  
C1D1 
Draw blood sample 
PD-01 
Prior to ARQ 087 administration  
C1D8 
Draw blood sample 
PD-02 
Prior to ARQ 087 administration 
C1D15 
Draw blood sample 
PD-03 
Prior to ARQ 087 administration 
C1D22 
Draw blood sample 
PD-04 
Prior to ARQ 087 administration 
CYCLE 2 DAY 1  
C2D1 
Draw blood sample 
PD-05 
Prior to ARQ 087 administration 
CYCLE 3 DAY 1  
C3D1 
Draw blood sample 
PD-06 
Prior to ARQ 087 administration 
CYCLE 4 DAY 1  
C4D1 
Draw blood sample 
PD-07 
Prior to ARQ 087 administration 
CYCLE 5 DAY 1  
C5D1 
Draw blood sample 
PD-08 
Prior to ARQ 087 administration 

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TUMOR TISSUE BIOPSY AND BLOOD COLLECTION SCHEDULES FOR 
PART 2: EXPANDED COHORT 
Tumor Tissue Biopsy Schedule for Pharmacodynamic Assessment (optional) 
Day 
Procedure 
Sample 
Recommended Time 
ARCHIVAL TISSUE 
-21 – 0 days 
 
 
Should be collected prior to Cycle 1 Day 1 
PAIRED BIOPSY (optional) 
BASELINE 
-21 – 0 days 
Tumor 
biopsy 
TB-01 
0 
(Prior to ARQ 087 administration) 
CYCLE 1 DAY 22 – CYCLE 2 DAY 1 
C1D22-C2D1 
(post-treatment biopsy) 
Tumor 
biopsy 
TB-02 
At least 1 hr after ARQ 087 administration 
Optional (additional) Biopsies 
> C3D1 
(post-treatment biopsy) 
Tumor 
biopsy 
TB-03 
At least 1 hr after ARQ 087 administration 
 
Blood Collection Schedule for Pharmacodynamic Assessment 
CxDx 
Procedure 
Sample 
Desired Time 
CYCLE 1 DAY 1 
C1D1 
Draw blood sample 
PD-01 
Prior to ARQ 087 administration 
CYCLE 2 DAY 1 
C2D1 
Draw blood sample 
PD-02 
Prior to ARQ 087 administration 
CYCLE 3 DAY 1 
C3D1 
Draw blood sample 
PD-03 
Prior to ARQ 087 administration 
CYCLE 4 DAY 1 
C4D1 
Draw blood sample 
PD-04 
Prior to ARQ 087 administration 
CYCLE 5 DAY 1 
C5D1 
Draw blood sample 
PD-05 
Prior to ARQ 087 administration 
CYCLE 6 DAY 1 
C6D1 
Draw blood sample 
PD-06 
Prior to ARQ 087 administration 

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APPENDIX 4: EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS 
AND INDUCERS FOR SPECIFIC CYP ENZYMES FOR STUDY 
CYP1A2 Ligands 
Following is a table of selected substrates, inducers and inhibitors of CYP1A2. 
Inhibitors of CYP1A2 can be classified by their potency, such as: 
 
Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC 
values, or more than 80% decrease in clearance.  
 
Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC 
values, or 50-80% decrease in clearance.  
 
Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in 
the plasma AUC values, or 20-50% decrease in clearance.  
Selected Inducers, Inhibitors, and Substrates of CYP1A2 
Substrates 
Inhibitors 
Inducers 
 
many antidepressants  
o 
amitriptyline (tricyclic 
antidepressant)  
o 
clomipramine (tricyclic 
antidepressant)  
o 
imipramine (tricyclic 
antidepressant)  
o 
agomelatine  
 
some atypical antipsychotics  
o 
clozapine  
o 
olanzapine  
 
haloperidol (typical 
antipsychotic)  
 
caffeine (stimulant)  
 
ropivacaine (local anaesthetic)  
 
theophylline (xanthine, in 
respiratory diseases)  
 
zolmitriptan (serotonin receptor 
agonist)  
 
melatonin (antioxidant, sleep-
inducer)  
 
tamoxifen (SERM)  
 
erlotinib (Tarceva, a tyrosine 
kinase inhibitor)  
 
cyclobenzaprine (muscle 
relaxant, depressant)  
 
estradiol (in hypoestrogenism)  
 
fluvoxamine (SSRI 
antidepressant)  
 
mexiletine (antiarrhythmic agent) 
 
naproxen (NSAID)  
 
ondansetron (5-HT3 antagonist)  
 
phenacetin (analgesic)  
Strong:  
 
ciprofloxacin (fluoroquinolone 
bactericidal)  
 
many other fluoroquinolones (broad-
spectrum antibiotics)  
 
fluvoxamine (SSRI antidepressant)  
 
verapamil (calcium channel blocker)  
Weak 
 
cimetidine (H2-receptor antagonist)  
Unspecified potency: 
 
amiodarone (antiarrhythmic agent)  
 
interferon (antiviral, antiseptic, 
antioncogenic)  
 
methoxsalen (in psoriasis)  
 
mibefradil (calcium channel blocker)  
Some foods  
o 
grapefruit juice (its bitter 
flavanone naringenin)   
o 
cumin  
o 
turmeric  
 
tobacco  
 
Some foods  
o 
broccoli  
o 
brussels sprouts  
o 
chargrilled meat  
o 
cauliflower  
o 
cauliflower  
 
insulin (in diabetes)  
 
methylcholanthrene 
(carcinogen)  
 
modafinil (eugeroic)  
 
nafcillin (beta-lactam 
antibiotic)  
 
beta-Naphthoflavone 
(chemopreventive)  
 
omeprazole (proton 
pump inhibitor)  

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Substrates 
Inhibitors 
Inducers 
 
paracetamol (analgesic, 
antipyretic)  
 
propranolol (beta blocker)  
 
riluzole (in amyotrophic lateral 
sclerosis)  
 
tacrine (parasympathomimetic)  
 
tizanidine (α-2 adrenergic 
agonist)  
 
verapamil (calcium channel 
blocker)  
 
warfarin (anticoagulant)  
 
zileuton (in asthma)  
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
CYP2D6 Ligands 
Following is a table of selected substrates, inducers and inhibitors of CYP2D6. Where 
classes of agents are listed, there may be exceptions within the class. Inhibitors of CYP2D6 
can be classified by their potency, such as: 
 
Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC 
values, or more than 80% decrease in clearance.  
 
Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC 
values, or 50-80% decrease in clearance.  
 
Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in 
the plasma AUC values, or 20-50% decrease in clearance.  
Selected Inducers, Inhibitors, and Substrates of CYP2D6 
Substrates 
↑ = bioactivation by CYP2D6 
Inhibitors 
Inducers 
 
All tricyclic antidepressants, e.g.  
o 
imipramine  
o 
amitriptyline  
o 
etc.  
 
Most SSRIs (antidepressant), e.g.  
o 
fluoxetine  
o 
paroxetine  
o 
fluvoxamine  
 
venlafaxine (SNRI antidepressant)  
 
mianserin (tetracyclic 
antidepressant)  
 
opioids  
o 
codeine↑ into morphine  
o 
tramadol↑  
o 
oxycodone  
 
antipsychotics, e.g.  
o 
haloperidol  
o 
risperidone  
Strong: 
 
SSRIs  
o 
fluoxetine  
o 
paroxetine  
 
bupropion (non-SSRI 
antidepressant)  
 
quinidine (class I antiarrhythmic 
agent)  
 
cinacalcet (calcimimetic)  
 
ritonavir (antiretroviral)  
Moderate 
 
sertraline (SSRI)  
 
duloxetine (SNRI  
 
dexamethasone 
(glucocorticoid)  
 
rifampicin 
(bactericidal)  
Strong: 
 
glutethimid 

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Substrates 
↑ = bioactivation by CYP2D6 
Inhibitors 
Inducers 
o 
perphenazine  
o 
thioridazine  
o 
zuclopenthixol  
o 
iloperidone  
o 
aripiprazole  
o 
chlorpromazine  
o 
levomepromazine  
o 
remoxipride  
 
minaprine (RIMA antidepressant)  
 
tamoxifen↑ (SERM)  
 
beta-blockers  
o 
metoprolol  
o 
timolol  
o 
alprenolol  
o 
carvedilol  
o 
bufuralol  
o 
nebivolol  
o 
propranolol  
 
debrisoquine (antihypertensive)  
 
Class I antiarrhythmics  
o 
flecainide  
o 
propafenone  
o 
encainide  
o 
mexiletine  
o 
lidocaine  
o 
sparteine  
 
ondansetron (antiemetic)  
 
donepezil (acetylcholinesterase 
inhibitor)  
 
phenformin (antidiabetic)  
 
tropisetron (5-HT3 receptor 
antagonist)  
 
amphetamine (in ADHD, 
narcolepsy)  
 
atomoxetine (in ADHD)  
 
chlorphenamine (antihistamine)  
 
dexfenfluramine (serotoninergic 
anorectic)  
 
dextromethorphan (antitussive) 
into psychoactive dextrorphan  
 
duloxetine (SNRI)  
 
metoclopramide (dopamine 
antagonist)  
 
Methoxyamphetamine  
 
perhexiline (antianginal agent)  
 
phenacetin (analgesic)  
 
promethazine (antihistamine 
antiemetic)  
 
terbinafine (antifungal)  
Weak: 
 
buprenorphine (in opioid addiction)  
 
amiodarone (antiarrhythmic)  
 
cimetidine (H2-receptor antagonist)  
Unspecified potency: 
 
antipsychotics  
o 
haloperidol  
o 
perphenazine  
o 
thioridazine  
o 
zuclopenthixol  
o 
risperidone  
o 
chlorpromazine  
 
bicalutamide  
 
hyperforin (St. Johns Wort)  
 
antihistamines (H1-receptor 
antagonists)  
o 
Promethazine  
o 
chlorphenamine  
o 
diphenhydramine  
o 
hydroxyzine  
o 
tripelennamine  
 
some SSRI antidepressants  
o 
citalopram  
o 
escitalopram  
 
clemastine (antihistamine and 
anticholinergic)  
 
celecoxib (NSAID)  
 
clomipramine (tricyclic 
antidepressant)  
 
cocaine (stimulant)  
 
doxorubicin (chemotherapeutic)  
 
metoclopramide (antiemetic, 
prokinetic)  
 
methadone (analgesic and anti-
addictive)  
 
moclobemide (antidepressant)  
 
ranitidine (H2-receptor antagonist)  
 
doxepin (tricyclic antidepressant, 
anxiolytic)  
 
halofantrine (in malaria)  
 
levomepromazine (antipsychotic)  
 
mibefradil (calcium channel 
blocker)  
 
midodrine (α1 agonist)  
 
ticlopidine[ (antiplatelet)  
Source: http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
 

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APPENDIX 5: EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS 
AND INDUCERS OF P-GLYCOPROTEIN 
Examples of In Vivo Substrates, Inhibitors and Inducers of P-glycoprotein1 
 
Transporter 
Substrates 
Inhibitors(2) 
Inducers(3) 
P-gp 
(Gene ABCB1) 
Aliskiren  
ambrisentan  
colchicine  
dabigatran etexilate 
digoxin  
everolimus  
fexofenadine  
imatinib  
lapatinib  
maraviroc,  
nilotinib  
posaconazole  
ranolazine  
saxagliptin  
sirolimus  
sitagliptin  
talinolol  
tolvaptan  
topotecan  
 
Amiodarone  
azithromycin(4)  
captopril  
carvedilol 
clarithromycin 
conivaptan  
cyclosporine 
diltiazem 
dronedarone 
erythromycin(5) 
felodipine  
itraconazole  
ketoconazole(4)  
lopinavir and 
ritonavir  
quercetin(4)  
quinidine  
ranolazine 
ticagrelor  
verapamil 
Avasimibe(6) 
carbamazepine(7) 
phenytoin  
rifampin  
St John’s wort(8) 
tipranavir/ritonavir 
Source: Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for 
Dosing, and Labeling Recommendations. 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf ) 
(1) Not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m080499.htm.  
(2) Inhibitors listed for P-gp are those that showed >25% increase in digoxin AUC or otherwise indicated if 
substrate is other than digoxin.  
(3) Inducers listed for P-gp are those that showed >20% decrease in digoxin AUC or otherwise indicated if 
substrate is other than digoxin.  
 (4) Inhibitors listed are those that showed >25% increase in fexofenadine AUC.  
(5) Inhibitors listed are those that showed >25% increase in talinolol AUC.  
(6) Not a marketed drug.  
(7) Inducers listed are those that showed >20% decrease in fexofenadine AUC.  
(8) Herbal product. 

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APPENDIX 6: ASSESSMENT OF ANTI-TUMOR ACTIVITY 
Assessment of tumor responses may be performed following the revised RECIST guidelines, 
version 1.1.34  Some of these definitions and criteria are highlighted below.  
Measurability of Tumor Baseline 
 
CT with IV contrast and MRI are the best currently available and reproducible methods 
to measure target lesions selected for response assessment.  Conventional CT and MRI 
should be performed with cuts of 10 mm or less in slice thickness contiguously.  Spiral 
CT should be performed using a 5 mm contiguous reconstruction algorithm. 
 
All imaging methods should be performed according to institutional standards with each 
subject having consistency of methods beginning from baseline through the course of the 
study. 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
Measurable  
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
 
20 mm by chest X-ray. 
Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, 
only the short axis will be measured and followed. See also notes below on ‘Baseline 
documentation of target and non-target lesions’ for information on lymph node measurement. 
Non-Measurable 
All other lesions, including small lesions (longest diameter < 10mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin (nevi) or 
lung, and abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 

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Bone lesions 
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 
Cystic lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 
Lesions with prior local treatment 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are not considered measurable unless there has been demonstrated 
progression in the lesion.  
Specifications by Methods of Measurements 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
NEVER more than 4 weeks before the beginning of the treatment. 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10mm diameter as assessed using calipers (e.g. skin (nevi) nodules). For the 
case of skin (nevi) lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 

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lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have a 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. In this 
study, only subjects with measurable disease at baseline should be included in the study.  
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where subjects have only one or two organ sites involved, a 
maximum of two and four lesions respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest 
lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor. As noted above, pathological nodes 
which are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of ≥ 15mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as 
two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). 
The smaller of these measures is the short axis. For example, an abdominal node which is 
reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node. In this example, 20 mm should be recorded as the node measurement. All 
other pathological nodes (those with short axis ≥ 10mm but < 15 mm) should be considered 
non-target lesions. Nodes that have a short axis < 10 mm are considered non-pathological 
and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of the diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into the 
sum. The baseline sum of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 

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All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g. ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).  
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
In this study, the minimum duration for SD is defined as 8 weeks (± 2 days). 
Special Notes on the Assessment of Target Lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to 
be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
Response Criteria subsequent evaluation, even when very small (e.g. 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline become so 
faint on CT scan that the radiologist may not feel comfortable assigning an exact measure 
and may report them as being ‘too small to measure’. When this occurs it is important that a 
value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as 

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in the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well). This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness). The measurement of these lesions is potentially 
non-reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is able 
to provide an actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time 
points specified in the protocol.  
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing 
non-target lesions. (Note: the appearance of one or more new lesions is also considered 
progression). 
Special Notes on the Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the subject also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy (see further details below). A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to quality for unequivocal progression status. The designation 
of overall progression solely on the basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare.  
Evaluation of New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 

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modality or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the subject’s baseline lesions show partial or complete response. 
For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic 
lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this 
is the subject who has visceral disease at baseline and while on study has a CT or MRI of the 
brain ordered which reveals metastases. The subject’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan.  
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment. No confirmatory measurement for CR or PR is required in this 
study.  
The subject’s best overall response assignment will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions.  
Time Point Response 
It is assumed that at each protocol specified time point, a response assessment occurs. The 
table below provides a summary of the overall response status calculation at each time point 
for subjects who have measurable disease at baseline. 
Time Point Response: Subjects with Target (+/– non-target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = not evaluable.  

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Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. For example, if a subject had a baseline sum of 50 mm with three measured lesions and 
at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the subject will 
have achieved PD status, regardless of the contribution of the missing lesion.  
Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in trials where confirmation of complete or partial response IS 
NOT required: Best response in these trials is defined as the best response across all time 
points (for example, a subject who has SD at first assessment, PR at second assessment, and 
PD on last assessment has a best overall response of PR). When SD is believed to be the best 
response, it must also meet the protocol specified minimum time from baseline of 8 weeks. If 
the minimum time is not met when SD is otherwise the best time point response, the 
subject’s best response depends on the subsequent assessments. For example, a subject who 
has SD at the first assessment, PD at second the assessment, and does not meet the minimum 
duration for SD, the subject will have a best response of PD. The same subject lost to follow-
up after the first SD assessment would be considered inevaluable. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (< 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in the size of the nodes. As noted earlier, this 
means that subjects with CR may not have a total sum of ‘zero’ on the case report form 
(CRF). 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted at Baseline, and then in 8-week intervals 
while the subject is on treatment or as clinically indicated until progression of disease, 

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withdrawal of consent, death, or loss to follow-up. Tumor measurement will also be 
performed during the End-of-Treatment visit if it is not done within 28 days of the visit date. 
Baseline tumor assessments must be performed within four weeks (28 days) of the first dose 
of treatment.  
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning methods, equipment, 
technique (including slice thickness and field of view), and the radiographic interpreter. 
The radiological evaluation must include CT or MRI scanning of the chest, abdomen, and 
pelvis.  Any additional suspected sites of disease should also be imaged. All evaluations 
should meet the standard of care for imaging of lesions in the respective organ(s).  
All target and non-target sites are evaluated at each time point of tumor assessment.  
Confirmatory Measurement/Duration of Response 
Confirmation 
Confirmation of PR and CR is NOT required in this study.  
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria 
that are first met for CR until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is 
the reference for calculation of PD). In this study, the minimum duration for SD is defined as 
8 weeks (±3 days). 

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INVESTIGATOR’S SIGNATURE 
Study Title: 
A Phase 1/2 Study of ARQ 087 in Adult Subjects with 
Advanced Solid Tumors with FGFR Genetic Alterations, 
Including Intrahepatic Cholangiocarcinoma with FGFR2 
Gene Fusion 
Study Number: 
ARQ 087-101  
 
I have read the protocol described above. I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol.  
 
 
Printed Name: _________________________________________ 
 
 
 
Signature: _________________________________________ Date: ____________________