Clinical trial NCT01178411
Conditions: Advanced Solid Tumors
Keywords: hepatocellular carcinoma renal cell carcinoma melanoma non-small cell lung cancer breast cancer ovarian cancer MiT tumors
Sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Start date: 2010-08-31; Completion date: 2019-01-14
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an extension study that will allow participants to continue to receive study therapy when the original studies into which they were enrolled have reached their designated end-dates. This extension study is designed to further evaluate the safety and tolerability of tivantinib (ARQ 197) monotherapy or in combination with other drug(s) when given to participants who tolerated previous treatment well and may benefit from the continuing treatment.

Detailed description:
This open label extension protocol enrolls participants who were treated in previous phase 1 (NCT01149720, NCT01517399, NCT01699061, NCT00612703, NCT00827177, and NCT00874042) and phase 2 (NCT00777309, NCT00557609, NCT00988741, NCT01395758 , and NCT01055067) tivantinib studies that have reached their designated end-dates. Participants enrolled in this extension protocol will provide further safety and tolerability information about tivantinib monotherapy or in combination with other drug(s) at the same dose(s), and same schedule(s) in which they were originally enrolled.

Arms: arm 1: Tivantinib 360 mg will be administered twice daily, orally, with meals, as a monotherapy or in combination with other drug therapies.
Interventions: intervention 1: Tivantinib intervention 2: Anti-Cancer Combination Therapy
Intervention descriptions: intervention 1: Tivantinib 360 mg (3 x 120 mg tablets or capsules) twice daily by mouth. intervention 2: Tivantinib 360 mg twice daily in combination with other anti-cancer therapy (eg, erlotinib,sorafenib, pemetrexed, docataxel, gemcitabine, irinotecan, and/or cetuximab) at the same dose and schedule in which they were administered in the original (previous) study.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT01178411
18-February-2014
Document Date: 
An Extension Protocol for Subjects Who Were Previously
Enrolled in Other Tivantinib (ARQ 197) Protocols


 
 
 
TITLE: 
An Extension Protocol for Subjects Who Were Previously 
Enrolled in Other Tivantinib (ARQ 197) Protocols 
PROTOCOL NUMBER: 
ARQ 197-299 
STUDY DRUG: 
Tivantinib (ARQ 197) 
EudraCT NUMBER: 
NCT NUMBER: 
2010-020151-31 
01178411 
SPONSOR: 
ArQule, Inc.  
19 Presidential Way 
Woburn, MA 01801 
Telephone: 
 
Fax:
 
SAFETY HOTLINE: 
North America: 
  
All others: 
 
SAFETY FAX: 
North America: 
 
All others: 
 
MEDICAL MONITOR 
 
DATE OF PROTOCOL: 
Original: 15 April 2010 
Amendment 1: 16 June 2010 
Amendment 2: 18 February 2014 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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SYNOPSIS 
Study Title 
An Extension Protocol for Subjects Who Were Previously Enrolled 
in Other Tivantinib (ARQ 197) Protocols 
Study Number 
ARQ 197-299 
Study Phase 
Phase 1/2/3, depending on the phase of the study into which subjects 
were originally enrolled. 
Primary Objective 
To provide subjects who participated in previous tivantinib studies 
that have reached their designated end-dates and who may have 
benefited from the treatment with access to the study drug(s).  
Secondary Objective 
To collect additional safety, tolerability, and efficacy information for 
tivantinib. 
Study Design 
Open label extension protocol for subjects who have participated in 
previous tivantinib studies. Subjects enrolled in this extension 
protocol will receive study drug(s) at the dose(s) and schedule(s) of 
the original protocols in which they were enrolled.  
 
Subjects who were previously treated with tivantinib as a single 
agent and who, in the opinion of the Investigator, may benefit from 
combination therapy will be allowed to receive combination therapy 
with the Sponsor’s approval. The combination therapy(ies) 
considered must have been evaluated in prior tivantinib combination 
studies. The combination therapy dose(s) and schedule(s) will be 
determined for each subject by the Investigator and with the 
Sponsor’s approval based on the combination drug(s) label(s) and 
prior tivantinib clinical trials.  
 
Subjects who were previously enrolled in tivantinib studies but did 
not receive tivantinib as part of their treatment, and who, in the 
opinion of the Investigator, may benefit from treatment with 
tivantinib as a single agent or in combination therapy, will be 
allowed to initiate treatment with tivantinib. The tivantinib 
monotherapy or combination therapy dose(s) and schedule(s) will be 
determined for each subject by the Investigator and with the 
Sponsor’s approval based on administration schedules tested in and 
defined by prior tivantinib clinical trials. 
 
Study Population 
Subjects who have been treated under other tivantinib protocols that 
have reached their designated end-dates. 
Test Product, Dose, and 
Mode of Administration 
Subjects will receive treatment with either tivantinib (monotherapy) 
or tivantinib in combination with other drug(s) (combination 
therapy) at the same dose(s) and same schedule(s) as in the original 
study protocol into which they were enrolled.  
 
Subjects who were previously treated with tivantinib only and who 
in the opinion of the Investigator and with the Sponsor’s approval 
may benefit from combination therapy will be allowed to receive 
combination therapy.  
 
Subjects who were previously enrolled in tivantinib studies but did 


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not receive tivantinib as part of their treatment, and who, in the 
opinion of the Investigator, may benefit from treatment with 
tivantinib as a single agent or in combination therapy, will be 
allowed to initiate treatment with tivantinib. The tivantinib 
monotherapy or combination therapy dose(s) and schedule(s) will be 
determined for each subject by the Investigator and with the 
Sponsor’s approval based on administration schedules tested in and 
defined by prior tivantinib clinical trials. 
 
The combination therapy(ies) considered must have been evaluated 
in prior tivantinib combination studies. The tivantinib monotherapy 
and combination therapy dose(s) and schedule(s) will be determined 
for each subject by the Investigator and with the Sponsor’s approval 
based on the combination drug(s) label(s) and prior tivantinib 
clinical trials.  
 
Tivantinib will be administered orally, twice a day, with meals 
(regardless of original protocol requirements). 
Duration of Treatment 
For an individual subject, treatment will continue until the 
discontinuation criteria are reached.  
 


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TABLE OF CONTENTS 
 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS ...........................................................................................................4 
LIST OF ABBREVIATIONS ....................................................................................................7 
1 
INTRODUCTION .............................................................................................................9 
1.1 
Overview of Clinical Experience ...........................................................................10 
1.1.1 
Safety in Clinical Studies .............................................................................10 
Myelosuppression ........................................................................................................11 
2 
STUDY OBJECTIVES ....................................................................................................23 
2.1 
Primary Objectives.................................................................................................23 
2.2 
Secondary Objectives.............................................................................................23 
3 
SELECTION OF STUDY POPULATION .....................................................................24 
3.1 
Inclusion Criteria ...................................................................................................24 
3.2 
Exclusion Criteria ..................................................................................................25 
3.3 
Number of Subjects................................................................................................25 
4 
INVESTIGATIONAL PLAN ..........................................................................................26 
4.1 
Overall Study Design .............................................................................................26 
4.2 
Rationale for Study Design ....................................................................................26 
4.3 
Administration Schedule ........................................................................................26 
4.4 
Study Duration .......................................................................................................26 
5 
STUDY VISITS ...............................................................................................................27 
5.1 
Pre-study Visit .......................................................................................................27 
5.2 
Monthly Visits (± 3 days) ......................................................................................28 
5.3 
Weekly Visits (if applicable; ± 3 days) ..................................................................28 
5.3.1 
Weekly Visits (applied for combination drug(s) administration; ± 3 
days) .............................................................................................................28 
5.3.2 
Weekly Visits (applied ONLY for tivantinib-naïve subjects; ± 3 days) ......28 
5.4 
End of Treatment Visit...........................................................................................29 
5.5 
30-day Safety Follow-up Visit ...............................................................................30 
5.6 
Discontinuation from Study ...................................................................................30 
6 
STUDY PROCEDURES .................................................................................................31 
6.1 
Informed Consent...................................................................................................31 
6.2 
Physical Examination.............................................................................................31 
6.3 
Clinical Laboratory Tests .......................................................................................31 
6.4 
Twelve-lead Electrocardiogram .............................................................................32 
6.5 
Tumor Assessment .................................................................................................32 
6.6 
Other Evaluations...................................................................................................32 


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7 
TREATMENT .................................................................................................................33 
7.1 
Tivantinib ...............................................................................................................33 
7.1.1 
Storage and Handling ...................................................................................33 
7.1.2 
Tivantinib Accountability ............................................................................33 
7.1.3 
Tivantinib Administration ............................................................................33 
7.1.4 
Tivantinib Missed or Vomited Doses ..........................................................34 
7.2 
Combination Drug Administration ........................................................................34 
7.3 
Dose Modification .................................................................................................34 
7.4 
Blinding..................................................................................................................36 
7.5 
Concomitant Medication ........................................................................................36 
7.5.1 
Permitted Treatment.....................................................................................37 
7.5.2 
Prohibited Treatment ...................................................................................37 
7.5.3 
Treatment to Avoid During Tivantinib Administration ...............................37 
8 
SAFETY ASSESSMENTS ..............................................................................................39 
8.1 
Definitions..............................................................................................................39 
8.1.1 
Adverse Event ..............................................................................................39 
8.1.2 
Serious Adverse Event (SAE) ......................................................................39 
8.1.3 
Adverse Event Severity................................................................................40 
8.1.4 
Causality Assessment...................................................................................40 
8.1.5 
Action Taken Regarding the Study Product ................................................40 
8.1.6 
Adverse Event Outcome ..............................................................................41 
8.1.7 
Other Action Taken for Event ......................................................................41 
8.2 
Responsibilities and Procedures ............................................................................41 
8.3 
Adverse Events or Serious Adverse Events Assessment Criteria ..........................42 
8.4 
Reporting Serious Adverse Events ........................................................................42 
8.5 
Post-treatment Safety Follow-up ...........................................................................43 
9 
ASSESSMENT OF ANTI-TUMOR ACTIVITY ............................................................44 
10 QUALITY CONTROL AND ASSURANCE .................................................................45 
11 PLANNED STATISTICAL METHODS ........................................................................46 
12 COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL 
CONSIDERATIONS AND INFORMED CONSENT ....................................................47 
12.1 
Institutional Review Board or Independent Ethics Committee Approval .............47 
12.2 
Compliance with GCP and Ethical Considerations ...............................................47 
12.3 
Subject Information and Consent...........................................................................47 
13 STUDY MANAGEMENT AND MATERIALS .............................................................49 
13.1 
Monitoring, Verification of Data, Audit, and Inspection.......................................49 
13.2 
Data Recording and Retention of Study Data ........................................................49 
13.3 
Electronic Case Report Forms ...............................................................................49 


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13.4 
Confidentiality, Publication, and Disclosure Policy ..............................................50 
14 REFERENCES ................................................................................................................51 
APPENDIX 1: SCHEDULE OF ASSESSMENTS .................................................................54 
APPENDIX 2: ECOG PERFORMANCE STATUS ...............................................................55 
APPENDIX 3: EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS, AND 
INDUCERS FOR SPECIFIC CYP ENZYMES ..............................................................56 
APPENDIX 4: DOSE MODIFICATION GUIDELINES FOR COMBINATION 
THERAPY .......................................................................................................................57 
SPONSOR SIGNATURE ........................................................................................................65 
INVESTIGATOR’S SIGNATURE .........................................................................................66 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophils count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate transaminase 
ATP 
adenosine triphospate 
AUC 
area under the time-concentration curve 
BID 
twice daily 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma drug concentration 
c-MET 
circulating mesenchymal-epithelial transition factor 
CNS 
central nervous system 
CRF/eCRF 
case report form/electronic case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EM 
extensive metabolizers 
EP 
erlotinib + placebo 
ESA 
erythropoietin stimulating agents 
ET 
erlotinib + tivantinib 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 


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ABBREVIATION 
DEFINITION 
G-CSF 
colony stimulating factors 
HCC 
hepatocellular carcinoma 
HGF 
hepatocyte growth factor 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
investigator’s brochure 
IC50 
inhibitor concentration required for 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
ILD 
interstitial lung disease 
INR 
international normalized ratio 
IRB 
institutional review board 
Ki 
inhibition constant 
LDH 
lactate dehydrogenase 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
PFS 
progression free survival 
PK 
pharmacokinetics 
PM 
poor metabolizers 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
WBC 
white blood cells 
 
 


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1 
INTRODUCTION 
Tivantinib is the most advanced representative of a newly discovered class of trans 3,4 
disubstituted pyrrolidine-2,5-diones having the potential to treat cancer.1  Tivantinib is a 
novel, small molecule inhibitor of c-MET receptor tyrosine kinase. The expression of c-MET 
is dysregulated in many types of human malignancies with overexpression of c-MET kinase, 
c-MET-activating genetic mutations, c-MET amplifications, and increased expression of the 
c-MET ligand hepatocyte growth factor (HGF). This dysregulation is implicated with a poor 
prognosis with greater tumor proliferation and increased angiogenesis with migration and 
invasion.2,3 
The c-MET receptor tyrosine kinase is the only known high-affinity receptor for HGF, also 
known as scatter factor. The binding of HGF to the c-MET extracellular ligand-binding 
domain results in receptor multimerization and phosphorylation of multiple tyrosine residues 
in the intracellular portion of c-MET.4,5 
Activation of c-MET results in the binding and phosphorylation of adaptor proteins such as 
growth factor receptor-bound-associated binder-1 (Gab-1), growth factor receptor-bound 
protein 2 (Grb-2), Src homology 2 domain-containing and Casitas B-lineage lymphoma 
progene (c-Cbl), and subsequent activation of signaling pathways, including 
phosphatidylinositol-3-kinase/activated protein kinase B (PI3K/Akt), focal adhesion kinase-1 
(FAK), signal transducers and activators of transcription protein (STAT), and mitogen-
activated protein kinase/ERK (Ras/MEK/Erk) pathways. Mesenchymal-epithelial transition 
factor and HGF are expressed in numerous tissues and their expression is normally confined 
predominantly to cells of epithelial and mesenchymal origin, respectively.6,7 Mesenchymal-
epithelial transition factor and HGF are deregulated in human cancers and may contribute to 
dysregulation of cell growth, tumor cell dissemination, and tumor invasion during disease 
progression and metastasis. Mesenchymal-epithelial transition factor and HGF are highly 
expressed relative to surrounding tissue in numerous cancers, and this expression correlates 
with poor subject prognosis.8,9,10,11 Mesenchymal-epithelial transition factor and HGF may 
protect tumors against cell death induced by deoxyribonucleic acid (DNA)-damaging agents 
and, as such, may contribute to chemoresistance and radioresistance of tumors. Therefore, 
inhibitors of c-MET may be useful as therapeutic agents in the treatment of proliferative 
disorders. 
Tivantinib selectively inhibits the inactive or unphosphorylated form of human c-MET and 
shows in vitro biochemical activity against recombinant c-MET with an inhibition constant 
(Ki) of approximately 355 nM. The potency of tivantinib inhibition of c-MET activity is 
independent of adenosine triphosphate (ATP) concentration, which suggests that tivantinib’s 
inhibition is of noncompetitive nature. Tivantinib was profiled against 230 protein kinases, 
and while tivantinib inhibits c-MET kinase activity, it is not a promiscuous kinase inhibitor. 
In nonclinical studies, tivantinib showed broad-spectrum in vitro anti-cancer activity against 
human tumor cell lines, including breast, colon, lung, pancreas, and gastric cancer cell lines. 
The potency of tivantinib in cancer cells expressing detectable c-MET in anti-proliferative 
assays yield IC50 values from 0.1 mM to 0.6 mM. The ability of tivantinib to inhibit c-MET 
phosphorylation correlated with its ability to inhibit growth in c-MET expressing cancer 
cells, thereby indicating its anti-cancer activity. In single-agent in vivo studies, tivantinib was 


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shown to be efficacious against multiple human cancer xenograft models and was well 
tolerated without drug-related clinical signs or deaths. 
The tivantinib development program is predicated on the hypothesis that tivantinib-mediated 
inhibition of the c-MET pathway, either alone or in combination with other anti-cancer 
compounds, will be beneficial in treating malignancies.  
Detailed information of the nonclinical and clinical studies is provided in the tivantinib 
Investigator’s Brochure (IB).12  
1.1 
Overview of Clinical Experience 
As of 23 Aug 2013, 30 Phase 1 and Phase 2 studies (completed and ongoing) have been 
conducted; refer to the IB for additional information on these studies.12–27 One Phase 3 study 
in subjects with non-small cell lung cancer (NSCLC) is ongoing (ARQ 197-006) and one is 
completed (ARQ 197-A-U302). A Phase 3 study in subjects with hepatocellular carcinoma 
(HCC) is ongoing (ARQ 197-A-U303). Completed and ongoing studies have included 
subjects with colorectal cancer, gastric cancer, HCC, microphthalmia transcription factor 
associated tumors, non-central nervous system germ cell tumors, NSCLC, and pancreatic 
adenocarcinoma. Approximately 127 healthy subjects have received tivantinib in completed 
Phase 1 studies.  Another 2691 subjects with cancer have been randomized in ongoing or 
completed Phase 1, 2, and 3 studies of tivantinib. Phase 1 and Phase 2 studies demonstrated 
early clinical activity of tivantinib as monotherapy and in combination with other anticancer 
agents (including erlotinib, sorafenib, gemcitabine, irinotecan, and cetuximab).  
In all studies, subjects have been treated with assigned therapy until unacceptable toxicity, 
documented progression of disease, or another criterion for discontinuation has been met.  
Clinical pharmacokinetic (PK) studies of tivantinib have been conducted in 14 Phase 1 
studies that include 127 healthy subjects and 426 subjects with cancer. In general, AUC and 
Cmax increased with an increasing dose of tivantinib, although this increase was not dose 
proportional.  
Following human oral administration with a meal, tivantinib is rapidly and almost completely 
absorbed. The drug is extensively metabolized by CYP3A4 and CYP2C19 isozymes with no 
parent compound being detected in the urine and only traces of parent compound being 
detected in the feces. Tivantinib exposure is affected by the following factors: CYP2C19 
genotype, history of hepatocellular carcinoma, coadministration of a CYP3A4 inhibitor, 
dosage form (i.e., crystalline vs. amorphous), formulation (capsule vs. tablet), and fed status 
during tivantinib administration. 
1.1.1 
Safety in Clinical Studies 
Tivantinib demonstrated a manageable safety profile with adverse drug reactions of 
myelosuppression (including anemia, neutropenia, febrile neutropenia, thrombocytopenia, 
leukopenia, pancytopenia, and neutropenic sepsis) and bradycardia. The majority of drug-
related adverse events (AEs) have been mild to moderate with manageable toxicities.  


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Myelosuppression 
Myelosuppression (including anemia, neutropenia, febrile neutropenia, thrombocytopenia, 
leukopenia, pancytopenia, and neutropenic sepsis) has been reported in single agent and 
combination therapy clinical studies of tivantinib.  There have been fatal outcomes for some 
neutropenic events. Complete blood count should be performed as advised in the protocols.  
Caution is advised when any CYP2C19 inhibitors and/or strong CYP3A4 inhibitors are used 
as concomitant therapy, and in subjects with known CYP2C19 poor metabolizer status. Dose 
modifications were made in the HCC studies because of higher incidences of neutropenia and 
febrile neutropenia, which were associated with higher drug levels in these subjects.  
Subjects who experience severe myelosuppression including neutropenia should be 
monitored more closely throughout the study, and dose modifications or interruptions should 
be made as specified in the original protocols. For subjects with severe neutropenia, febrile 
neutropenia, or neutropenic sepsis, supportive care, including use of haematopoietic growth 
factors and antibiotics should be considered. 
Bradycardia 
Bradycardia has been reported in single agent and combination therapy clinical studies of 
tivantinib. In general, bradycardia was most commonly reported as a nonserious adverse 
event. Most of these events were mild to moderate in severity (Grade 1–2.) Most subjects 
were asymptomatic and recovered without additional therapy, though the bradycardic effect 
may be prolonged. However, cases of bradycardia requiring hospitalization have been 
reported, and some subjects received placement of permanent pacemakers. 
Subjects who appear to be at a greater risk for severe bradycardia are those with pre-existing 
bradycardia or sick sinus syndrome or those patients receiving beta-blocker therapy. In these 
patients, tivantinib should be used with caution. 
Electrocardiogram (ECG) monitoring is recommended prior to initiation of tivantinib therapy 
and is to be repeated at any visit when a subject has a heart rate ≤50 beats per minute (bpm), 
or as clinically indicated. In general, heart rate and ECG should be monitored as specified in 
the original protocol, and dose reduction should be considered for subjects with persistent 
bradycardia and symptomatic hypotension.     
Interstitial Lung Disease 
There have been reports of interstitial lung disease (ILD) or similar events in subjects 
enrolled in tivantinib studies. The reported events included ILD, pneumonitis, acute 
respiratory distress syndrome, acute lung injury, and diffuse alveolar damage.  
In the majority of the reports, tivantinib was given in combination with agents with known 
association with ILD, including erlotinib and gemcitabine. An association of tivantinib and 
ILD has not been established. However, it is recommended to investigate the cause for a 
marked increase in respiratory symptoms in subjects participating in tivantinib studies, 
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MONOTHERAPY STUDIES 
ARQ 197-101 
ARQ 197-101 was an open-label study of tivantinib in subjects with metastatic solid tumors, 
including renal cell carcinoma (RCC) and other c-MET-expressing tumors, that were 
refractory to available systemic therapies or for whom no standard effective systemic therapy 
existed. A total of 79 subjects were enrolled and treated in this study.  The most common 
reasons for discontinuing treatment were disease progression (59.5%), symptomatic 
deterioration without evidence of progression (19.0%), and subject request (10.1%). The 
most common (≥ 10%) AEs were fatigue (40.5%), nausea and vomiting (27.8% each), 
anemia/hemoglobin decreased (24.0%), and diarrhea (21.5%). One subject had an AE 
(neutropenia) that led to a dose reduction, which was considered drug-related. A total of 
28 of 79 (35.4%) subjects reported serious adverse events (SAEs).  The most common SAEs 
were disease progression and dehydration, each experienced by 5 (6.3%) subjects. There 
were eight deaths within 30 days of the last dose of study drugs; five of the deaths resulted 
from disease progression.  The other deaths, one each, were due to the following: cardio-
pulmonary arrest, pancytopenia, and respiratory failure. 
ARQ 197-103 
ARQ 197-103 was an open-label study of tivantinib in subjects with advanced solid tumors 
who were refractory to available therapy or for whom no standard effective systemic therapy 
existed, including subjects with advanced prostate cancer. A total of 51 subjects were 
enrolled and treated in this study.  The most common reasons for discontinuing treatment 
were progressive disease (74.5%), AE (13.7%), and symptomatic deterioration without 
evidence of progression (5.9%). The most common AEs were fatigue (49.0%), nausea 
(29.4%), anemia (27.5%), vomiting (25.5%), anorexia and constipation (23.5% each), and 
back pain and weight decreased (21.6% each). Seven (13.7%) subjects experienced AEs that 
led to treatment discontinuation. Two subjects discontinued treatment due to 
hyperbilirubinaemia and one subject each discontinued treatment due to chest infection, 
infection, fatigue, palmar-plantar erythrodysesthesia syndrome, febrile neutropenia, and 
nausea. Serious adverse events were reported in 22 (43.1%) subjects.  Serious adverse events 
reported at a ≥ 5% incidence (more than one subject) were febrile neutropenia (5.9%) and 
disease progression (9.8%). There were five deaths during treatment or within 30 days of the 
last dose of study drug.  All deaths were due to disease progression and were judged to be not 
related to study drug. 
ARQ 197-114 
ARQ 197-114 was an open-label study of tivantinib in cirrhotic subjects with HCC who had 
received not more than two prior systemic regimens. A total of 21 subjects were enrolled and 
treated in this study. The most common reasons for discontinuing treatment were progressive 
disease by Response Evaluation Criteria in Solid Tumors (RECIST) (61.9%), clinically 
unacceptable toxicities (19.0%), and clinical disease progression (9.5%). The most common 
AEs were asthenia and neutropenia (57.1% each), anemia (52.4%), anorexia (47.6%), 
leukopenia (38.1%), and fatigue, edema peripheral, and diarrhea (33.3% each). In this study, 
AEs leading to dose reduction occurred in 4 of 21 (19.0%) subjects and all were considered 


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to be drug-related.  One subject had a dose reduction due to neutropenia and anemia. A 
second subject had dose reduction due to bradycardia and dyspnea. A third subject had dose 
reduction due to anemia. The fourth subject had a dose reduction due to asthenia. Serious 
adverse events reported for more than one subject were neutropenia (three subjects), and 
anemia, leukopenia, and disease progression (two subjects each). Five subjects died during 
treatment or within 30 days of the last dose of study drug. The cause of death in one subject 
(septic shock) was considered related to study drug. Other deaths were considered unrelated 
to study drug and were the result of the following causes: disease progression (two subjects), 
peritoneal hemorrhage (one subject), and pneumonia (one subject). 
ARQ 197-A-U157 
ARQ 197-A-U157 was an open-label, randomized, two-treatment, two-period, two-way 
crossover, relative bioavailability study of a capsule and a tablet formulation of tivantinib in 
subjects with advanced solid tumors. A total of 26 subjects were enrolled in the study and 
25 (96.2%) completed the 14-day crossover study phase. One subject withdrew from the 
14-day crossover study phase due to disease progression, and 25 (96.2%) subjects continued 
in the extension phase. Bradycardia was reported for 6 of 26 (23.1%) subjects and 6 of 
25 (24.0%) subjects in the cross-over and extension phases, respectively; the majority of the 
events of bradycardia were considered related to study treatment. Neutropenia was reported 
for 4 of 25 (16.0%) subjects in the extension phase; 2 subjects had neutropenia that was 
considered to be study-drug related. Most of the AEs were Grade 1 or Grade 2. Grade ≥3 
events in the extension phase of the study included anemia, neutropenia, pneumonia, failure 
to thrive, haemoptysis, respiratory failure (Grade 5), lactic acidosis, and bone pain, which 
were experienced by 1 subject (4.0%) each, and Grade ≥3 dyspnoea, experienced by 
2 subjects (8.0%). There were no SAEs reported during the crossover phase of the study. 
During the extension phase of the study, four subjects had SAEs considered unrelated to 
study treatment and three of these subjects died due to the SAEs, which included progressive 
disease (fatal), respiratory failure (fatal), and metastatic NSCLC (fatal). None of the deaths 
were considered related to study treatment. 
ARQ 197-0701 
ARQ 197-0701 was an open-label study of tivantinib in Japanese subjects with advanced or 
recurrent solid tumors who had been classified as extensive metabolizers (EM) or poor 
metabolizers (PM) based on CYP2C19 genotype, including 25 subjects with NSCLC, and 
who were refractory to available therapy or for whom no standard therapy existed. A total of 
47 subjects were enrolled and treated in the study. The most common reason for 
discontinuing treatment was disease progression (43 subjects). Sixteen SAEs were reported 
in 11 subjects.  Two SAEs were reported more than once: neutrophil count decreased 
(2 subjects) and white blood cell count decreased (2 subjects). No subjects died during the 
study or within 30 days of the last dose of study drug. 
ARQ 197-A-U158 
ARQ 197-A-U158 was a Phase 1, open-label, single-sequence, crossover study to determine 
the effect of multiple doses of tivantinib on the single-dose PK of omeprazole/S-
warfarin/caffeine/midazolam and digoxin when co-administered with tivantinib in cancer 


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subjects. A total of 28 subjects were enrolled into the study. All 28 subjects completed Probe 
Reference Treatment and initiated tivantinib.  Twenty-two (78.6%) subjects completed the 
Primary Objective Phase. Of the six (21.4%) subjects who discontinued from the Primary 
Objective Phase, three (10.7%) discontinued due to an AE, two (7.1%) due to other reasons, 
and one (3.6%) due to progressive disease.  The most commonly reported AEs were fatigue 
(7 [25.0%] subjects), constipation (5 [17.9%] subjects), and vomiting (5 [17.9%] subjects). 
Twenty-four SAEs were reported in 13 subjects.  Disease progression was reported in 
4 subjects, anemia was reported in 3 subjects, and neutropenia, nausea, vomiting, and white 
blood cell count decreased were each reported in 2 subjects. No subject died due to an 
adverse event during the Primary Objective Phase of the study or during the Extension Phase. 
Three subjects died after completing the Primary Objective Phase and one subject died 
before completing the Primary Objective Phase, all due to disease progression.   
ARQ 197-A-U159 
ARQ 197-A-U159 was a single-blind, single-sequence study assessing the effect of tivantinib 
on the QTc interval in subjects with cancer. A total of 38 subjects were enrolled in the study; 
1 subject was discontinued from the study prior to dosing with tivantinib.  The remaining 
37 (97.4%) subjects all completed the Primary Objective Phase.  All of the 37 subjects 
entered the Extension Phase.  Of these, 30 received tivantinib in combination with one or two 
other drugs while 7 continued on tivantinib monotherapy. Adverse events were reported in 
37 (97.4%) subjects during the study. During the Primary Objective Phase, the most 
commonly (≥ 5% ) reported AEs occurring after tivantinib dosing were fatigue (6 [16.2%] 
subjects), nausea (3 [8.1%] subjects), vomiting (2 [5.4%] subjects), and headache (2 [5.4%] 
subjects). During the Extension Phase, AEs reported by ≥ 10% of subjects included 
neutropenia (11 [29.7%] subjects); nausea, fatigue (9 [24.3%] subjects each); diarrhea 
(8 [21.6%] subjects); constipation, dyspnea (7 [18.9%] subjects each); anemia, dermatitis 
acneiform (6 [16.2%] subjects each); and decreased appetite, tumor pain, and alopecia 
(5 [13.5%] subjects each).  No subject had an SAE during the Primary Objective Phase, and 
4 (10.8%) subjects experienced SAEs during the Extension Phase. No subject was 
discontinued due to AEs during any phase of the study. No subject died during the study due 
to an AE.  One subject died during the Extension Phase due to disease progression.   
ARQ 197-004 
ARQ 197-004 was an open-label study of tivantinib in gastric cancer subjects following 
gastrectomy, to determine exposure and progression free survival (PFS) rate in gastric 
cancer. A total of 31 subjects were enrolled and treated in this study. The most common 
reason for discontinuing treatment was progressive disease (27 [87.1%] subjects). The most 
common AEs were anorexia (33.3%), nausea (30.0%), alkaline phosphatase increased, 
anemia, and fatigue (each 23.3%), and abdominal pain, aspartate aminotransferase (AST) 
increased, and constipation (each 20.0%). There were no deaths during study treatment or 
within 30 days after the last dose of study drug.  
ARQ 197-204 
ARQ 197-204 was an open-label study of tivantinib in subjects 13 years of age or older with 
histologically or cytologically confirmed MiT tumors (alveolar soft part sarcoma, clear cell 


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sarcoma, or translocation associated RCC). A total of 47 subjects were enrolled and treated in 
the study. The most common reason for discontinuing treatment was disease progression 
(31 [66.0%] subjects discontinued due to progressive disease by RECIST and 7 [14.9%] 
subjects discontinued due to clinical progression). Of the 47 enrolled subjects, 18 received 
tivantinib 120 mg twice daily (BID) (capsule formulation), 21 received tivantinib 360 mg 
BID (capsule formulation), and 8 initiated treatment with tivantinib 120 mg BID and had 
their dose escalated to 360 mg BID. The most common (≥ 10%) AEs were the following: 
fatigue (66.0%), nausea (51.1%), vomiting (38.3%), anemia (25.5%), cough (25.5%), and 
bradycardia/sinus bradycardia, diarrhea, and headache (21.3% for each). Seven subjects 
(14.9%) experienced neutropenia. Six subjects (12.8%) experienced leukopenia. One 
additional event of febrile neutropenia was reported as an SAE. In this study, 2 of 47 (4.3%) 
subjects discontinued treatment due to an AE. One subject in the 360 mg BID treatment 
group experienced thrombocytopenia, and one subject in the 120 mg BID treatment group 
experienced diarrhea, fatigue, headache, and cough. In this study, AEs leading to dose 
reduction (neutropenia, leukopenia, and febrile neutropenia) occurred in 3 of 47 (6.4%) 
subjects. Disease progression was reported in two subjects during the treatment phase of the 
study. Three subjects had SAEs (febrile neutropenia, thrombocytopenia, and deep vein 
thrombosis) that were considered possibly related to study treatment; all three of these events 
resolved (the deep vein thrombosis resolved with sequelae). There were two deaths during 
the study or within 30 days of the last dose of study drug. Both deaths resulted from disease 
progression and were not attributed to study drug. 
ARQ 197-205 
ARQ 197-205 was an open-label study comparing tivantinib to gemcitabine in treatment-
naïve subjects with unresectable locally advanced or metastatic pancreatic adenocarcinoma. 
A total of 43 subjects were enrolled and randomized in this study and 40 subjects received 
study drug. All subjects in the tivantinib group received 120 mg BID (capsule formulation) in 
the fasted state. The most common reason for discontinuation was progressive disease 
(12 [63.2%] and 13 [61.9%] subjects in the tivantinib and gemcitabine groups, respectively). 
Three subjects (15.8%) and 2 subjects (9.5%) in the tivantinib and gemcitabine groups, 
respectively, discontinued treatment due to AEs. The most common (≥ 10%) AEs were 
fatigue (42.1%), edema peripheral, anorexia, and ascites (26.3% for each), and nausea, 
abdominal pain, and blood alkaline phosphatase increased (21.1% for each). Five subjects in 
the gemcitabine group (23.8%) experienced neutropenia and two subjects in the gemcitabine 
group (9.5%) experienced leukopenia.  There were no events of neutropenia or leukopenia in 
the tivantinib group. There were no events of bradycardia reported in this study. There were 
13 subjects (32.5%), 5 (26.3%) in the tivantinib treatment arm and 8 (38.1%) in the 
gemcitabine treatment arm, who discontinued treatment due to an AE. Adverse events 
leading to treatment discontinuation in the tivantinib arm included ascites (2 subjects), 
vomiting (1 subject), malignant neoplasm progression (1 subject), and cholangitis (1 subject). 
Adverse events leading to treatment discontinuation in the gemcitabine arm included 
abdominal pain upper (1 subject), fatigue (3 subjects), malignant neoplasm progression 
(2 subjects), pneumonia (1 subject), and hip fracture (1 subject). Malignant neoplasm 
progression was the most common SAE, occurring in 13 (32.5%) subjects; anemia and 
fatigue were the second most common SAEs, occurring in 3 (7.5%) subjects each. Thirteen 
(32.5%) subjects died during study treatment or within 30 days of the last dose of study drug, 


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including 9 subjects who received tivantinib and 4 subjects who received gemcitabine. None 
of the AEs leading to death was considered related to treatment. Malignant neoplasm was the 
reason for death for all 9 subjects in the tivantinib treatment group.  
ARQ 197-215 
ARQ 197-215 was a randomized, placebo-controlled study of tivantinib in subjects with 
HCC who had radiographic disease progression after systemic first-line therapy or were 
unable to tolerate the therapy. Subjects randomized to placebo were given the opportunity to 
receive tivantinib under open-label crossover after they had documented radiographic disease 
progression during the double-blind portion.   
Based on healthy volunteer studies and on previous clinical trials in subjects with cancer, a 
dosing regimen of crystalline tivantinib at 360 mg BID (capsule formulation) was 
recommended for all clinical trials.  Following notification of a Grade 5 pancytopenia event, 
a detailed review of all cases of Grade ≥ 3 neutropenia was conducted. A review of the data 
identified 10 subjects who developed Grade ≥ 3 neutropenia.  Eight severe neutropenia 
events occurred within the first month of treatment with study drug; one case occurred in the 
first week of Cycle 2, and one transient Grade 3 neutropenia occurred in Cycle 3. Three 
subjects who developed Grade 4 (febrile) neutropenia in Cycle 1 died within 30 days from 
the onset of the event, though the study drug was not held as recommended by the revised 
protocol. The review showed a higher rate of Grade ≥ 3 neutropenia, occurring in 
approximately 20% of HCC subjects, compared to approximately 5% in the total population 
of subjects who received tivantinib. Based on this observation, coupled with the higher 
exposure found in the HCC subject population, the decision was made to reduce the dose of 
tivantinib to 240 mg BID (capsule formulation) for all subjects in this study.  
A total of 107 subjects were enrolled and treated in this study. The most common reasons for 
discontinuing treatment during the double-blind period were disease progression (68.2%) and 
death (13.1%).  Twenty-three of the 36 subjects who had been randomized to the placebo 
group entered the crossover period and were treated with tivantinib. The most common 
(≥ 10%) AEs during the double-blind period of the study were asthenia (24.3%), fatigue 
(23.4%), decreased appetite (22.4%), diarrhea (19.6%), edema peripheral (19.6%), 
neutropenia (18.7%), ascites (16.8%), anemia (15.9%), abdominal pain (15.0%), cough 
(13.1%), pyrexia (12.1%), and nausea (11.2%). Severe AEs that occurred in at least a 2-fold 
greater frequency in tivantinib-treated subjects compared to placebo-treated subjects included 
neutropenia (14.1% versus 0) and anemia (12.7% versus 0). The frequency of these severe 
AEs was lower in the 240 mg BID group compared to the 360 mg BID group (neutropenia 
[6.1% versus 21.1%], anemia [9.1% versus 15.8%]). Severe AEs of myelosuppression were 
reported only in the tivantinib treatment group. Twenty-one of 107 (19.6%) subjects had AEs 
that led to treatment discontinuation during the double-blind period, including 6 of 
33 (18.2%) subjects in the tivantinib 240 mg BID group, 7 of 38 (18.4%) subjects in the 
tivantinib 360 mg BID group, and 8 of 36 (22.2%) subjects in the placebo group.  The most 
common AE leading to discontinuation from study treatment was disease progression 
(6.5%).Three of 23 (13.0%) subjects had AEs that led to treatment discontinuation during the 
crossover period, including asthenia (1 subject) and disease progression (2 subjects).  SAEs 
were reported for 38 of 107 (35.5%) subjects, including 24 of 71 (33.8%) subjects treated 
with tivantinib and 14 of 36 (38.9%) subjects treated with placebo. The most common 


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(≥ 5%) SAE reported in this study was disease progression (7.5%).  In this study, 23 (21.5%) 
subjects died on treatment or within 30 days of the last dose of study drug during the double-
blind period (13 [18.3%] tivantinib-treated subjects and 10 [27.8%] placebo-treated subjects). 
The 13 deaths that occurred during the double-blind period for tivantinib-treated subjects 
were attributed to the following causes: disease progression (4 subjects), neutropenic sepsis 
(3 subjects, including one subject who died both of neutropenic sepsis and multiorgan 
failure), hepatic failure (3 subjects), cachexia (1 subject), hemorrhage (1 subject), and 
metabolic acidosis (1 subject). The 10 deaths that occurred during the double-blind period for 
placebo-treated subjects were attributed to the following causes: disease progression 
(4 subjects), cachexia (2 subjects), portal hypertension (1 subject), acute coronary syndrome 
and pulmonary edema (1 subject), upper gastrointestinal hemorrhage (1 subject), and suicide 
(1 subject). Three of 23 (13.0%) subjects had AEs resulting in death during the crossover 
period, including disease progression (2 subjects) and hepatic failure (1 subject).   
ARQ 197-A-U251 
ARQ 197-A-U251 was an open-label study of tivantinib in subjects with relapsed or 
refractory non-central nervous system (CNS) germ cell tumors. Twenty-seven subjects were 
enrolled and treated in this study. The primary reason for discontinuation was disease 
progression in 24 (88.9%) subjects. The most common (≥ 10%) AEs were fatigue (37.0%), 
nausea (25.9%), cough and dyspnea (22.2% each), vomiting, edema peripheral, and 
decreased appetite (14.8% each), and constipation, back pain, and neuropathy peripheral 
(11.1% each). AEs of Grade 3 or higher occurred in 12 subjects (44.4%). These included 
anemia, vision blurred, peritoneal hemorrhage, fatigue, hypersensitivity, cellulitis, 
pneumonia, neutrophil count decreased, pain in extremity, aphasia, cerebral hemorrhage, 
headache, hemiplegia, paraparesis, sciatica, spinal cord compression, syncope, insomnia, 
cough, dyspnea, and superior vena caval occlusion, which were reported in 1 subject (3.7%) 
each and back pain, which was reported in 2 subjects (7.4%).  The events of pneumonia and 
syncope were considered drug-related; all other events of Grade 3 or higher were considered 
not related to treatment. Three subjects (11.1%) discontinued study treatment due to AEs. 
Three subjects (3.7% each) discontinued study treatment due to Grade 2 ascites, Grade 4 
cerebral hemorrhage, or Grade 3 sciatica.  Of these AEs, Grade 4 cerebral hemorrhage and 
Grade 3 sciatica were SAEs.  The primary reason of study treatment discontinuation was 
progressive disease for all 3 subjects. There were no deaths during treatment or within 
30 days of the last dose.   
ARQ 197-A-U303 
ARQ 197-A-U303 is an ongoing Phase 3 randomized, double-blind study of tivantinib in 
subjects with MET diagnostic-high inoperable HCC treated with one prior systemic therapy. 
In August 2013, following a higher than expected incidence of neutropenia-related adverse 
events, the study Data Monitoring Committee (DMC) evaluated all available unblinded data 
including preliminary pharmacokinetics. The DMC advised that the tivantinib starting dose 
should be reduced to 120 mg BID (tablet formulation). The protocol was amended 
accordingly and enrollment continues. This study remains blinded. 


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COMBINATION THERAPY STUDIES 
ARQ 197-111 
ARQ 197-111 was an open-label study of tivantinib in combination with erlotinib, in subjects 
with locally advanced or metastatic solid tumors that had progressed after at least one prior 
treatment regimen. A total of 32 subjects were enrolled and treated in this study. Progressive 
disease (23 [71.9%] subjects) was the most common reason for treatment discontinuation. 
The most common (≥ 10%) AEs were fatigue (37.5%), nausea (31.3%), diarrhea (28.1%), 
bradycardia/sinus bradycardia (28.1%), abdominal pain (28.1%), and anemia (21.9%). There 
were 14 events of myelosuppression (7 anemia, 3 neutropenia, 2 thrombocytopenia, 
1 lymphopenia, and 1 leukopenia) reported in 9 subjects. Among them, 10 events (5 anemia, 
3 neutropenia, 1 thrombocytopenia, and 1 leukopenia) occurred in 6 subjects and were 
considered drug-related. Thirteen of the 15 events (86.7%) occurred when subjects were 
receiving tivantinib at a dose of 360 mg BID (capsule formulation). In this study, a total of 
14 cardiac events (9 sinus bradycardia, 2 bradycardia, 1 cardio-respiratory arrest, 
1 palpitations, and 1 sick sinus syndrome) were reported in 10 subjects. The majority of 
bradycardia events were asymptomatic and resolved. Five of 9 subjects with sinus 
bradycardia, bradycardia, or sick sinus syndrome had a history of bradycardia and/or an 
abnormal ECG finding of sinus arrhythmia at baseline. Three severe cardiac-related events 
occurred in 3 subjects including one Grade 3 sinus bradycardia, one Grade 3 sick sinus 
syndrome, and one Grade 5 cardiac arrest. AEs leading to treatment discontinuation occurred 
in 7 of 32 (21.9%) subjects. Four of the 7 subjects were discontinued from study medication 
due to 5 possible or probable drug-related AEs (neutropenia, hypoglycemia, fatigue, nausea, 
and vomiting). Two of the 8 (25%) AEs that resulted in study drug discontinuation were 
SAEs: one of life-threatening severity (neutropenia Grade 4) and the other that resulted in 
death (disease progression Grade 5). Other AEs leading to treatment discontinuation were 
comprised of hypoglycemia, hyperbilirubinemia, and pleural effusion, each occurring in 
1 subject. Two of 32 (6.3%) subjects had AEs (both fatigue) that led to treatment reductions. 
One of the events of fatigue was considered to be related to study drug. Serious adverse 
events were reported for 13 subjects.  There were no predominant SAEs, although disease 
progression was reported most often (3 of 32 subjects [9.4%]).  There were three SAEs 
involving cardiac events, sinus bradycardia, cardio-respiratory arrest, and sick sinus 
syndrome and 2 reports of syncope possibly related to bradycardia. Five of 32 subjects 
(15.6%) had 6 SAEs that were considered related to combination treatment, including sinus 
bradycardia (Grade 3) in one subject, sick sinus syndrome (Grade 3) in one subject, 
neutropenia (Grade 4) in one subject, neutropenia and leukopenia (both Grade 4) in one 
subject, and syncope (Grade 3) in one subject. Six (18.8%) deaths occurred during the study 
or within 30 days of study treatment.  All deaths were considered by Investigators to be not 
related to combination treatment and were the result of the following: cardiac arrest (1), 
disease progression (3), hepatic failure (1), and dyspnea (1). 
ARQ 197-116 
Study ARQ 197-116 was a study of tivantinib in combination with sorafenib in subjects with 
solid tumors, including RCC, HCC, NSCLC, and melanoma. A total of 87 subjects were 
enrolled and treated in this study. The most common reason for discontinuing treatment was 


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progressive disease (71.3% for radiographic progression and 6.9% for clinical progression). 
The most common (≥ 20% of subjects) AEs were diarrhea (46%), fatigue (43.7%), rash 
(43.7%), anorexia (39.1%), weight decreased (37.9%), hypophosphatemia (28.7%), alopecia 
(27.6%), hyperglycemia (26.4%), nausea (25.3%), hypertension (24.1%), vomiting (21.8%), 
hypernatremia (21.8%), palmar-plantar erythrodysesthesia syndrome (21.8%), and 
lymphopenia (20.7%). The distribution of AEs was similar among all cancer types. The drug-
related AEs reported most frequently (≥ 20% of subjects) were rash (40.2%), diarrhea 
(37.9%), anorexia (33.3%), fatigue (31.0%), alopecia (25.3%), palmar-plantar 
erythrodysesthesia syndrome (21.8%), and weight decreased (20.7%). Severe AEs 
(≥ Grade 3) were experienced by 61 (70.1%) of the 87 subjects.  The severe AEs occurring in 
≥ 5% of subjects were hypertension (11.5%), palmar-plantar erythrodysesthesia syndrome 
(8%), fatigue (6.9%), hyponatremia (6.9%), hypophosphatemia (6.9%), disease progression 
(5.7%), hyperbilirubinemia (5.7%), pneumonia (5.7%), hyperuricemia (5.7%), and rash 
(5.7%). Serious adverse events including deaths were reported by 33 (37.9%) of the 
87 subjects in the study. Infections and infestations, gastrointestinal disorders, and general 
disorders and administration site conditions were the most frequent system organ classes 
(SOC) with 9.2%, 8.0%, and 6.9% of subjects, respectively. There were 9 subjects with AEs 
that led to death: 3 with HCC, 2 with lung cancer, and 1 each with RCC, melanoma, breast 
cancer, or other cancer (adenocarcinoma of the esophagus). In four of these subjects, the AE 
leading to death was progressive disease.   
ARQ 197-117 
ARQ 197-117 was an open-label study of tivantinib in combination with gemcitabine in 
subjects with locally advanced, inoperable, or metastatic primary solid tumors, including 
breast cancer, cholangiocarcinoma, ovarian cancer, and pancreatic cancer. A total of 
74 subjects were enrolled and treated in this study. The most common reason for 
discontinuing tivantinib and gemcitabine treatments was radiographically confirmed disease 
progression (42 [56.8%] and 40 [54.1%], respectively). The most common AEs were 
thrombocytopenia (56 [75.7%] subjects), anemia (54 [73.0%] subjects), neutropenia 
(51 [68.9%] subjects), fatigue (43 [58.1%] subjects), and nausea (39 [52.7%] subjects). 
Severe AEs (≥ Grade 3) were thrombocytopenia (22 [29.7%] subjects), anemia (28 [37.8%] 
subjects), neutropenia (32 [43.2%] subjects), leukopenia (5 [6.8%] subjects), febrile 
neutropenia (3 [4.1%] subjects), and pancytopenia (1 [1.4%] subjects). There were 19 cardiac 
events (4 tachycardia, 3 palpitations, 2 atrial fibrillation, 2 congestive cardiac failure, 1 acute 
myocardial infarction, 1 atrial flutter, 1 bradycardia, 1 cardiomyopathy, 1 cardiopulmonary 
failure, 1 cyanosis, 1 left ventricular failure, and 1 mitral valve incompetence) reported in 
12 subjects. Overall, 1 of 74 (1.4%) subjects experienced bradycardia, 2 (2.7%) experienced 
atrial fibrillation, 3 (4.1%) experienced palpitations, and 3 (4.1%) experienced tachycardia. 
At the time of the last recorded evaluation, 11 of the 19 (57.9%) cardiac-related events were 
resolved, 7 (36.8%) were ongoing, and 1 (5.3%) subject died. Seventeen of 74 (23.0%) 
subjects had a total of 21 AEs that led to treatment discontinuation. Seven of the 17 subjects 
discontinued due to myelosuppressive events, including neutropenia (4 subjects), 
thrombocytopenia (2 subjects), anemia (2 subjects), and febrile neutropenia (1 subject). Other 
AEs leading to study drug discontinuation were single events each of breast cancer, wound 
complication, bacteremia, gastrointestinal hemorrhage, sepsis, fatigue, acute respiratory 
failure, dyspnea, respiratory failure, disease progression, small bowel obstruction, and 


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pneumonitis. Four of 74 (5.4%) subjects each had one tivantinib dose reduction during the 
study period, from 360 mg BID to 240 mg BID (capsule formulation). Adverse events 
leading to dose reductions in these 4 subjects included neutropenia (3 subjects) and fatigue 
(1 subject).  All four subjects were among the 32 subjects who experienced AEs leading to a 
reduction in gemcitabine. All dose reductions for gemcitabine were due to myelosuppressive 
AEs. Serious adverse events were reported for 39 of 74 (52.7%) subjects.  The most 
commonly reported SAEs were anemia (6 [8.1%] subjects) and disease progression 
(9 [12.2%] subjects. Overall, 15 (20.3%) deaths occurred during study treatment or within 
30 days of the last dose, which resulted from the following: disease progression (8 subjects), 
acute respiratory failure (1 subject), cardiopulmonary failure (1 subject), hepatic failure 
(1 subject), neutropenia (1 subject), sepsis (1 subject), upper gastrointestinal hemorrhage 
(1 subject), and death (1 subject).    
ARQ 197-209 
ARQ 197-209 was a randomized, double-blind study of erlotinib plus tivantinib treatment 
compared with erlotinib plus placebo, in subjects with inoperable locally advanced or 
metastatic (Stage IIIB/IV) NSCLC who had received at least one prior chemotherapy 
regimen (other than erlotinib or other EGFR-inhibiting agents). A total of 167 subjects 
enrolled in this study; 84 subjects received erlotinib plus tivantinib and 83 subjects received 
erlotinib plus placebo during the double-blind period. Thirty-five of 83 (42.2%) subjects who 
had initiated treatment with erlotinib plus placebo crossed over to receive erlotinib plus 
tivantinib. The most common AEs reported in the tivantinib combination arm group were 
rash (65.5%), diarrhea (47.6%), fatigue (33.3%), anorexia (28.6%), nausea and vomiting 
(26.2% each), and pruritus, dry skin, and dyspnea (22.6%, each). Neutropenia was 
experienced by 8 subjects in this study who were treated with erlotinib plus tivantinib. No 
neutropenia events were experienced by subjects during erlotinib plus placebo treatment. 
Sinus bradycardia was reported for 3 of 84 (3.6%) subjects randomized to the tivantinib 
combination arm (2 drug-related), and 2 of 35 (5.7%) additional subjects treated with 
erlotinib plus tivantinib during the crossover period (1 drug-related), for a total of 5 of 
119 (4.2%) subjects treated with erlotinib plus tivantinib in the study (3 drug-related). 
Bradycardia was reported for 1 of 84 (1.2%) subjects in the randomized tivantinib 
combination arm (considered drug-related) and 1 of 35 (2.9%) subjects in the crossover 
population (not drug-related), for a total of 2 of 119 (1.7%) subjects treated with erlotinib 
plus tivantinib. Adverse events leading to treatment discontinuation were reported for 18 of 
84 (21.4%) subjects randomized to the tivantinib combination arm and 17 of 83 (20.5%) 
subjects randomized to the placebo combination arm, including 7 of 35 (20.0%) subjects 
randomized to the placebo combination arm who crossed over to receive the tivantinib 
combination treatment. Three subjects had dose reductions, 1 subject in the erlotinib plus 
tivantinib group (due to Grade 3 diarrhea, Grade 3 vomiting, and Grade 2 nausea) and 2 in 
the erlotinib plus placebo group (due to Grade 2 rash pustular in one subject and due to 
Grade 4 diarrhea, Grade 3 dehydration, Grade 3 renal failure acute, and Grade 3 palmar-
plantar erythrodysesthesia syndrome in another subject). In this study, 74 subjects (44.3%) 
experienced SAEs. The most common SAE in both treatment arms was disease progression, 
reported for 6 (7.1%) and 7 (8.4 %) subjects in the tivantinib and placebo combination arms, 
respectively. Adverse events with an outcome of death were reported in 38 subjects (22.8%) 
during study treatment or within 30 days of the last dose of the study drug; 17 (20.2%) deaths 


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occurred in subjects randomized to the tivantinib combination arm and 21 (25.3%) occurred 
in subjects randomized to the placebo combination arm, including 7 subjects who died after 
crossing over to the tivantinib combination arm. The most frequent cause of death in the 
tivantinib combination and crossover subjects was disease progression (9 subjects). Among 
subjects in the tivantinib combination arm, 2 subjects died due to AEs considered at least 
possibly related to both tivantinib and erlotinib (leukopenia and pneumonia).    
ARQ 197-A-U252 
ARQ 197-A-U252 was a Phase 1/2 study of tivantinib in combination with irinotecan and 
cetuximab in subjects with colorectal cancer with wild-type KRAS. A total of 131 subjects 
enrolled in this study and 130 were treated. The primary reason for discontinuing treatment 
was progressive disease (79 [60.3%]). All 130 treated subjects (100%) in both Phase 1 and 
Phase 2 experienced at least one AE. In Phase 1, the most common AEs were fatigue 
(77.8%), nausea and rash (66.7% each), and diarrhea and alopecia (55.6% each). In Phase 2, 
the most common AEs that occurred in either treatment group were rash, diarrhea, and 
nausea. The most common AEs reported in the tivantinib combination arm were rash 
(59.2%), diarrhea (53.5%), nausea (46.5%), fatigue (43.7%), vomiting (33.8%), neutropenia 
(31.0%), and infections and infestations (29.6%). The proportions of placebo-treated subjects 
versus the proportions of tivantinib-treated subjects with any grade of myelosuppression 
events were as follows: febrile neutropenia (1.7 % vs. 1.6%), leukopenia (5.1% vs. 8.1%), 
and thrombocytopenia (1.7% vs. 8.1%). Among cardiac disorder AEs of special interest, 
bradycardia and sinus bradycardia were reported by 0% of placebo-treated subjects vs. 
3.2% (bradycardia) and 4.8% (sinus bradycardia) of tivantinib-treated subjects and atrial 
fibrillation was reported by 0% of placebo-treated subjects vs. 3.2% of tivantinib-treated 
subjects. Acute renal failure was reported by 0% of placebo-treated subjects and 3.6% of 
tivantinib-treated subjects during Phase 2. In Phase 1, two subjects discontinued study drug 
because of an AE. In Phase 2, a higher proportion of tivantinib-treated subjects than placebo-
treated subjects discontinued study drug due to an AE (19.4% vs. 11.9%). The most common 
AEs leading to discontinuation of study treatment were neutropenia and rash. One subject 
each had serious Grade 4 unrelated AEs of renal failure (acute), respiratory failure, or 
urosepsis that led to discontinuation from study medication. No deaths were reported for any 
of the 9 subjects in the Phase 1 portion of the study. In Phase 2, two subjects in each 
treatment group died within 30 days of the end of study drug administration due to a SAE. 
An additional 3 subjects in each treatment group died due to disease progression after that 
time period. No AEs leading to death were considered related to study drug.   
ARQ 197-A-U302 
ARQ 197-A-U302 was a randomized, double-blinded, placebo-controlled study of tivantinib 
in combination with erlotinib in subjects with locally advanced or metastatic, non-squamous 
NSCLC. The study enrolled 1048 subjects, and 1037 subjects were included in the safety 
analysis. Nine hundred seventy-eight (93.3%) subjects discontinued treatment. The most 
common reason for discontinuation was progressive disease; 645 (61.5%) subjects 
discontinued for radiographically confirmed progressive disease and another 90 (8.6%) 
subjects discontinued for clinical disease progression. Adverse events were the reason for 
discontinuation for 113 (10.8%) subjects. The most common AEs within the erlotinib plus 


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tivantinib (ET) and the erlotinib plus placebo (EP) groups were diarrhea (ET: 34.6%, 
EP: 41.0%), rash (ET: 33.1%, EP: 37.3%), decreased appetite (ET: 29.0%, EP: 28.8%), 
dyspnea (ET: 26.2%, EP: 22.6%), and fatigue (ET: 26.2%, EP: 21.9%). The AEs indicative 
of myelosuppression were more frequent in the ET group compared with the EP group: 
neutropenia by any preferred term (ET: 13.8%, EP: 2.3%), febrile neutropenia (ET: 3.3%, 
EP: 0.4%), leukopenia (ET: 5.8%, EP: 1.0%), and anemia by any preferred term (ET: 16.7%, 
EP: 10.3%). The occurrence of these AEs at a severity of ≥ Grade 3 was also more common 
in the ET group. Bradycardia was reported in 2.7% of subjects in the ET group and in no 
subjects in the EP group; however, only 2 of the 14 cases in the ET group were of Grade 3 or 
higher severity. Overall, 138 subjects (79 subjects [15.2%] in the tivantinib combination arm, 
59 subjects [11.4%] in the placebo combination arm) were discontinued from treatment 
because of AEs. Overall, there were 410 (39.5%) subjects with SAEs reported during the 
study; the most commonly reported SAEs were respiratory events including dyspnea and 
pulmonary embolism, reported in 5.2% and 3.4% of subjects overall. Overall, 614 subjects 
died during the study or within 30 days of the last dose of study drug, most frequently as the 
result of disease progression as attributed by the Investigator. A total of 142 subjects had 
deaths associated with AEs: ET: 77 subjects, EP: 65 subjects. However, the Investigator 
ultimately determined that many of these AEs were part of the underlying disease and 
attributed the deaths to disease progression. Using this revised Investigator attribution, 
66 subjects died as a result of AEs (other than disease progression): ET: 32 subjects; 
EP: 34 subjects. Of these deaths associated with AEs (other than disease progression), the 
most common AEs were respiratory failure (ET: 5 subjects, EP: 6 subjects), sepsis or septic 
shock (ET: 5 subjects, EP: 1 subject), and pneumonia or bronchopneumonia (ET: 3 subjects, 
EP: 5 subjects). Five deaths in the ET group and 3 deaths in the EP group were considered by 
the Investigator to be related to tivantinib/placebo.   
Detailed data describing the clinical administration of tivantinib and complete safety 
information can be found in the Tivantinib Investigator’s Brochure.12 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objective of this extension protocol is to provide subjects who participated in 
previous tivantinib studies that have reached their designated end-dates with access to 
tivantinib if, in the opinion of the Investigator and the Sponsor, they may benefit from the 
treatment.   
2.2 
Secondary Objectives 
The secondary objective of this study is to collect additional safety, tolerability, and efficacy 
information for tivantinib treatment. 


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3 
SELECTION OF STUDY POPULATION 
Enrollment to this study is open to any subject who has previously been enrolled in any 
tivantinib studies that have reached its designated end-dates and who may, in the opinion of 
the Investigator and the Sponsor, benefit from treatment. This protocol will allow eligible 
subjects to continue to receive treatment at the dose(s) and schedule(s) of their original 
protocols. Subjects who were previously treated with tivantinib only and who, in the opinion 
of the Investigator and with the Sponsor’s approval, may benefit from combination therapy 
will be allowed to receive combination therapy. Subjects who were previously enrolled in 
tivantinib studies but did not receive tivantinib as part of their treatment, and who, in the 
opinion of the Investigator and with Sponsor’s approval, may benefit from the treatment with 
tivantinib as a single agent or in combination therapy, will be allowed to initiate treatment 
with tivantinib. The tivantinib monotherapy or combination therapy dose(s) and schedule(s) 
will be determined for each subject by the Investigator and with the Sponsor’s approval 
based on administration schedules tested in and defined by prior tivantinib clinical trials.  
The combination therapy(ies) considered must have been evaluated in prior tivantinib 
combination studies. The combination therapy dose(s) and schedule(s) will be determined to 
each subject by the Investigator and with the Sponsor’s approval based on the combination 
drug(s) label(s) and prior tivantinib clinical trials.  
3.1 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study: 
1. Signed written informed consent to Study ARQ 197-299 
2. Male or female subjects of the age defined in the original protocol they were enrolled  
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 3 (or ≤ 2 for 
tivantinib-naïve subjects) (see Appendix 2) 
4. Adequate bone marrow, liver, and renal function tests: 
- 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
- 
Hemoglobin ≥ 8.0 g/dL (or ≥ 9.0 g/dL for tivantinib-naïve subjects) 
- 
Platelet count ≥ 75 x 109/L (or ≥ 60 x 109/L for HCC subjects) 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x upper limit of 
normal (ULN) (or ≤ 5 x ULN for subjects with liver metastases)  
- 
Total bilirubin ≤ 2mg/dL 
- 
Serum creatinine ≤ 1.5 x ULN 
5. Enrollment within 14 days of the completion of the End of Treatment Visit of the original 
study 
6. Measurable disease as defined by RECIST. Eligibility assessment must be performed 
within 28 days (4 weeks) of the first dose of study drug (Day 1) 
7. Subjects, who participated in previous tivantinib studies that have reached their 
designated end-dates, who did not meet discontinuation criteria in their original study, 
and who may, in the opinion of the Investigator and the Sponsor, benefit from treatment 
8. Women of childbearing potential must have a negative pregnancy test performed within 
14 days of the start of study drug. “Women of childbearing potential” is defined as 
sexually mature women who have not undergone a hysterectomy and who have not been 
naturally postmenopausal for the last 12 consecutive months prior to the first dose of 


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tivantinib (Day 1). Both men and women enrolled in this study must agree to use 
adequate birth control measures while on study 
 
3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Known or suspected allergy to tivantinib 
2. Substance abuse, medical, psychological, or social conditions that may interfere with the 
subject’s participation in the study or evaluation of the study results 
3. Any condition that is unstable or which could jeopardize the safety of the subject and 
his/her compliance in the study 
- 
For tivantinib-naïve subjects: active coronary disease, clinically significant 
bradycardia, or other uncontrolled cardiac arrhythmia defined as ≥ Grade 3 according 
to NCI CTCAE v. 4.03, or uncontrolled hypertension 
4. A serious, uncontrolled medical disorder/condition that in the opinion of the Investigator 
would impair the ability of the subject to receive protocol therapy 
5. Requirement to receive other concurrent chemotherapy (excluding combination therapy 
defined in original protocol), immunotherapy, radiotherapy, or any other investigational 
drug while on study. Palliative radiotherapy is allowed provided that: 
- 
In the opinion of the Investigator, the subject does not have progressive disease 
- 
The radiation field does not encompass a target lesion 
- 
No more than 10% of the subject’s bone marrow is irradiated 
 
3.3 
Number of Subjects 
The exact number of subjects for this study is dependent on the number of subjects who will 
be eligible to continue treatment with tivantinib once their original protocols have reached 
their designated end-dates. 


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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is an open label extension protocol for subjects who have been treated in previous 
tivantinib studies that have reached their designated end-dates. Subjects enrolled in this 
extension protocol will receive either tivantinib as monotherapy or in combination with other 
drug(s) at the same dose(s), and same schedule(s) in which they were originally enrolled. 
Subjects who were previously treated with tivantinib only and who in the opinion of the 
Investigator and with the Sponsor’s approval may benefit from combination therapy will be 
allowed to receive combination therapy. The combination therapies considered must have 
been evaluated in prior tivantinib combination studies. The combination therapy dose(s) and 
schedule(s) will be determined for each subject by the Investigator and with the Sponsor’s 
approval based on the combination drug(s) label(s) and prior tivantinib clinical trials. 
Subjects who were previously enrolled in tivantinib studies but did not receive tivantinib 
(tivantinib-naïve) as part of their treatment, and who, in the opinion of the Investigator, may 
benefit from treatment with tivantinib as a single agent or in combination therapy, will be 
allowed to receive treatment with tivantinib. The tivantinib monotherapy or combination 
therapy dose(s) and schedule(s) will be determined for each subject by the Investigator and 
with the Sponsor’s approval based on administration schedules tested in and defined by prior 
tivantinib clinical trials. 
This extension study is designed to further evaluate the safety and tolerability of tivantinib 
monotherapy or in combination with other drug(s) when given to subjects who tolerated 
previous treatment well and may benefit from the continuing treatment. Tivantinib will be 
administered twice daily, orally, with meals (regardless of the original protocol 
requirements). 
4.2 
Rationale for Study Design 
This is an extension study that will allow subjects to continue to receive study treatment 
when the original studies into which they were enrolled have reached their designated end-
dates.  
4.3 
Administration Schedule 
Subjects will be treated according to the original treatment protocols into which they were 
enrolled or per administration schedules tested in other tivantinib clinical trials. Subjects will 
be treated until any discontinuation criterion is met. Dose may be delayed or reduced for 
clinically significant toxicities, but dose escalation is not allowed (see Section 7.3 and 
Appendix 4). 
4.4 
Study Duration 
For an individual subject, treatment will continue until unacceptable toxicity, disease 
progression (clinical or radiologic), or another discontinuation criterion is met. 


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5 
STUDY VISITS 
Prior to administration of any study-related procedures including evaluation of the subject’s 
eligibility to continue/receive treatment with tivantinib, a signed written informed consent 
has to be obtained from each potential subject or his/her legal representative. Study visits will 
consist of a brief Pre-study Visit, during which the subject’s eligibility to continue treatment 
will be evaluated; Weekly or Monthly Visits during which the subject’s treatment eligibility 
will be re-assessed and the study drug(s) will be administered; End of Treatment Visit; 30day 
Safety Follow-up Visit. (see Appendix 1: Schedule of Assessment) 
5.1 
Pre-study Visit 
After written informed consent is obtained, the subject’s study eligibility to receive treatment 
will be assessed. The following assessments and procedures should be completed prior to the 
subject’s enrollment into this study: 
• Inclusion/Exclusion criteria 
• Physical examination, including vital signs, weight, and height (see Section 6.2) 
• ECOG PS (see Appendix 2)  
• Hematology (see Section 6.3) 
• Coagulation tests (see Section 6.3) 
• Blood chemistry (see Section 6.3) 
• Liver function tests (see Section 6.3) 
• Electrolytes (see Section 6.3) 
• Serum pregnancy test (if applicable, see Section 6.3) 
• Urinalysis (see Section 6.3) 
• 12-lead ECG (see Section 6.4) 
• Tumor assessment (see Section 6.5) 
• Tumor markers assessment (if applicable) 
• Adverse event (AE) assessment: any sign or symptom continuing from the original 
tivantinib study or beginning after the last visit of the original study, but prior to the first 
dose of study drug (Day 1) of the Extension study must be documented on a Medical 
History eCRF page. Resolved AEs from the original tivantinib study are captured in the 
original study records and will not be re-recorded for this study.  
Note: The data collected during the End-of-Treatment Visit of the original study may be used 
as a pre-study/safety assessment for enrollment into this Extension Study if the visit was 
done within the following time period:  
1. Laboratory tests (hematology, blood chemistry, liver function tests, electrolytes, and 
serum pregnancy test) and ECG within 14 days of the first dose of study drug (Day 1) 
2. Tumor assessment within 28 days (4 weeks) of the first dose of study drug (Day 1) 


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5.2 
Monthly Visits (± 3 days) 
Subjects should be seen every four weeks throughout the treatment period. The following 
assessments and procedures will be performed at each visit: 
• Physical examination, including vital signs and weight (see Section 6.2) 
• ECOG PS (see Appendix 2) 
• Hematology (see s Section 6.3) 
• Coagulation tests (see s Section 6.3) 
• Blood chemistry (see Section 6.3) 
• Liver function tests (see Section 6.3) 
• Electrolytes (see Section 6.3) 
• AE assessment 
• Concomitant medications assessment  
• Tivantinib dispensation as per schedule  
• Combination drug(s) administration/dispensation as per schedule (if applicable) 
• Tumor markers assessment (if applicable)  
• Tumor assessment (every 12 weeks unless current disease specific standard of care 
requires performing imaging more often)  
• 12-lead ECG (ONLY for subjects with a heart rate of <50 bpm) (see Section 6.4) 
Note: Subjects who do not experience Grade 3/4 toxicity and continue to benefit from the 
treatment after 12 cycles of treatment can be evaluated every two or three months upon 
agreement between the Investigator and the Sponsor.  
5.3 
Weekly Visits (if applicable; ± 3 days) 
Tivantinib-naïve subjects or subjects who require weekly administration of combination 
drug(s) should be seen according to the schedule as per the original protocol.  
5.3.1 
Weekly Visits (applied for combination drug(s) administration; ± 3 days) 
At a minimum, the following assessments and procedures will be performed at each visit: 
• Vital signs (see Section 6.2) 
• Hematology (see Section 6.3) 
• AE assessment 
• Concomitant medications assessment  
• Combination drug(s) administration per schedule 
 
5.3.2 
Weekly Visits (applied ONLY for tivantinib-naïve subjects; ± 3 days) 
Subjects who did not receive tivantinib when enrolled in the original tivantinib study and 
who, in the opinion of the Investigator and with the Sponsor’s approval, may benefit from 


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treatment with tivantinib should have weekly visits during the first four weeks of treatment 
with tivantinib. After the first four weeks, these subjects will follow the original protocol 
visit schedule to which they were assigned. 
At a minimum, the following assessments and procedures will be performed at each visit: 
• Physical examination, including vital signs (see Section 6.2) 
• ECOG PS (see Appendix 2) 
• Hematology (see Section 6.3) 
• Coagulation tests (see Section 6.3) 
• Blood chemistry (see Section 6.3) 
• Liver function tests (see Section 6.3) 
• Electrolytes (see Section 6.3) 
• AE assessment 
• Concomitant medications assessment  
• Tivantinib dispensation as per schedule  
• Combination drug(s) administration/dispensation as per schedule (if applicable) 
• 12-lead ECG (ONLY for subjects with a heart rate of <50 bpm) 
 
Tivantinib-naïve subjects who do not experience Grade 3 /4 toxicity during the first four 
weeks of treatment and to whom the weekly combination treatment visit schedule does not 
apply can be evaluated monthly (Cycle 2+) upon agreement between the Investigator and the 
Sponsor . 
5.4 
End of Treatment Visit 
Subjects, who have been discontinued from the study, should have the End of Treatment 
Visit within 7 (+3) days of the discontinuation decision. The following assessments and 
procedures should be done at the End of Treatment Visit: 
• Physical examination, including vital signs and weight (see Section 6.2) 
• ECOG PS (see Appendix 2) 
• Hematology (see Section 6.3) 
• Coagulation tests (see Section 6.3) 
• Blood chemistry (see Section 6.3) 
• Liver function tests (see Section 6.3) 
• Electrolytes (see Section 6.3) 
• Serum pregnancy test (if applicable, see Section 6.3) 
• Urinalysis (see Section 6.3) 
• AE assessment 
• Concomitant medications assessment  
• Tumor markers assessment (if applicable)  


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• Tumor assessment (if not done within 14 days) 
• 12-lead ECG (see Section 6.4)  
 
5.5 
30-day Safety Follow-up Visit 
In this study, the post-treatment safety follow-up period ends 30 days after administration of 
the last dose of tivantinib. All subjects must have a follow-up visit or phone call.   
Subjects with unresolved protocol-therapy related AEs at the time of treatment 
discontinuation will be followed for 30 days after the last dose of tivantinib or until all study 
related toxicities have, in the opinion of the Investigator, resolved to baseline, stabilized, or 
been deemed to be irreversible whichever is later. Treatment-related AEs that occur during 
the 30-day follow-up period will be followed for a minimum of 30 days from the onset or 
until all study-related toxicities have, in the opinion of the Investigator, resolved to baseline, 
stabilized, or been deemed to be irreversible, whichever is later.  
If a subject receives other anticancer therapy within the 30-day follow-up period, the follow-
up and recording for AEs will cease, beginning the first day of the new therapy. 
5.6 
Discontinuation from Study 
Subjects will stop study treatment(s) at any time if they meet any of the following criteria: 
• Documented radiographic progression of disease. (However, if, in the Investigator’s 
opinion, treatment with tivantinib, as a monotherapy or in combination therapy, is 
providing clinical benefit to a subject with radiological progression of disease, the subject 
may continue to receive the treatment after consultation with the ArQule, Inc. [ArQule] 
Medical Monitor or designee.)    
• Noncompliance with any part of the study protocol, as evaluated by the Investigator and 
the ArQule Medical Monitor or designee 
• Clinically unacceptable toxicities 
• Withdrawal of consent to treatment 
• Lost to follow-up 
• Death 
 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
A sample Informed Consent Form (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 Investigational Review Board/Independent 
Ethics Committee (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) 
Good Clinical Practice (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.  
6.2 
Physical Examination 
Complete physical examination of the major body systems, vital signs (height [on screening 
visit only], weight, blood pressure, heart rate, respiratory rate, temperature [oral, axillary or 
tympanic]), and ECOG PS (see Appendix 2). 
6.3 
Clinical Laboratory Tests 
Safety laboratory assessments will be done at a local laboratory and will include hematology, 
blood chemistry, liver function tests, coagulation, electrolytes and urinalyses as described 
below: 
• Hematology
• 
: Complete blood count (CBC) including hemoglobin, hematocrit, white 
blood cell count with 5-part differential, red blood cell and platelet count  
Coagulation:
• 
 (at Baseline and End of Treatment; and if clinically indicated): prothrombin 
time, international normalized ratio (INR) and partial thromboplastin time.  
Blood chemistry
• 
: calcium, phosphorus, magnesium, albumin, glucose, serum creatinine, 
uric acid, total protein and blood urea nitrogen (BUN)  
Liver function tests
• 
: AST, ALT, lactate dehydrogenase (LDH), alkaline phosphatase, 
total and direct bilirubin  
Electrolytes
• 
: sodium, potassium, and chloride  
Serum pregnancy test
• 
 (at Baseline and End of Treatment only) for female subjects of 
childbearing potential  
Routine urinalysis 
 
(at Baseline and End of Treatment only; and if clinically indicated): 
dipstick and microscopy (only if clinically indicated or dipstick is not done) including 
protein, specific gravity, glucose and blood  


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6.4 
Twelve-lead Electrocardiogram  
Twelve-lead electrocardiograms (ECG) should be conducted at the Pre-study and End of 
Treatment visits. Additional ECG(s) may be conducted if clinically indicated. Subjects with 
bradycardia, a heart rate of <50 bpm, should have an ECG done on Day 1 of every cycle. A 
local ECG laboratory will be employed for ECG testing. 
6.5 
Tumor Assessment 
In this study, tumor measurement will follow the RECIST guidelines version 1.0 or 1.1 (in 
accordance with the original protocol into which each subject was originally enrolled) and be 
conducted every 12 weeks unless current disease specific standard of care requires 
performing imaging more often or as clinically indicated until progression of disease, 
withdrawal of consent, death, or loss to follow-up. Tumor assessment will also be performed 
during the End of Treatment Visit if it was not done within 14 days. 
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, 
technique (including slice thickness and field of view), and radiographic interpreter. 
The radiographic 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 lesions are evaluated at each time point of tumor assessment.  
6.6 
Other Evaluations 
All other study tests and evaluations should be conducted according to the original study 
protocol under which subjects were enrolled. 


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7 
TREATMENT 
7.1 
Tivantinib  
Tivantinib capsules or tablets, provided by the Sponsor, are labeled as investigational agent 
according to relevant guidelines. Compositions of tivantinib capsules or tablets are described 
in the study pharmacy manual.  
7.1.1 
Storage and Handling 
At a study site, tivantinib should be stored at controlled room temperature (15-30°C; 
59-86°F). Tivantinib is stable at controlled room temperature (15-30°C; 59-86°F) for up to 
24 months. The storage instruction must appear on the label of the container in which 
capsules or tablets are delivered to the subject. Until dispensed to the subject, the study drug 
will be stored in a secure locked area, accessible to authorized personnel only. 
7.1.2 
Tivantinib Accountability 
The authorized site recipient will acknowledge to ArQule or designee the receipt of the drug, 
indicating the shipment contents and condition.  Damaged supplies will be replaced.  
Drug accountability records will be maintained by the research site and must accurately 
document quantities of study drug received and quantities dispensed to subjects. The records 
will include the lot number, date dispensed, amount dispensed, subject identifier number, 
subject initials, protocol number, dose administered, unused quantity returned, balance 
remaining, and initials of the person dispensing the drug.   
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 clinical trial monitor or designated representative, all unopened drug is to be returned 
to ArQule or designee in the original container.  
7.1.3 
Tivantinib Administration 
All subjects will receive tivantinib capsules or tablets at the dose and schedule depending on 
the original study protocol they were enrolled into. Tivantinib will be administered orally, 
twice daily, once in the morning and once in the evening with meals (regardless of original 
protocol requirements). 
Subjects who were previously enrolled in tivantinib studies but did not receive tivantinib as 
part of their treatment, and who, in the opinion of the Investigator, may benefit from 
treatment with tivantinib as a single agent or in combination therapy, will be allowed to 
initiate treatment with tivantinib The tivantinib monotherapy or combination therapy dose(s) 
and schedule(s) will be determined for each subject by the Investigator and with the 
Sponsor’s approval based on administration schedules tested in and defined by prior 
tivantinib clinical trials. 
If a subject stops receiving tivantinib due to tivantinib-related toxicity, he/she should be 
discontinued from the study. 


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For individual subjects, treatment will continue until unacceptable toxicity, disease 
progression (clinical or radiological) or other discontinuation criterion is met.   
7.1.4 
Tivantinib Missed or Vomited Doses 
A missed or vomited dose should not be replaced. The subject should be instructed to take 
next scheduled dose at the regularly scheduled time. 
7.2 
Combination Drug Administration 
Combination therapy (if applicable) will be administered at the same dose(s) and same 
schedule(s) as in the original study protocol into which subjects were enrolled. If a subject 
discontinues receiving a combination drug(s) due to the combination drug-related toxicity 
he/she may continue to receive tivantinib.  
Subjects who were previously treated with tivantinib only and who, in the opinion of the 
Investigator and with the Sponsor’s approval, may benefit from combination therapy will be 
allowed to receive combination therapy. The combination therapies considered must have 
been evaluated in prior tivantinib combination studies. The combination therapy dose(s) and 
schedule(s) will be determined for each subject by the Investigator and with the Sponsor’s 
approval based on the combination drug(s) label(s) and prior tivantinib clinical trials. 
7.3 
Dose Modification 
In principle, when clinically significant tivantinib-related toxicity occurs, the tivantinib dose 
may be reduced, but a combination therapy drug (if applicable) can be administered at the 
scheduled dose level. When a clinically significant combination therapy drug related-toxicity 
occurs, combination therapy drug dose may be reduced (following dose modification 
guidelines for this drug), but tivantinib can be administered at the scheduled dose level. 
When a clinically significant toxicity that could be related to either drug occurs, doses of 
both drugs may be reduced.   
Dose administration may be delayed to allow for recovery from toxicity. Combination 
therapy drug dose modification should follow the original protocol guidelines (see 
Appendix 4).  
In general, once the tivantinib dose has been modified for a subject, all subsequent cycles 
should be administered to that subject at the modified dose unless additional dose 
modifications may be required. The modified dose will be considered the maximum dose for 
that subject for all subsequent cycles. 
Dose modification schema: 
• 240 mg BID (capsules or tablets) 
• 120 mg BID (capsules or tablets) 
• 120 mg once a day (capsules or tablets) 
Further instructions for tivantinib dose modification due to non-hematologic or hematologic 
toxicities are listed in the following tables and provided in the original study protocols. 


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For HCC subjects
Table 7.1 Dose Delays/Reductions for Non-hematological Toxicity Related to 
Tivantinib (non-HCC subjects) 
 enrolled in the extension protocol, dose reduction and management of non-
hematologic and hematologic toxicities should strictly follow the original protocol 
guidelines. 
Event Severity 
Action 
Grade 1 or 2 
Continue current dose level 
Grade 3 
 
Withhold tivantinib administration for up to 21 days until recovery to Grade 1 or 
Baseline. Administer tivantinib at the next lower dose for subsequent cycles, 
unless further dose reduction is required. If a second hold is required for the same 
event, administer tivantinib at the next lower dose for all subsequent cycles. 
Grade 4 
 
Withhold tivantinib administration for up to 21 days until recovery to Grade 1 or 
Baseline. Consult with ArQule’s Medical Monitor or designee prior to restarting 
tivantinib. If the Investigator and Medical Monitor concur, administer tivantinib 
at the next lower dose for subsequent cycles, unless further dose reduction is 
required. If a second hold is required for the same event, administer tivantinib at 
the next lower dose for all subsequent cycles. 
* If an event fails to recover to Grade 1 or Baseline and the dose must be delayed >21 days, the 
subject will be withdrawn from all study treatment, but should continue to undergo all follow-up 
evaluations. 
Table 7.2 Dose Delays/Reductions for Hematological Toxicity Related to Tivantinib 
(non-HCC subjects) 
Event/Severity 
Action 
Grade 1 
Continue current dose level 
Grade 2 
Neutropenia  
Thrombocytopenia  
 
Withhold tivantinib administration for up to 21 days and monitor 
hematology weekly until relevant lab value(s) recover to Grade 1 or: 
• If the relevant lab value recovers in less than 7 days
• If the relevant lab value takes 
 to: ≥1.5×109/L for 
ANC, or ≥75×109/L for platelets, resume tivantinib treatment at the 
same dose level 
more than 7 days
If a second hold is required for the same event, 
 to recover to the level 
described above, restart tivantinib administration at the next lower dose 
level 
whichever the grade, 
administer tivantinib at the next lower dose once lab values allow doing so 


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Event/Severity 
Action 
Neutropenia  
Grade 3 
Thrombocytopenia  
Anaemia  
 
Withhold tivantinib administration for up to 21 days and monitor 
hematology and/or chemistry weekly until relevant lab value(s) recover to 
Grade 1 or: 
• If the relevant lab value recovers in less than 14 days
• If the relevant lab value takes 
 to: ≥1.5×109/L for 
ANC, 8 g/dL for hemoglobin, or ≥60×109/L for platelet, resume 
tivantinib treatment at the same dose level.  
more than 14 days to recover to the level 
described above, treatment with growth factors for neutropenia is 
recommended. Restart tivantinib administration at the next lower dose 
once lab values allow doing so
• If a second hold is required for the same event, administer tivantinib at 
the next lower dose 
.  
once lab values allow doing so.   
Neutropenia  
Grade 4   
Thrombocytopenia 
Anaemia  
Febrile Neutropenia  
 
Withhold tivantinib administration for up to 21 days, and monitor 
hematology and/or chemistry weekly until relevant lab value(s) recover to 
Grade 1 or:  
• 
If the relevant lab value recovers in less than 14 days to: ≥1.5×109/L 
for ANC, ≥8 g/dL for hemoglobin, or ≥60×109/L for platelet, resume 
treatment at the next lower dose once lab values allow doing
Treatment with growth factors and antibiotics is strongly recommended 
for Grade 4 neutropenia and febrile neutropenia (as per 2006 ASCO 
guidelines) 
 so, unless 
further dose reduction is required. 
* If an event fails to recover to Grade 1 or baseline and the dose must be delayed >21 days, the 
subject will be withdrawn from all study treatment, but should continue to undergo all follow-up 
evaluations. 
The following precautions will be taken to manage neutropenia risk during the study: 
• For tivantinib-naïve subjects, ANC levels should be checked weekly during the first four 
weeks of therapy with tivantinib, and monthly thereafter. Subjects who experience 
Grade ≥3 neutropenia should be monitored weekly for four consecutive cycles (months). 
• Prophylactic treatment with growth factors and antibiotic is suggested for subjects who 
experience Grade ≥3 neutropenia and febrile neutropenia  
If questions or considerations regarding dose modification arise or a specific dose 
modification is needed, ArQule’s Medical Monitor or designee should be consulted. 
7.4 
Blinding 
This is an open label study. Neither the subject nor the Investigator and site research staff 
will be blinded to the administered treatment. 
7.5 
Concomitant Medication 
All information regarding concomitant treatments (medications or procedures) must be 
recorded on the subject’s CRF (including the name of the medication or procedure and 
duration of treatment). Palliative and supportive care for disease-related symptoms will be 


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offered to all subjects in this study. Complete information of analgesic consumption should 
be obtained and recorded. 
7.5.1 
Permitted Treatment 
• Standard therapies for concurrent medical conditions 
• Erythropoietin Stimulating Agents (ESA): Please follow ASCO or MEDICARE 
guidelines for the use of ESA in subjects diagnosed with cancer, drug labels and the Food 
and Drug Administration (FDA) alerts dated 9 March 2007, 8 November 2007, 12 March 
2008, 31 July 2008, 2 December 2008 (Q&As), 16 February 2010, and any future alerts.  
• Hematopoietic growth factors including filgrastim (Neupogen®) or other colony-
stimulating factors (G-CSF). ASCO or institutional guidelines should be followed for the 
use of WBC growth factors: http://jco.ascopubs.org/content/24/19/3187.full. 
• Prophylactic and supportive antiemetics may be administered according to standard 
practice 
• Megestrol acetate (Megace®) 
• Supportive therapy for toxicities associated with combination therapy drug(s), according 
to the FDA approved label or institutional practice 
• Use of topical corticosteroids, topical antibiotics, and systemic antibiotics according to 
standard of care or institutional guidelines 
• Treatment with non-conventional therapies (i.e., herbs or acupuncture), and 
vitamin/mineral supplements are acceptable, provided that they do not interfere with 
study treatment, in the opinion of the Investigator 
• Bisphonates for bone metastases 
• Palliative radiotherapy for local pain control provided that the subject does not meet 
criteria of progressive disease and treated lesion(s) will not be included in the target/non-
target lesion assessment  
 
7.5.2 
Prohibited Treatment 
• Any concurrent anticancer therapy including but not limited to chemotherapy, 
radiotherapy, hormonal therapy (except megestrol acetate as supportive care), 
immunotherapy, or 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 or premedication for imaging studies) 
 
7.5.3 
Treatment to Avoid During Tivantinib Administration 
• CYP3A4 inhibitors such as atanazavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandomycin (TAO), or voriconazole  


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• CYP3A4 inducers such as rifampicin, rifabutin, rifapentin, phenytoin, carbamazepine, 
phenobarbital and St. John’s Wort  
• CYP 2C19 substrates or inhibitors such as omeprazole, esoprazole, lansoprazole, 
pantoprazole, fluvoxamine, moclobemide  
• Grapefruits and grapefruit juice should be avoided within four hours before and after 
dosing 
As tivantinib is metabolized by hepatic cytochrome P450 enzymes, primarily CYP 2C19 and 
CYP 3A4, interactions with drugs metabolized via the same enzyme system are possible. 
Caution should be applied when any CYP 2C19 inhibitors and/or strong CYP 3A4 inhibitors 
are used as concomitant therapy. 
 


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8 
SAFETY ASSESSMENTS 
8.1 
Definitions 
8.1.1 
Adverse Event 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (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 (ICH E2A Guideline. Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting, Oct 1994). 
All AEs/SAEs occurring during the study period from the first day of study drug 
administration (Day 1 of this study) to the last day of the follow-up period will be captured.  
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal lab findings which should be considered adverse 
events. 
8.1.2 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline.  Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events 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 in the 
definition above.  Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse. 
Notes: 
• A procedure is not an AE or SAE, but the reason for the procedure may be an AE 
• Pre-planned (prior to signing the Informed Consent Form) surgeries or hospitalizations 
for pre-existing conditions which do not worsen in severity are not SAEs 


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8.1.3 
Adverse Event Severity 
All AEs will be graded (1 to 5; see below) according to the NCI CTCAE, version 3.0 
(publish date: 09 Aug 2006), version 4.0 (publish date: 29 May 2009), or version 4.03 
(publish date: 14 Jun 2010) depending on the original protocol.  
• Grade 1: Mild AE 
• Grade 2: Moderate AE 
• Grade 3: Severe AE 
• Grade 4: Life-threatening or disabling AE 
• Grade 5: Death related to AE 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself, however, may be of relatively minor medical significance (such as severe 
headache).  This is not the same as "seriousness," which is based on subject/event outcome at 
the time of the event.  For example, 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. 
8.1.4 
Causality Assessment 
The relationship between an adverse event and the study drug or combination therapy drug(s) 
will be determined by the Investigator on the basis of his/her clinical judgment and the 
following definitions: 
• Related 
- 
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, concurrent diseases, and concomitant medications) 
- 
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 
• Not Related 
- 
The AE does not follow a reasonable 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) 
 
8.1.5 
Action Taken Regarding the Study Product 
• None 
- 
No change in study drug dosage was made 
• Discontinued Permanently 
- 
The study product was permanently stopped 


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• Reduced 
- 
The dosage of study product was reduced 
• Interrupted 
- 
The study product was temporarily stopped 
• Increased 
- 
The dosage of study product was increased 
 
8.1.6 
Adverse Event Outcome 
• Recovered/Resolved 
- 
The subject fully recovered from the adverse event with no residual effect observed 
• Recovered/Resolved with Sequelae 
- 
The residual effects of the adverse event are still present and observable 
- 
Identify sequelae/residual effects 
• Not Recovered/Not Resolved 
- 
The adverse event itself is still present and observable 
• Fatal 
• Unknown 
 
8.1.7 
Other Action Taken for Event 
• None 
- 
No treatment was required 
• Medication required 
- 
Prescription and/or OTC medication was required to treat the adverse event 
• Hospitalization or prolongation of hospitalization required 
- 
Hospitalization was required or prolonged due to the adverse event, whether or not 
medication was required 
• Other 
 
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 AEs and SAEs they experience.   
Investigators must capture, evaluate and document all AEs and SAEs that are continuing 
from the original tivantinib protocol or begins after the last visit in the previous study or 
worsens from baseline of the previous study including the protocol-defined 30-day post-
treatment follow-up period (21 Code of Federal Regulations [CFR] §312.64[b]) as source 
documents.  
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.  


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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.   
In cases of SUSAR, Investigators or their designees 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 Events or Serious Adverse Events Assessment Criteria 
Adverse events and SAEs should be evaluated and graded using NCI CTCAE guidelines, 
version 3.0, 4.0, or 4.03. The criteria can be found at: 
http://ctep.cancer.gov/reporting/ctc.htm. 
8.4 
Reporting Serious Adverse Events 
The Investigators are obligated to immediately report to the Sponsor or designee each SAE 
that occurs during this investigation, within 24 hours from knowledge of the event, whether 
or not it is considered study-drug related. SAE follow-up information including 
supplementary documents (e.g., discharge letter, autopsy report, etc.), relevant data (e.g., 
electrocardiograms, lab tests, discharge summaries, post mortem results, etc.) must be 
reported within 24 hours as well after available. If any questions or considerations regarding 
a SAE arise, ArQule’s Medical Monitor or designee should be consulted. 
Safety Hotline and Fax 
 
ArQule Medical Monitor 
North America: 
  
All others: 
 
 
Telephone: 
 
email: 
 
Fax for North America: 
 
Fax for all others: 
 
Fax: 
 
 
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 (the Investigator must provide a causality assessment for all 
SAEs and all study drugs, including comparators; however, the SAE must be reported 
even if the Investigator’s causality assessment was unavailable with the initial report) 
 
If full 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. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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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 tivantinib trials in an expedited manner (within 7 days or 
15 days of knowledge) and to all Investigators involved in tivantinib clinical trials. 
The Investigators or designee(s) must in turn notify their governing IRB/IEC. 
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/SAEs occurring during the study period from the first 
day of study drug treatment (Day 1 of this study) 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(s). All subjects should be instructed to report AEs or SAEs occurring during the 30-day 
post treatment safety follow-up period.  Subjects with unresolved protocol therapy-related 
AEs at the time of treatment discontinuation will be followed for 30 days after the last dose 
of tivantinib or until all study-related toxicities have, in the opinion of the Investigator, 
resolved to baseline, stabilized, or been deemed to be irreversible whichever is later. 
Treatment-related AEs that occur during the 30-day follow-up period will be followed for a 
minimum of 30 days from the onset or until all study-related toxicities have, in the opinion of 
the Investigator, resolved to baseline, stabilized, or been deemed to be irreversible whichever 
is later.  
All SAEs that occur during the 30-day follow-up period should be reported to the Sponsor or 
its designee within 24 hours following the SAE report procedures described in Section 8.4.   
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.  


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9 
ASSESSMENT OF ANTI-TUMOR ACTIVITY 
Tumor response measurements will be made at the time of the enrollment into the Extension 
protocol and every 12 weeks after unless current disease specific standard of care requires 
performing imaging more often. It will be performed following RECIST guidelines, version 
1.0 or 1.1 depending on the version used in the original protocol (the guidelines can be found 
at http://imaging.cancer.gov/clinicaltrials/imaging.  Throughout the study, the identical 
lesions to those identified and measured at baseline must be evaluated using the same 
technique and preferably by the same Investigator. 
MRI/CT scans must meet the standard of care for imaging of lesions of the respective tumor 
type(s).  


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


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11 PLANNED STATISTICAL METHODS 
Because of the nature of this study, no formal statistical analysis is planned. Analyses on all 
baseline, efficacy and safety will consist primarily of listings and descriptive summaries (i.e., 
descriptive statistics and graphs). Details of all analyses will be included in a separate 
statistical analysis plan. 


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12 COMPLIANCE WITH GOOD CLINICAL PRACTICE, ETHICAL 
CONSIDERATIONS AND INFORMED CONSENT 
12.1 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 study, 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. 
12.2 Compliance with GCP 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. 
12.3 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 the start of 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 Federal regulations (21 CFR Part 50) and the 
ICH document “Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance” 
dated April 1996.  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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13 STUDY MANAGEMENT AND MATERIALS 
13.1 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 CRFs and original source documents for accuracy 
of data recording, study drug accountability, and correspondence.  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.   
13.2 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 tivantinib 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. 
13.3 Electronic Case Report Forms 
An Electronic Data Capture (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 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 


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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. 
13.4 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 tivantinib.  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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cell lung carcinomas correlates with anchorage-independent cell survival. J Cell 
Biochem. 2002;86:665-77. 
9. Beviglia L, Matsumoto K, Lin CS, et al. Expression of the c-Met/HGF receptor in human 
breast carcinoma: correlation with tumor progression. Int J Cancer (Pred. Oncol). 
1997;74:301-9. 
10. Takeuchi H, Bilchik A, Saha S, et al. c-MET expression level in primary colon cancer: a 
predictor of tumor invasion and lymph node metastases. Clin Cancer Res. 2003;9:1480-8. 
11. Qian CN, Guo X, Cao B, et al. Met protein expression level correlates with survival in 
subjects with late-stage nasopharyngeal carcinoma. Cancer Res. 2002;62:589-96. 
12. Tivantinib (ARQ 197) Investigator’s Brochure, Version 9.0, Dated: 06 November, 2013. 
13. Rosen L, Garcia A, Mulay M, et al. A Phase 1 dose escalation study of ARQ 197, a 
selective inhibitor of the cMet receptor in subjects with metastatic solid tumors. Eur J 
Cancer Supplements. 2006;4:196.  


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14. Garcia A, Rosen L, Cunningham C, et al. Phase 1 study of ARQ 197, a selective inhibitor 
of the c-Met RTK in subjects with metastatic solid tumors reaches recommended phase 2 
dose. J Clin Oncol. 2007;25(18S part I):144s. 
15. Rosen L, Senzer N, Nemunaitis J, et al. A phase 1dose escalation study and signs of anti-
metastatic activity of ARQ 197, a selective c-Met inhibitor. AACR-NCI-EORTC 
International Conference. 2007; abstract # B91. 
16. Yap TA. Harris D, Barriuso J, et al. Phase I trial to determine the dose range for the c-
Met inhibitor ARQ 197 that inhibits c-Met and FAK phosphorylation, when administered 
by an oral twice-a-day schedule, J Clin Oncol, 2008 ASCO Annual Meeting Proceedings 
(Post-Meeting Edition). 2008;26(15S):3584 
17. Yap TA, Barriuso J, Frentzas S, et al. Pharmacokinetic (PK) and pharmacodynamic (PD) 
phase I study of an oral c-Met inhibitor ARQ197 reaches maximum tolerated dose 
(MTD) in a twice daily (BID) dosing schedule. Eur J Cancer. 2008; 6(12):39 
18. Laux I, Goldman J, Just R, et al. Phase I dose escalation study (ARQ 197-111) evaluating 
combination of selective c-Met inhibitor ARQ 197 and erlotinib. J Clin Oncol. 
2009;27:Suppl;abstr 3549. 
19. Mekhail T, Rich T, Rosen L, et al. Final results: A dose escalation phase I study of 
ARQ 197, a selective c-MET inhibitor, in patients with metastatic solid tumors. 2009 
ASCO Annual Meeting. J Clin Oncol. 2009; 27:15s(suppl;abstr 3548). 
20. Rosen LS, Senzer N, Mekhail T et al. A phase I dose-escalation study of Tivantinib in 
adult patients with metastatic solid tumors. Clin Cancer Res. 2011;17:7754-64. 
21. Sequist LV, von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus 
tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. 
J Clin Oncol. 2011;29:3307-15. 
22. Adjei AA, Schwartz B, Garmey E. Early clinical development of ARQ 197, a selective, 
non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of 
advanced cancers. Oncologist. 2011;16:788-99. 
23. Rimassa L, Porta C, Borbath I, et al. Tivantinib versus placebo in patients (Pts) with 
hepatocellular carcinoma (HCC) who failed one systemic therapy: Results of a 
randomized controlled phase II trial (RCT). Program and abstracts of the American 
Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, 
Illinois. Abstract 4006. 
24. Goldman JW, Laux I, Chai F, et al. Phase 1 dose-escalation trial evaluating the 
combination of the selective MET (mesenchymal-epithelial transition factor) inhibitor 
tivantinib plus erlotinib. Cancer. 2012;118:5903-11. 
25. Eng C. HL, Severtsev A, et al. A randomized, placebo-controlled, phase I/II study of 
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wild-type (WT) metastatic colorectal cancer (CRC) who had received previous front-line 
systemic therapy. J Clin Oncol. 2013;31(suppl;abstr 3508). 
26. Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced 
hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 
2013;14:55-63. 
27. Scagliotti GN, Ramlau, R, et al. MARQUEE: A randomized, double-blind, placebo-
controlled, phase 3 trial of tivantinib plus erlotinib versus placebo plus erlotinib in 
previously treated patients with locally advanced or metastatic, non-squamous, non-
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2013;(abstract E17-1821). 


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APPENDIX 1: SCHEDULE OF ASSESSMENTS 
 
Pre-
Study 
Visit 
Monthly 
Weekly 1 
(combination 
tx) 
Weekly 
(tivantinib
-naïve tx) 
End of 
Treatment 
Visit 
30-Day 
Safety 
FU 
Tests and Procedures/ 
Window (days) 
-14 to 
Day 1 
±3 days 
± 3 days 
± 3 days 
within 
7 (+3) days 
 
Written informed consent2 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
X3 
X 
 
ECOG PS  
X 
X 
 
X3 
X 
 
Vital signs and weight3 
X 
X 
X3 
X3 
X 
 
Hematology 
X 
X 
X3 
X3 
X 
 
Chemistry panel 
X 
X 
 
X3 
X 
 
Electrolyte panel 
X 
 
 
X3 
X 
 
Liver Function test 
X 
 
 
X3 
 
 
Coagulation panel 
X 
 
 
 
X 
 
Serum pregnancy test (if 
applicable)  
X 
 
 
 
X 
 
12-Lead ECG 
X 
 
 
 
X 
 
Tumor assessment4 
X 
X 
 
 
X 
 
Tumor markers assessment (if 
applicable) 
X 
X 
 
 
X 
 
Concomitant medications 
X 
X 
X 
 
X 
X 
AE assessment 
X5 
X 
X 
 
X 
X 
Tivantinib dispensation 
X 
X 
 
 
 
 
Combination therapy drug(s) 
dispensation/ administration 
(if applicable) 
X 
 
X 
X 
 
 
 
Telephone call 
 
 
 
 
 
X 
1. 
Weekly visits may be required for administration of combination therapy drug(s) or for tivantinib-naïve subjects 
during the first four weeks of treatment with tivantinib  
2. 
Must be obtained before any study related procedures 
3. 
Weight is NOT required for weekly visits  
4. 
Should be done every 12 weeks unless current disease specific standard of care requires performing imaging more 
often  
5. 
All AEs/SAEs occurring during the study period from the first day of study-drug treatment (Day 1 of this study) to 
the last day of the 30-day post-treatment follow-up period will be captured. AEs that continue from the original 
tivantinib study or begin after the last visit of the original study but prior to Day 1 of the Extension study must be 
documented on a Medical History eCRF page. Resolved AEs from the original tivantinib study are captured in the 
original study records and will not be re-recorded for this study. 


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APPENDIX 2: ECOG PERFORMANCE STATUS 
Grade 
Description 
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: EXAMPLES OF IN VIVO SUBSTRATES, INHIBITORS, 
AND INDUCERS FOR SPECIFIC CYP ENZYMES 
CYP 
Substrate 
Inhibitor 
Inducer 
2C19  
omeprazole, esoprazole,  
lansoprazole, pantoprazole  
omeprazole, fluvoxamine, 
moclobemide  
rifampin  
3A4/  
3A5  
   
midazolam, buspirone,  
felodipine,  
lovastatin, eletriptan, 
sildenafil, simvastatin, 
triazolam  
atazanavir, clarithromycin, 
indinavir, itraconazole, 
ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, 
telithromycin  
rifampin, 
carbamazepine  
Note: This is not an exhaustive list (created May 1, 2006). Adopted from 
http://www.fda.gov/Cder/drug/drugInteractions/tableSubstrates.htm#classInhibit 
 
Substrates for any particular CYP enzyme listed in this table are those having plasma AUC 
values increased by 2-fold or higher when co-administered with inhibitors of that CYP 
enzyme; for CYP3A, only those with plasma AUC increased by 5-fold or higher are listed.  
Inhibitors listed are those that increase plasma AUC values of substrates for that CYP 
enzyme by 2-fold or higher. For CYP3A inhibitors, only those that increase AUC of CYP3A 
substrates by 5-fold or higher are listed.  
Inducers listed are those that decrease plasma AUC values of substrates for that CYP enzyme 
by 30% or higher. 


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APPENDIX 4: DOSE MODIFICATION GUIDELINES FOR 
COMBINATION THERAPY 
When during combination therapy co-drug related toxicity is observed, dose delays and/or 
reduction s in co-drug administration are allowed as described below or may follow 
institutional guidelines/standard of care.  
Temporary dose interruption and/or dose reduction may be necessary due to adverse events. 
For recommendations for skin adverse events, see Table A4-1. If dose reduction is necessary, 
the sorafenib dose may be reduced to once a day. If further dose reduction is necessary, 
sorafenib may be given once every other day. 
Sorafenib (Nexavar) Dose Modification 
Table A4-1 
Sorafenib Dose Modifications for Dermatologic Toxicity 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 1: Numbness, 
dysesthesia, paresthesia, 
tingling, painless swelling, 
erythema, or discomfort of 
the hands or feet that does 
NOT disrupt the subject’s 
normal activities 
Any occurrence 
Continue treatment with 
sorafenib and consider topical 
therapy for symptomatic relief. 
Grade 2: Painful erythema 
and swelling of the hands 
or feet and/or discomfort 
affecting the subject’s 
normal activities 
1st occurrence 
Continue treatment with 
sorafenib and consider topical 
therapy for symptom relief. 
No improvement within 7 days 
or 2nd or 3rd occurrence 
Interrupt sorafenib treatment 
until toxicity resolves to Grade 0 
or 1. When resuming treatment, 
decrease sorafenib dose by 1 
dose level (dosing once a day or 
once every other day). 
4th occurrence 
Discontinue sorafenib treatment. 
Grade 3: Moist 
desquamation, ulceration, 
blistering, or severe pain of 
the hands or feet, or severe 
discomfort that causes the 
subject to be unable to 
work or perform activities 
of daily living 
1st or 2nd occurrence 
Interrupt sorafenib treatment 
until toxicity resolves to Grade 0 
or 1. When resuming therapy, 
decrease sorafenib by 1 dose 
level (dosing once a day or once 
every other day). 
3rd occurrence 
Discontinue sorafenib treatment. 
Please refer to the approved sorafenib (Nexavar) package insert for details. 
 
 


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Gemcitabine (Gemzar) Dose Modification 
Dosage adjustment of gemcitabine is based upon the degree of hematologic toxicity 
experienced by the subjects. Subjects receiving gemcitabine should be monitored prior to 
each dose with a complete blood count, including differential and platelet count. If marrow 
suppression is detected, therapy should be modified or suspended according to the guidelines 
in Table A4-2. 
Table A4-2 
Gemcitabine Dosage Reduction Guidelines 
Absolute Granulocyte 
Count ( × 106/L) 
Platelet Count ( × 106/L) 
Percent of Full Dose (%) 
≥ 1000 and 
≥ 100,000 
100 
500 – 999 or 
50,000 – 99,999 
75 
< 500 or 
< 50,000 
Hold 
Laboratory evaluation of renal and hepatic function, including transaminases and serum 
creatinine, should be performed prior to initiation of therapy and periodically thereafter. 
Gemcitabine should be administered with caution in subjects who have evidence of 
significant renal or hepatic impairment, as there is insufficient information from clinical 
studies to allow clear dose recommendation for these subject populations. 
Refer to the approved gemcitabine (Gemzar) package insert for details.  
Erlotinib (Tarceva) Dose Reduction 
When dose reduction is necessary, the erlotinib dose should be reduced by a 50 mg 
decrement. For this study, no more than 1 dose reduction will be allowed. 
Pulmonary Symptoms: In subjects who develop an acute onset of new or progressive 
pulmonary symptoms, such as dyspnea, cough, or fever, treatment with erlotinib should be 
interrupted pending diagnostic evaluation. If interstitial lung disease is diagnosed, erlotinib 
should be discontinued and appropriate treatment instituted, as necessary. 
Diarrhea: Diarrhea can usually be managed with loperamide. Subjects with severe diarrhea 
who are unresponsive to loperamide or who become dehydrated may require dose reduction 
or temporary interruption of therapy. 
Skin Reactions: Skin reactions experienced by subjects receiving erlotinib tend to be 
managed easily with topical therapies and do not require treatment interruption or dose 
modification (please refer to package insert for details). However, rare subjects with severe 
skin reactions may also require dose reduction or temporary interruption of therapy. 
Concomitant CYP3A4 Inhibitors: In subjects concomitantly treated with a strong CYP3A4 
inhibitor, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, or voriconazole, 
a dose reduction should be considered if severe adverse reactions occur. 
Hepatic Impairment: Erlotinib is eliminated by hepatic metabolism and biliary excretion. 
Therefore, caution should be used when administering erlotinib to subjects with hepatic 
impairment. Dose reduction or interruption of erlotinib should be considered if severe 


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adverse reactions occur. For additional dose modification information, please refer to the 
package insert for erlotinib (Tarceva).  
Irinotecan (Camptosar) and Cetuximab (Erbitux) Dose Reductions 
Refer to the locally applicable irinotecan and cetuximab package inserts for dose reductions, 
modifications, or delays due to irinotecan- or cetuximab-related toxicities. The recommended 
dose levels for reductions in irinotecan and cetuximab are shown in Table A4-3. General 
recommendations for dose modifications are provided in Table A4-4. 
Supportive therapy for toxicities associated with irinotecan and/or cetuximab therapy may be 
given, according to institutional practice. 
A new cycle of treatment may begin when the ANC is ≥ 1.5 × 109/L, the platelet count is 
≥ 100 × 109/L, and any treatment-related gastrointestinal toxicity is resolved to ≤ Grade 1. 
The ANC level at baseline must be ≥ 1.5 × 109/L and platelet count ≥ 100 × 109/L. If the 
initiation of a new cycle or treatment during a cycle is delayed for 4 weeks or longer, the 
subject should be removed from study treatment. Doses that are withheld are not to be made 
up. 
 
Table A4-3 
Recommended Irinotecan and Cetuximab Dose Reductions 
Agent 
Initial Dose 
Level -1 
Level -2a 
Irinotecan 
180 mg/m2 
150 mg/m2 
120 mg/m2 
Cetuximab 
400 mg/m2 
250 mg/m2 
200 mg/m2 
a: If a reduction below Level -2 is indicated, discontinue treatment with that agent 


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Table A4-4 
Dose Modifications to Irinotecan and Cetuximab Dose Due to 
Irinotecan- or Cetuximab-Toxicity 
Event 
Action 
Hematologic 
Grade 2 Hematologic 
Reduce irinotecan 1 dose level for the remainder of the cycle. For 
subsequent cycles, resume at the previous dose levels, provided 
ANC ≥ 1.5 × 109/L and platelets ≥ 100 × 109/L. 
Grade 3 to 4 Hematologic 
Hold irinotecan. If counts recover to ANC ≥ 1.5 × 109/L and 
platelets to ≥ 100 × 109/L, may be resumed at 1 lower dose level for 
the remainder of the cycle. For subsequent cycles, continue both 
agents at the reduced dose levels from the previous cycle. 
Febrile neutropenia 
Hold irinotecan. If fever resolves and counts recover to ANC ≥ 1.5 x 
109/L and platelets to ≥ 100 x 109/L, both agents may be resumed at 
1 lower dose level for the remainder of the cycle. For subsequent 
cycles, continue both agents at the reduced dose levels from the 
previous cycle. 
Diarrhea 
Grade 2 Diarrhea 
Reduce irinotecan for 1 dose level for the remainder of the cycle. If 
diarrhea persists, hold cetuximab until fully resolved. For 
subsequent cycles, resume all agents at the previous dose levels, 
provided diarrhea has fully resolved. 
Grade 3 to 4 Diarrhea 
Hold irinotecan and cetuximab. If diarrhea resolves to ≤ Grade 2, 
both agents may be resumed at 1 lower dose level for the remainder 
of the cycle. If diarrhea persists, hold cetuximab until fully resolved. 
For subsequent cycles, continue both agents at the reduced dose 
levels from the previous cycle. 
Nausea/Vomitinga 
Grade 3 Nausea and/or 
Vomiting 
Reduce irinotecan 1 dose level for the remainder of the cycle. For 
subsequent cycles, continue irinotecan at the reduced dose level 
from the previous cycle. 
Grade 4 Nausea and/or 
Vomiting 
Reduce irinotecan 1 dose level for the remainder of the cycle. For 
subsequent cycles, continue irinotecan at the reduced dose levels 
from the previous cycle. 
a: Dose modifications for nausea and/or vomiting should be made only if nausea and/or vomiting persist or 
occur despite 2 treatments with adequate (combination) antiemetics therapy. 
b: Including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial ischemia. 
c: Note that the NCI CTCAE defines hypersensitivity and infusion reactions differently: “Cytokine release 
syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, although some 
of the manifestations are common to both AEs. An acute infusion reaction may occur with an agent that 
causes cytokine release (eg, monoclonal antibodies or other biological agents). Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.” See the “Syndromes” section of the NCI CTCAE Version 4 for a complete list of 
signs and symptoms of “cytokine release syndrome/acute infusion reaction” and see the 
“Allergy/Immunology” section for a description of hypersensitivity. 
AE = adverse event; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LV = left ventricular; NCI = National Cancer 
Institute. 


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Table A4-4 
Dose Modifications to Irinotecan and Cetuximab Dose Due to 
Irinotecan- or Cetuximab-Toxicity (Continued) 
Event 
Action 
Mucositis 
Grade 2 Mucositis 
Reduce irinotecan 1 dose level for the remainder of the cycle. For 
subsequent cycles, continue at the reduced dose levels from the 
previous cycle. No modifications (or delays) will be made for 
cetuximab. 
Grade 3 Mucositis 
Hold irinotecan. If mucositis resolves to ≤ Grade 2, treatment may 
be resumed at 1 lower dose level for the remainder of the cycle. For 
subsequent cycles, continue at the reduced dose level from the 
previous cycle. No modifications (or delays) will be made for 
cetuximab. 
Grade 4 Mucositis 
Hold ALL study treatment, including irinotecan, cetuximab, and 
tivantinib. If mucositis resolves to ≤ Grade 2, irinotecan may be 
resumed at 1 lower dose level for the remainder of the cycle. 
Cetuximab will be resumed at the prior dose. For subsequent cycles, 
continue all agents at the dose level from the previous cycle. 
Pulmonary 
Grade 2 or worsening 
pulmonary symptoms 
unrelated to underlying 
cancer 
Cetuximab treatment should be stopped and symptoms investigated. 
Cetuximab treatment may resume at 1 lower dose level when 
symptoms resolve to ≤ Grade 1 and cetuximab-related pneumonitis 
is ruled out. 
≥ Grade 3 cough, dyspnea, 
hypoxia, pneumonitis, or 
pulmonary infiltrates 
Hold cetuximab until interstitial lung disease is ruled out. Continue 
irinotecan. Discontinue all study treatment if interstitial lung disease 
is confirmed. 
Hypomagnesemia 
Grade 3 or 4 
hypomagnesemia 
Hold cetuximab until hypomagnesemia resolves to ≤ Grade 2, then 
restart cetuximab at the same dose. For any Grade of 
hypomagnesemia, magnesium supplementation should be provided. 
a: Dose modifications for nausea and/or vomiting should be made only if nausea and/or vomiting persist or 
occur despite 2 treatments with adequate (combination) antiemetics therapy. 
b: Including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial ischemia. 
c: Note that the NCI CTCAE defines hypersensitivity and infusion reactions differently: “Cytokine release 
syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, although some 
of the manifestations are common to both AEs. An acute infusion reaction may occur with an agent that 
causes cytokine release (eg, monoclonal antibodies or other biological agents). Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.” See the “Syndromes” section of the NCI CTCAE Version 4 for a complete list 
of signs and symptoms of “cytokine release syndrome/acute infusion reaction” and see the 
“Allergy/Immunology” section for a description of hypersensitivity. 
AE = adverse event; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LV = left ventricular; NCI = National Cancer 
Institute. 
 


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Table A4-4 
Dose Modifications to Irinotecan and Cetuximab Dose Due to 
Irinotecan- or Cetuximab-Toxicity (Continued) 
Event 
Action 
Venous thrombotic events 
Grade 3 venous 
thrombosis or 
asymptomatic pulmonary 
embolism 
Hold treatment with cetuximab. If the planned duration of full-dose 
anticoagulation is ≤ 2 weeks, treatment should be held until the full-
dose anticoagulation period is over. If the planned duration of full-
dose anticoagulation is ≥ 2 weeks, treatment may be resumed during 
the period of full-dose anticoagulation, if all of the following criteria 
are met: 
• The subject must have an in-range INR (usually between 2 and 
3) on a stable dose of warfarin or be on a stable dose of low 
molecular weight heparin prior to restarting treatment. 
• The subject must not have pathological conditions that carry a 
high risk of bleeding (eg, tumor involving major vessels). 
• The subject must not have had hemorrhagic events while on 
study. 
Grade 4 or 
recurrent/worsening 
venous thromboembolic 
events 
Discontinue all study treatment, including tivantinib, irinotecan, and 
cetuximab. 
Symptomatic pulmonary 
embolism 
Discontinue all study treatment, including tivantinib, irinotecan, and 
cetuximab. 
Arterial thrombotic events 
Grade 3 cardiac 
ischemia/infarction 
Discontinue all study treatment, including tivantinib, irinotecan, and 
cetuximab. 
Any Grade 4 arterial 
thrombotic eventb 
Discontinue all study treatment, including tivantinib, irinotecan, and 
cetuximab. 
LV dysfunction 
Grade 3 LV dysfunction 
Discontinue cetuximab. Subjects may continue other study 
treatment. 
Grade 4 LV dysfunction 
Discontinue all study treatment, including tivantinib, irinotecan, and 
cetuximab. 
a: Dose modifications for nausea and/or vomiting should be made only if nausea and/or vomiting persist or 
occur despite 2 treatments with adequate (combination) antiemetics therapy. 
b: Including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial ischemia. 
c: Note that the NCI CTCAE defines hypersensitivity and infusion reactions differently: “Cytokine release 
syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, although some 
of the manifestations are common to both AEs. An acute infusion reaction may occur with an agent that 
causes cytokine release (eg, monoclonal antibodies or other biological agents). Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 24 hours 
of completion of infusion.” See the “Syndromes” section of the NCI CTCAE Version 4 for a complete 
list of signs and symptoms of “cytokine release syndrome/acute infusion reaction” and see the 
“Allergy/Immunology” section for a description of hypersensitivity. 
AE = adverse event; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LV = left ventricular; NCI = National Cancer 
Institute. 


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Table A4-4 
Dose Modifications to Irinotecan and Cetuximab Dose Due to 
Irinotecan- or Cetuximab-Toxicity (Continued) 
Event 
Action 
Hemorrhage/bleeding 
Grade 3 
hemorrhage/bleeding 
Hold tivantinib treatment; once hemorrhage or bleeding resolves, 
tivantinib treatment may be continued at the Investigator’s 
discretion. 
Grade 4 
hemorrhage/bleeding 
Discontinue all study treatment, including tivantinib, irinotecan, and 
cetuximab. 
Rash 
Grade 3 rash 
(1st occurrence) 
Hold cetuximab infusion 1 to 2 weeks: 
• 
If improvement, continue at 500 mg/m2. 
• 
If no improvement, discontinue cetuximab. 
Grade 3 rash 
(2nd occurrence) 
Hold cetuximab infusion 1 to 2 weeks: 
• 
If improvement, reduce to 400 mg/m2. 
• 
If no improvement, discontinue cetuximab. 
Grade 3 rash 
(3rd occurrence) 
Hold cetuximab infusion 1 to 2 weeks: 
• 
If improvement, reduce to 300 mg/m2. 
• 
If no improvement, discontinue cetuximab. 
Grade 3 rash 
(4th occurrence) 
Discontinue cetuximab. 
Grade 4 rash 
(1st occurrence) 
Discontinue cetuximab. 
Hypersensitivityc 
Grade 1 hypersensitivity 
reactions (all agents) 
Decrease the infusion rate for all agents by 50% until symptoms 
resolve; then resume at the initial planned rate (except for 
cetuximab, see below). 
Grade 2 hypersensitivity 
reactions (all agents) 
Stop infusion. Administer histamine 1 and/or histamine 2 blockers, 
and/or steroids according to institutional policy. Restart the infusion 
when symptoms resolve and pre-treat before all subsequent doses. 
Treat according to institutional policy. 
Grade 3 or Grade 4 
hypersensitivity reactions 
(all agents) 
Stop the infusion. Permanently discontinue all study treatment and 
notify the Study Coordinator. 
Grade 1 or 2 cetuximab 
infusion reactions 
Stop the infusion until symptoms resolve, then restart cetuximab at a 
50% lower rate of infusion. All subsequent doses should be 
administered at the lower infusion rate. 
≥ Grade 3 cetuximab 
infusion reactions 
Discontinue cetuximab. Other study treatment may be continued. 
Other nonhematologic 
Grade 3 or higher 
nonhematologic toxicities 
not described above 
Hold ALL study treatment, including irinotecan, cetuximab, and 
tivantinib, and monitor toxicity at least weekly. If toxicity resolves 
to Grade 1 or lower within 4 weeks, treatment may be resumed, with 
cetuximab and irinotecan at 1 lower dose level. 
a: Dose modifications for nausea and/or vomiting should be made only if nausea and/or vomiting persist or 
occur despite 2 treatments with adequate (combination) antiemetics therapy. 


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b: Including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial ischemia. 
c: Note that the NCI CTCAE defines hypersensitivity and infusion reactions differently: “Cytokine release 
syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, although some 
of the manifestations are common to both AEs. An acute infusion reaction may occur with an agent that 
causes cytokine release (eg, monoclonal antibodies or other biological agents). Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.” See the “Syndromes” section of the NCI CTCAE Version 4 for a complete list 
of signs and symptoms of “cytokine release syndrome/acute infusion reaction” and see the 
“Allergy/Immunology” section for a description of hypersensitivity. 
AE = adverse event; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LV = left ventricular; NCI = National Cancer 
Institute. 
 
 
 


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INVESTIGATOR’S SIGNATURE 
 
 
Study Title: 
An Extension Protocol for Subjects Who Were Previously 
Enrolled in Other ARQ 197 Protocols 
Study Number: 
ARQ 197-299 
 
 
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: ________________ 
 
 
 


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Summary of Changes 
 
Amendment 1 
Amendment 2 
Title page 
An Extension Protocol for Subjects Who Were 
Previously Enrolled in Other ARQ 197 
Protocols 
An Extension Protocol for Subjects Who Were 
Previously Enrolled in Other Tivantinib (ARQ 197) 
Protocols 
 
Added 
NCT Number: 01178411 
Medical Monitor: 
 
Medical Monitor: 
 
Synopsis: Study Design (p.2) 
The combination therapy dose(s) and 
schedule(s) will be determined for each subject 
by the Investigator based on the combination 
drug(s) label(s). 
The combination therapy dose(s) and schedule(s) 
will be determined for each subject by the 
Investigator and with the Sponsor’s approval based 
on the combination drug(s) label(s) and prior 
tivantinib clinical trials. 
 
Subjects who were previously enrolled in tivantinib 
studies but did not receive tivantinib as part of their 
treatment, and who, in the opinion of the 
Investigator, may benefit from treatment with 
tivantinib as a single agent or in combination 
therapy, will be allowed to initiate treatment with 
tivantinib. The tivantinib monotherapy or 
combination therapy dose(s) and schedule(s) will 
be determined for each subject by the Investigator 
and with the Sponsor’s approval based on 
administration schedules tested in and defined by 
prior tivantinib clinical trials.  
Added 
Synopsis: Test Product, Dose, and Mode of Administration (p.3) 
 
Subjects who were previously enrolled in tivantinib 
studies but did not receive tivantinib as part of their 
treatment, and who, in the opinion of the 
Investigator, may benefit from treatment with 
tivantinib as a single agent or in combination 
therapy, will be allowed to initiate treatment with 
tivantinib. The tivantinib monotherapy or 
combination therapy dose(s) and schedule(s) will 
be determined for each subject by the Investigator 
and with the Sponsor’s approval based on 
administration schedules tested in and defined by 
prior tivantinib clinical trials. 
Added 
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The combination therapies considered must 
have been evaluated in prior ARQ 197 
combination studies. The combination therapy 
dose(s) and schedule(s) will be determined to 
each subject by the Investigator based on the 
combination drug(s) label(s). ARQ 197 will be 
administered orally, twice a day, with meals 
(regardless of original protocol requirements). 
 
 
The combination therapy(ies) considered must have 
been evaluated in prior tivantinib combination 
studies. The tivantinib monotherapy and 
combination therapy dose(s) and schedule(s) will 
be determined for each subject by the Investigator 
and with the Sponsor’s approval based on the 
combination drug(s) label(s) and prior tivantinib 
clinical trials.  
Tivantinib will be administered orally, twice a day, 
with meals (regardless of original protocol 
requirements). 
1 Introduction (pp.9-10) 
ARQ 197 is the most advanced representative 
of a newly discovered class of trans 3,4 
disubstituted pyrrolidine-2,5-diones having the 
potential to treat cancer.  ARQ 197 selectively 
inhibits tyrosine kinase, c-Met, which has been 
implicated in tumor invasiveness and 
metastasis.  
Tivantinib is the most advanced representative of a 
newly discovered class of trans 3,4 disubstituted 
pyrrolidine-2,5-diones having the potential to treat 
cancer.  Tivantinib is a novel, small molecule 
inhibitor of c-MET receptor tyrosine kinase. The 
expression of c-MET is dysregulated in many types 
of human malignancies with overexpression of c-
MET kinase, c-MET-activating genetic mutations, 
c-MET amplifications, and increased expression of 
the c-MET ligand hepatocyte growth factor (HGF). 
This dysregulation is implicated with a poor 
prognosis with greater tumor proliferation and 
increased angiogenesis with migration and 
invasion.  
Activation of c-Met results in the binding and 
phosphorylation of adaptor proteins such as 
Gab-1, Grb-2, Shc, and c-Cbl, and subsequent 
activation of signal transducers such as PI3K, 
PLC-g, STATs, ERK1 and 2 and FAK.  c-Met 
and HGF are expressed in numerous tissues 
and their expression is normally confined 
predominantly to cells of epithelial and 
mesenchymal origin, respectively.  c-Met and 
HGF are dysregulated in human cancers and 
may contribute to dysregulation of cell growth, 
tumor cell dissemination, and tumor invasion 
during disease progression and metastasis.  c-
Met and HGF are highly expressed relative to 
surrounding tissue in numerous cancers and 
this expression correlates with poor subject 
prognosis.  c-Met and HGF may protect tumors 
against cell death induced by DNA-damaging 
Deleted 
 


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agents and, as such, may contribute to 
chemoresistance and radioresistance of tumors.  
Therefore, inhibitors of c-Met may be useful as 
therapeutic agents in the treatment of malignant 
proliferative disorders.  
 
Activation of c-MET results in the binding and 
phosphorylation of adaptor proteins such as growth 
factor receptor-bound-associated binder-1 (Gab-1), 
growth factor receptor-bound protein 2 (Grb-2), Src 
homology 2 domain-containing and Casitas 
B-lineage lymphoma progene (c-Cbl), and 
subsequent activation of signaling pathways, 
including phosphatidylinositol-3-kinase/activated 
protein kinase B (PI3K/Akt), focal adhesion 
kinase-1 (FAK), signal transducers and activators 
of transcription protein (STAT), and mitogen-
activated protein kinase/ERK (Ras/MEK/Erk) 
pathways. Mesenchymal-epithelial transition factor 
and HGF are expressed in numerous tissues and 
their expression is normally confined 
predominantly to cells of epithelial and 
mesenchymal origin, respectively. Mesenchymal-
epithelial transition factor and HGF are deregulated 
in human cancers and may contribute to 
dysregulation of cell growth, tumor cell 
dissemination, and tumor invasion during disease 
progression and metastasis. Mesenchymal-
epithelial transition factor and HGF are highly 
expressed relative to surrounding tissue in 
numerous cancers, and this expression correlates 
with poor subject prognosis. Mesenchymal-
epithelial transition factor and HGF may protect 
tumors against cell death induced by 
deoxyribonucleic acid (DNA)-damaging agents 
and, as such, may contribute to chemoresistance 
and radioresistance of tumors. Therefore, inhibitors 
of c-MET may be useful as therapeutic agents in 
the treatment of proliferative disorders. 
Added 
Tivantinib selectively inhibits the inactive or 
unphosphorylated form of human c-MET and 
shows in vitro biochemical activity against 
recombinant c-MET with an inhibition constant 
(Ki) of approximately 355 nM. The potency of 
tivantinib inhibition of c-MET activity is 


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independent of adenosine triphosphate (ATP) 
concentration, which suggests that tivantinib’s 
inhibition is of noncompetitive nature. Tivantinib 
was profiled against 230 protein kinases, and while 
tivantinib inhibits c-MET kinase activity, it is not a 
promiscuous kinase inhibitor. 
In nonclinical studies, tivantinib showed broad-
spectrum in vitro anti-cancer activity against 
human tumor cell lines, including breast, colon, 
lung, pancreas, and gastric cancer cell lines. The 
potency of tivantinib in cancer cells expressing 
detectable c-MET in anti-proliferative assays yield 
IC50 values from 0.1 mM to 0.6 mM. The ability of 
tivantinib to inhibit c-MET phosphorylation 
correlated with its ability to inhibit growth in c-
MET expressing cancer cells, thereby indicating its 
anti-cancer activity. In single-agent in vivo studies, 
tivantinib was shown to be efficacious against 
multiple human cancer xenograft models and was 
well tolerated without drug-related clinical signs or 
deaths. 
The tivantinib development program is predicated 
on the hypothesis that tivantinib-mediated 
inhibition of the c-MET pathway, either alone or in 
combination with other anti-cancer compounds, 
will be beneficial in treating malignancies.  
1.1 Overview of Clinical Experience (pp.10-11) 
ARQ 197 has been or is currently being 
evaluated in ten Phase 1 clinical studies, four in 
healthy normal volunteers to assess 
pharmacokinetics (PK) and bioavailability 
(ARQ 197-110 (to assess different 
polymorphic forms), ARQ 197-112 (to assess 
PK in CYP2C19 poor and normal 
metabolizers), ARQ 197-113 (to assess 
different polymorphic forms), and ARQ 197-
A-U151) and six dose escalation studies 
involving subjects with advanced solid tumors 
(ARQ 197-101, ARQ 197-103, ARQ 197-111, 
ARQ 197-114, ARQ 197-116, and ARQ 197-
117).  Five Phase 2 studies are being 
conducted, including one randomized placebo 
controlled combination study with erlotinib in 
subjects with previously treated non small-cell 
As of 23 Aug 2013, 30 Phase 1 and Phase 2 studies 
(completed and ongoing) have been conducted; 
refer to the IB for additional information on these 
studies. One Phase 3 study in subjects with non-
small cell lung cancer (NSCLC) is ongoing (ARQ 
197-006) and one is completed (ARQ 197-A-
U302). A Phase 3 study in subjects with 
hepatocellular carcinoma (HCC) is ongoing (ARQ 
197-A-U303). Completed and ongoing studies have 
included subjects with colorectal cancer, gastric 
cancer, HCC, microphthalmia transcription factor 
associated tumors, non-central nervous system 
germ cell tumors, NSCLC, and pancreatic 
adenocarcinoma. Approximately 127 healthy 
subjects have received tivantinib in completed 
Phase 1 studies.  Another 2691 subjects with cancer 
have been randomized in ongoing or completed 


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lung cancer (ARQ 197-209), one single agent 
open label study in subjects with 
microphthalmia transcription factor associated 
tumors (ARQ 197-204), one randomized, 
placebo controlled single agent study in 
subjects with unresectable hepatocellular 
carcinoma (ARQ 197-215), one single agent 
open label study in subjects with relapsed or 
refractory germ cell tumors (ARQ 197-A-
U251), and one randomized, placebo controlled 
combination study irinotecan and cetuximab in 
subjects with previously treated wild-type 
KRAS   metastatic colorectal cancer (ARQ 
197-A-U252). In addition, one Phase 2 
randomized, open-label single agent (ARQ 197 
vs. gemcitabine) study (now terminated) was 
conducted in subjects with advanced pancreatic 
carcinoma (ARQ 197-205). 
Phase 1, 2, and 3 studies of tivantinib. Phase 1 and 
Phase 2 studies demonstrated early clinical activity 
of tivantinib as monotherapy and in combination 
with other anticancer agents (including erlotinib, 
sorafenib, gemcitabine, irinotecan, and cetuximab).  
 
Clinical PK data from multiple ARQ 197 
clinical studies demonstrated that the Cmax 
increased with increasing doses of ARQ 197; 
however, the exposure was not dose 
proportional. Inter-subject variability in PK 
appears to be due in part to CYP 2C19 genetic 
polymorphism. In healthy normal volunteers 
(Study ARQ 197-112) the PK of ARQ 197 was 
compared in CYP 2C19 poor metabolizers 
(PMs) vs CYP 2C19 extensive metabolizers 
(EMs).  The study confirmed that CYP 2C19 
PMs had much higher exposure as reflected by 
AUC(0-48) and Cmax (11-fold and 3-fold higher, 
respectively and lower clearance (mean of 2.4 
L/hr versus mean of 33.9 L/hr) than EMs.   
Clinical pharmacokinetic (PK) studies of tivantinib 
have been conducted in 14 Phase 1 studies that 
include 127 healthy subjects and 426 subjects with 
cancer. In general, AUC and Cmax increased with an 
increasing dose of tivantinib, although this increase 
was not dose proportional.  
Following human oral administration with a meal, 
tivantinib is rapidly and almost completely 
absorbed. The drug is extensively metabolized by 
CYP3A4 and CYP2C19 isozymes with no parent 
compound being detected in the urine and only 
traces of parent compound being detected in the 
feces. Tivantinib exposure is affected by the 
following factors: CYP2C19 genotype, history of 
hepatocellular carcinoma, coadministration of a 
CYP3A4 inhibitor, dosage form (i.e., crystalline vs. 
amorphous), formulation (capsule vs. tablet), and 
fed status during tivantinib administration. 
1.1.1 Summary of the Most Common Drug 
Related AEs and SAEs (pp.11-29) 
1.1.1 Safety in Clinical Trials (pp.11-29) 
 
Added 
Tivantinib demonstrated a manageable safety 
profile with adverse drug reactions of 
myelosuppression (including anemia, neutropenia, 
febrile neutropenia, thrombocytopenia, leukopenia, 
pancytopenia, and neutropenic sepsis) and 


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bradycardia. The majority of drug-related adverse 
events (AEs) have been mild to moderate with 
manageable toxicities.  
Myelosuppression 
Myelosuppression (including anemia, neutropenia, 
febrile neutropenia, thrombocytopenia, leukopenia, 
pancytopenia, and neutropenic sepsis) has been 
reported in single agent and combination therapy 
clinical studies of tivantinib.  There have been fatal 
outcomes for some neutropenic events. Complete 
blood count should be performed as advised in the 
protocols.  Caution is advised when any CYP2C19 
inhibitors and/or strong CYP3A4 inhibitors are 
used as concomitant therapy, and in subjects with 
known CYP2C19 poor metabolizer status. Dose 
modifications were made in the HCC studies 
because of higher incidences of neutropenia and 
febrile neutropenia, which were associated with 
higher drug levels in these subjects.  Subjects who 
experience severe myelosuppression including 
neutropenia should be monitored more closely 
throughout the study, and dose modifications or 
interruptions should be made as specified in the 
original protocols. For subjects with severe 
neutropenia, febrile neutropenia, or neutropenic 
sepsis, supportive care, including use of 
haematopoietic growth factors and antibiotics 
should be considered. 
Bradycardia 
Bradycardia has been reported in single agent and 
combination therapy clinical studies of tivantinib. 
In general, bradycardia was most commonly 
reported as a nonserious adverse event. Most of 
these events were mild to moderate in severity 
(Grade 1–2.) Most subjects were asymptomatic and 
recovered without additional therapy, though the 
bradycardic effect may be prolonged. However, 
cases of bradycardia requiring hospitalization have 
been reported, and some subjects received 
placement of permanent pacemakers. 
Subjects who appear to be at a greater risk for 
severe bradycardia are those with pre-existing 
bradycardia or sick sinus syndrome or those 
patients receiving beta-blocker therapy. In these 
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Electrocardiogram (ECG) monitoring is 
recommended prior to initiation of tivantinib 
therapy and is to be repeated at any visit when a 
subject has a heart rate ≤50 beats per minute (bpm), 
or as clinically indicated. In general, heart rate and 
ECG should be monitored as specified in the 
original protocol, and dose reduction should be 
considered for subjects with persistent bradycardia 
and symptomatic hypotension.     
Interstitial Lung Disease 
There have been reports of interstitial lung disease 
(ILD) or similar events in subjects enrolled in 
tivantinib studies. The reported events included 
ILD, pneumonitis, acute respiratory distress 
syndrome, acute lung injury, and diffuse alveolar 
damage.  
In the majority of the reports, tivantinib was given 
in combination with agents with known association 
with ILD, including erlotinib and gemcitabine. An 
association of tivantinib and ILD has not been 
established. However, it is recommended to 
investigate the cause for a marked increase in 
respiratory symptoms in subjects participating in 
tivantinib studies, particularly in Asian patients. 
MONOTHERAPY STUDIES 
ARQ 197-101 
ARQ 197-101 was an open-label study of tivantinib 
in subjects with metastatic solid tumors, including 
renal cell carcinoma (RCC) and other c-MET-
expressing tumors, that were refractory to available 
systemic therapies or for whom no standard 
effective systemic therapy existed. A total of 79 
subjects were enrolled and treated in this study.  
The most common reasons for discontinuing 
treatment were disease progression (59.5%), 
symptomatic deterioration without evidence of 
progression (19.0%), and subject request (10.1%). 
The most common (≥ 10%) AEs were fatigue 
(40.5%), nausea and vomiting (27.8% each), 
anemia/hemoglobin decreased (24.0%), and 
diarrhea (21.5%). One subject had an AE 
(neutropenia) that led to a dose reduction, which 
was considered drug-related. A total of 28 of 79 
(35.4%) subjects reported serious adverse events 
(SAEs).  The most common SAEs were disease 


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progression and dehydration, each experienced by 5 
(6.3%) subjects. There were eight deaths within 
30 days of the last dose of study drugs; five of the 
deaths resulted from disease progression.  The 
other deaths, one each, were due to the following: 
cardio-pulmonary arrest, pancytopenia, and 
respiratory failure. 
ARQ 197-103 
ARQ 197-103 was an open-label study of tivantinib 
in subjects with advanced solid tumors who were 
refractory to available therapy or for whom no 
standard effective systemic therapy existed, 
including subjects with advanced prostate cancer. A 
total of 51 subjects were enrolled and treated in this 
study.  The most common reasons for discontinuing 
treatment were progressive disease (74.5%), AE 
(13.7%), and symptomatic deterioration without 
evidence of progression (5.9%). The most common 
AEs were fatigue (49.0%), nausea (29.4%), anemia 
(27.5%), vomiting (25.5%), anorexia and 
constipation (23.5% each), and back pain and 
weight decreased (21.6% each). Seven (13.7%) 
subjects experienced AEs that led to treatment 
discontinuation. Two subjects discontinued 
treatment due to hyperbilirubinaemia and one 
subject each discontinued treatment due to chest 
infection, infection, fatigue, palmar-plantar 
erythrodysesthesia syndrome, febrile neutropenia, 
and nausea. Serious adverse events were reported 
in 22 (43.1%) subjects.  Serious adverse events 
reported at a ≥ 5% incidence (more than one 
subject) were febrile neutropenia (5.9%) and 
disease progression (9.8%). There were five deaths 
during treatment or within 30 days of the last dose 
of study drug.  All deaths were due to disease 
progression and were judged to be not related to 
study drug. 
ARQ 197-114 
ARQ 197-114 was an open-label study of tivantinib 
in cirrhotic subjects with HCC who had received 
not more than two prior systemic regimens. A total 
of 21 subjects were enrolled and treated in this 
study. The most common reasons for discontinuing 
treatment were progressive disease by Response 
Evaluation Criteria in Solid Tumors (RECIST) 


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(61.9%), clinically unacceptable toxicities (19.0%), 
and clinical disease progression (9.5%). The most 
common AEs were asthenia and neutropenia 
(57.1% each), anemia (52.4%), anorexia (47.6%), 
leukopenia (38.1%), and fatigue, edema peripheral, 
and diarrhea (33.3% each). In this study, AEs 
leading to dose reduction occurred in 4 of 21 
(19.0%) subjects and all were considered to be 
drug-related.  One subject had a dose reduction due 
to neutropenia and anemia. A second subject had 
dose reduction due to bradycardia and dyspnea. A 
third subject had dose reduction due to anemia. The 
fourth subject had a dose reduction due to asthenia. 
Serious adverse events reported for more than one 
subject were neutropenia (three subjects), and 
anemia, leukopenia, and disease progression (two 
subjects each). Five subjects died during treatment 
or within 30 days of the last dose of study drug. 
The cause of death in one subject (septic shock) 
was considered related to study drug. Other deaths 
were considered unrelated to study drug and were 
the result of the following causes: disease 
progression (two subjects), peritoneal hemorrhage 
(one subject), and pneumonia (one subject). 
ARQ 197-A-U157 
ARQ 197-A-U157 was an open-label, randomized, 
two-treatment, two-period, two-way crossover, 
relative bioavailability study of a capsule and a 
tablet formulation of tivantinib in subjects with 
advanced solid tumors. A total of 26 subjects were 
enrolled in the study and 25 (96.2%) completed the 
14-day crossover study phase. One subject 
withdrew from the 14-day crossover study phase 
due to disease progression, and 25 (96.2%) subjects 
continued in the extension phase. Bradycardia was 
reported for 6 of 26 (23.1%) subjects and 6 of 
25 (24.0%) subjects in the cross-over and extension 
phases, respectively; the majority of the events of 
bradycardia were considered related to study 
treatment. Neutropenia was reported for 4 of 25 
(16.0%) subjects in the extension phase; 2 subjects 
had neutropenia that was considered to be study-
drug related. Most of the AEs were Grade 1 or 
Grade 2. Grade ≥3 events in the extension phase of 
the study included anemia, neutropenia, 


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pneumonia, failure to thrive, haemoptysis, 
respiratory failure (Grade 5), lactic acidosis, and 
bone pain, which were experienced by 1 subject 
(4.0%) each, and Grade ≥3 dyspnoea, experienced 
by 2 subjects (8.0%). There were no SAEs reported 
during the crossover phase of the study. During the 
extension phase of the study, four subjects had 
SAEs considered unrelated to study treatment and 
three of these subjects died due to the SAEs, which 
included progressive disease (fatal), respiratory 
failure (fatal), and metastatic NSCLC (fatal). None 
of the deaths were considered related to study 
treatment. 
ARQ 197-0701 
ARQ 197-0701 was an open-label study of 
tivantinib in Japanese subjects with advanced or 
recurrent solid tumors who had been classified as 
extensive metabolizers (EM) or poor metabolizers 
(PM) based on CYP2C19 genotype, including 25 
subjects with NSCLC, and who were refractory to 
available therapy or for whom no standard therapy 
existed. A total of 47 subjects were enrolled and 
treated in the study. The most common reason for 
discontinuing treatment was disease progression 
(43 subjects). Sixteen SAEs were reported in 11 
subjects.  Two SAEs were reported more than once: 
neutrophil count decreased (2 subjects) and white 
blood cell count decreased (2 subjects). No subjects 
died during the study or within 30 days of the last 
dose of study drug. 
ARQ 197-A-U158 
ARQ 197-A-U158 was a Phase 1, open-label, 
single-sequence, crossover study to determine the 
effect of multiple doses of tivantinib on the single-
dose PK of omeprazole/S-warfarin/caffeine/ 
midazolam and digoxin when co-administered with 
tivantinib in cancer subjects. A total of 28 subjects 
were enrolled into the study. All 28 subjects 
completed Probe Reference Treatment and initiated 
tivantinib.  Twenty-two (78.6%) subjects 
completed the Primary Objective Phase. Of the six 
(21.4%) subjects who discontinued from the 
Primary Objective Phase, three (10.7%) 
discontinued due to an AE, two (7.1%) due to other 
reasons, and one (3.6%) due to progressive disease.  


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The most commonly reported AEs were fatigue (7 
[25.0%] subjects), constipation (5 [17.9%] 
subjects), and vomiting (5 [17.9%] subjects). 
Twenty-four SAEs were reported in 13 subjects.  
Disease progression was reported in 4 subjects, 
anemia was reported in 3 subjects, and neutropenia, 
nausea, vomiting, and white blood cell count 
decreased were each reported in 2 subjects. No 
subject died due to an adverse event during the 
Primary Objective Phase of the study or during the 
Extension Phase. Three subjects died after 
completing the Primary Objective Phase and one 
subject died before completing the Primary 
Objective Phase, all due to disease progression.   
ARQ 197-A-U159 
ARQ 197-A-U159 was a single-blind, single-
sequence study assessing the effect of tivantinib on 
the QTc interval in subjects with cancer. A total of 
38 subjects were enrolled in the study; 1 subject 
was discontinued from the study prior to dosing 
with tivantinib.  The remaining 37 (97.4%) subjects 
all completed the Primary Objective Phase.  All of 
the 37 subjects entered the Extension Phase.  Of 
these, 30 received tivantinib in combination with 
one or two other drugs while 7 continued on 
tivantinib monotherapy. Adverse events were 
reported in 37 (97.4%) subjects during the study. 
During the Primary Objective Phase, the most 
commonly (≥ 5% ) reported AEs occurring after 
tivantinib dosing were fatigue (6 [16.2%] subjects), 
nausea (3 [8.1%] subjects), vomiting (2 [5.4%] 
subjects), and headache (2 [5.4%] subjects). During 
the Extension Phase, AEs reported by ≥ 10% of 
subjects included neutropenia (11 [29.7%] 
subjects); nausea, fatigue (9 [24.3%] subjects 
each); diarrhea (8 [21.6%] subjects); constipation, 
dyspnea (7 [18.9%] subjects each); anemia, 
dermatitis acneiform (6 [16.2%] subjects each); and 
decreased appetite, tumor pain, and alopecia 
(5 [13.5%] subjects each).  No subject had an SAE 
during the Primary Objective Phase, and 4 (10.8%) 
subjects experienced SAEs during the Extension 
Phase. No subject was discontinued due to AEs 
during any phase of the study. No subject died 
during the study due to an AE.  One subject died 


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during the Extension Phase due to disease 
progression.   
ARQ 197-004 
ARQ 197-004 was an open-label study of tivantinib 
in gastric cancer subjects following gastrectomy, to 
determine exposure and progression free survival 
(PFS) rate in gastric cancer. A total of 31 subjects 
were enrolled and treated in this study. The most 
common reason for discontinuing treatment was 
progressive disease (27 [87.1%] subjects). The 
most common AEs were anorexia (33.3%), nausea 
(30.0%), alkaline phosphatase increased, anemia, 
and fatigue (each 23.3%), and abdominal pain, 
aspartate aminotransferase (AST) increased, and 
constipation (each 20.0%). There were no deaths 
during study treatment or within 30 days after the 
last dose of study drug.  
ARQ 197-204 
ARQ 197-204 was an open-label study of tivantinib 
in subjects 13 years of age or older with 
histologically or cytologically confirmed MiT 
tumors (alveolar soft part sarcoma, clear cell 
sarcoma, or translocation associated RCC). A total 
of 47 subjects were enrolled and treated in the 
study. The most common reason for discontinuing 
treatment was disease progression (31 [66.0%] 
subjects discontinued due to progressive disease by 
RECIST and 7 [14.9%] subjects discontinued due 
to clinical progression). Of the 47 enrolled subjects, 
18 received tivantinib 120 mg twice daily (BID) 
(capsule formulation), 21 received tivantinib 360 
mg BID (capsule formulation), and 8 initiated 
treatment with tivantinib 120 mg BID and had their 
dose escalated to 360 mg BID. The most common 
(≥ 10%) AEs were the following: fatigue (66.0%), 
nausea (51.1%), vomiting (38.3%), anemia 
(25.5%), cough (25.5%), and bradycardia/sinus 
bradycardia, diarrhea, and headache (21.3% for 
each). Seven subjects (14.9%) experienced 
neutropenia. Six subjects (12.8%) experienced 
leukopenia. One additional event of febrile 
neutropenia was reported as an SAE. In this study, 
2 of 47 (4.3%) subjects discontinued treatment due 
to an AE. One subject in the 360 mg BID treatment 
group experienced thrombocytopenia, and one 


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subject in the 120 mg BID treatment group 
experienced diarrhea, fatigue, headache, and cough. 
In this study, AEs leading to dose reduction 
(neutropenia, leukopenia, and febrile neutropenia) 
occurred in 3 of 47 (6.4%) subjects. Disease 
progression was reported in two subjects during the 
treatment phase of the study. Three subjects had 
SAEs (febrile neutropenia, thrombocytopenia, and 
deep vein thrombosis) that were considered 
possibly related to study treatment; all three of 
these events resolved (the deep vein thrombosis 
resolved with sequelae). There were two deaths 
during the study or within 30 days of the last dose 
of study drug. Both deaths resulted from disease 
progression and were not attributed to study drug. 
ARQ 197-205 
ARQ 197-205 was an open-label study comparing 
tivantinib to gemcitabine in treatment-naïve 
subjects with unresectable locally advanced or 
metastatic pancreatic adenocarcinoma. A total of 43 
subjects were enrolled and randomized in this study 
and 40 subjects received study drug. All subjects in 
the tivantinib group received 120 mg BID (capsule 
formulation) in the fasted state. The most common 
reason for discontinuation was progressive disease 
(12 [63.2%] and 13 [61.9%] subjects in the 
tivantinib and gemcitabine groups, respectively). 
Three subjects (15.8%) and 2 subjects (9.5%) in the 
tivantinib and gemcitabine groups, respectively, 
discontinued treatment due to AEs. The most 
common (≥ 10%) AEs were fatigue (42.1%), 
edema peripheral, anorexia, and ascites (26.3% for 
each), and nausea, abdominal pain, and blood 
alkaline phosphatase increased (21.1% for each). 
Five subjects in the gemcitabine group (23.8%) 
experienced neutropenia and two subjects in the 
gemcitabine group (9.5%) experienced leukopenia.  
There were no events of neutropenia or leukopenia 
in the tivantinib group. There were no events of 
bradycardia reported in this study. There were 13 
subjects (32.5%), 5 (26.3%) in the tivantinib 
treatment arm and 8 (38.1%) in the gemcitabine 
treatment arm, who discontinued treatment due to 
an AE. Adverse events leading to treatment 
discontinuation in the tivantinib arm included 


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ascites (2 subjects), vomiting (1 subject), malignant 
neoplasm progression (1 subject), and cholangitis 
(1 subject). Adverse events leading to treatment 
discontinuation in the gemcitabine arm included 
abdominal pain upper (1 subject), fatigue (3 
subjects), malignant neoplasm progression 
(2 subjects), pneumonia (1 subject), and hip 
fracture (1 subject). Malignant neoplasm 
progression was the most common SAE, occurring 
in 13 (32.5%) subjects; anemia and fatigue were the 
second most common SAEs, occurring in 3 (7.5%) 
subjects each. Thirteen (32.5%) subjects died 
during study treatment or within 30 days of the last 
dose of study drug, including 9 subjects who 
received tivantinib and 4 subjects who received 
gemcitabine. None of the AEs leading to death was 
considered related to treatment. Malignant 
neoplasm was the reason for death for all 9 subjects 
in the tivantinib treatment group.  
ARQ 197-215 
ARQ 197-215 was a randomized, placebo-
controlled study of tivantinib in subjects with HCC 
who had radiographic disease progression after 
systemic first-line therapy or were unable to 
tolerate the therapy. Subjects randomized to 
placebo were given the opportunity to receive 
tivantinib under open-label crossover after they had 
documented radiographic disease progression 
during the double-blind portion.   
Based on healthy volunteer studies and on previous 
clinical trials in subjects with cancer, a dosing 
regimen of crystalline tivantinib at 360 mg BID 
(capsule formulation) was recommended for all 
clinical trials.  Following notification of a Grade 5 
pancytopenia event, a detailed review of all cases 
of Grade ≥ 3 neutropenia was conducted. A review 
of the data identified 10 subjects who developed 
Grade ≥ 3 neutropenia.  Eight severe neutropenia 
events occurred within the first month of treatment 
with study drug; one case occurred in the first week 
of Cycle 2, and one transient Grade 3 neutropenia 
occurred in Cycle 3. Three subjects who developed 
Grade 4 (febrile) neutropenia in Cycle 1 died 
within 30 days from the onset of the event, though 
the study drug was not held as recommended by the 


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revised protocol. The review showed a higher rate 
of Grade ≥ 3 neutropenia, occurring in 
approximately 20% of HCC subjects, compared to 
approximately 5% in the total population of 
subjects who received tivantinib. Based on this 
observation, coupled with the higher exposure 
found in the HCC subject population, the decision 
was made to reduce the dose of tivantinib to 240 
mg BID (capsule formulation) for all subjects in 
this study.  
A total of 107 subjects were enrolled and treated in 
this study. The most common reasons for 
discontinuing treatment during the double-blind 
period were disease progression (68.2%) and death 
(13.1%).  Twenty-three of the 36 subjects who had 
been randomized to the placebo group entered the 
crossover period and were treated with tivantinib. 
The most common (≥ 10%) AEs during the double-
blind period of the study were asthenia (24.3%), 
fatigue (23.4%), decreased appetite (22.4%), 
diarrhea (19.6%), edema peripheral (19.6%), 
neutropenia (18.7%), ascites (16.8%), anemia 
(15.9%), abdominal pain (15.0%), cough (13.1%), 
pyrexia (12.1%), and nausea (11.2%). Severe AEs 
that occurred in at least a 2-fold greater frequency 
in tivantinib-treated subjects compared to placebo-
treated subjects included neutropenia (14.1% 
versus 0) and anemia (12.7% versus 0). The 
frequency of these severe AEs was lower in the 240 
mg BID group compared to the 360 mg BID group 
(neutropenia [6.1% versus 21.1%], anemia [9.1% 
versus 15.8%]). Severe AEs of myelosuppression 
were reported only in the tivantinib treatment 
group. Twenty-one of 107 (19.6%) subjects had 
AEs that led to treatment discontinuation during the 
double-blind period, including 6 of 33 (18.2%) 
subjects in the tivantinib 240 mg BID group, 7 of 
38 (18.4%) subjects in the tivantinib 360 mg BID 
group, and 8 of 36 (22.2%) subjects in the placebo 
group.  The most common AE leading to 
discontinuation from study treatment was disease 
progression (6.5%).Three of 23 (13.0%) subjects 
had AEs that led to treatment discontinuation 
during the crossover period, including asthenia (1 
subject) and disease progression (2 subjects).  
SAEs were reported for 38 of 107 (35.5%) subjects, 


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including 24 of 71 (33.8%) subjects treated with 
tivantinib and 14 of 36 (38.9%) subjects treated 
with placebo. The most common (≥ 5%) SAE 
reported in this study was disease progression 
(7.5%).  In this study, 23 (21.5%) subjects died on 
treatment or within 30 days of the last dose of study 
drug during the double-blind period (13 [18.3%] 
tivantinib-treated subjects and 10 [27.8%] placebo-
treated subjects). The 13 deaths that occurred 
during the double-blind period for tivantinib-treated 
subjects were attributed to the following causes: 
disease progression (4 subjects), neutropenic sepsis 
(3 subjects, including one subject who died both of 
neutropenic sepsis and multiorgan failure), hepatic 
failure (3 subjects), cachexia (1 subject), 
hemorrhage (1 subject), and metabolic acidosis (1 
subject). The 10 deaths that occurred during the 
double-blind period for placebo-treated subjects 
were attributed to the following causes: disease 
progression (4 subjects), cachexia (2 subjects), 
portal hypertension (1 subject), acute coronary 
syndrome and pulmonary edema (1 subject), upper 
gastrointestinal hemorrhage (1 subject), and suicide 
(1 subject). Three of 23 (13.0%) subjects had AEs 
resulting in death during the crossover period, 
including disease progression (2 subjects) and 
hepatic failure (1 subject).   
 
ARQ 197-A-U251 
ARQ 197-A-U251 was an open-label study of 
tivantinib in subjects with relapsed or refractory 
non-central nervous system (CNS) germ cell 
tumors. Twenty-seven subjects were enrolled and 
treated in this study. The primary reason for 
discontinuation was disease progression in 24 
(88.9%) subjects. The most common (≥ 10%) AEs 
were fatigue (37.0%), nausea (25.9%), cough and 
dyspnea (22.2% each), vomiting, edema peripheral, 
and decreased appetite (14.8% each), and 
constipation, back pain, and neuropathy peripheral 
(11.1% each). AEs of Grade 3 or higher occurred in 
12 subjects (44.4%). These included anemia, vision 
blurred, peritoneal hemorrhage, fatigue, 
hypersensitivity, cellulitis, pneumonia, neutrophil 
count decreased, pain in extremity, aphasia, 


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cerebral hemorrhage, headache, hemiplegia, 
paraparesis, sciatica, spinal cord compression, 
syncope, insomnia, cough, dyspnea, and superior 
vena caval occlusion, which were reported in 1 
subject (3.7%) each and back pain, which was 
reported in 2 subjects (7.4%).  The events of 
pneumonia and syncope were considered drug-
related; all other events of Grade 3 or higher were 
considered not related to treatment. Three subjects 
(11.1%) discontinued study treatment due to AEs. 
Three subjects (3.7% each) discontinued study 
treatment due to Grade 2 ascites, Grade 4 cerebral 
hemorrhage, or Grade 3 sciatica.  Of these AEs, 
Grade 4 cerebral hemorrhage and Grade 3 sciatica 
were SAEs.  The primary reason of study treatment 
discontinuation was progressive disease for all 3 
subjects. There were no deaths during treatment or 
within 30 days of the last dose.   
ARQ 197-A-U303 
ARQ 197-A-U303 is an ongoing Phase 3 
randomized, double-blind study of tivantinib in 
subjects with MET diagnostic-high inoperable 
HCC treated with one prior systemic therapy. In 
August 2013, following a higher than expected 
incidence of neutropenia-related adverse events, the 
study Data Monitoring Committee (DMC) 
evaluated all available unblinded data including 
preliminary pharmacokinetics. The DMC advised 
that the tivantinib starting dose should be reduced 
to 120 mg BID (tablet formulation). The protocol 
was amended accordingly and enrollment 
continues. This study remains blinded. 
COMBINATION THERAPY STUDIES 
ARQ 197-111 
ARQ 197-111 was an open-label study of tivantinib 
in combination with erlotinib, in subjects with 
locally advanced or metastatic solid tumors that had 
progressed after at least one prior treatment 
regimen. A total of 32 subjects were enrolled and 
treated in this study. Progressive disease (23 
[71.9%] subjects) was the most common reason for 
treatment discontinuation. The most common (≥ 
10%) AEs were fatigue (37.5%), nausea (31.3%), 
diarrhea (28.1%), bradycardia/sinus bradycardia 
(28.1%), abdominal pain (28.1%), and anemia 


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(21.9%). There were 14 events of 
myelosuppression (7 anemia, 3 neutropenia, 2 
thrombocytopenia, 1 lymphopenia, and 1 
leukopenia) reported in 9 subjects. Among them, 
10 events (5 anemia, 3 neutropenia, 1 
thrombocytopenia, and 1 leukopenia) occurred in 6 
subjects and were considered drug-related. Thirteen 
of the 15 events (86.7%) occurred when subjects 
were receiving tivantinib at a dose of 360 mg BID 
(capsule formulation). In this study, a total of 14 
cardiac events (9 sinus bradycardia, 2 bradycardia, 
1 cardio-respiratory arrest, 1 palpitations, and 1 
sick sinus syndrome) were reported in 10 subjects. 
The majority of bradycardia events were 
asymptomatic and resolved. Five of 9 subjects with 
sinus bradycardia, bradycardia, or sick sinus 
syndrome had a history of bradycardia and/or an 
abnormal ECG finding of sinus arrhythmia at 
baseline. Three severe cardiac-related events 
occurred in 3 subjects including one Grade 3 sinus 
bradycardia, one Grade 3 sick sinus syndrome, and 
one Grade 5 cardiac arrest. AEs leading to 
treatment discontinuation occurred in 7 of 32 
(21.9%) subjects. Four of the 7 subjects were 
discontinued from study medication due to 5 
possible or probable drug-related AEs (neutropenia, 
hypoglycemia, fatigue, nausea, and vomiting). Two 
of the 8 (25%) AEs that resulted in study drug 
discontinuation were SAEs: one of life-threatening 
severity (neutropenia Grade 4) and the other that 
resulted in death (disease progression Grade 5). 
Other AEs leading to treatment discontinuation 
were comprised of hypoglycemia, 
hyperbilirubinemia, and pleural effusion, each 
occurring in 1 subject. Two of 32 (6.3%) subjects 
had AEs (both fatigue) that led to treatment 
reductions. One of the events of fatigue was 
considered to be related to study drug. Serious 
adverse events were reported for 13 subjects.  
There were no predominant SAEs, although disease 
progression was reported most often (3 of 32 
subjects [9.4%]).  There were three SAEs involving 
cardiac events, sinus bradycardia, cardio-
respiratory arrest, and sick sinus syndrome and 2 
reports of syncope possibly related to bradycardia. 
Five of 32 subjects (15.6%) had 6 SAEs that were 


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considered related to combination treatment, 
including sinus bradycardia (Grade 3) in one 
subject, sick sinus syndrome (Grade 3) in one 
subject, neutropenia (Grade 4) in one subject, 
neutropenia and leukopenia (both Grade 4) in one 
subject, and syncope (Grade 3) in one subject. Six 
(18.8%) deaths occurred during the study or within 
30 days of study treatment.  All deaths were 
considered by Investigators to be not related to 
combination treatment and were the result of the 
following: cardiac arrest (1), disease progression 
(3), hepatic failure (1), and dyspnea (1). 
ARQ 197-116 
Study ARQ 197-116 was a study of tivantinib in 
combination with sorafenib in subjects with solid 
tumors, including RCC, HCC, NSCLC, and 
melanoma. A total of 87 subjects were enrolled and 
treated in this study. The most common reason for 
discontinuing treatment was progressive disease 
(71.3% for radiographic progression and 6.9% for 
clinical progression). The most common (≥ 20% of 
subjects) AEs were diarrhea (46%), fatigue 
(43.7%), rash (43.7%), anorexia (39.1%), weight 
decreased (37.9%), hypophosphatemia (28.7%), 
alopecia (27.6%), hyperglycemia (26.4%), nausea 
(25.3%), hypertension (24.1%), vomiting (21.8%), 
hypernatremia (21.8%), palmar-plantar 
erythrodysesthesia syndrome (21.8%), and 
lymphopenia (20.7%). The distribution of AEs was 
similar among all cancer types. The drug-related 
AEs reported most frequently (≥ 20% of subjects) 
were rash (40.2%), diarrhea (37.9%), anorexia 
(33.3%), fatigue (31.0%), alopecia (25.3%), 
palmar-plantar erythrodysesthesia syndrome 
(21.8%), and weight decreased (20.7%). Severe 
AEs (≥ Grade 3) were experienced by 61 (70.1%) 
of the 87 subjects.  The severe AEs occurring in ≥ 
5% of subjects were hypertension (11.5%), palmar-
plantar erythrodysesthesia syndrome (8%), fatigue 
(6.9%), hyponatremia (6.9%), hypophosphatemia 
(6.9%), disease progression (5.7%), 
hyperbilirubinemia (5.7%), pneumonia (5.7%), 
hyperuricemia (5.7%), and rash (5.7%). Serious 
adverse events including deaths were reported by 
33 (37.9%) of the 87 subjects in the study. 


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Infections and infestations, gastrointestinal 
disorders, and general disorders and administration 
site conditions were the most frequent system 
organ classes (SOC) with 9.2%, 8.0%, and 6.9% of 
subjects, respectively. There were 9 subjects with 
AEs that led to death: 3 with HCC, 2 with lung 
cancer, and 1 each with RCC, melanoma, breast 
cancer, or other cancer (adenocarcinoma of the 
esophagus). In four of these subjects, the AE 
leading to death was progressive disease.   
ARQ 197-117 
ARQ 197-117 was an open-label study of tivantinib 
in combination with gemcitabine in subjects with 
locally advanced, inoperable, or metastatic primary 
solid tumors, including breast cancer, 
cholangiocarcinoma, ovarian cancer, and pancreatic 
cancer. A total of 74 subjects were enrolled and 
treated in this study. The most common reason for 
discontinuing tivantinib and gemcitabine treatments 
was radiographically confirmed disease progression 
(42 [56.8%] and 40 [54.1%], respectively). The 
most common AEs were thrombocytopenia (56 
[75.7%] subjects), anemia (54 [73.0%] subjects), 
neutropenia (51 [68.9%] subjects), fatigue (43 
[58.1%] subjects), and nausea (39 [52.7%] 
subjects). Severe AEs (≥ Grade 3) were 
thrombocytopenia (22 [29.7%] subjects), anemia 
(28 [37.8%] subjects), neutropenia (32 [43.2%] 
subjects), leukopenia (5 [6.8%] subjects), febrile 
neutropenia (3 [4.1%] subjects), and pancytopenia 
(1 [1.4%] subjects). There were 19 cardiac events 
(4 tachycardia, 3 palpitations, 2 atrial fibrillation, 2 
congestive cardiac failure, 1 acute myocardial 
infarction, 1 atrial flutter, 1 bradycardia, 1 
cardiomyopathy, 1 cardiopulmonary failure, 1 
cyanosis, 1 left ventricular failure, and 1 mitral 
valve incompetence) reported in 12 subjects. 
Overall, 1 of 74 (1.4%) subjects experienced 
bradycardia, 2 (2.7%) experienced atrial 
fibrillation, 3 (4.1%) experienced palpitations, and 
3 (4.1%) experienced tachycardia. At the time of 
the last recorded evaluation, 11 of the 19 (57.9%) 
cardiac-related events were resolved, 7 (36.8%) 
were ongoing, and 1 (5.3%) subject died. 
Seventeen of 74 (23.0%) subjects had a total of 21 


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AEs that led to treatment discontinuation. Seven of 
the 17 subjects discontinued due to 
myelosuppressive events, including neutropenia (4 
subjects), thrombocytopenia (2 subjects), anemia (2 
subjects), and febrile neutropenia (1 subject). Other 
AEs leading to study drug discontinuation were 
single events each of breast cancer, wound 
complication, bacteremia, gastrointestinal 
hemorrhage, sepsis, fatigue, acute respiratory 
failure, dyspnea, respiratory failure, disease 
progression, small bowel obstruction, and 
pneumonitis. Four of 74 (5.4%) subjects each had 
one tivantinib dose reduction during the study 
period, from 360 mg BID to 240 mg BID (capsule 
formulation). Adverse events leading to dose 
reductions in these 4 subjects included neutropenia 
(3 subjects) and fatigue (1 subject).  All four 
subjects were among the 32 subjects who 
experienced AEs leading to a reduction in 
gemcitabine. All dose reductions for gemcitabine 
were due to myelosuppressive AEs. Serious 
adverse events were reported for 39 of 74 (52.7%) 
subjects.  The most commonly reported SAEs were 
anemia (6 [8.1%] subjects) and disease progression 
(9 [12.2%] subjects. Overall, 15 (20.3%) deaths 
occurred during study treatment or within 30 days 
of the last dose, which resulted from the following: 
disease progression (8 subjects), acute respiratory 
failure (1 subject), cardiopulmonary failure (1 
subject), hepatic failure (1 subject), neutropenia (1 
subject), sepsis (1 subject), upper gastrointestinal 
hemorrhage (1 subject), and death (1 subject).    
ARQ 197-209 
ARQ 197-209 was a randomized, double-blind 
study of erlotinib plus tivantinib treatment 
compared with erlotinib plus placebo, in subjects 
with inoperable locally advanced or metastatic 
(Stage IIIB/IV) NSCLC who had received at least 
one prior chemotherapy regimen (other than 
erlotinib or other EGFR-inhibiting agents). A total 
of 167 subjects enrolled in this study; 84 subjects 
received erlotinib plus tivantinib and 83 subjects 
received erlotinib plus placebo during the double-
blind period. Thirty-five of 83 (42.2%) subjects 
who had initiated treatment with erlotinib plus 


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placebo crossed over to receive erlotinib plus 
tivantinib. The most common AEs reported in the 
tivantinib combination arm group were rash 
(65.5%), diarrhea (47.6%), fatigue (33.3%), 
anorexia (28.6%), nausea and vomiting (26.2% 
each), and pruritus, dry skin, and dyspnea (22.6%, 
each). Neutropenia was experienced by 8 subjects 
in this study who were treated with erlotinib plus 
tivantinib. No neutropenia events were experienced 
by subjects during erlotinib plus placebo treatment. 
Sinus bradycardia was reported for 3 of 84 (3.6%) 
subjects randomized to the tivantinib combination 
arm (2 drug-related), and 2 of 35 (5.7%) additional 
subjects treated with erlotinib plus tivantinib during 
the crossover period (1 drug-related), for a total of 
5 of 119 (4.2%) subjects treated with erlotinib plus 
tivantinib in the study (3 drug-related). Bradycardia 
was reported for 1 of 84 (1.2%) subjects in the 
randomized tivantinib combination arm (considered 
drug-related) and 1 of 35 (2.9%) subjects in the 
crossover population (not drug-related), for a total 
of 2 of 119 (1.7%) subjects treated with erlotinib 
plus tivantinib. Adverse events leading to treatment 
discontinuation were reported for 18 of 84 (21.4%) 
subjects randomized to the tivantinib combination 
arm and 17 of 83 (20.5%) subjects randomized to 
the placebo combination arm, including 7 of 35 
(20.0%) subjects randomized to the placebo 
combination arm who crossed over to receive the 
tivantinib combination treatment. Three subjects 
had dose reductions, 1 subject in the erlotinib plus 
tivantinib group (due to Grade 3 diarrhea, Grade 3 
vomiting, and Grade 2 nausea) and 2 in the 
erlotinib plus placebo group (due to Grade 2 rash 
pustular in one subject and due to Grade 4 diarrhea, 
Grade 3 dehydration, Grade 3 renal failure acute, 
and Grade 3 palmar-plantar erythrodysesthesia 
syndrome in another subject). In this study, 74 
subjects (44.3%) experienced SAEs. The most 
common SAE in both treatment arms was disease 
progression, reported for 6 (7.1%) and 7 (8.4 %) 
subjects in the tivantinib and placebo combination 
arms, respectively. Adverse events with an 
outcome of death were reported in 38 subjects 
(22.8%) during study treatment or within 30 days 
of the last dose of the study drug; 17 (20.2%) 


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deaths occurred in subjects randomized to the 
tivantinib combination arm and 21 (25.3%) 
occurred in subjects randomized to the placebo 
combination arm, including 7 subjects who died 
after crossing over to the tivantinib combination 
arm. The most frequent cause of death in the 
tivantinib combination and crossover subjects was 
disease progression (9 subjects). Among subjects in 
the tivantinib combination arm, 2 subjects died due 
to AEs considered at least possibly related to both 
tivantinib and erlotinib (leukopenia and 
pneumonia).    
ARQ 197-A-U252 
ARQ 197-A-U252 was a Phase 1/2 study of 
tivantinib in combination with irinotecan and 
cetuximab in subjects with colorectal cancer with 
wild-type KRAS. A total of 131 subjects enrolled 
in this study and 130 were treated. The primary 
reason for discontinuing treatment was progressive 
disease (79 [60.3%]). All 130 treated subjects 
(100%) in both Phase 1 and Phase 2 experienced at 
least one AE. In Phase 1, the most common AEs 
were fatigue (77.8%), nausea and rash (66.7% 
each), and diarrhea and alopecia (55.6% each). In 
Phase 2, the most common AEs that occurred in 
either treatment group were rash, diarrhea, and 
nausea. The most common AEs reported in the 
tivantinib combination arm were rash (59.2%), 
diarrhea (53.5%), nausea (46.5%), fatigue (43.7%), 
vomiting (33.8%), neutropenia (31.0%), and 
infections and infestations (29.6%). The 
proportions of placebo-treated subjects versus the 
proportions of tivantinib-treated subjects with any 
grade of myelosuppression events were as follows: 
febrile neutropenia (1.7 % vs. 1.6%), leukopenia 
(5.1% vs. 8.1%), and thrombocytopenia (1.7% vs. 
8.1%). Among cardiac disorder AEs of special 
interest, bradycardia and sinus bradycardia were 
reported by 0% of placebo-treated subjects vs. 
3.2% (bradycardia) and 4.8% (sinus bradycardia) of 
tivantinib-treated subjects and atrial fibrillation was 
reported by 0% of placebo-treated subjects vs. 
3.2% of tivantinib-treated subjects. Acute renal 
failure was reported by 0% of placebo-treated 
subjects and 3.6% of tivantinib-treated subjects 


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during Phase 2. In Phase 1, two subjects 
discontinued study drug because of an AE. In 
Phase 2, a higher proportion of tivantinib-treated 
subjects than placebo-treated subjects discontinued 
study drug due to an AE (19.4% vs. 11.9%). The 
most common AEs leading to discontinuation of 
study treatment were neutropenia and rash. One 
subject each had serious Grade 4 unrelated AEs of 
renal failure (acute), respiratory failure, or 
urosepsis that led to discontinuation from study 
medication. No deaths were reported for any of the 
9 subjects in the Phase 1 portion of the study. In 
Phase 2, two subjects in each treatment group died 
within 30 days of the end of study drug 
administration due to a SAE. An additional 3 
subjects in each treatment group died due to disease 
progression after that time period. No AEs leading 
to death were considered related to study drug.   
ARQ 197-A-U302 
ARQ 197-A-U302 was a randomized, double-
blinded, placebo-controlled study of tivantinib in 
combination with erlotinib in subjects with locally 
advanced or metastatic, non-squamous NSCLC. 
The study enrolled 1048 subjects, and 1037 
subjects were included in the safety analysis. Nine 
hundred seventy-eight (93.3%) subjects 
discontinued treatment. The most common reason 
for discontinuation was progressive disease; 645 
(61.5%) subjects discontinued for radiographically 
confirmed progressive disease and another 90 
(8.6%) subjects discontinued for clinical disease 
progression. Adverse events were the reason for 
discontinuation for 113 (10.8%) subjects. The most 
common AEs within the erlotinib plus tivantinib 
(ET) and the erlotinib plus placebo (EP) groups 
were diarrhea (ET: 34.6%, EP: 41.0%), rash (ET: 
33.1%, EP: 37.3%), decreased appetite (ET: 29.0%, 
EP: 28.8%), dyspnea (ET: 26.2%, EP: 22.6%), and 
fatigue (ET: 26.2%, EP: 21.9%). The AEs 
indicative of myelosuppression were more frequent 
in the ET group compared with the EP group: 
neutropenia by any preferred term (ET: 13.8%, EP: 
2.3%), febrile neutropenia (ET: 3.3%, EP: 0.4%), 
leukopenia (ET: 5.8%, EP: 1.0%), and anemia by 
any preferred term (ET: 16.7%, EP: 10.3%). The 


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occurrence of these AEs at a severity of ≥ Grade 3 
was also more common in the ET group. 
Bradycardia was reported in 2.7% of subjects in the 
ET group and in no subjects in the EP group; 
however, only 2 of the 14 cases in the ET group 
were of Grade 3 or higher severity. Overall, 138 
subjects (79 subjects [15.2%] in the tivantinib 
combination arm, 59 subjects [11.4%] in the 
placebo combination arm) were discontinued from 
treatment because of AEs. Overall, there were 410 
(39.5%) subjects with SAEs reported during the 
study; the most commonly reported SAEs were 
respiratory events including dyspnea and 
pulmonary embolism, reported in 5.2% and 3.4% 
of subjects overall. Overall, 614 subjects died 
during the study or within 30 days of the last dose 
of study drug, most frequently as the result of 
disease progression as attributed by the 
Investigator. A total of 142 subjects had deaths 
associated with AEs: ET: 77 subjects, EP: 65 
subjects. However, the Investigator ultimately 
determined that many of these AEs were part of the 
underlying disease and attributed the deaths to 
disease progression. Using this revised Investigator 
attribution, 66 subjects died as a result of AEs 
(other than disease progression): ET: 32 subjects; 
EP: 34 subjects. Of these deaths associated with 
AEs (other than disease progression), the most 
common AEs were respiratory failure (ET: 5 
subjects, EP: 6 subjects), sepsis or septic shock 
(ET: 5 subjects, EP: 1 subject), and pneumonia or 
bronchopneumonia (ET: 3 subjects, EP: 5 subjects). 
Five deaths in the ET group and 3 deaths in the EP 
group were considered by the Investigator to be 
related to tivantinib/placebo.   
Detailed data describing the clinical administration 
of tivantinib and complete safety information can 
be found in the Tivantinib Investigator’s Brochure.0 
As of 01 May 2009, 175 subjects with solid tumors had been treated with ARQ 197 monotherapy.  
The most common adverse events (AEs) (≥10% of subjects) are listed in Table 1.1. 
Deleted 
Table 1.1. Number and Percent of ARQ 197 (Single Agent)-Treated Subjects with Solid 
Tumors with AEs that Occurred in 10% or More of Subjects 


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MedDRA System Organ Class 
Preferred term 
ARQ 197 
(N=175) 
n (%) 
General disorders and administration site 
conditions 
Fatigue 
75 (42.9) 
Pyrexia 
21 (12.0) 
Oedema peripheral 
20 (11.4) 
Gastrointestinal disorders 
Nausea 
50 (28.6) 
Vomiting 
37 (21.1) 
Diarrhoea 
27 (15.4) 
Abdominal pain 
18 (10.3) 
Metabolism and nutrition disorders 
Anorexia 
28 (16.0) 
Musculoskeletal and connective tissue disorders 
Back pain 
19 (10.9) 
Respiratory, thoracic and mediastinal disorders 
Dyspnoea 
32 (18.3) 
Blood and lymphatic system disorders 
Anaemia 
75 (42.9) 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities  
The most common drug-related AEs (≥5% and ≥2 events) for ARQ 197 monotherapy are listed in 
Table 1.2. 
Table 1.2. Number and Percent of ARQ 197 Treated Subjects with Solid Tumors with Related 
AEs that Occurred in 5% or More of Subjects (≥2 Events) 
MedDRA System Organ Class 
Preferred term 
ARQ 197 
(N=175) 
n (%) 
Gastrointestinal disorders 
Nausea 
32 (18.3) 
Vomiting 
16 (9.1) 
Diarrhoea 
11 (6.3) 
General disorders and administration site 
conditions 
Fatigue 
35 (20.0) 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities  
A total of 17 drug-related serious adverse events (SAEs) occurred in nine (5.1%) of these 175 
subjects (Table 1.3).  Among them, seven SAEs in five (2.9%) subjects were myelosuppression 
events, including febrile neutropenia, neutropenia, leucopenia and thrombocytopenia; five SAEs in 
two (1.1%) subjects were gastrointestinal disorders, and the other five SAEs in four (2.3%) subjects 
were disorders belonging to other system organ classes.  All myelosuppression events occurred in 
subjects treated at a dose of 360 mg BID or higher. 
Table 1.3. Number and Percent of Subjects with Solid Tumors Treated with ARQ 197 
Monotherapy Who Had Drug-Related SAEs  
MedDRA System Organ Class 
Preferred term 
ARQ 197 
(N=175) 
n (%) 
Dose Level 
(mg BID) 


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Blood and lymphatic system disorders 
Febrile neutropenia 
3 (1.7) 
360, 400, 400 
Neutropenia 
1 (0.6) 
360 
Leukopenia 
1 (0.6) 
360 
Thrombocytopenia 
2 (1.1) 
360, 360 
Gastrointestinal disorders 
Nausea 
2 (1.1) 
120, 360 
Vomiting 
2 (1.1) 
120, 360 
Abdominal pain 
1 (0.6) 
120 
Other system organ classes 
Dehydration 
1 (0.6) 
360 
Fatigue 
1 (0.6) 
200 
Palmar-plantar 
erythrodysaesthesia 
syndrome 
1 (0.6) 
400 
Hepatic failure 
1 (0.6) 
120 
Mucosal 
inflammation 
1 (0.6) 
400 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities 
 Among the 175 subjects with tumors treated with ARQ 197 monotherapy as of 01 May 2009, a total 
of three events of drug-related febrile neutropenia (all Grade 3), three events of drug-related 
neutropenia (Grade 2, Grade 3 and Grade 4), and one event of drug-related leucopenia (Grade 4) 
occurred in six (3.4%) subjects.  One event of Grade 3 neutropenia occurred in one subject treated at 
150 mg BID, and the other six events (one Grade 2, three Grade 3 and two Grade 4) occurred in five 
subjects treated at doses of 300 mg BID or higher.  All events were reversible.  Three events of drug-
related thrombocytopenia occurred in three (1.7%) subjects; one of these events of thrombocytopenia 
was Grade 3, and the other two were Grade 4.  All three subjects were treated at a dose of 360 mg 
BID or 400 mg BID.  All events were reversible. 
A total of 16 episodes (all Grade 1) of sinus bradycardia/bradycardia (15 sinus bradycardia, one 
unspecified bradycardia) were reported in five of 175 (2.9%) subjects. Fourteen of 16 episodes 
occurred in three subjects treated at 360 mg BID continuously, and the other two episodes occurred in 
two subjects treated at 120 mg BID continuously.  As of 01 May 2009, 14 of 16 were resolved and 
two were ongoing. 
As of 01 May 2009, 111 subjects with solid tumors had been treated with ARQ 197/placebo 
(ARQ 197-209 study) or in combination with another drug (ARQ 197-111 study).  The most common 
ARQ 197/placebo-related or combination-related AEs (≥ 5% and ≥2 events) are listed in Table 1.4. 
Table 1.4:  Number and Percent of the Most Common Related Adverse Events in Subjects with 
Solid Tumors in Combination Studies 
 
 
No. Subjects (%) (N=111) 
 
 
ARQ 197-111 
ARQ 197-209 
Total 
MedDRA System Organ 
Class (SOC) 
MedDRA preferred 
term 
(N=32) 
(N=79) 
(N=111) 
Skin and subcutaneous 
tissue disorders 
Rash 
6( 18.8) 
26(32.9) 
32 
(28.8) 


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Table 1.4:  Number and Percent of the Most Common Related Adverse Events in Subjects with 
Solid Tumors in Combination Studies 
 
 
No. Subjects (%) (N=111) 
 
 
ARQ 197-111 
ARQ 197-209 
Total 
MedDRA System Organ 
Class (SOC) 
MedDRA preferred 
term 
(N=32) 
(N=79) 
(N=111) 
 
Dermatitis acneiform 
4( 12.5) 
6( 7.6) 
10 (9.0) 
 
Pruritus 
5( 15.6) 
2 (2.5) 
7 (6.3) 
Gastrointestinal disorders 
Diarrhoea 
6( 18.8) 
9(11.4) 
15 
(13.5) 
 
Nausea 
4( 12.5) 
3 (3.8) 
7 (6.3) 
General disorders and 
administration site 
conditions 
Fatigue 
8( 25.0) 
5( 6.3) 
13 
(11.7) 
Cardiac disorders 
Sinus bradycardia 
/bradycardia 
8 (25.0) 
1 (1.3) 
9 (8.1) 
Blood and lymphatic 
system disorders 
Anaemia 
4( 12.5) 
2 (2.5) 
6 (5.4) 
Metabolism and nutrition 
disorders 
Anorexia 
2(  6.3) 
4( 5.1) 
6 (5.4) 
 
Decrease appetite 
0 (0.0) 
8(10.1) 
8 (7.2) 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnoea 
0 (0.0) 
6( 7.6) 
6 (5.4) 
 
A total of 20 ARQ 197/placebo related (in ARQ 197-209 study) or combination-related (in 
ARQ 197-111 study) SAEs occurred in 11 (9.9%) subjects in these two combination studies.  Among 
them, seven events in five (4.5%) subjects were myelosuppression events including one anaemia, two 
neutropenia, one neutrophils/ANC (G4), one leukopenia, and one thrombocytopenia; two events of 
dehydration in two subjects, two events of diarrhoea in two subjects, two events of pulmonary 
embolism in two subjects, two events of sinus bradycardia in two subjects, and one event each of 
pneumonia, vomiting, septic knee, recurrent left knee pain and acute renal failure (Table 1.5).  All 
ARQ 197/placebo-related or combination-related SAEs occurred in subjects treated with ARQ 197 at 
dose of 360 mg BID and erlotinib at dose of 150 mg QD except one sinus bradycardia in a subject 
treated with ARQ 197 at 240 mg BID and erlotinib at 150 mg QD.


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Table 1.5:  Drug-Related SAEs in Two Combination Studies of ARQ 197 and Erlotinib 
Study 
ID 
Subject 
ID 
ARQ 197 
dose at 
time of 
event 
(mg BID) 
Erlotinib 
dose at 
time of 
event 
(mg QD) 
Event 
Relationship 
to ARQ 197/ 
placebo 
and/or 
erlotinib 
CTCAE 
Grade 
Outcome 
209 
360 
150 
Acute renal failure 
Related 
3 
Resolved 
with 
Sequelae 
209 
360 
150 
Anaemia 
Related 
4 
Resolved 
209 
360 
150 
Dehydration 
Related 
4 
Resolved 
with 
Sequelae 
209 
360 
150 
Dehydration 
Related 
3 
Resolved 
209 
360 
150 
Diarrhoea 
Related 
4 
Resolved 
with 
Sequelae 
209 
360 
150 
Diarrhoea 
Related 
3 
Ongoing 
209 
360 
150 
Leucopenia 
Related 
5 
Death 
111 
360 
150 
Leukocytes 
Related 
4 
Resolved 
209 
360 
150 
Neutropenia 
Related 
4 
Ongoing 
111 
360 
150 
Neutropenia 
Related 
4 
Resolved 
111 
360 
150 
Neutrophils/anc 
Related 
4 
Resolved 
209 
360 
150 
Pneumonia 
Related 
5 
Death 
209 
360 
150 
Pulmonary 
embolism 
Related 
5 
Death 
209 
360 
150 
Pulmonary 
embolism 
Related 
4 
Resolved 
209 
360 
150 
Recurrent left 
knee pain 
Related 
3 
Unknown 
209 
360 
150 
Septic knee 
Related 
3 
Ongoing 
209 
360 
150 
Sinus bradycardia 
Related 
2 
Resolved 
111 
240 
150 
Sinus bradycardia 
Related 
3 
Resolved 
with Seq. 
111 
360 
150 
Thrombocytopenia 
Related 
3 
Resolved 
209 
360 
150 
Vomiting 
Related 
3 
Resolved 
with 
Sequelae 
 
As of 01 May 2009, there were 32 subjects enrolled and treated with ARQ 197 in ARQ 197-111 
study (Phase 1 study of ARQ 197 in combination with erlotinib). As of 12 May 2009, there were 
79 subjects enrolled and treated with ARQ 197 or placebo (there subjects have 50% chance to 
receive placebo) in ARQ 197-209 study (Phase 2 randomized and blinded study of ARQ 197 in 
combination with erlotinib). In total, 111 subjects have received combination treatment of ARQ 
197/placebo and erlotinib. Among them a total of 18 events of myelosuppression (nine anaemia, 
three thrombocytopenia, two neutropenia, one neutrophils/ANC, one leucopenia, one leukocytes, 
one lymphopenia) were reported in 12 (10.8%) subject (Table 1.6) of which 13 events (seven 
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anaemia,  two neutropenia, one neutrophils/ANC, one leukopenia, one leukocytes, and one 
thrombocytopenia) in nine (8.1%) subjects were reported to be related to ARQ 197/placebo or to 
combination treatment. Seven drug-related events were resolved, five were ongoing and the 
outcome was death for the other event (leucopenia). All events occurred when subjects receiving 
ARQ 197/placebo at 360 mg BID and erlotinib at 150 mg QD. 
A total of nine events of anaemia were reported in these two studies of which seven events (six 
Grade 2 and one Grade 4) in six (5.4%) subjects were related to ARQ 197/placebo or to 
combination studies. All subjects were treated with ARQ 197 at dose of 360 mg BID and 
erlotinib at 150 mg QD. Four of seven ARQ 197/placebo or combination treatment-related events 
were ongoing and three resolved.  
Anaemia 
A total of five events (two neutropenia (both Grade 4), one neutrophils (Grade 4), one leucopenia 
(Grade 5) and one leukocytes (Grade 4)) were reported in three subjects in these two studies.  All 
five events were related to ARQ 197/placebo or combination treatment. All three subjects were 
receiving ARQ 197/placebo at dose of 360 mg BID and erlotinib at 150 mg QD when these 
events occurred. Three events (one neutropenia, one neutrophils, one leukocytes) were resolved, 
one event (neutropenia) was ongoing. The outcome of the event of leucopenia was death.  
Neutropenia/leucopenia 
A total of three events (one Grade 2, one Grade 3 and one Grade 5) of thrombocytopenia were 
reported in three subjects in these two studies. Of which one event in one subject (Grade 3) was 
considered to be related to combination treatment. All subjects were treated with ARQ 197 at 
dose of 360 mg BID and erlotinib at dose of 150 mg QD. The related event was resolved. 
Thrombocytopenia 
Table 1.6:  List of Subjects with Myelosuppression AEs in Two Combination Studies of 
ARQ 197 and Erlotinib 
Study 
Number 
Subject 
ID 
ARQ 
197 
dose 
at 
time 
of 
event 
(mg 
BID) 
Erlotinib 
dose at 
time of 
event 
(mg QD) 
Event 
Worst 
NCI 
Grade 
Relationship 
to ARQ 197 
/placebo 
Relationship 
to erlotinib 
Outcome 
111 
360 
150 
Anaemia 
2 
Related 
Related 
Ongoing 
111 
360 
150 
Anaemia 
1 
Unrelated 
Unrelated 
Ongoing 
111 
360 
150 
Anaemia 
2 
Related 
Related 
Ongoing 
111 
360 
150 
Anaemia 
2 
Unrelated 
Unrelated 
Ongoing 
111 
360 
150 
Anaemia 
2 
Related 
Related 
Resolved 
111 
360 
150 
Anaemia 
2 
Related 
Related 
Resolved 
111 
360 
150 
Anaemia 
2 
Related 
Related 
Ongoing 
209 
360 
150 
Anaemia 
2 
Related 
Related 
Ongoing 
209 
360 
150 
Anaemia 
4 
Related 
Unrelated 
Resolved 
209 
360 
150 
Leukopenia 
5 
Related 
Related 
Death 
111 
360 
150 
Leukocytes 
4 
Related 
Related 
Resolved 
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Table 1.6:  List of Subjects with Myelosuppression AEs in Two Combination Studies of 
ARQ 197 and Erlotinib 
Study 
Number 
Subject 
ID 
ARQ 
197 
dose 
at 
time 
of 
event 
(mg 
BID) 
Erlotinib 
dose at 
time of 
event 
(mg QD) 
Event 
Worst 
NCI 
Grade 
Relationship 
to ARQ 197 
/placebo 
Relationship 
to erlotinib 
Outcome 
111 
360 
150 
Lymphopenia 
2 
Unrelated 
Unrelated 
Resolved 
111 
360 
150 
Neutropenia 
4 
Related 
Related 
Resolved 
209 
360 
150 
Neutropenia 
4 
Related 
Unrelated 
Ongoing 
111 
360 
150 
Neutrophils/ANC 
4 
Related 
Related 
Resolved 
111 
360 
150 
Thrombocytopenia 
5 
Unrelated 
Unrelated 
Death 
111 
360 
150 
Thrombocytopenia 
2 
Unrelated 
Unrelated 
Resolved 
111 
360 
150 
Thrombocytopenia 
3 
Related 
Related 
Resolved 
 
Among the 111 subjects enrolled and treated in the two ARQ 197 combination studies of 
ARQ 197 and erlotinib (ARQ 197-111 [N=32] and ARQ 197-209 [N=79]),  total of 12 episodes 
(eight Grade 1, three Grade 2 and one Grade 3) of sinus bradycardia/bradycardia (nine sinus 
bradycardia, three unspecified) were reported in nine (8.1%) subjects. All 12 events were related 
to ARQ 197 and 11 events were also related to erlotinib (Table 1.7).  
Five drug-related episodes occurred in four subjects treated with ARQ 197 at 360 mg BID, three 
events occurred in two subjects treated at 240 mg BID, and the other four events occurred in four 
subjects treated at 120 mg BID. All subjects received erlotinib at 150 mg QD. Eight events were 
resolved and four were ongoing. 
Table 1.7:  Sinus Bradycardia/Bradycardia in Two Combination Studies of ARQ 197 and 
Erlotinib 
Study 
Number 
Subject 
ID 
Dose of 
ARQ 
197/ 
placebo 
at time of 
event 
(mg BID) 
Dose of 
erlotinib 
at time 
of event 
(mg QD) 
Event 
 
CTCAE 
Grade 
Relationship 
to ARQ 197 
Relationship 
to erlotinib 
Outcome 
 
111 
120 
150 
Sinus 
bradycardia 
1 
Related 
Related 
Resolved 
111 
120 
150 
Bradycardia 
1 
Related 
Related 
Resolved 
111 
240 
150 
Sinus 
bradycardia 
1 
Related 
Related 
Ongoing 
 
240 
150 
Sinus 
bradycardia 
3 
Related 
Related 
Resolved 
with 
Sequelae 
111 
120 
150 
Sinus 
bradycardia 
1 
Related 
Related 
Resolved 
111 
120 
150 
Bradycardia 
1 
Related 
Related 
Resolved 
 
240 
150 
Bradycardia 
1 
Related 
Related 
Ongoing 
PPD
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Table 1.7:  Sinus Bradycardia/Bradycardia in Two Combination Studies of ARQ 197 and 
Erlotinib 
Study 
Number 
Subject 
ID 
Dose of 
ARQ 
197/ 
placebo 
at time of 
event 
(mg BID) 
Dose of 
erlotinib 
at time 
of event 
(mg QD) 
Event 
 
CTCAE 
Grade 
Relationship 
to ARQ 197 
Relationship 
to erlotinib 
Outcome 
 
111 
360 
150 
Sinus 
bradycardia 
2 
Related 
Related 
Resolved 
with 
Sequelae 
 
360 
150 
Sinus 
bradycardia 
1 
Related 
Related 
Ongoing 
111 
360 
150 
Sinus 
bradycardia 
2 
Related 
Related 
Ongoing 
111 
360 
150 
Sinus 
bradycardia 
1 
Related 
Related 
Resolved 
209 
360 
150 
Sinus 
bradycardia 
2 
Related 
Unrelated 
Resolved 
Detailed data describing the clinical administration of ARQ 197 in subjects can be found in the 
ARQ 197 Investigator’s Brochure. 
3    Selection of Study Population (p. 31)  
 
Added 
Subjects who were previously enrolled in tivantinib 
studies but did not receive tivantinib as part of their 
treatment, and who, in the opinion of the Investigator and 
with Sponsor’s approval, may benefit from the treatment 
with tivantinib as a single agent or in combination 
therapy, will be allowed to initiate treatment with 
tivantinib. The tivantinib monotherapy or combination 
therapy dose(s) and schedule(s) will be determined for 
each subject by the Investigator and with the Sponsor’s 
approval based on administration schedules tested in and 
defined by prior tivantinib clinical trials.  
The combination therapy dose(s) and 
schedule(s) will be determined to 
each subject by the Investigator 
based on the combination drug(s) 
label(s) clinical trials. 
The combination therapy dose(s) and schedule(s) will be 
determined to each subject by the Investigator and with 
the Sponsor’s approval based on the combination drug(s) 
label(s) and prior tivantinib clinical trials.  
3.1    Inclusion Criteria (pp. 31-32) 
Each subject must meet the following 
criteria to be enrolled in this study: 
1. Signed written informed consent 
to Study ARQ 197-299 
Each subject must meet the following criteria to be 
enrolled in this study: 
1. Signed written informed consent to Study ARQ 197-
299 
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2. Male or female subjects of the 
age defined in the original 
protocol they were enrolled  
3. Eastern Cooperative Oncology 
Group (ECOG) performance 
status (PS) ≤ 3 (see Appendix 2) 
4. Adequate bone marrowfunction: 
- 
Absolute neutrophil count 
(ANC) ≥ 1.5 x 109/L 
- 
Hemoglobin ≥ 8.0 g/dL   
5. Enrollment within 14 days of the 
completion of the End of Study 
Visit of the original study 
6. Subjects, who participated in 
previous  studies that have 
reached their designated end-
dates, who did not meet 
discontinuation criteria in their 
original study, and who may, in 
the opinion of the Investigator 
and the Sponsor, benefit from 
treatment 
7. Women of childbearing potential 
must have a negative pregnancy 
test performed within 14 days of 
the start of study drug. Both men 
and women enrolled in this study 
must agree to use adequate birth 
control measures while on study 
 
2. Male or female subjects of the age defined in the 
original protocol they were enrolled  
3. Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) ≤ 3 (or ≤ 2 for tivantinib-
naïve subjects) (see Appendix 2) 
4. Adequate bone marrow, liver, and renal function 
tests: 
- 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
- 
Hemoglobin ≥ 8.0 g/dL (or ≥ 9.0 g/dL for 
tivantinib-naïve subjects) 
- 
Platelet count ≥ 75 x 109/L (or ≥ 60 x 109/L for 
HCC subjects) 
- 
Aspartate transaminase (AST) and alanine 
transaminase (ALT) ≤ 3 x upper limit of normal 
(ULN) (or ≤ 5 x ULN for subjects with liver 
metastases)  
- 
Total bilirubin ≤ 2mg/dL 
- 
Serum creatinine ≤ 1.5 x ULN 
5. Enrollment within 14 days of the completion of the 
End of Treatment Visit of the original study 
6. Measurable disease as defined by RECIST. 
Eligibility assessment must be performed within 28 
days (4 weeks) of the first dose of study drug (Day 1) 
7. Subjects, who participated in previous tivantinib 
studies that have reached their designated end-dates, 
who did not meet discontinuation criteria in their 
original study, and who may, in the opinion of the 
Investigator and the Sponsor, benefit from treatment 
8. Women of childbearing potential must have a 
negative pregnancy test performed within 14 days of 
the start of study drug. “Women of childbearing 
potential” is defined as sexually mature women who 
have not undergone a hysterectomy and who have 
not been naturally postmenopausal for the last 12 
consecutive months prior to the first dose of 
tivantinib (Day 1). Both men and women enrolled in 
this study must agree to use adequate birth control 
measures while on study. 
3.2    Exclusion Criteria (p.32) 
3. Any condition that is unstable or 
which could jeopardize the safety of 
the subject and his/her compliance in 
the study 
3. Any condition that is unstable or which could 
jeopardize the safety of the subject and his/her 
compliance in the study 
- For tivantinib-naïve subjects: active coronary disease, 
clinically significant bradycardia, or other uncontrolled 
cardiac arrhythmia defined as ≥ Grade 3 according to 
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4.1    Overall Study Design (p.32) 
The combination therapy dose(s) and 
schedule(s) will be determined for 
each subject by the Investigator 
based on the combination drug(s) 
label(s). 
The combination therapy dose(s) and schedule(s) will be 
determined for each subject by the Investigator and with 
the Sponsor’s approval based on the combination drug(s) 
label(s) and prior tivantinib clinical trials. 
 
Subjects who were previously enrolled in tivantinib 
studies but did not receive tivantinib (tivantinib-naïve) as 
part of their treatment, and who, in the opinion of the 
Investigator, may benefit from treatment with tivantinib 
as a single agent or in combination therapy, will be 
allowed to receive treatment with tivantinib. The 
tivantinib monotherapy or combination therapy dose(s) 
and schedule(s) will be determined for each subject by 
the Investigator and with the Sponsor’s approval based 
on administration schedules tested in and defined by 
prior tivantinib clinical trials. 
Added 
4.3 Administration Schedule (p.33) 
Subjects will be treated according to 
the original treatment protocols into 
which they were enrolled until any 
discontinuation criterion is met. Dose 
may be delayed or reduced for 
clinically significant toxicities, but 
dose escalation is not allowed (see 
Section 7.3). 
Subjects will be treated according to the original 
treatment protocols into which they were enrolled or per 
administration schedules tested in other tivantinib 
clinical trials. Subjects will be treated until any 
discontinuation criterion is met. Dose may be delayed or 
reduced for clinically significant toxicities, but dose 
escalation is not allowed (see Section 7.3 and 
Appendix 4). 
5.1 Pre-study Visit (p.34-35) 
• Physical examination ECOG PS 
Vital signs (blood pressure, heart 
rate, respiratory rate, body 
temperature) and weight 
• Complete blood count (CBC, 
hemoglobin, hematocrit, red 
blood cell count, platelet count, 
white blood cell count including 
differential neutrophil, 
lymphocyte, monocyte, basophil 
and eosinophil counts) 
• Chemistry panel (aspartate 
• Physical examination, including vital signs, weight, 
and height (see Section 6.2) 
• ECOG PS (see Appendix 2)  
• Hematology (see Section 6.3) 
• Coagulation tests (see Section 6.3) 
• Blood chemistry (see Section 6.3) 
• Liver function tests (see Section 6.3) 
• Electrolytes (see Section 6.3) 
• Serum pregnancy test (if applicable, see Section 6.3) 
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aminotransferase, alanine 
aminotransferase, bilirubin, 
alkaline phosphatase, uric acid, 
total protein, albumin, calcium, 
lipase, amylase, phosphate, lactic 
dehydrogenase, glucose, 
creatinine, blood urea nitrogen or 
urea and bicarbonate (if clinically 
indicated)) 
• Electrolyte panel (sodium, 
potassium, and chloride) 
• Coagulation panel (International 
Normalized Ratio (INR) or 
prothrombin time (PT), and 
partial thromboplastin time 
(PTT)) 
• Serum pregnancy test 
• 12-lead ECG  
• Tumor assessment 
• Tumor markers assessment (if 
applicable) 
• 12-lead ECG (see Section 6.4) 
• Tumor assessment (see Section 6.5) 
• Tumor markers assessment (if applicable) 
• Adverse event (AE) assessment: any sign or 
symptom continuing from the original tivantinib 
study or beginning after the last visit of the original 
study, but prior to the first dose of study drug (Day 
1) of the Extension study must be documented on a 
Medical History eCRF page. Resolved AEs from the 
original tivantinib study are captured in the original 
study records and will not be re-recorded for this 
study.  
5.2 Monthly Visit (± 3 days) (p. 35) 
Subjects should be seen every four 
weeks throughout treatment period. 
The following assessments and 
procedures will be performed at each 
visit: 
Physical examination  
ECOG PS 
Vital signs and weight  
CBC 
Blood chemistry 
Electrolytes 
AE assessment 
Concomitant medications assessment  
ARQ 197 dispensation as per 
schedule  
Combination drug(s) 
administration/dispensation as per 
schedule (if applicable) 
Subjects should be seen every four weeks throughout the 
treatment period. The following assessments and 
procedures will be performed at each visit: 
•Physical examination, including vital signs and weight 
(see Section 6.2) 
•ECOG PS (see Appendix 2) 
•Hematology (see s Section 6.3) 
•Coagulation tests (see s Section 6.3) 
•Blood chemistry (see Section 6.3) 
•Liver function tests (see Section 6.3) 
•Electrolytes (see Section 6.3) 
•AE assessment 
•Concomitant medications assessment  
•Tivantinib dispensation as per schedule  
•Combination drug(s) administration/dispensation as per 
schedule (if applicable) 
•Tumor markers assessment (if applicable)  


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Tumor markers assessment (if 
applicable) 
Tumor assessment (every 12 weeks 
unless current disease specific 
standard of care requires performing 
imaging more often)  
12-lead ECG (ONLY for bradycardic 
subjects with a heart rate <50 beats 
per minute) 
 
•Tumor assessment (every 12 weeks unless current 
disease specific standard of care requires performing 
imaging more often)  
•12-lead ECG (ONLY for subjects with a heart rate of 
<50 bpm) (see Section 6.4) 
Note: Subjects who do not experience Grade 3/4 toxicity 
and continue to benefit from the treatment after 12 cycles 
of treatment can be evaluated every two or three months 
upon agreement between the Investigator and the 
Sponsor. 
5.3 
Weekly Visits (if applicable; ± 3 days) (pp.35-37) 
Subjects who require weekly 
administration of combination 
drug(s) should be seen according to 
the schedule as per the original 
protocol. 
Tivantinib-naïve subjects or subjects who require weekly 
administration of combination drug(s) should be seen 
according to the schedule as per the original protocol.  
The following assessments and 
procedures will be performed at each 
visit: 
• Vital signs  
• CBC 
5.3.1 
Weekly Visits (applied for combination drug(s) 
administration; ± 3 days) 
At a minimum, the following assessments and 
procedures will be performed at each visit: 
• 
Vital signs (see Section 6.2) 
• 
Hematology (see Section 6.3) 
 
5.3.2 Weekly Visits (applied ONLY for tivantinib-naïve 
subjects; ± 3 days) 
Added 
Subjects who did not receive tivantinib when enrolled in 
the original tivantinib study and who, in the opinion of 
the Investigator and with the Sponsor’s approval, may 
benefit from treatment with tivantinib should have 
weekly visits during the first four weeks of treatment 
with tivantinib. After the first four weeks, these subjects 
will follow the original protocol visit schedule to which 
they were assigned. 
At a minimum, the following assessments and 
procedures will be performed at each visit: 
• Physical examination, including vital signs (see 
Section 6.2) 


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• ECOG PS (see Appendix 2) 
• Hematology (see Section 6.3) 
• Coagulation tests (see Section 6.3) 
• Blood chemistry (see Section 6.3) 
• Liver function tests (see Section 6.3) 
• Electrolytes (see Section 6.3) 
• AE assessment 
• Concomitant medications assessment  
• Tivantinib dispensation as per schedule  
• Combination drug(s) administration/dispensation as 
per schedule (if applicable) 
• 12-lead ECG (ONLY for subjects with a heart rate of 
<50 bpm) 
 
Tivantinib-naïve subjects who do not experience Grade 3 
/4 toxicity during the first four weeks of treatment and to 
whom the weekly combination treatment visit schedule 
does not apply can be evaluated monthly (Cycle 2+) 
upon agreement between the Investigator and the 
Sponsor 
5.4 End of Treatment Visit (pp. 37-38) 
Subjects, who have been 
discontinued from the study, should 
have the End of Study Visit within 7 
days of the discontinuation decision. 
The following assessments and 
procedures should be done at the End 
of Study Visit:  
• Physical examination  
• ECOG PS 
• Vital signsand weight  
• CBC 
• Chemistry panel 
• Electrolyte panel 
• Coagulation panel 
• Serum pregnancy test 
• 12-lead ECG 
• AE assessment 
Subjects, who have been discontinued from the study, 
should have the End of Treatment Visit within 7 (+3) 
days of the discontinuation decision. The following 
assessments and procedures should be done at the End of 
Treatment Visit: 
• Physical examination, including vital signs and 
weight (see Section 6.2) 
• ECOG PS (see Appendix 2) 
• Hematology (see Section 6.3) 
• Coagulation tests (see Section 6.3) 
• Blood chemistry (see Section 6.3) 
• Liver function tests (see Section 6.3) 
• Electrolytes (see Section 6.3) 
• Serum pregnancy test (if applicable, see Section 6.3) 
• Urinalysis (see Section 6.3) 
• AE assessment 
• Concomitant medications assessment  


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• Concomitant medications 
assessment  
• Tumor markers assessment if 
applicable 
• Tumor assessment (if not done 
within 14 days)  
• Tumor markers assessment (if applicable)  
• Tumor assessment (if not done within 14 days) 
• 12-lead ECG (see Section 6.4)  
5.6    Discontinuation from Study (p.38) 
• Documented radiographic 
progression of disease. 
• Documented radiographic progression of disease. 
(However, if, in the Investigator’s opinion, treatment 
with tivantinib, as a monotherapy or in combination 
therapy, is providing clinical benefit to a subject with 
radiological progression of disease, the subject may 
continue to receive the treatment after consultation 
with the ArQule, Inc. [ArQule] Medical Monitor or 
designee.)    
6.3 
Clinical Laboratory Tests (p.39) 
• Hematology: complete blood 
count (CBC) including 
hemoglobin, hematocrit, white 
blood cell count (WBC) with 5-
part differential, red blood cell 
(RBC) and platelet count 
• Coagulation (at baseline and end 
of study, only): prothrombin 
time, international normalized 
ratio, and partial thromboplastin 
time  
• Blood chemistry: calcium, 
phosphorus, magnesium, 
albumin, glucose, serum 
creatinine, uric acid, total protein, 
and blood urea nitrogen (BUN)  
• Liver function tests: AST, ALT, 
lactate dehydrogenase (LDH), 
alkaline phosphatase, total and 
direct bilirubin  
• Electrolytes: sodium, potassium, 
and chloride  
• Routine urinalysis: dipstick and 
microscopy (only if clinically 
indicated) including protein, 
specific gravity, glucose, and 
blood 
• Serum pregnancy test for female 
• Hematology: Complete blood count (CBC) including 
hemoglobin, hematocrit, white blood cell count with 
5-part differential, red blood cell and platelet count  
• Coagulation: (at Baseline and End of Treatment; and 
if clinically indicated): prothrombin time, 
international normalized ratio (INR) and partial 
thromboplastin time.  
• Blood chemistry: calcium, phosphorus, magnesium, 
albumin, glucose, serum creatinine, uric acid, total 
protein and blood urea nitrogen (BUN)  
• Liver function tests: AST, ALT, lactate 
dehydrogenase (LDH), alkaline phosphatase, total 
and direct bilirubin  
• Electrolytes: sodium, potassium, and chloride  
• Serum pregnancy test (at Baseline and End of 
Treatment only) for female subjects of childbearing 
potential  
• Routine urinalysis (at Baseline and End of Treatment 
only; and if clinically indicated): dipstick and 
microscopy (only if clinically indicated or dipstick is 
not done) including protein, specific gravity, glucose 
and blood  


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subjects of childbearing potential 
7.1.3     Tivantinib Administration (p.41) 
All subjects will receive at the dose 
and schedule depending on the 
original study protocol they were 
enrolled into. 
All subjects will receive tivantinib capsules or tablets at 
the dose and schedule depending on the original study 
protocol they were enrolled into. 
 
Subjects who were previously enrolled in tivantinib 
studies but did not receive tivantinib as part of their 
treatment, and who, in the opinion of the Investigator, 
may benefit from treatment with tivantinib as a single 
agent or in combination therapy, will be allowed to 
initiate treatment with tivantinib The tivantinib 
monotherapy or combination therapy dose(s) and 
schedule(s) will be determined for each subject by the 
Investigator and with the Sponsor’s approval based on 
administration schedules tested in and defined by prior 
tivantinib clinical trials. 
Added 
7.2 
Combination Drug Administration (p.42)  
The combination therapy dose(s) and 
schedule(s) will be determined for 
each subject by the Investigator 
based on the combination drug(s) 
label(s). 
The combination therapy dose(s) and schedule(s) will be 
determined for each subject by the Investigator and with 
the Sponsor’s approval based on the combination drug(s) 
label(s) and prior tivantinib clinical trials. 
7.3 
Dose Modification (p. 42) 
Dose administration may be delayed 
to allow for recovery from toxicity. 
Combination therapy drug dose 
modification should follow the 
original protocol guidelines.  
In general,  dose reduction should be 
done according to the following 
guidelines: 
• 240 mg BID 
• 120 mg BID 
• 120 mg once a day 
 
Dose administration may be delayed to allow for 
recovery from toxicity. Combination therapy drug dose 
modification should follow the original protocol 
guidelines (see Appendix 4).  
In general, once the tivantinib dose has been modified for 
a subject, all subsequent cycles should be administered to 
that subject at the modified dose unless additional dose 
modifications may be required. The modified dose will 
be considered the maximum dose for that subject for all 
subsequent cycles. 
Dose modification schema: 
• 240 mg BID (capsules or tablets) 
• 120 mg BID (capsules or tablets) 


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• 120 mg once a day (capsules or tablets) 
Further instructions for tivantinib dose modification due 
to non-hematologic or hematologic toxicities are listed in 
the following tables and provided in the original study 
protocols. 
For HCC subjects
Dose Delays/ Reduction Tables (pp. 43-44) 
 enrolled in the extension protocol, 
dose reduction and management of non-hematologic and 
hematologic toxicities should strictly follow the original 
protocol guidelines. 
Dose Delays/Reductions for Non-hematological Toxicity 
Event Severity 
Action 
Grade 1 or 2 
Continue current dose level 
Grade 3 
 
Withhold until recovery to Grade 1 or Baseline. Administer  at the next 
lower dose for subsequent cycles, unless further dose reduction is required. If 
a second hold is required for the same event, administer  at lower dose for 
subsequent cycles. 
Grade 4 
 
Withhold  until recovery to Grade 1 or Baseline. Consult with ArQule’s 
Medical Monitor or designee prior to restarting . If the Investigator and 
Medical Monitor concur, administer  at the next lower dose for subsequent 
cycles, unless further dose reduction is required. If a second hold is required 
for the same event, administer  at lower dose for subsequent cycles. 
 
Dose Delays/Reductions for Hematological Toxicity 
Event/Severity 
Action 
Grade 1 
Continue current dose level 
Grade 2 
Neutropenia  
Thrombocytopenia  
 
Withhold  and monitor hematology and/or chemistry weekly until 
relevant lab value(s) recover to Grade 1 or: 
• If the relevant lab value recovers in less than 7 days to: 1.5×109/L for 
ANC, or 75×109/L for platelets, resume  treatment at the same dose 
level 
• If the relevant lab value takes more than 7 days to recover to the level 
described above, restart  administration at the next lower dose 
If a second hold is required for the same event, whichever the grade, 
administer at the next lower dose once lab values allow doing so 


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Grade 3 
Neutropenia  
Thrombocytopenia  
Anaemia  
 
Withhold  and monitor hematology and/or chemistry weekly until 
relevant lab value(s) recover to Grade 1 or: 
• If the relevant lab value recovers in less than 7 days to: 1.5×109/L for 
ANC, 8 g/dL for hemoglobin, or 75×109/L for platelet, resume  
treatment at the same dose level.  
• If the relevant lab value takes more than 7 days to recover to the level 
described above, treatment with growth factors for neutropenia is 
recommended. Restart  administration at the next lower dose once lab 
values allow doing so.  
• If a second hold is required for the same event, administer  at the next 
lower dose once lab values allow doing so.   
Grade 4   
Neutropenia  
Thrombocytopenia 
Anaemia  
Febrile Neutropenia  
 
Withhold  , and monitor hematology and/or chemistry weekly until 
relevant lab value(s) recover to Grade 1 or:  
• 
If the relevant lab value recovers to: 1.5×109/L for ANC, 8 g/dL for 
hemoglobin, or 75×109/L for platelet, resume treatment at the next 
lower dose once lab values allow doing so, unless further dose 
reduction is required. 
Treatment with growth factors is strongly recommended for Grade 4 
neutropenia and febrile neutropenia (as per 2006 ASCO guidelines) 
 
Table 7.1 Dose Delays/Reductions for Non-hematological Toxicity Related to 
Tivantinib (non-HCC subjects) 
Revised 
Event Severity 
Action 
Grade 1 or 2 
Continue current dose level 
Grade 3 
 
Withhold tivantinib administration for up to 21 days until recovery to Grade 
1 or Baseline. Administer tivantinib at the next lower dose for subsequent 
cycles, unless further dose reduction is required. If a second hold is required 
for the same event, administer tivantinib at the next lower dose for all 
subsequent cycles. 
Grade 4 
 
Withhold tivantinib administration for up to 21 days until recovery to Grade 
1 or Baseline. Consult with ArQule’s Medical Monitor or designee prior to 
restarting tivantinib. If the Investigator and Medical Monitor concur, 
administer tivantinib at the next lower dose for subsequent cycles, unless 
further dose reduction is required. If a second hold is required for the same 
event, administer tivantinib at the next lower dose for all subsequent cycles. 
* If an event fails to recover to Grade 1 or Baseline and the dose must be delayed >21 days, the 
subject will be withdrawn from all study treatment, but should continue to undergo all follow-
up evaluations. 
Table 7.2 Dose Delays/Reductions for Hematological Toxicity Related to 
Tivantinib (non-HCC subjects) 
Event/Severity 
Action 
Grade 1 
Continue current dose level 


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Grade 2 
Neutropenia  
Thrombocytopenia  
 
Withhold tivantinib administration for up to 21 days and monitor 
hematology weekly until relevant lab value(s) recover to Grade 1 or: 
• If the relevant lab value recovers in less than 7 days to: ≥1.5×109/L for 
ANC, or ≥75×109/L for platelets, resume tivantinib treatment at the 
same dose level 
• If the relevant lab value takes more than 7 days to recover to the level 
described above, restart tivantinib administration at the next lower 
dose level 
If a second hold is required for the same event, whichever the grade, 
administer tivantinib at the next lower dose once lab values allow doing 
so 
Grade 3 
Neutropenia  
Thrombocytopenia  
Anaemia  
 
Withhold tivantinib administration for up to 21 days and monitor 
hematology and/or chemistry weekly until relevant lab value(s) recover 
to Grade 1 or: 
• If the relevant lab value recovers in less than 14 days to: ≥1.5×109/L 
for ANC, 8 g/dL for hemoglobin, or ≥60×109/L for platelet, resume 
tivantinib treatment at the same dose level.  
• If the relevant lab value takes more than 14 days to recover to the 
level described above, treatment with growth factors for neutropenia 
is recommended. Restart tivantinib administration at the next lower 
dose once lab values allow doing so.  
• If a second hold is required for the same event, administer tivantinib 
at the next lower dose once lab values allow doing so.   
Grade 4   
Neutropenia  
Thrombocytopenia 
Anaemia  
Febrile Neutropenia  
 
Withhold tivantinib administration for up to 21 days, and monitor 
hematology and/or chemistry weekly until relevant lab value(s) recover 
to Grade 1 or:  
• 
If the relevant lab value recovers in less than 14 days to: ≥1.5×109/L 
for ANC, ≥8 g/dL for hemoglobin, or ≥60×109/L for platelet, 
resume treatment at the next lower dose once lab values allow doing 
so, unless further dose reduction is required. 
Treatment with growth factors and antibiotics is strongly 
recommended for Grade 4 neutropenia and febrile neutropenia (as per 
2006 ASCO guidelines) 
* If an event fails to recover to Grade 1 or baseline and the dose must be delayed >21 days, the 
subject will be withdrawn from all study treatment, but should continue to undergo all follow-
up evaluations. 
The following precautions will be taken to manage neutropenia risk during the study: 
• For tivantinib-naïve subjects, ANC levels should be checked weekly during the first four 
weeks of therapy with tivantinib, and monthly thereafter. Subjects who experience Grade ≥3 
neutropenia should be monitored weekly for four consecutive cycles (months). 
• Prophylactic treatment with growth factors and antibiotic is suggested for subjects who 
experience Grade ≥3 neutropenia and febrile neutropenia  


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7.5.1 
Permitted Treatment (p. 45) 
Hematopoietic growth factors 
including filgrastim (Neupogen®) or 
other colony-stimulating factors. 
ASCO or institutional guidelines 
should be followed for the use of 
WBC growth factors. 
Hematopoietic growth factors including filgrastim 
(Neupogen®) or other colony-stimulating factors (G-
CSF). ASCO or institutional guidelines should be 
followed for the use of WBC growth factors: 
http://jco.ascopubs.org/content/24/19/3187.full 
 
Added 
• Megestrol acetate (Megace®) 
• Supportive therapy for toxicities associated with 
combination therapy drug(s), according to the FDA 
approved label or institutional practice 
• Use of topical corticosteroids, topical antibiotics, and 
systemic antibiotics according to standard of care or 
institutional guidelines 
• Treatment with non-conventional therapies (i.e., 
herbs or acupuncture), and vitamin/mineral 
supplements are acceptable, provided that they do 
not interfere with study treatment, in the opinion of 
the Investigator 
• Bisphonates for bone metastases 
• Palliative radiotherapy for local pain control 
provided that the subject does not meet criteria of 
progressive disease and treated lesion(s) will not be 
included in the target/non-target lesion assessment  
7.5.2 
Prohibited Treatment (p. 45) 
Any concurrent anticancer therapy 
including but not limited to 
chemotherapy, radiotherapy, 
hormonal therapy (except megestrol 
acetate as supportive care), 
immunotherapy, or locoregional 
therapy 
Any concurrent anticancer therapy including but not 
limited to chemotherapy, radiotherapy, hormonal therapy 
(except megestrol acetate as supportive care), 
immunotherapy 
Immunosuppressive therapies 
Immunosuppressive therapies including systemic 
corticosteroids (except up to a 25 mg/day prednisone-
equivalent dose or when used intermittently in an 
antiemetic regimen or premedication for imaging studies) 


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7.5.3 
Treatment to Avoid (pp. 
45-46) 
7.5.3 
Treatment to Avoid During Tivantinib 
Administration (pp. 45-46) 
•Bisphosphonates, unless initiated 
before screening 
Deleted 
 
 
As tivantinib is metabolized by hepatic cytochrome P450 
enzymes, primarily CYP 2C19 and CYP 3A4, 
interactions with drugs metabolized via the same enzyme 
system are possible. Caution should be applied when any 
CYP 2C19 inhibitors and/or strong CYP 3A4 inhibitors 
are used as concomitant therapy. 
Added 
8.1.1 
Adverse Event (p. 47) 
 
All AEs/SAEs occurring during the study period from 
the first day of study drug administration (Day 1 of this 
study) to the last day of the follow-up period will be 
captured. 
Added 
8.4 
Reporting Serious Adverse Events/ArQule Medical Monitor (p. 50) 
14 
REFERENCES  
(Added) 
Munshi N, Jeay S, Li Y, et al. ARQ 197, a novel and selective inhibitor of the human c-Met 
receptor tyrosine kinase with antitumor activity. Mol Cancer Ther. 2010;9:1544-53. 
Tivantinib (ARQ 197) Investigator’s Brochure, Version 9.0, Dated: 06 November, 2013. 
Laux I, Goldman J, Just R, et al. Phase I dose escalation study (ARQ 197-111) evaluating 
combination of selective c-Met inhibitor ARQ 197 and erlotinib. J Clin Oncol. 
2009;27:Suppl;abstr 3549. 
Mekhail T, Rich T, Rosen L, et al. Final results: A dose escalation phase I study of ARQ 197, a 
selective c-MET inhibitor, in patients with metastatic solid tumors. 2009 ASCO Annual Meeting. 
J Clin Oncol. 2009; 27:15s(suppl;abstr 3548). 
Rosen LS, Senzer N, Mekhail T et al. A phase I dose-escalation study of Tivantinib in adult 
patients with metastatic solid tumors. Clin Cancer Res. 2011;17:7754-64. 
Sequist LV, von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus 
PPD


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tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin 
Oncol. 2011;29:3307-15. 
Adjei AA, Schwartz B, Garmey E. Early clinical development of ARQ 197, a selective, non-
ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. 
Oncologist. 2011;16:788-99. 
Rimassa L, Porta C, Borbath I, et al. Tivantinib versus placebo in patients (Pts) with 
hepatocellular carcinoma (HCC) who failed one systemic therapy: Results of a randomized 
controlled phase II trial (RCT). Program and abstracts of the American Society of Clinical 
Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 4006. 
Goldman JW, Laux I, Chai F, et al. Phase 1 dose-escalation trial evaluating the combination of 
the selective MET (mesenchymal-epithelial transition factor) inhibitor tivantinib plus erlotinib. 
Cancer. 2012;118:5903-11. 
Eng C. HL, Severtsev A, et al. A randomized, placebo-controlled, phase I/II study of tivantinib in 
combination with cetuximab and irinotecan in patients (pts) with KRAS wild-type (WT) 
metastatic colorectal cancer (CRC) who had received previous front-line systemic therapy. J Clin 
Oncol. 2013;31(suppl;abstr 3508). 
Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced 
hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 
2013;14:55-63. 
Scagliotti GN, Ramlau, R, et al. MARQUEE: A randomized, double-blind, placebo-controlled, 
phase 3 trial of tivantinib plus erlotinib versus placebo plus erlotinib in previously treated patients 
with locally advanced or metastatic, non-squamous, non-small-cell lung cancer (NSCLC). 
European Society for Medical Oncology conference. 2013;(abstract E17-1821). 
 
ADDED 
APPENDIX 4: DOSE MODIFICATION GUIDELINES FOR COMBINATION THERAPY 
When during combination therapy co-drug related toxicity is observed, dose delays and/or 
reduction s in co-drug administration are allowed as described below or may follow institutional 
guidelines/standard of care.  
Temporary dose interruption and/or dose reduction may be necessary due to adverse events. For 
recommendations for skin adverse events, see Table A4-1. If dose reduction is necessary, the 
sorafenib dose may be reduced to once a day. If further dose reduction is necessary, sorafenib 
may be given once every other day. 
Sorafenib (Nexavar) Dose Modification 
Table A4-1 
Sorafenib Dose Modifications for Dermatologic Toxicity 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 1: Numbness, 
dysesthesia, paresthesia, 
tingling, painless swelling, 
Any occurrence 
Continue treatment with 
sorafenib and consider topical 
therapy for symptomatic relief. 


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erythema, or discomfort of 
the hands or feet that does 
NOT disrupt the subject’s 
normal activities 
Grade 2: Painful erythema 
and swelling of the hands 
or feet and/or discomfort 
affecting the subject’s 
normal activities 
1st occurrence 
Continue treatment with 
sorafenib and consider topical 
therapy for symptom relief. 
No improvement within 7 days 
or 2nd or 3rd occurrence 
Interrupt sorafenib treatment 
until toxicity resolves to 
Grade 0 or 1. When resuming 
treatment, decrease sorafenib 
dose by 1 dose level (dosing 
once a day or once every other 
day). 
4th occurrence 
Discontinue sorafenib 
treatment. 
Grade 3: Moist 
desquamation, ulceration, 
blistering, or severe pain 
of the hands or feet, or 
severe discomfort that 
causes the subject to be 
unable to work or perform 
activities of daily living 
1st or 2nd occurrence 
Interrupt sorafenib treatment 
until toxicity resolves to 
Grade 0 or 1. When resuming 
therapy, decrease sorafenib by 1 
dose level (dosing once a day or 
once every other day). 
3rd occurrence 
Discontinue sorafenib 
treatment. 
Please refer to the approved sorafenib (Nexavar) package insert for details. 
 
Gemcitabine (Gemzar) Dose Modification 
Dosage adjustment of gemcitabine is based upon the degree of hematologic toxicity experienced 
by the subjects. Subjects receiving gemcitabine should be monitored prior to each dose with a 
complete blood count, including differential and platelet count. If marrow suppression is detected, 
therapy should be modified or suspended according to the guidelines in Table A4-2. 
Table A4-2 
Gemcitabine Dosage Reduction Guidelines 
Absolute Granulocyte 
Count ( × 106/L) 
Platelet Count ( × 106/L) 
Percent of Full Dose (%) 
≥ 1000 and 
≥ 100,000 
100 
500 – 999 or 
50,000 – 99,999 
75 
< 500 or 
< 50,000 
Hold 
Laboratory evaluation of renal and hepatic function, including transaminases and serum 
creatinine, should be performed prior to initiation of therapy and periodically thereafter. 
Gemcitabine should be administered with caution in subjects who have evidence of significant 


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renal or hepatic impairment, as there is insufficient information from clinical studies to allow 
clear dose recommendation for these subject populations. 
Refer to the approved gemcitabine (Gemzar) package insert for details.  
Erlotinib (Tarceva) Dose Reduction 
When dose reduction is necessary, the erlotinib dose should be reduced by a 50 mg decrement. 
For this study, no more than 1 dose reduction will be allowed. 
Pulmonary Symptoms: In subjects who develop an acute onset of new or progressive pulmonary 
symptoms, such as dyspnea, cough, or fever, treatment with erlotinib should be interrupted 
pending diagnostic evaluation. If interstitial lung disease is diagnosed, erlotinib should be 
discontinued and appropriate treatment instituted, as necessary. 
Diarrhea: Diarrhea can usually be managed with loperamide. Subjects with severe diarrhea who 
are unresponsive to loperamide or who become dehydrated may require dose reduction or 
temporary interruption of therapy. 
Skin Reactions: Skin reactions experienced by subjects receiving erlotinib tend to be managed 
easily with topical therapies and do not require treatment interruption or dose modification 
(please refer to package insert for details). However, rare subjects with severe skin reactions may 
also require dose reduction or temporary interruption of therapy. 
Concomitant CYP3A4 Inhibitors: In subjects concomitantly treated with a strong CYP3A4 
inhibitor, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, or voriconazole, a dose reduction 
should be considered if severe adverse reactions occur. 
Hepatic Impairment: Erlotinib is eliminated by hepatic metabolism and biliary excretion. 
Therefore, caution should be used when administering erlotinib to subjects with hepatic 
impairment. Dose reduction or interruption of erlotinib should be considered if severe adverse 
reactions occur. For additional dose modification information, please refer to the package insert 
for erlotinib (Tarceva).  
Irinotecan (Camptosar) and Cetuximab (Erbitux) Dose Reductions 
Refer to the locally applicable irinotecan and cetuximab package inserts for dose reductions, 
modifications, or delays due to irinotecan- or cetuximab-related toxicities. The recommended 
dose levels for reductions in irinotecan and cetuximab are shown in Table A4-3. General 
recommendations for dose modifications are provided in Table A4-4. 
Supportive therapy for toxicities associated with irinotecan and/or cetuximab therapy may be 
given, according to institutional practice. 
A new cycle of treatment may begin when the ANC is ≥ 1.5 × 109/L, the platelet count is 
≥ 100 × 109/L, and any treatment-related gastrointestinal toxicity is resolved to ≤ Grade 1. 
The ANC level at baseline must be ≥ 1.5 × 109/L and platelet count ≥ 100 × 109/L. If the initiation 
of a new cycle or treatment during a cycle is delayed for 4 weeks or longer, the subject should be 
removed from study treatment. Doses that are withheld are not to be made up. 
 


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Table A4-3 
Recommended Irinotecan and Cetuximab Dose Reductions 
Agent 
Initial Dose 
Level -1 
Level -2a 
Irinotecan 
180 mg/m2 
150 mg/m2 
120 mg/m2 
Cetuximab 
400 mg/m2 
250 mg/m2 
200 mg/m2 
a: If a reduction below Level -2 is indicated, discontinue treatment with that agent 
 
Table A4-4 
Dose Modifications to Irinotecan and Cetuximab Dose Due to 
Irinotecan- or Cetuximab-Toxicity 
Event 
Action 
Hematologic 
Grade 2 Hematologic 
Reduce irinotecan 1 dose level for the remainder of the cycle. For 
subsequent cycles, resume at the previous dose levels, provided 
ANC ≥ 1.5 × 109/L and platelets ≥ 100 × 109/L. 
Grade 3 to 4 Hematologic 
Hold irinotecan. If counts recover to ANC ≥ 1.5 × 109/L and 
platelets to ≥ 100 × 109/L, may be resumed at 1 lower dose level 
for the remainder of the cycle. For subsequent cycles, continue 
both agents at the reduced dose levels from the previous cycle. 
Febrile neutropenia 
Hold irinotecan. If fever resolves and counts recover to ANC ≥ 
1.5 x 109/L and platelets to ≥ 100 x 109/L, both agents may be 
resumed at 1 lower dose level for the remainder of the cycle. For 
subsequent cycles, continue both agents at the reduced dose 
levels from the previous cycle. 
Diarrhea 
Grade 2 Diarrhea 
Reduce irinotecan for 1 dose level for the remainder of the cycle. 
If diarrhea persists, hold cetuximab until fully resolved. For 
subsequent cycles, resume all agents at the previous dose levels, 
provided diarrhea has fully resolved. 
Grade 3 to 4 Diarrhea 
Hold irinotecan and cetuximab. If diarrhea resolves to ≤ Grade 2, 
both agents may be resumed at 1 lower dose level for the 
remainder of the cycle. If diarrhea persists, hold cetuximab until 
fully resolved. For subsequent cycles, continue both agents at the 
reduced dose levels from the previous cycle. 
Nausea/Vomitinga 
Grade 3 Nausea and/or 
Vomiting 
Reduce irinotecan 1 dose level for the remainder of the cycle. For 
subsequent cycles, continue irinotecan at the reduced dose level 
from the previous cycle. 
Grade 4 Nausea and/or 
Vomiting 
Reduce irinotecan 1 dose level for the remainder of the cycle. For 
subsequent cycles, continue irinotecan at the reduced dose levels 
from the previous cycle. 
a: Dose modifications for nausea and/or vomiting should be made only if nausea and/or vomiting persist 
or occur despite 2 treatments with adequate (combination) antiemetics therapy. 
b: Including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial 
ischemia. 
c: Note that the NCI CTCAE defines hypersensitivity and infusion reactions differently: “Cytokine 
release syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, 


ArQule, Inc. 
 
21 February 2014 
 
ARQ 197-299 
 
Confidential 
Page 50 of 53 
 
although some of the manifestations are common to both AEs. An acute infusion reaction may occur 
with an agent that causes cytokine release (eg, monoclonal antibodies or other biological agents). 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.” See the “Syndromes” section of the NCI 
CTCAE Version 4 for a complete list of signs and symptoms of “cytokine release syndrome/acute 
infusion reaction” and see the “Allergy/Immunology” section for a description of hypersensitivity. 
AE = adverse event; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LV = left ventricular; NCI = National Cancer 
Institute. 
Table A4-4 
Dose Modifications to Irinotecan and Cetuximab Dose Due to 
Irinotecan- or Cetuximab-Toxicity (Continued) 
Event 
Action 
Mucositis 
Grade 2 Mucositis 
Reduce irinotecan 1 dose level for the remainder of the cycle. For 
subsequent cycles, continue at the reduced dose levels from the 
previous cycle. No modifications (or delays) will be made for 
cetuximab. 
Grade 3 Mucositis 
Hold irinotecan. If mucositis resolves to ≤ Grade 2, treatment may 
be resumed at 1 lower dose level for the remainder of the cycle. 
For subsequent cycles, continue at the reduced dose level from the 
previous cycle. No modifications (or delays) will be made for 
cetuximab. 
Grade 4 Mucositis 
Hold ALL study treatment, including irinotecan, cetuximab, and 
tivantinib. If mucositis resolves to ≤ Grade 2, irinotecan may be 
resumed at 1 lower dose level for the remainder of the cycle. 
Cetuximab will be resumed at the prior dose. For subsequent 
cycles, continue all agents at the dose level from the previous 
cycle. 
Pulmonary 
Grade 2 or worsening 
pulmonary symptoms 
unrelated to underlying 
cancer 
Cetuximab treatment should be stopped and symptoms 
investigated. Cetuximab treatment may resume at 1 lower dose 
level when symptoms resolve to ≤ Grade 1 and cetuximab-related 
pneumonitis is ruled out. 
≥ Grade 3 cough, 
dyspnea, hypoxia, 
pneumonitis, or 
pulmonary infiltrates 
Hold cetuximab until interstitial lung disease is ruled out. 
Continue irinotecan. Discontinue all study treatment if interstitial 
lung disease is confirmed. 
Hypomagnesemia 
Grade 3 or 4 
hypomagnesemia 
Hold cetuximab until hypomagnesemia resolves to ≤ Grade 2, 
then restart cetuximab at the same dose. For any Grade of 
hypomagnesemia, magnesium supplementation should be 
provided. 
a: Dose modifications for nausea and/or vomiting should be made only if nausea and/or vomiting persist 
or occur despite 2 treatments with adequate (combination) antiemetics therapy. 
b: Including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial 
ischemia. 
c: Note that the NCI CTCAE defines hypersensitivity and infusion reactions differently: “Cytokine 
release syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, 


ArQule, Inc. 
 
21 February 2014 
 
ARQ 197-299 
 
Confidential 
Page 51 of 53 
 
although some of the manifestations are common to both AEs. An acute infusion reaction may occur 
with an agent that causes cytokine release (eg, monoclonal antibodies or other biological agents). 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.” See the “Syndromes” section of the NCI 
CTCAE Version 4 for a complete list of signs and symptoms of “cytokine release syndrome/acute 
infusion reaction” and see the “Allergy/Immunology” section for a description of hypersensitivity. 
AE = adverse event; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LV = left ventricular; NCI = National Cancer 
Institute. 
Table A4-4 
Dose Modifications to Irinotecan and Cetuximab Dose Due to 
Irinotecan- or Cetuximab-Toxicity (Continued) 
Event 
Action 
Venous thrombotic events 
Grade 3 venous 
thrombosis or 
asymptomatic pulmonary 
embolism 
Hold treatment with cetuximab. If the planned duration of full-
dose anticoagulation is ≤ 2 weeks, treatment should be held until 
the full-dose anticoagulation period is over. If the planned 
duration of full-dose anticoagulation is ≥ 2 weeks, treatment may 
be resumed during the period of full-dose anticoagulation, if all of 
the following criteria are met: 
• The subject must have an in-range INR (usually between 
2 and 3) on a stable dose of warfarin or be on a stable dose 
of low molecular weight heparin prior to restarting 
treatment. 
• The subject must not have pathological conditions that carry 
a high risk of bleeding (eg, tumor involving major vessels). 
• The subject must not have had hemorrhagic events while on 
study. 
Grade 4 or 
recurrent/worsening 
venous thromboembolic 
events 
Discontinue all study treatment, including tivantinib, irinotecan, 
and cetuximab. 
Symptomatic pulmonary 
embolism 
Discontinue all study treatment, including tivantinib, irinotecan, 
and cetuximab. 
Arterial thrombotic events 
Grade 3 cardiac 
ischemia/infarction 
Discontinue all study treatment, including tivantinib, irinotecan, 
and cetuximab. 
Any Grade 4 arterial 
thrombotic eventb 
Discontinue all study treatment, including tivantinib, irinotecan, 
and cetuximab. 
LV dysfunction 
Grade 3 LV dysfunction 
Discontinue cetuximab. Subjects may continue other study 
treatment. 
Grade 4 LV dysfunction 
Discontinue all study treatment, including tivantinib, irinotecan, 
and cetuximab. 
a: Dose modifications for nausea and/or vomiting should be made only if nausea and/or vomiting persist 
or occur despite 2 treatments with adequate (combination) antiemetics therapy. 
b: Including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial 
ischemia. 
c: Note that the NCI CTCAE defines hypersensitivity and infusion reactions differently: “Cytokine 


ArQule, Inc. 
 
21 February 2014 
 
ARQ 197-299 
 
Confidential 
Page 52 of 53 
 
release syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, 
although some of the manifestations are common to both AEs. An acute infusion reaction may occur 
with an agent that causes cytokine release (eg, monoclonal antibodies or other biological agents). 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.” See the “Syndromes” section of the NCI 
CTCAE Version 4 for a complete list of signs and symptoms of “cytokine release syndrome/acute 
infusion reaction” and see the “Allergy/Immunology” section for a description of hypersensitivity. 
AE = adverse event; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LV = left ventricular; NCI = National Cancer 
Institute. 
Table A4-4 
Dose Modifications to Irinotecan and Cetuximab Dose Due to 
Irinotecan- or Cetuximab-Toxicity (Continued) 
Event 
Action 
Hemorrhage/bleeding 
Grade 3 
hemorrhage/bleeding 
Hold tivantinib treatment; once hemorrhage or bleeding resolves, 
tivantinib treatment may be continued at the Investigator’s 
discretion. 
Grade 4 
hemorrhage/bleeding 
Discontinue all study treatment, including tivantinib, irinotecan, 
and cetuximab. 
Rash 
Grade 3 rash 
(1st occurrence) 
Hold cetuximab infusion 1 to 2 weeks: 
• 
If improvement, continue at 500 mg/m2. 
• 
If no improvement, discontinue cetuximab. 
Grade 3 rash 
(2nd occurrence) 
Hold cetuximab infusion 1 to 2 weeks: 
• 
If improvement, reduce to 400 mg/m2. 
• 
If no improvement, discontinue cetuximab. 
Grade 3 rash 
(3rd occurrence) 
Hold cetuximab infusion 1 to 2 weeks: 
• 
If improvement, reduce to 300 mg/m2. 
• 
If no improvement, discontinue cetuximab. 
Grade 3 rash 
(4th occurrence) 
Discontinue cetuximab. 
Grade 4 rash 
(1st occurrence) 
Discontinue cetuximab. 
Hypersensitivityc 
Grade 1 hypersensitivity 
reactions (all agents) 
Decrease the infusion rate for all agents by 50% until symptoms 
resolve; then resume at the initial planned rate (except for 
cetuximab, see below). 
Grade 2 hypersensitivity 
reactions (all agents) 
Stop infusion. Administer histamine 1 and/or histamine 2 
blockers, and/or steroids according to institutional policy. Restart 
the infusion when symptoms resolve and pre-treat before all 
subsequent doses. Treat according to institutional policy. 
Grade 3 or Grade 4 
hypersensitivity reactions 
(all agents) 
Stop the infusion. Permanently discontinue all study treatment and 
notify the Study Coordinator. 
Grade 1 or 2 cetuximab 
infusion reactions 
Stop the infusion until symptoms resolve, then restart cetuximab 
at a 50% lower rate of infusion. All subsequent doses should be 
administered at the lower infusion rate. 


ArQule, Inc. 
 
21 February 2014 
 
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Page 53 of 53 
 
≥ Grade 3 cetuximab 
infusion reactions 
Discontinue cetuximab. Other study treatment may be continued. 
Other nonhematologic 
Grade 3 or higher 
nonhematologic toxicities 
not described above 
Hold ALL study treatment, including irinotecan, cetuximab, and 
tivantinib, and monitor toxicity at least weekly. If toxicity resolves 
to Grade 1 or lower within 4 weeks, treatment may be resumed, 
with cetuximab and irinotecan at 1 lower dose level. 
a: Dose modifications for nausea and/or vomiting should be made only if nausea and/or vomiting persist 
or occur despite 2 treatments with adequate (combination) antiemetics therapy. 
b: Including cerebrovascular ischemia, cardiac ischemia/infarction, peripheral or visceral arterial 
ischemia. 
c: Note that the NCI CTCAE defines hypersensitivity and infusion reactions differently: “Cytokine 
release syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, 
although some of the manifestations are common to both AEs. An acute infusion reaction may occur 
with an agent that causes cytokine release (eg, monoclonal antibodies or other biological agents). 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.” See the “Syndromes” section of the NCI 
CTCAE Version 4 for a complete list of signs and symptoms of “cytokine release syndrome/acute 
infusion reaction” and see the “Allergy/Immunology” section for a description of hypersensitivity. 
AE = adverse event; ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for 
Adverse Events; INR = international normalized ratio; LV = left ventricular; NCI = National Cancer 
Institute. 
 
 


PPD
PPD


PPD