Phase Ib Study of the Combination of Pazopanib, an Oral VEGFR Inhibitor, and ARQ 197 (Tivantinib), an Oral MET Inhibitor, in Patients With Refractory Advanced Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: National Cancer Institute (NCI)



CTEP Protocol #8880 
Clinical Center Protocol # 12-C-0009 
 
 
 
 
 
2
CTEP Monitors:  
 
 
John J. Wright, MD, PhD 
 
 
NCI Supplied Agents:  
Pazopanib (NSC 737754) 
ARQ 197 (NSC 750832)  
 
 
Protocol Version Date: 
October 16, 2017  
 
 
NCT Number: 
NCT01468922 
 
 
Roles: Aobtains information by intervening or interacting with living individuals for research purposes; 
Bobtains identifiable private information about living individuals; Cobtains the voluntary informed 
consent of individuals to be subjects; Dmakes decisions about subject eligibility; Estudies, interprets, or 
analyzes identifiable private information or data/specimens for research purposes 

CTEP Protocol #8880 
Clinical Center Protocol # 12-C-0009 
 
 
 
 
 
3
PRÉCIS 
Background: 
• Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) signal 
transduction pathways have synergistic effects on promoting angiogenesis and growth factor 
expression.  Hypoxia caused by treatment with VEGF inhibitors results in the upregulation of 
c-MET, the receptor for HGF.  In a mouse model, combined blockade of VEGFR and c-Met 
significantly prolonged survival compared with inhibition of either target alone. 
• We hypothesize that co-administration of the MET inhibitor ARQ 197 will prevent the adaptive 
response to hypoxia resulting from treatment with the VEGFR inhibitor pazopanib, and conversely, 
that co-administration of pazopanib will prevent the effect of increased VEGF and reduced 
thrombospondin 1 in tumors after treatment with ARQ 197.  Therefore, the combination of these 
agents may result in improved antitumor effects. 
Objectives: 
• Establish the safety and tolerability of the combination of pazopanib with ARQ 197 in patients with 
refractory advanced solid tumors. 
• Establish the maximum tolerated dose (MTD) of the combination of pazopanib with ARQ 197 in 
patients with refractory advanced solid tumors. 
• Evaluate changes in MET and phospho-MET following treatment with pazopanib and ARQ 197 in 
patients with refractory advanced solid tumors. 
• Determine the pharmacokinetics (PK) of pazopanib and ARQ 197.  
• Determine and compare levels of total MET, phospho MET, HIF-1α, and epithelial-mesenchymal 
transition markers (e-cadherin, beta catenin) in tumor biopsy samples prior to and following 
administration of the study drugs. 
• Determine and compare levels of circulating levels of HGF, soluble MET (sMET), VEGF-A, and 
soluble VEGFR2 (sVEGFR2) prior to and following administration of the study drugs. 
• Determine polymorphisms in the CYP2C19 and correlate these with the observed toxicities, and the 
PK of ARQ 197.  
• Evaluate antitumor activity of the combination of pazopanib and ARQ 197 in patients with 
refractory advanced solid tumors.  
Eligibility: 
• Adults with advanced, refractory solid tumors.  Patients enrolling in the expansion cohorts must 
have advanced sarcoma, gastric cancer, and MET-expressing malignancies, have disease amenable 
to biopsy, and be willing to undergo pre-and post-treatment biopsies. 
Study Design: 
• ARQ 197 will be administered orally twice daily and pazopanib orally once daily, in 28-day cycles. 
• Dose escalation will proceed using the traditional 3+3 design.   
• Once the MTD is established, an additional cohort will be accrued for pharmacodynamic (PD) 
studies in tumor biopsies (required in the expansion phase).  For the first week, patients will receive 
pazopanib alone to compare PK and PD results; combination therapy will be given from week 2 
onwards. 

CTEP Protocol #8880 
Clinical Center Protocol # 12-C-0009 
 
 
 
 
 
4
SCHEMA: DOSE ESCALATION PHASE 
 
 
 
 
 
 
 
 
P + Aa 
D1 
D15 
D22 
D8 
D28 
P + Aa 
D1 
D15 
D22 
D8 
D28 
Tumor 
Biopsyb 
PD 
Samplingc 
Cycle 1 
Cycle 2 onwards 
D1 
D15 
C2 D1 
PK 
Samplingd 
D15 
D1 
PG 
Samplinge 
D8 
a  Pazopanib (P) po q day and ARQ 197 (A) po bid continuously throughout in patients on the dose 
escalation phase.  Pazopanib will be taken on an empty stomach 1 hour before a meal and ARQ 197 will 
be taken with food. 
b  Tumor biopsies (optional during the dose escalation phase) will be performed at baseline (pre-treatment) 
and on C1D8, 8-12 hours after the Day 7 evening dose of ARQ 197 (taken 1 hour after pazopanib). 
c Blood samples for PD analyses collected at baseline (pre-treatment), on C1D1 (2, 4, and 6 hours after 
pazopanib), on C1D15 (pre-study drug administration), and on C2D1 (pre-study drug administration). 
d Blood samples for PK analyses will be collected on C1D1, before drug administration and 1, 2, 4, 6, and 
12 hours after administration of pazopanib (12-hour time point is pre-second dose of ARQ 197), and on 
C1D15 before drug administration and 1, 2, 4, and 6 hours after administration of pazopanib.  
e  A blood sample for pharmacogenomic (PG) analyses will be collected prior to drug administration on 
C1D1. 

CTEP Protocol #8880 
Clinical Center Protocol # 12-C-0009 
 
 
 
 
 
5
SCHEMA: EXPANSION PHASE 
 
 
a  Pazopanib (P) po q day taken on an empty stomach 1 hour before a meal and ARQ 197 (A) po bid taken 
with food.   
Cohort A: Single-agent pazopanib from C1D1 to D7, then the combination of ARQ 197 and pazopanib 
from C1D8. 
b  Tumor biopsies (mandatory during the expansion phase) for Cohort A at baseline (pretreatment) and on 
C1D8 after pazopanib but before the first dose of ARQ 197. 
c Blood samples for PD analyses collected at baseline (pre-treatment), on C1D1 (2, 4, and 6 hours after 
pazopanib), on C1D8 (pre-study drug administration), and on C2D1 (pre-study drug administration). 
d Blood samples for PK analyses will be collected prior to drug administration and at multiple time points 
after drug administration in cycle 1 only:  
Cohort A: D1, pre-dose and 1, 2, 4, 6, and 12 hours after administration of pazopanib; D7, pre-dose and 
1, 2, 4, and 6 hours after administration of pazopanib. 
e  A blood sample for pharmacogenomic (PG) analyses will be collected prior to drug administration on 
C1D1. 
D1 
D15 
D22 
D8 
D28 D1 
D15 
D22 
D8 
D28 
Tumor 
Biopsyb 
PD 
Samplingc 
Cycle 1 
Cycle 2 onwards  
D1 
C2 D1 
PK 
Samplingd 
D1 
D8 
D7 
D8 
P 
P + A 
P + A 
Cohort Aa 
PG 
Samplinge 

CTEP Protocol #8880 
Clinical Center Protocol # 12-C-0009 
 
 
 
 
 
6
Dose Escalation: 
 
 
 
Dose Level 
 
Pazopanib 
po q day 
 
ARQ 197 
po 
-2 
200 mg 
120 mg QD 
-1 
400 mg 
120 mg QD 
1  
(starting dose) 
400 mg 
120 mg BID 
2 
600 mg 
120 mg BID 
3 
600 mg 
240 mg BID 
4 
800 mg 
240 mg BID 
5 
800 mg 
360 mg BID 
6* 
600 mg 
360 mg BID 
*If dose level 5 is above the MTD, dose level 6 will be evaluated.  

CTEP Protocol #8880 
Clinical Center Protocol # 12-C-0009 
 
 
 
 
 
7
TABLE OF CONTENTS 
PRÉCIS .......................................................................................................................................... 3 
SCHEMA: DOSE ESCALATION PHASE ................................................................................ 4 
SCHEMA: EXPANSION PHASE ............................................................................................... 5 
1 
OBJECTIVES ....................................................................................................................... 9 
1.1 
Primary Objectives.......................................................................................................... 9 
1.2 
Secondary Objectives...................................................................................................... 9 
2 
BACKGROUND ................................................................................................................... 9 
2.1 
Targeting the VEGF and HGF Pathways ........................................................................ 9 
2.2 
Pazopanib ...................................................................................................................... 11 
2.3 
ARQ 197 ....................................................................................................................... 15 
2.4 
Correlative Studies Background ................................................................................... 21 
2.5 
Rationale ....................................................................................................................... 26 
3 
PATIENT SELECTION .................................................................................................... 26 
3.1 
Eligibility Criteria ......................................................................................................... 26 
3.2 
Exclusion Criteria ......................................................................................................... 28 
3.3 
Inclusion of Women and Minorities ............................................................................. 30 
3.4 
Screening Evaluation .................................................................................................... 30 
4 
REGISTRATION PROCEDURES ................................................................................... 31 
5 
TREATMENT PLAN ......................................................................................................... 32 
5.1 
Agent Administration.................................................................................................... 33 
5.2 
Definition of Dose-Limiting Toxicity ........................................................................... 35 
5.3 
General Concomitant Medication and Supportive Care Guidelines ............................. 36 
5.4 
Duration of Therapy ...................................................................................................... 39 
5.5 
Duration of Follow Up .................................................................................................. 40 
5.6 
Criteria for Removal from Study .................................................................................. 40 
6 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 40 
6.1 
Dose Reduction ............................................................................................................. 41 
7 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................... 48 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ........................ 48 
7.2 
Adverse Event Characteristics ...................................................................................... 54 
7.3 
Expedited Adverse Event Reporting ............................................................................. 55 
7.4 
Routine Adverse Event Reporting ................................................................................ 60 
7.5 
Secondary Malignancy.................................................................................................. 61 
7.6 
Second Malignancy ....................................................................................................... 61 
8 
PHARMACEUTICAL INFORMATION ......................................................................... 61 
8.1 
Pazopanib (GW786034) (NSC 737754) ....................................................................... 61 
8.2 
ARQ 197 (NSC 750832) ............................................................................................... 62 
8.3 
Agent Ordering ............................................................................................................. 64 
8.4 
Agent Accountability .................................................................................................... 64 

CTEP Protocol #8880 
Clinical Center Protocol # 12-C-0009 
 
 
 
 
 
8
9 
CORRELATIVE/SPECIAL STUDIES ............................................................................ 64 
9.1 
Pharmacodynamics ....................................................................................................... 64 
9.2 
Pharmacokinetics .......................................................................................................... 69 
9.3 
Pharmacogenetics (PG) ................................................................................................. 71 
10 STUDY CALENDAR ......................................................................................................... 72 
10.1 
Dose Escalation Phase .................................................................................................. 73 
10.2 
Expansion Phase ........................................................................................................... 75 
11 MEASUREMENT OF EFFECT ....................................................................................... 77 
11.1 
Antitumor Effect – Solid Tumors ................................................................................. 77 
11.2 
Methods for Evaluation of Measurable Disease ........................................................... 78 
11.3 
Response Criteria .......................................................................................................... 80 
11.4 
Duration of Response .................................................................................................... 82 
11.5 
Confirmatory Measurement .......................................................................................... 83 
12 DATA REPORTING / REGULATORY REQUIREMENTS ........................................ 83 
12.1 
Data Reporting .............................................................................................................. 83 
12.2 
CTEP Multicenter Guidelines ....................................................................................... 83 
12.3 
Collaborative Agreements Language ............................................................................ 83 
13 STATISTICAL CONSIDERATIONS .............................................................................. 85 
13.1 
Study Design/Endpoints................................................................................................ 85 
13.2 
Sample Size/Accrual Rate ............................................................................................. 85 
13.3 
Analysis of Secondary Endpoints ................................................................................. 86 
13.4 
Reporting and Exclusions ............................................................................................. 86 
14 HUMAN SUBJECTS PROTECTIONS ............................................................................ 87 
14.1 
Justification for Subject Selection ................................................................................ 87 
14.2 
Evaluation of Benefits and Risks/Discomforts ............................................................. 87 
14.3 
Consent and Assent Process and Documentation ......................................................... 87 
14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks......................... 88 
14.5 
Patient Advocate ........................................................................................................... 88 
REFERENCES ............................................................................................................................ 89 
APPENDIX A: PERFORMANCE STATUS CRITERIA....................................................... 92 
APPENDIX B: POTENTIAL DRUG INTERACTIONS ........................................................ 93 
APPENDIX C: MEDICATIONS THAT MAY CAUSE QTc PROLONGATION .............. 98 
APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC 
DISEASE ................................................................................................................................... 100 
APPENDIX E: PATIENT’S MEDICATION DIARY........................................................... 101 
APPENDIX F: LVEF DOSE MODIFICATION TABLE ..................................................... 103 
APPENDIX G: FACSIMILE TRANSMISSION FORM FOR SAMPLE SHIPMENT .... 105 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
9 
1 OBJECTIVES 
1.1 
Primary Objectives  
• Establish the safety and tolerability of the combination of pazopanib with ARQ 197 in 
patients with refractory advanced solid tumors. 
• Establish the maximum tolerated dose (MTD) of the combination of pazopanib with 
ARQ 197 in patients with refractory advanced solid tumors. 
• Evaluate changes in MET and phospho-MET following treatment with pazopanib and ARQ 
197 in patients with refractory advanced solid tumors. 
1.2 
Secondary Objectives 
• Determine the pharmacokinetics (PK) of pazopanib and ARQ 197. 
• Determine and compare levels of total MET, phospho MET, HIF-1α, and epithelial-
mesenchymal transition markers (e-cadherin, beta catenin) in tumor biopsy samples prior to 
and following administration of the study drugs.   
• Determine and compare levels of circulating levels of HGF, soluble MET (sMET), VEGF-A, 
and soluble VEGFR2 (sVEGFR2) prior to and following administration of the study drugs. 
• Determine polymorphisms in the CYP2C19 and correlate these with the observed toxicities, 
and the PK of ARQ 197. 
• Evaluate antitumor activity of the combination of pazopanib and ARQ 197 in patients with 
refractory advanced solid tumors. 
 
 
2 BACKGROUND 
2.1 
Targeting the VEGF and HGF Pathways  
Activation of the independent vascular endothelial growth factor (VEGF) and  hepatocyte growth 
factor (HGF) signal transduction pathways has synergistic effects on promoting the formation of 
new blood vessels and inducing the expression of a number of growth factors, chemokines, and 
cytokines, including c-MET, the tyrosine kinase receptor for HGF [1-3].  The mechanism for this 
synergistic interaction is not known, but overexpression of HGF and c-MET are associated with 
aggressive tumors and poor prognosis in several cancers [4-6].  Combination therapy with 
inhibitors of HGF and VEGF signaling might therefore have superior anti-angiogenic activity in 
patients with cancer than either agent alone [7].   
Sennino and colleagues  investigated whether inhibiting VEGF and c-MET had an effect on 
tumor growth and survival in a mouse model using XL184 (BMS-907351), a tyrosine kinase 
inhibitor that blocks VEGFR and c-MET, and an antibody selective for mouse VEGF [8].  This 
study also evaluated whether treatment with a VEGF inhibitor upregulates the expression of c-
MET, as no in vitro data indicates that treatment with VEGF inhibitors results in both antitumor 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
10 
activity and promotion of metastasis [9-11].  It has been suggested that one response to the 
hypoxia caused by treatment with VEGF inhibitors is upregulation of c-MET [12]. 
As shown in Figure 1, combination blockade of VEGFR and c-MET with XL184 significantly 
(P < 0.05) prolongs survival compared to treatment with vehicle or anti-VEGFR antibody alone 
in the RIP-Tag2 transgenic mouse model, a spontaneous and highly vascularized pancreatic islet 
cell cancer [8]. 
 
Figure 1: Increased survival 
of RIP-Tag2 transgenic mice 
following treatment with the 
VEGFR and c-MET inhibitor 
XL184 compared to 
treatment with anti-VEGF 
antibody or vehicle.   
 
 
 
The extent of liver metastasis was also less in RIP-Tag2 mice treated with combination blockade 
of VEGFR and c-MET than in mice treated with anti-VEGF antibody alone (Figure 2). 
  
Figure 2: Confocal micrographs of liver sections stained for SV40 T-antigen (expression is 
limited to islet insulin-producing β cells) from RIP-Tag2 mice treated from 14 to 17 weeks of 
age with vehicle (A), anti-VEGF antibody (B) or XL184 (C).  The number and size of liver 
metastases (indicated with white arrows) are greatest after treatment with anti-VEGF antibody, 
less prevalent (i.e., smaller and scattered) after treatment with vehicle, and undetectable after 
treatment with XL184 (P < 0.05, measured mm2). 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
11 
Of relevance to this protocol is that c-MET expression was significantly increased in pancreatic 
islet cell tumors in RIP-Tag2 mice after treatment with anti-VEGF antibody (Figure 3) [8].  
Overexpression of c-MET is sufficient to induce hepatocellular carcinomas in transgenic mice 
[13, 14].  Data from the Vande Woude lab also support a role for HGF in promoting 
angiogenesis through upregulated expression of VEGF and downregulated expression of 
thrombospondin 1 (TSP-1), a key negative regulator of angiogenesis [4].  Agents that inhibit 
c-MET and VEGF are therefore of great clinical interest [7, 13, 15, 16].   
 
Figure 3: PCR measurements of c-MET expression in 
pancreatic islet cell tumors in transgenic RIP-Tag2 mice after 
treatment with vehicle or anti-VEGF antibody for 1 week.   
N = 5 mice/group.  *P < 0.05 vs. vehicle. 
 
 
 
 
 
2.2 
Pazopanib 
Pazopanib is a highly selective and potent inhibitor of VEGFR-1, -2 and -3, PDGFR-alpha, 
PDGFR-beta, and c-kit tyrosine kinases which are integral components of several cell signaling 
pathways aberrantly activated during carcinogenesis (Figure 4) [17-19].  Pazopanib has been 
shown to selectively inhibit VEGF-induced endothelial cell proliferation, angiogenesis and 
tumor growth in multiple human tumor xenograft models, including prostate, colon, lung, 
melanoma, breast, and renal cancer.  Preclinical PK/PD studies have shown that a plasma 
concentration of ≥40 µmol/L pazopanib is required for optimal inhibition of VEGFR-2 in vivo 
[17].  
 
Clinically, pazopanib has demonstrated activity in patients with renal cell cancer; current 
Phase I, II, and III trials of pazopanib as single therapy and in combination with paclitaxel or the 
tyrosine kinase inhibitor of HER2 and EGFR, lapatinib, are ongoing or planned.  These trials are 
accruing patients with several tumor types including liver cancer, metastatic renal cell 
carcinoma, malignant glioma, non-small cell lung cancer, advanced breast cancer, multiple 
myeloma, ovarian cancer, and various types of sarcomas.   
 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
12 
 
Figure 4:  Outline of Pazopanib targets in multiple signaling pathways involved in tumor 
angiogenesis, proliferation, and survival [18]. 
 
Clinical Experience 
Approximately 3000 subjects with cancer have been enrolled in clinical studies of pazopanib as 
of September 2009.  In October 2009, the FDA approved pazopanib tablets for the treatment of 
subjects with advanced renal cell carcinoma (RCC).  In addition, several clinical studies 
evaluating pazopanib in non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, soft 
tissue sarcoma (STS), cervical cancer, hepatocellular cancer (HCC), multiple myeloma (MM), 
and glioma are in progress or have been completed.   
 
Clinical Efficacy 
In a randomized, double-blind, placebo-controlled phase 3 study evaluating the efficacy and 
safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated subjects with 
advanced RCC, the median progression-free-survival (PFS) was significantly prolonged with 
pazopanib compared with placebo in the overall study population (9.2 vs. 4.2 months).  The 
objective response rate (RR) was 30% with pazopanib and only 3% with placebo (28).  In 
subjects with ovarian cancer, 31% of subjects experienced a CA-125 response to pazopanib, with 
a median time to response of 29 days and median duration of response of 113 days 
(Investigator’s Brochure, 2010).  Median PFS was 84 days and the overall RR was 18%.  In 
advanced or metastatic STS, the rate of PFS at 12 weeks was 43.9% for leiomyosarcoma, 48.6% 
for synovial sarcoma, 26.3% for adipocytic sarcoma, and 39% for other types of sarcoma (29).  
In a phase 2 trial of subjects with early-stage NSCLC, 86% of subjects experienced a reduction 
in tumor volume after short-term, preoperative use of pazopanib (~2-6 weeks) as assessed by 
high-resolution CT scanning (30).  Interim results from a phase 2 study of pazopanib in subjects 
with recurrent or metastatic breast invasive breast cancer showed that the clinical benefit rate 
was 26% (31).  The median TTP was 3.7 months, and 50% of subjects with measurable target 
lesions had some decrease in size.  PFS at 3 and 6 months was 55% and 28%, respectively.  
Preliminary results from a randomized study in subjects with first-line advanced ErbB2-positive 
advanced or metastatic breast cancer showed that a higher response rate (36.2% vs. 22.2%) was 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
13 
observed in subjects on combination lapatinib 1000 mg once daily + pazopanib 400 mg once 
daily compared to monotherapy lapatanib 1500 mg once daily (32).  In a randomized phase 2 
study of pazopanib vs. lapatinib vs. the combination of pazopanib/lapatinib in advanced and 
recurrent cervical cancer, there was a 34% reduction in risk for progression in subjects receiving 
pazopanib relative to lapatinib.  The median PFS was 17.1 weeks in the lapatinib group and 18.1 
weeks in the pazopanib group (33).  Interim analysis of data from 26 subjects showed that 
pazopanib has both a favorable toxicity profile and promising clinical activity in subjects with 
advanced and progressive differentiated thyroid cancers (34).  Five confirmed partial responses 
(PRs) (19%) were reported.  Pazopanib has not shown efficacy in phase 2 studies conducted in 
MM or glioma (Investigator’s Brochure, 2010) 
 
Safety  
The randomized, phase 3 study in mRCC subjects provided a key comparison of safety with 
pazopanib compared to placebo (28).  The overall frequency of adverse events (AEs) reported 
during the study was higher in the pazopanib arm (92%) compared with placebo (74%).  The 
most common AEs reported in >20% of subjects in the pazopanib arm were diarrhea (52%), 
hypertension (40%), hair color change (depigmentation; 38%), nausea (26%), anorexia (22%), 
and vomiting (21%).  Most of the events were grade 1 or 2.  A higher number of grade 3 AEs 
were reported in the pazopanib arm (33%) compared with the placebo arm (14%).  The most 
frequent grade 3 AEs in the pazopanib arm were increased alanine aminotransferase (ALT), 
increased aspartate aminotransferase (AST), hypertension, and diarrhea.  The frequency of grade 
4 and grade 5 AEs was similar between the pazopanib and placebo arms:  grade 4 in 7% and 6%, 
respectively; grade 5 in 4% and 3%, respectively. 
 
A comprehensive review of all completed and ongoing pazopanib clinical trials with a cut-off 
date of September 2009, lists 15 most commonly occurring serious AEs (SAEs) (Investigator’s 
Brochure, 2010).  Vomiting and diarrhea are the most commonly reported SAEs across all the 
pazopanib studies.  As a consequence of this, dehydration is also seen with pazopanib treatment.  
For most reports, the AEs resolved after supportive treatment such as antiemetics, antidiarrheal 
agents, and IV fluids.  GI perforation is commonly associated with VEGF pathway inhibitors.  
This may manifest as abdominal pain which is not uncommon in cancer subjects for many 
reasons.  Of the 42 subjects in pazopanib trials with SAEs of abdominal pain, only three had a 
documented underlying intestinal perforation.  In July 2006, the DCTD, NCI, issued an Action 
Letter to investigators using pazopanib describing the occurrence of bowel perforations in 
subjects on pazopanib clinical trials. 
 
Dyspnea is also frequently seen in pazopanib-treated subjects and may reflect the underlying 
disease under treatment.  Anemia is commonly seen in cancer subjects in association with 
chemotherapy, hemorrhage, or infection.  The SAEs of pyrexia were attributed to multiple 
causes:  concurrent infections, the underlying malignancy, hepatic events, other concomitant 
medications, and unknown causes.  Hepatic events are thought to be on-target tyrosine kinase 
inhibitor (TKI) class effects, as hepatic enzyme elevations have been seen with other agents of 
this class.  Careful clinical evaluation is, therefore, warranted in subjects with hepatic 
abnormalities.  Pneumonia can be a complication of chemotherapy or can result from debilitation 
and advanced disease.  Review of the 33 SAEs showed the presence of an underlying cause other 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
14 
than pazopanib in 19 of the 30 subjects.  Fatigue and asthenia are commonly reported and have 
multiple causes. 
 
Hypertension observed with pazopanib is a known class effect.  There have been 30 SAEs of 
hypertension and 3 SAEs of hypertensive crisis in pazopanib clinical trials.  There were 28 
subjects who were effectively treated with antihypertensive medication initiation or dose 
adjustment, while 4 had no such treatment.  Although there were 29 SAEs of pleural effusion, 
the body of data does not suggest that any of these cases were due to pazopanib.  There have 
been 24 SAEs of pulmonary embolism (PE) reported in pazopanib trials.  This is of particular 
relevance since other members of this class have been associated with PE and other venous 
thromboembolic events. 
 
In addition, there have been reports of cardiac and cerebral ischemic events, GI perforation or 
hemorrhage, pulmonary hemorrhage, cerebrovascular hemorrhage, QT prolongation, and 
Torsades de Pointes in pazopanib clinical trials. 
 
Cases of hepatic failure, including fatalities, have been reported during the use of pazopanib.  
Two of 977 patients (0.2%) died with disease progression and hepatic failure in trials that 
supported the renal cell carcinoma (RCC) indication.  One of 240 patients (0.4%) died of hepatic 
failure in the randomized soft tissue sarcoma (STS) trial.  In RCC monotherapy trials using 
pazopanib, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have 
been reported as very common (≥10%), and abnormal hepatic function and hyperbilirubinemia 
have been reported as common (≥1% to <10%) adverse reactions.  In STS monotherapy trials 
using pazopanib, increased ALT and AST have been reported as common (≥1% to <10%) 
adverse reactions. 
 
Elevated ALT (>3X ULN) and concurrent elevated ALT (>3X ULN) and bilirubin (>2X ULN) 
have been observed primarily between weeks 3 and 9 of therapy in pazopanib clinical trials.  A 
comparison across trials with pazopanib indicates ALT >3X ULN in 1% and approximately 5% 
of treated patients at weeks 2 and 3, respectively.  Most new cases of ALT >3X ULN occurred 
by week 9.  More frequent monitoring between weeks 3 and 9 may lead to earlier detection of 
elevated serum liver tests and hepatotoxicity in patients taking pazopanib. 
 
 
Clinical Pharmacokinetics 
The oral bioavailability of pazopanib reflects absorption that is limited by solubility above doses 
of 800 mg once daily (Investigator’s Brochure, 2010).  Increases in doses above 800 mg to 
2000 mg, in the fasted state will not result in increased systemic exposure.  Geometric mean 
pazopanib t½ values ranged from 18.1-52.3 hours.  The mean t½ was 30.9 hours in the 800 mg 
once daily group, in phase 2 and 3 trials.  Oral absorption is significantly enhanced when dosed 
with food; therefore, it is recommended to administer pazopanib on an empty stomach, at least 1-
2 hours after a meal.   
 
Preliminary information on the pharmacokinetics (PK) of pazopanib administered in 
combination with lapatinib has been reported (35).  Thirty-three subjects received doses of 
lapatinib ranging from 750-1500 mg once daily along with pazopanib at doses of 200-500 mg 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
15 
daily.  Preliminary mean plasma concentrations 24 hours after administration (C24) on day 22 
were ~19 mcg/mL and 23 mcg/mL after pazopanib doses of 250 mg and 500 mg, respectively.  
These values are similar to the mean C24 values observed after administration of 800 mg 
pazopanib alone (23.1 mcg/mL).  Plasma lapatinib concentrations at 750-1500 mg daily were 
similar to those observed after monotherapy.  Concurrent administration of pazopanib and 
lapatinib was generally well tolerated; coadministration of lapatinib may alter the PK of 
pazopanib (Dejonge et al., 2006). 
 
Preliminary PK information on the combination of pazopanib and paclitaxel administered to 
subjects with advanced cancer has been reported (36).  Twelve subjects received paclitaxel (15-
80 mg/m2 on days 1, 8, and 15 every 28 days) and pazopanib at 400 or 800 mg/day starting on 
day 2 of the first cycle.  Coadministration of pazopanib increased paclitaxel mean Cmax and 
AUC0-8 approximately 20-35% (36). 
 
Age, body weight, gender, and race had no significant influence on pazopanib PK. 
 
Potential Drug Interactions 
Pazopanib is metabolized primarily by CYP3A4, and systemic exposure to pazopanib is altered 
by inhibitors and inducers of this enzyme.  The concomitant use of strong CYP3A4 inhibitors 
should be avoided.  If co-administration of a strong CYP3A4 inhibitor is warranted, a dose 
reduction to 400 mg is recommended.  Grapefruit may also increase plasma concentrations of 
pazopanib and should be avoided.  CYP3A4 inducers such as rifampicin may decrease plasma 
concentrations; therefore, an alternative concurrent medication with none or minimal enzyme 
induction should be used.  Concommitant use of medications that have narrow therapeutic 
windows and that are substrates of CYP3A4, CYP2D6 or CYP2C8 should occur only with 
caution. 
 
Concommitant medications that have narrow therapeutic windows and are substrates of CYP3A4, 
CYP2D6 or CYP2C8 should be used with caution.  If possible, medications that are not 
substrates for these enzymes and/or do not have narrow therapeutic windows should be 
substituted.  
2.3 
ARQ 197 
The c-MET RTK mediates the signals for a variety of physiological processes that have 
implications for oncogenesis, including migration, invasion, cell proliferation, and angiogenesis.  
A wide variety of human cancers exhibit constitutively dysregulated c-MET activity, either 
through over-expression of the c-MET kinase, activating mutations in c-MET, or increased 
autocrine or paracrine secretion of the c-MET ligand hepatocyte growth factor/scatter factor 
(HGF/SF).  These alterations have been strongly implicated in tumor progression and metastasis 
in a variety of cancers, and a high constitutive activation of the c-MET RTK has been correlated 
with poor clinical prognosis. 
 
c-MET can be activated in both a ligand-dependent manner, by the overexpression of c-MET 
and/or its ligand HGF, or a ligand-independent manner as in the case of activating mutations of 
c-MET such as those described in certain gastric carcinoma-derived cell lines.  The cell line 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
16 
MKN-45, has amplified MET gene in the absence of mutation and superabundance of MET 
protein at the cell surface, which is fully active in the complete absence of HGF.  Activation and 
autophosphorylation of c-MET results in the binding and phosphorylation of adaptor proteins 
such as Gab1, Grb2, Shc and c-Cbl, and results in the subsequent activation of signaling 
pathways, including the PI3K/Akt, FAK, STAT and Ras/MEK/Erk pathways that play various 
roles in cell survival, proliferation, invasion, and angiogenesis.  In the melanocyte lineage, c-
MET expression is upregulated by microphthalmia-associated transcription factor (MITF), which 
has been implicated in the oncogenesis of melanoma and other cancers [20, 21].  The presence of 
c-MET in most cancers, and its role in controlling multiple signal transduction pathways 
involved in tumor growth render this enzyme a logical therapeutic target for human cancer. 
 
ARQ 197 is a potent non-ATP competitive RTK inhibitor with high selectivity for the c-MET 
RTK, as determined by biochemical and cellular assays.  ARQ 197 has growth inhibitory activity 
in breast, prostate, colon and pancreatic carcinoma xenograft models.  ARQ 197 has also been 
shown to inhibit metastasis in a metastatic orthotopic colon cancer xenograft model [13, 22, 23].  
A comprehensive review of ARQ 197 can be found in the ARQ 197 Investigator’s Brochure 
(2010). 
2.3.1 Nonclinical Pharmacology 
In Vitro Efficacy 
ARQ 197 selectively inhibits the in vitro biochemical activity of recombinant c-MET 
with a Ki of approximately 355 nM.  The potency of ARQ 197 inhibition of c-MET 
activity was independent of ATP concentration, suggesting that the mode of inhibition of 
ARQ 197 is of a non-competitive nature.  While ARQ 197 inhibits c-MET kinase activity, 
it is not a promiscuous kinase inhibitor.  When ARQ 197 was profiled against 230 protein 
kinases at a nominal concentration of 5 or 10 μM, ARQ 197 inhibited only 4 protein 
kinases greater than 20%.  These data suggest that ARQ 197 is a highly selective c-MET 
kinase inhibitor. 
 
In cell-based kinase assays, ARQ 197 inhibited HGF-induced activation of c-MET 
(gauged by autophosphorylation) with an IC50 between 0.1–0.5 μM in multiple human 
cancer cell lines.  This suppression was effective for at least 8 to 12 hours after 
withdrawal of ARQ 197, demonstrating a sustained durability of c-MET inhibition by 
ARQ 197.  Furthermore, ARQ 197 decreased phosphorylation of most of the c-MET 
downstream effectors including FAK, STAT-3, Erk-1 and Erk-2, but not Akt.  This 
suggests that, through c-MET inhibition, ARQ 197 also induces a decrease in the 
phosphorylation and activation of many downstream targets in the pathways served by 
this oncogenic kinase.   
 
ARQ 197 showed broad-spectrum in vitro anticancer activity against human tumor lines, 
including those derived from breast, pancreas, colon, gastric, and lung.  The potency of 
ARQ 197 in cancer cells expressing detectable c-MET ranges from 0.1–0.6 μM.  By 
contrast, human cells lacking or minimally expressing c-MET such as NCI-H661 (non-
small cell lung cancer; NSCLC) and NCI-H446 (small cell lung cancer) yielded IC50 
values approximately 10-fold higher, indicating a correlation between the presence of c-

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
17 
MET and the sensitivity of the cells towards ARQ 197.  The ability of ARQ 197 to inhibit 
c-MET phosphorylation correlates with its ability to inhibit growth and induce apoptosis 
in c-MET expressing cancer cells.   
 
Overexpression of c-MET correlates with tumor cell migration and invasiveness, and 
invasion assays demonstrated that ARQ 197 potently inhibited invasion in c-MET 
expressing tumor cell lines (IC50s of approximately 0.3–0.45 μM), but less so in non-c-
MET expressing lines (IC50 = 5.4 μM).  In a wound healing assay, ARQ 197 also 
inhibited migration of NCI-H441 cells (human lung adenocarcinoma) in response to HGF.  
Overall, these results indicate that ARQ 197 has anticancer activity, an effect which is 
mediated via c-MET inhibition. 
 
Another study assessed a panel of 64 human cancer cell lines encompassing a spectrum 
of genotypes and tissue origins.  The combination of ARQ 197 and sorafenib showed 
synergistic cytotoxicity in nine cell lines, including three NSCLC cell lines, two breast 
cancer cell lines, a melanoma cell line, a renal clear cell carcinoma cell line, a cervical 
carcinoma cell line, and a squamous cell carcinoma cell line.  An additive effect was seen 
with the ARQ 197/sorafenib combination across a wide range of 40 human cancer cell 
lines including, but not limited to, 5 colon cancer lines, 5 breast cancer cell lines, 4 
additional NSCLC cell lines, and 3 hepatocellular carcinomas (HCC). 
 
In Vivo Efficacy 
When administered via daily oral dosing, ARQ 197 was efficacious against multiple 
human cancer xenograft models.  Beginning at a dose level of 200 mg/kg, tumor growth 
inhibition was seen in breast (79%), colon (39%), pancreatic (58%), prostate (72%), and 
gastric (52%) models.  Increasing the dose to 300 mg/kg improved tumor inhibition in 
colon (55%), pancreatic (60%), and prostate (77%) models.  ARQ 197 was well tolerated 
in these studies with no drug related clinical signs or deaths.  There was no significant 
change in body weight at any of the dose levels tested.  Furthermore, the antitumor 
activity of ARQ 197 is accompanied by the ablation of c-MET activity, as assessed by the 
decreased level of phosphorylated c-MET in the dissected xenograft tumor tissue.  This 
suggests a potential mechanism-based clinical biomarker. 
 
A study conducted with the NCI-H522 NSCLC cell line suggests that antitumor effects of 
ARQ 197 and sorafenib were modestly additive in human tumor xenograft models.  The 
combination was well tolerated, with no body weight changes or deaths observed. 
 
Nonclinical Pharmacokinetics 
The pharmacokinetics of ARQ 197 were evaluated and compared in mice, rats, and dogs 
using different dosing routes, levels, and formulations.  In general, exposure to ARQ 197 
increased as the dose was increased.  Overall, the corresponding increases in AUC0-inf and 
Cmax were not dose proportional.  The t1/2 of ARQ 197 generally ranged from 1–4.5 hours 
across all studies and all species, though there were some exceptions.  For instance, rats 
displayed a highly variable t1/2 (1.48 – 37.8 hours), the reason for which is unknown.  
Bioavailability after single dosing was somewhat variable between species: 16-35% in 
rats, 33-60% in dogs, and 21-37% in mice.  After multiple dosing in 7- day, 28- day, 8- 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
18 
week, and 26- week studies, there were no consistent changes in Cmax and AUC values in 
rat or dog, indicating no marked accumulation of ARQ 197. 
 
Metabolism 
Mass balance and tissue distribution studies indicated that the primary route of 
elimination of ARQ 197 is fecal and that ARQ 197 generally did not accumulate (after 96 
hours) in any of the tissues tested.  Data from in vitro metabolism studies suggest that 
ARQ 197 is relatively stable in human liver microsomes with a t1/2 of 29 min.  The t1/2 of 
ARQ 197 in male dog liver microsomes was similar to that of human liver microsomes 
with a t1/2 of 29 min (t1/2 in female dog liver microsomes was 20.5 min).   
 
From studies conducted with individual CYP P450 isozymes, ARQ 197 was rapidly 
metabolized by CYP2C19 (t1/2 = 2.83 min) and moderately metabolized by CYP 3A4 (t1/2 
= 16.3 min).  The t1/2 values for the other CYP P450s (1A2, 2C9, 2D6, and 2C8) tested 
were all greater than 27.4 min.  Drugs which affect the activity of CYP2C19 or CYP3A4 
may markedly alter the plasma concentration of ARQ 197.  The IC50 of ARQ 197 was 
evaluated for each CYP 450 isoform (1A2, 2C8, 2C9, 2C19, 2E1 and 3A4), and all were 
greater than 10 μM. 
 
Nonclinical Toxicology 
Preclinical toxicity for ARQ 197 was assessed in the rat and beagle dog in single and 
repeat dose studies of up to 26 weeks in duration.  In 28-day repeat-dose studies, clinical 
pathology signs typically observed at the high dose (45 mg/kg) included lower red cell 
mass, lower absolute reticulocyte count, and lower absolute neutrophil and monocyte 
counts for males and females.  In addition, females had lower absolute lymphocyte and 
eosinophil counts.  Microscopic findings at high doses included depletion of lymphocytes 
in the thymus, femur and sternum bone marrow depletion, and hypertrophy and 
vacuolation in peripherolobular hepatocytes.  Importantly, these clinical and anatomic 
pathology findings were reversed by 2 weeks after cessation of dosing. 
2.3.2 Clinical Experience 
The pharmacokinetics, metabolism, safety, and efficacy of ARQ 197 have been 
investigated in multiple phase 1 and 2 clinical trials in cancer patients.  Two phase 1 dose 
escalation trials (ARQ 197-101 and ARQ 197-103) have defined the maximum tolerated 
dose (MTD) and recommended phase 2 dose (RP2D) for continuous doses of ARQ 197 
as a single agent.  Another phase 1 study (ARQ 197-111) evaluated the MTD and RP2D 
of ARQ 197 administered in combination with erlotinib on a continuous schedule.  
Additional ongoing phase 1 and phase 1/2 trials evaluating ARQ 197 include ARQ 197-
114 (monotherapy in HCC); ARQ 197-116 (combination with sorafenib); and ARQ 197-
117 (combination with gemcitabine). 
 
In addition, there are two active phase 2 clinical trials: ARQ 197-204 is evaluating the 
efficacy of ARQ 197 in patients with MITF-associated tumors, while ARQ 197-209 is an 
ongoing global, randomized, placebo controlled, double-blind phase 2 trial comparing 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
19 
treatment with erlotinib plus ARQ 197 versus treatment with erlotinib plus placebo in 
patients with previously treated NSCLC. 
 
Clinical experience to date suggests that ARQ 197 has a favorable safety profile [23]. 
Detailed information for each of these studies, including pharmacokinetic data, can be 
found in the Investigator’s Brochure (2010).  Safety and efficacy results are summarized 
below. 
 
Phase 1 Studies 
Studies ARQ 197-101 and ARQ 197-103 were phase 1 dose escalation trials of ARQ 197 
in adult patients with locally advanced or metastatic solid tumors.  In ARQ 197-101 trial, 
13 dose levels ranged from 10–360 mg BID and 2 dosing schedules (intermittent versus 
continuous) were explored and no dose-limiting toxicities (DLTs) were reported at doses 
below 360 mg BID.  In ARQ 197-103 trial, ARQ 197 was given twice daily continuously 
and the MTD was found to be 360 mg BID.  The most common drug-related adverse 
events (AEs; ≥5% and ≥2 events) seen in these studies were fatigue (13.9% and 15.7%, 
respectively), nausea (13.9%, 13.7%), vomiting (10.1%, 11.8%), and diarrhea (6.3%, 
7.8%).  Serious adverse events (SAEs) reported at a >3% incidence were disease 
progression, dehydration, anemia, nausea, renal failure acute, and vomiting, febrile 
neutropenia.   
 
Study ARQ 197-114 is an ongoing safety study of ARQ 197 in cirrhotic subjects with 
HCC.  ARQ 197 is administered continuously at a dose level of 360 mg BID.  The most 
common drug-related AEs (>5% and >2 events) are asthenia (47.6%), neutropenia 
(42.9%), anemia (42.9%), leukopenia (38.1%), anorexia (38.1%), diarrhea (28.6%), 
alopecia (19.0%), thrombocytopenia (14.3%), vomiting (14.3%), hepatobiliary disorders 
(14.3%), hyperbilirubinemia (14.3%), lymphopenia (9.5%), bradycardia (9.5%), 
dysgeusia (9.5%), and oropharyngeal pain (9.5%).  Drug-related SAEs leading to 
discontinuation from the study include three cases of neutropenia.   
 
Study ARQ 197-111 is an ongoing phase 1 dose escalation trial of ARQ 197 
administered in combination with erlotinib in adult patients with advanced solid tumors.  
A dose of 360 mg ARQ 197 BID in combination with erlotinib 150 mg daily has been 
identified as the RP2D (one DLT of neutropenia).  The most commonly-reported drug-
related AE in this study was bradycardia, with 15 episodes reported in 4 patients; these 
events were generally mild and asymptomatic (grade 1), and 14 of these events occurred 
at the 360 mg BID dose level of ARQ 197.   
 
Phase 2 Studies 
Protocol ARQ 197-204 is a phase 2 study of ARQ 197 in patients with MITF-associated 
tumors, including translocation-associated renal cell carcinoma (t-RCC), alveolar soft-
part sarcoma (ASPS), and clear-cell sarcoma (CCS).  The initially enrolled patients 
received 120 mg ARQ 197 BID; patients enrolled after the RP2D was determined (in 
ARQ 197-103) received 360 mg ARQ 197 BID.  Among 47 patients treated in this study, 
ARQ 197 demonstrated a favorable safety profile and was well tolerated at both doses.  
The most common (≥5% and ≥2 events) drug-related AEs were fatigue, pyrexia, nausea, 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
20 
vomiting, diarrhea, retching, anemia, lymphopenia, pain in extremity, anorexia, headache, 
insomnia, dyspnea, cough, neutrophil count decreased, decreased white blood cell count, 
increased alanine aminotransferase level, increased aspartate aminotransferase level, 
decreased hemoglobin level, sinus bradycardia, and rash.  To date, 45 patients are 
evaluable for efficacy.  One patient with CCS demonstrated a confirmed PR.  Twenty-
seven patients demonstrated SD, including 21 with ASPS, three with t-RCC, and three 
with CCS.  Overall, 12 subjects have had SD for >24 weeks.  Currently, two phase 2 
trials are ongoing; ARQ 197 plus erlotinib versus ARQ 197 plus placebo in patients with 
previously treated NSCLC (ARQ 197-209) and single agent ARQ 197 in patients with 
HCC (ARQ 197-215).   
 
Pharmacokinetics 
Approximately 345 subjects with cancer and over 100 healthy subjects participated in 
phase 1 studies of ARQ 197.  Clinical PK data are available from multiple clinical studies 
using ARQ 197 as either the amorphous solid or 1 of 2 crystalline forms designated form 
A or form B.  Overall, following oral administration ARQ 197 is moderately absorbed 
with a Tmax ranging from 2–6 hours.  In general, ARQ 197 exposure increases with 
increases in dose; however, exposure is not dose proportional.  There is wide intersubject 
variability in ARQ 197 PK.  Based on population pharmacokinetic (PopPK) analysis, this 
variability is partly due to CYP2C19 polymorphism, fed status during ARQ 197 
administration, ARQ 197 form (amorphous versus crystalline A versus crystalline B), and 
also possibly ethnicity differences (Caucasian versus Japanese).   
 
In vitro human liver microsome studies indicate involvement of both CYP2C19 and 
cytochrome P450 3A4 (CYP3A4) in ARQ 197 metabolism.  In humans, ARQ 197 
showed a genotype exposure relationship dictated mainly by CYP2C19 genotype.  In 
healthy subjects, CYP2C19 poor metabolizers (PMs) had much higher exposure than 
extensive metabolizers (EMs), as reflected by AUC0-48 and Cmax (11-fold and 3-fold 
higher, respectively) and lower clearance (mean of 2.4 L/h versus mean of 33.9 L/h).  
However, based on steady state exposure data in cancer subjects the PM exposure (AUC0-
12) is only 1.4- to 4-fold greater than EM exposure.  Hence, differences in CYP2C19 
metabolism will contribute to variability in PK between subjects.  In a phase 1 dose-
escalation study, 10 of 43 patients were characterized as PMs.  Additional studies 
comparing the PK of the amorphous form of ARQ 197 to the crystalline forms A and B 
of ARQ 197 showed that the amorphous form of ARQ 197 resulted in higher exposure 
(Cmax, AUC) than either crystalline form A or B.  Specifically, Cmax was approximately 
60% to 70% lower for forms A and B, respectively, compared with the amorphous form.  
Similarly, AUC was 20% to 30% lower for crystalline forms A and B, respectively, 
relative to the amorphous form.  
 
When ARQ 197 was administered immediately after a high-fat meal to healthy subjects, 
the exposure was 3 times greater than the exposure under fasted conditions (fasted versus 
fed:  AUC0-last, 4858 +1793 ng/hr/mL versus 13356 +5385 ng/hr/mL and AUC0-inf, 6166 
+2393 versus 13558 +6397 ng/hr/mL).  However, the observed exposure under fed 
conditions was similar to that observed in the prior clinical studies in subjects with cancer 
and less than the MTD exposure.  Additionally, in cancer subjects (study ARQ 197-117), 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
21 
the exposure when ARQ 197 crystalline B was administered 360 mg BID (the phase 3 
dose) under fed versus fasting (at least 1 hour before and 2 hours after a meal) condition 
were similar (fed versus fasting: 12251 versus 10453 ng/hr/mL).  Furthermore, when 
administered under fed conditions, the variability in ARQ 197 exposure is generally 
lower compared with the fasted condition.  
 
2.4 
Correlative Studies Background 
2.4.1 Measurement of MET in tumor biopsies by immunoassay 
Serial evaluation of the tumor biopsy samples will be performed with quantitative 
sandwich chemiluminescence immunoassays to measure drug effect on modulation of 
intact c-MET and 2 known key domains in intact c-MET: the tyrosine kinase (TK) 
domain and the C-terminal signaling/mediator docking domain (multiple docking site).  
Phosphorylation status of tyrosine at positions 1235 and 1356 denotes the activation state 
of the TK domain and multiple docking site, respectively.  Three quantitative ELISA-
based immunoassay for the measurement of c-MET (intact MET) and two c-MET 
phosphorylated isoforms (pY1235 and pY1356) have been developed in the laboratory of 
Dr. Apurva Srivastava, SAIC-Frederick, and are currently under validation for use to 
assess target modulation.  The amount of intact MET serves as a denominator to 
determine the fraction of MET phosphorylated at either pY1235 or pY1356.  Assay 
readout is based on relative light units from a Tecan luminometer after addition of 
chemiluminescent substrate.  Six quantitative MET standards over a 30-fold range are 
loaded into a plate along with testing samples for calculating the MET values.  Two assay 
controls (low-C and High-C) are included in each run plate to monitor consistency of the 
assay.  Manuscripts describing these assays are in preparation.  
 
Analytical validation and fit-for-purpose modeling in preclinical studies are currently 
underway.  Preliminary results indicate adequate analytical performance, and >60% 
inhibition in phosphorylation of Y1235 within 4 hours of treatment with two selective c-
MET inhibitors, as compared to the vehicle-treated group.  Intra-tumor variability of c-
MET was 18-37% in biopsy specimens among vehicle treated groups.   
 
Sequencing for known mutations in the MET kinase and ligand binding domains will also 
be performed in tumor biopsies. 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
22 
 
 
Figure 5:  Inhibition of MET and pMET after treatment with the MET inhibitor 
PF02341066 over a period of 10 days.  Drug was given daily for 10 days and biopsies 
were collected 4 hours after each dose on days 1, 3, 6, 8 and 10.  At the 25 mg/kg dose, 
mean intra-tumor MET levels (A) were significantly lower on day 1 and day 3.  However, 
mean intra-tumor levels of normalized pY1235 MET (B) and pY1356 MET (C) were 
consistently lower (50-80%) in treated mice on days 3, 6, 8, and 10, as compared to 
pMET levels in vehicle treated group.  
2.4.1.1 Measurement of MET/phospho-MET 
With Amendment D (12/7/2012), the primary study objective dealing with 
biomarker endpoints was revised from determining reduction of phospho-MET in 
tumor biopsy samples following administration of ARQ 197 in light of preclinical 
findings and published observations about ARQ 197’s mechanism of action.  Data 
suggest that ARQ 197 blocks MET by locking the inactive conformation of MET, 
thus preventing further activation [24].  In contrast, ARQ 197’s effects on 
constitutively phosphorylated Y1234/35 MET are unclear [25].  We tested ARQ 
197 modulation of phospho-MET in gastric tumor xenograft models with 
constitutively active c-MET (SNU5 and MKN45) [26].  ARQ 197 administered at 
doses of 200-400 mg/kg/day did not significantly change phospho-MET levels in 
either the SNU5 or MKN45 model (Figure 6); however, when ARQ 197 was co-
administered with pazopanib in the SNU5 model, ARQ 197 prevented pazopanib-
induced activation of phospho-MET (Figure 6A and 6B).  These results generally 
support the hypothesis underlying combination clinical trials of VEGFR and MET 
inhibitors [27], specifically, that ARQ 197 treatment reverses MET activation by 
pazopanib.   
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
23 
Unfortunately, the mechanism by which ARQ 197 prevents adaptive response to 
VEGFR inhibition could not be verified by the phospho-MET biomarker 
response.  Therefore, the objectives of this trial were modified to address 
evaluation of phospho-MET as an exploratory biomarker for MET activation by 
pazopanib and subsequent blunting of pazopanib-induced activation of MET by 
ARQ 197.  The study design was revised to support this objective.  The number of 
cohorts in the expansion phase was reduced from 3 to 2 as the originally planned 
cohort with a 7-day single-agent ARQ 197 lead-in will be less informative and of 
less potential benefit to patients.  Confirmation of MET expression by 
immunohistochemistry in archival tissue is no longer an eligibility criterion for 
the expansion phase; MET and pMET levels will be determined from on-study 
biopsies only, thus expansion–phase eligibility is now open to patients with 
refractory advanced solid tumors rather than MET-expressing malignancies. 
 
 
Figure 6 (A and B) Treatment of SNU5 xenograft biopsy specimens with ARQ 197 (200 
mg/kg/day QD and 400 mg/kg/day BID) alone did not significantly change total MET, 
pY1235-MET, or pY1356-MET levels compared to vehicle.  In contrast, pazopanib (100 
mg/kg) significantly increased the pY1235-MET/MET ratio (A) and the pY1356-
MET/MET ratio at 4-hours (B) after the day 8 dose compared to vehicle.  This increase 
was inhibited when pazopanib was administered in combination with ARQ 197 (p<0.05).  
(C and D). In the MKN45 xenograft model, biopsy specimens did not show any 
significant changes in the pY1235-MET/MET ratio compared to vehicle in any treatment 
regimen (C – 4 hr; D – 10 hr after treatment on day 8).  Intact MET was significantly 
lower in the combination group compared to vehicle (p<0.05).  Most of the needle biopsy 
A 
C 
B 
D 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
25 
 
2.4.3 Circulating levels of HGF, soluble MET (sMET), VEGF-A, and soluble 
VEGFR2 (sVEGFR2) in patients treated with MET and VEGFR inhibitors 
Many proteins are proteolytically released from the cell surface by a process known as 
ectodomain shedding.  Shedding occurs under normal physiologic conditions and can be 
increased in certain pathologies.  MET is among the many receptors for which 
ectodomain shedding has been demonstrated.  HGF stimulates mitogenesis, motogenesis, 
and morphogenesis in a variety of cellular targets during development, homeostasis and 
tissue regeneration.  Inappropriate HGF signaling resulting in unregulated cell 
proliferation, motility, and invasion occurs in several human malignancies.  This can 
occur through paracrine signaling, autocrine loop formation, receptor mutation, gene 
amplification or gene rearrangement accompanied frequently with overexpression of 
ligand and/or receptor proteins.  Working under the hypothesis that aberrant MET 
pathway activation in cancer might result in increased ectodomain shedding MET could 
be a useful biomarker of tumor progression, Athauda et al. developed a sensitive 
electrochemiluminescent immunoassay to quantitate MET protein in biological samples 
[29].  Their study showed significant direct correlations between malignant potential and 
sMET production in tumor-derived and genetically engineered cell lines, and between 
tumor burden and plasma sMET levels in mice harboring human tumor xenografts [29].  
These preclinical studies supported the hypothesis that sMET might indicate malignant 
potential and/or tumor burden for cancers where the pathway is active. 
 
Several studies of human clinical samples are now underway to investigate the potential 
utility of sMET to aid diagnosis and patient selection, and as a pharmacodynamic marker 
for drugs that directly target MET kinase activity.  Among these is an ongoing 
collaboration between GlaxoSmithKline (GSK) and the NCI Urologic Oncology Branch 
to measure plasma sMET, HGF, VEGF-A and sVEGFR2 in patients in Phase I and II 
clinical trials of GSK1363089 (GSK’089), an inhibitor of MET and VEGFR2 tyrosine 
kinases.  In a Phase II gastric cancer study, patients treated with GSK’089 on an 
intermittent dosing schedule showed significantly increased plasma sMET and VEGF-A 
during the treatment periods and decreases during drug holidays.  Follow-up cell-based 
studies show that inhibition of MET kinase activity blocks receptor internalization, 
resulting in increased exposure to cell surface MET sheddase(s), suggesting a direct 
short-term relationship between sMET levels and drug target inhibition.  Increased 
VEGF-A levels have been reported as a response to VEGFR inhibitors in previous 
clinical studies.  Median tumor burden did not change significantly over the course of the 
gastric study, so it was not possible to determine whether sMET levels could also reflect 
tumor burden.  This question will be better assessed in an ongoing Phase II clinical trial 
of GSK’089 in patients with papillary renal cell carcinoma, where changes in tumor 
burden meeting RECIST criteria were reported in an interim trial report [30]. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
26 
2.4.4 Pharmacogenetic (PG) assessment of CYP2C19 in patients treated with 
ARQ 197  
ARQ 197 is metabolized mainly by CYP2C19.  As described earlier in this section, there 
is wide inter-subject variability in ARQ 197 PK. Based on population pharmacokinetic 
analysis, this variability is partly due to CYP 2C19 polymorphism, fed status during ARQ 
197 administration, ARQ 197 form (amorphous versus Crystalline A versus Crystalline 
B), and also possibly ethnicity differences (Caucasian versus Japanese).  In healthy 
subjects, CYP 2C19 poor metabolizers (PMs) had much higher exposure than extensive 
metabolizers (EMs), as reflected by AUC0-48 and Cmax (11-fold and 3-fold higher, 
respectively) and lower clearance (mean of 2.4 L/h versus mean of 33.9 L/h).  However, 
based on steady state exposure data in cancer subjects, the PM exposure is only 1.4 to 4-
fold greater than EM exposure.  Hence, differences in CYP 2C19 metabolism will 
contribute to variability in PK between subjects.  As a part of this study, a blood sample 
at screening will be taken to evaluate the CYP2C19 genotype of subjects.  The sample 
will be analyzed only for genes involved in the pharmacokinetics, safety, and efficacy of 
ARQ 197.  It will provide information on how individuals metabolize and react to the 
study medication.  This information may be useful in increasing the knowledge of 
differences among individuals in the way they metabolize the study medication as well as 
helping in the development of new drugs or improvement of existing drugs. 
2.5 
Rationale 
We hypothesize that co-administration of the MET inhibitor ARQ 197 will prevent the adaptive 
response to hypoxia resulting from treatment with the VEGFR inhibitor pazopanib, and 
conversely, that co-administration of pazopanib will prevent the effect of increased VEGF and 
reduced TSP-1 in tumors after treatment with ARQ 197.  Therefore, the combination of these 
agents may result in improved antitumor effects. 
 
 
3 PATIENT SELECTION 
3.1 
Eligibility Criteria 
3.1.1 Patients with histologically confirmed (by the Laboratory of Pathology, NIH) 
solid tumors that have progressed following at least one line of standard therapy 
or for whom no standard treatment options exist. 
3.1.2 Patients must have measurable or evaluable disease. 
3.1.3 Patients enrolling in the expansion cohorts must have disease amenable to biopsy, 
and be willing to undergo pre-and post-treatment biopsies. 
3.1.4 Patients must have completed any chemotherapy, radiation therapy, or biologic 
therapy ≥ 4 weeks prior to entering the study (6 weeks for nitrosoureas or 
mitomycin C).  Patients must be ≥ 2 weeks since any prior administration of a 
study drug in a phase 0 or equivalent study.  Patients must have recovered to 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
27 
eligibility levels from prior toxicity or adverse events.  Treatment with 
bisphosphonates is permitted. 
3.1.5 Patients who have had prior treatment with any anti-angiogenic therapy and/or 
c-MET inhibitor are eligible in the dose escalation phase unless the anti-
angiogenic therapy and/or c-MET inhibitor were administered within the 4 weeks 
prior to entering the study.  In the expansion phase, prior c-MET inhibitor is not 
allowed, and anti-angiogenic therapy is not allowed within the 3 months prior to 
entering the study. 
3.1.6 Age ≥ 18 years.  Because no dosing or adverse event data are currently available 
on the use of pazopanib in combination with ARQ 197 in patients < 18 years of 
age, children are excluded from this study.   
3.1.7 Life expectancy > 3 months. 
3.1.8 ECOG performance status 0 or 1 (see Appendix A). 
3.1.9 Patients must have normal organ and marrow function as defined below: 
 
- 
Absolute neutrophil count 
 
≥1,500/µL 
- 
Platelets 
 
 
 
≥100,000/µL 
- 
Total bilirubin  
 
 
≤1.5 X institutional ULN 
- 
AST (SGOT)/ALT (SGPT)  
≤2.5 X institutional ULN 
- 
Creatinine 
 
 
 
≤1.5 mg/dL (133 mcmol/L); OR 
- 
Measured creatinine  
 
≥60 mL/minute for patients with 
 
 
 
clearance 
 
 
 
creatinine levels >1.5 mg/dL 
- 
Urine protein/creatinine ratio  
<1 OR  
                                                             24-hour urine protein <1 gram 
 
 
 
 
Subjects who have both bilirubin >ULN and AST/ALT >ULN are not eligible. 
3.1.10 Subjects in the expansion cohort must have PT/INR/PTT ≤ 1.2 X institutional 
ULN, except patients with confirmed positive lupus anticoagulant test. 
3.1.11 Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and 
90 mmHg (diastolic) for eligibility.  Initiation or adjustment of BP medication is 
permitted prior to study entry provided that the average of three BP readings at a 
visit prior to enrollment is less than 140/90 mmHg. 
3.1.12 The effects of study drugs on the developing human fetus are unknown.  For this 
reason, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study participation, and for at least 2 months after 
dosing with study drugs ceases.  Should a woman become pregnant or suspect she 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
28 
is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.  Women of child-bearing potential 
must have a negative pregnancy test prior to entry.   
3.1.13 Patients must be able to swallow whole tablets or capsules.  Nasogastric or G-tube 
administration is not allowed. 
3.1.14 Ability to understand and the willingness to sign a written informed consent 
document. 
3.2 
Exclusion Criteria 
3.2.1 Patients who are receiving any other investigational agents. 
3.2.2 Patients with active brain metastases or carcinomatous meningitis are excluded 
from this clinical trial.  Patients whose brain metastatic disease status has 
remained stable for ≥ 4 weeks following treatment of the brain metastases are 
eligible to participate.  
3.2.3 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to pazopanib or ARQ 197. 
3.2.4 Eligibility of subjects receiving any medications or substances known to affect or 
with the potential to affect the activity or pharmacokinetics of pazopanib or ARQ 
197 will be determined following review of their cases by the Principal 
Investigator (see Sections 3.2.5-3.2.6 for further information).  Efforts should be 
made to switch subjects with gliomas or brain metastases who are taking enzyme-
inducing anticonvulsant agents to other medications. 
3.2.5 Certain medications that act through the CYP450 system are specifically 
prohibited in subjects receiving pazopanib and ARQ 197 and others should be 
avoided or administered with extreme caution.   
• Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinivir, retonavir, 
saquinavir, telithromycin, voriconazole may increase pazopanib 
concentrations and are prohibited; although, in exceptional circumstances 
they may be administered in conjunction with lowering the dose of 
pazopanib by 50% of what would otherwise be administered.  Grapefruit 
juice is also an inhibitor of CYP450 and should not be taken with pazopanib. 
• Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib 
concentrations, are strictly prohibited.  (See Appendix B) 
• Medications which have narrow therapeutic windows and are substrates 
of CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, 
administered with caution.  (See Appendix B) 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
29 
• Inhibitors or inducers of CYP2C19 should be avoided and, if necessary, 
administered with caution.  (See Appendix B) 
3.2.6 Cardiovascular baseline QTc ≥ 480 msec will exclude patients from entry on 
study.  Medications that may cause QTc interval prolongation are listed in 
Appendix C, and should be avoided by patients entering on trial.  Patients for 
whom a given medication that may cause QTc interval prolongation cannot be 
discontinued may be eligible at the discretion of the study PI.  A comprehensive 
list of agents with the potential to cause QTc prolongation can be found at 
http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm.  (Note:  If subjects 
must take medications with a risk or possible risk of Torsades de Pointes, they 
should be watched carefully for symptoms of Torsades de Pointes, such as 
syncope.  Performing additional EKGs on subjects who must take one or more of 
these medications is not required; however, additional investigations, including 
EKGs, may be performed as per the treating physician’s judgment.) 
3.2.7 Subjects with any of the following cardiovascular conditions within the past 6 
months: 
• cerebrovascular accident (CVA) or transient ischemic attack (TIA) 
• clinically significant bradycardia or other uncontrolled cardiac arrhythmia 
• admission for unstable angina or myocardial infarction 
• cardiac angioplasty or stenting 
• coronary artery bypass graft surgery 
• pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT 
which has been treated with therapeutic anticoagulation for less than 6 
weeks 
• arterial thrombosis 
• symptomatic peripheral vascular disease 
• Class III or IV heart failure as defined by the NYHA functional 
classification system (see Appendix D).  A subject who has a history of 
Class II heart failure and is asymptomatic on treatment may be considered 
eligible 
3.2.8 History of serious or non-healing wound, ulcer, or bone fracture. 
3.2.9 Patients who received major surgery within the past 4 weeks  
3.2.10 Subjects with any condition that may impair the ability to swallow or absorb oral 
medications/investigational product including: 
• any lesion, whether induced by tumor, radiation or other conditions,  
which makes it difficult to swallow capsules or pills 
• prior surgical procedures affecting absorption including, but not limited to 
major resection of stomach or small bowel 
• active peptic ulcer disease 
• malabsorption syndrome 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
30 
 
3.2.11 Subjects with any condition that may increase the risk of gastrointestinal bleeding 
or gastrointestinal perforation, including 
• active peptic ulcer disease 
• known intraluminal metastatic lesions 
• inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease) or 
other gastrointestinal conditions which increase the risk of perforation 
• history of abdominal fistula, gastrointestinal perforation or intra-
abdominal abscess within 28 days prior to beginning study treatment 
3.2.12 History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to 
first dose of study drug. 
3.2.13 Urine protein/creatinine ratio should be screened by urine analysis.  If protein is 
1+ or higher, 24-hour urine protein should be obtained and the level should be  
< 1 g for patient enrollment.  Patients with < 1+ proteinuria are eligible following 
initial determination by urinalysis within 1 week prior to enrollment and do not 
need the urinalysis repeated.    
3.2.14 Patients with clinically significant intercurrent illnesses, including but not limited 
to, life threatening infection, psychiatric illness/social situations that would limit 
compliance with study requirements will not be eligible to participate.     
3.2.15 Pregnant women are excluded from this study because the effects of the study 
drugs on the developing fetus are unknown.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the 
mother with the study drugs, breastfeeding should be discontinued prior to the 
first dose of study drug and women should refrain from nursing throughout the 
treatment period and for 14 days following the last dose of study drug.  
3.2.16 HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for PK interactions.   
3.2.17 Patients who require use of coumarin-derivative anticoagulants such as warfarin 
are excluded.  Low molecular weight heparin is permitted for prophylactic use, 
but not therapeutic use.  
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.   
3.4 
Screening Evaluation 
3.4.1 Histologic confirmation: By the Laboratory of Pathology, NIH.  A block or 
stained slides of primary tumor tissue or of known recurrence will be required 
from each participant to confirm diagnosis. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
31 
3.4.2 History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, performance score, EKG) will be conducted 
within 72 hours week prior to enrollment.  Echocardiogram or MUGA scan for 
assessment of LV ejection fraction will be performed within 4 weeks prior to 
enrollment.  
3.4.3 Imaging Studies (Baseline): Every participant should have an evaluation of 
known sites of disease as part of the baseline evaluation.  All patients will be 
required to undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of 
disease within 28 days prior to enrollment.  MRI or CT scan with contrast of the 
brain, MRI liver, MRI for other disease sites, or bone scan may be done as 
clinically indicated. 
3.4.4 Laboratory Evaluation: Baseline laboratory data are to be obtained within 
72 hours prior to enrollment: 
• Hematological Profile: CBC with differential.  
• Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN, 
calcium, creatinine, glucose, phosphorus, total protein, SGOT[AST], 
SGPT[ALT], magnesium, potassium, and sodium. 
• Coagulation Profile: PT, PTT, INR  
• Serum or urine pregnancy test for female participants of childbearing 
potential. 
• Urinalysis for urine protein/creatinine ratio or 24-hour urine for proteinuria if 
patients have 1+ or greater urine protein/creatinine ratio. 
• Serum liver tests (AST, ALT, serum bilirubin) will be performed as part of a 
risk mitigation plan before initiation of treatment with pazopanib.  
 
4 REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and faxed to 
.  After confirmation of eligibility at Central Registration Office, CRO staff will call 
pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of 
any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail.  Please note that it is very important for all registrars to acquire encrypted e-mail from NIH 
Help Desk, since the verification of registration includes patient’s information.  A recorder is 
available during non-working hours.   
 
Off-Study Procedure: Authorized staff must notify the Central Registration Office (CRO) when 
a patient is taken off-study.  An off-study form from the Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
faxed to 
. 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
32 
5 TREATMENT PLAN 
This is an open-label Phase I trial evaluating the combination of pazopanib, an oral VEGFR 
inhibitor, and ARQ 197, an oral MET inhibitor, in patients with refractory advanced solid 
tumors.  Reported adverse events and potential risks for pazopanib and ARQ 197 are described 
in Section 7.  Appropriate dose modifications for pazopanib and ARQ 197 are described in 
Section 6.  No investigational or commercial agents or therapies other than pazopanib and 
ARQ 197 may be administered with the intent to treat the patient's malignancy.   
 
The study will be carried out in 2 phases, as described in Section 5.1.  The drugs will be 
administered in 28-day cycles (± 1 day for scheduling).  Pazopanib tablets should be 
administered orally without food (at least 1 hour before or 2 hours after eating) once a day.  
ARQ 197 tablets should be administered orally with food twice daily approximately every 
12 hours.  A missed or vomited dose should not be replaced.  The patient should be instructed to 
take the next scheduled dose at the regularly scheduled time.  Patients will be asked to maintain a 
Study Medication Diary (Appendix E) and record each dose of medication.  Patients will be 
given instructions for completing the medication diary and will be asked to return it to the clinic 
staff at the end of each cycle.   
 
With Amendment H, dated 09/26/2013: For patients who have been on study for six or more 
cycles and are tolerating treatment well, two months worth of drug may be dispensed at a 
time; labs and blood pressure monitoring will only be performed once every 2 cycles (every  
2 months).  More frequent labs and assessment can be performed as clinically indicated.     
 
History and physical examination can be done up to 3 days before start of a new cycle. 
Patients will be examined on D1, D8 (only for patients who will have tumor biopsy), and D15 in 
the dose escalation phase, or D1 and D8 in the expansion phase, at the clinical center for the first 
cycle and prior to every new cycle.  Blood pressure (BP) will be checked every 2 weeks during 
the first 2 cycles in the dose escalation phase and on D1 and D8 of cycle 1 in the expansion 
phase, and then at the beginning of subsequent cycles.  Mid-cycle blood pressure monitoring can 
be performed by any healthcare provider. 
 
Labs (CBC with differential; serum chemistries, including glucose) will be performed as follows: 
− Dose escalation phase: every week for the first cycle, then every 2 weeks for cycle 2 and then   
at the start of each cycle (up to 3 days before start of a new cycle) for the remainder of the study. 
− Expansion phase: D1 and D8 of cycle 1, then at the start of each cycle (up to 3 days before 
start of a new cycle). 
 
EKG will be performed as follows: 
− Dose escalation phase: at baseline, on C1D1 (3-6 hours after the first dose of ARQ 197) and on 
C1D15 (3-6 hours after the morning dose of ARQ 197) and as clinically indicated.   
− Expansion phase: at baseline, on C1D1 (3-6 hours after pazopanib), on C1D8 (3-6 hours after 
pazopanib), on C2D1 (3-6 hours after the morning dose of ARQ 197), and as clinically indicated.   
 
Evaluation of urine protein/creatinine ratio will be performed as follows: 
− Dose escalation phase: at baseline, on C1D15, then at the start of each cycle.   

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
33 
− Expansion phase: at baseline, on C1D8, then at the start of each cycle, and as clinically indicated. 
 
Echocardiogram or MUGA scan for assessment of LV ejection fraction will be performed at 
baseline and as clinically indicated. 
 
CT scans will be performed at baseline, and repeat imaging scans will be performed every 
2 cycles.   
 
As part of a risk mitigation plan for possible hepatic failure, serum liver tests (AST, ALT, serum 
bilirubin) will be monitored before initiation of treatment with pazopanib and at weeks 3, 5, 7, 
and 9.  Thereafter, monitoring will occur at months 3 and 4, and as clinically indicated.  Periodic 
monitoring will continue after month 4. 
 
5.1 
Agent Administration 
5.1.1 Dose Escalation Phase 
A primary objective of the trial is to establish the safety, tolerability, and MTD of the 
combination.  Pazopanib will be administered QD, starting at 400 mg, and ARQ 197 will 
be administered BID, starting at 120 mg (dose level 1).  The duration of a cycle will be 
28 days (± 1 day for scheduling).  Dose escalation will proceed in cohorts of 3 patients 
each (3+3 design) as outlined below (Table 2): 
 
Table 2: Dose Escalation Scheme 
 
Dose Level 
Pazopanib 
ARQ 197 
-2 
200 mg QD 
120 mg QD 
-1 
400 mg QD 
120 mg QD 
1 
(starting dose) 
400 mg QD 
120 mg BID 
2 
600 mg QD 
120 mg BID 
3 
600 mg QD 
240 mg BID 
4 
800 mg QD 
240 mg BID 
5 
800 mg QD 
360 mg BID 
6* 
600 mg QD 
360 mg BID 
*If dose level 5 is above the MTD, dose level 6 will be evaluated. 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
34 
Tumor biopsies will be optional during the escalation phase.  For the escalation phase, 
3 patients should have completed at least one cycle of therapy prior to considering dose 
escalation in the next cohort of patients.  Dose escalation will proceed according to the 
following scheme.  DLT is defined in Section 5.2.  Determination of DLT will be based 
on toxicities observed in the first cycle of therapy.  Patients are considered evaluable for 
toxicity for the purpose of cohort dose escalation decisions if they either 1) experienced 
DLT or 2) have received at least 80% of the planned 28-day doses of treatment in one 
cycle of therapy and have been followed for one full cycle without DLT.  All toxicities 
will be reported for all patients who receive any amount of study drug on this study.  
Evaluation of toxicity will begin with study drug administration on cycle 1 day 1. 
 
Number of Patients with DLT at 
a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose (highest 
dose administered).  Three (3) additional patients will 
be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended Phase II dose.  At 
least 6 patients must be entered at the recommended 
Phase II dose. 
 
5.1.2 Expansion Phase 
Once the MTD is established, an additional cohort of patients will initially be treated with 
pazopanib alone, and tumor biopsies will be obtained to assess target inhibition, as 
outlined below.  Tumor biopsies will be mandatory during the expansion phase of the 
study.  Biopsies will be obtained at the time points outlined below.  Depending on the 
results obtained from the tumor biopsies in the first few patients, the timing of the biopsy 
can be adjusted, but the number of tumor biopsies and the procedure will not change.  
Any change in the timing of the tumor biopsy will be discussed with the patient prior to 
obtaining informed consent.  
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
35 
The cohort and dosing regimens after establishment of the MTD are described below.  
When administered as a single agent during the expansion phase, the dose of pazopanib 
will correspond to the dose determined for the combination MTD if the MTD is 
determined at dose level 5 (ARQ 197 360 mg BID/pazopanib 800 mg QD) or 6 (ARQ 
197 360 mg BID/pazopanib 600 mg QD).  Otherwise, the dose of pazopanib will be 
determined after discussion with CTEP.  Once the MTD is established, the data will be 
discussed with CTEP prior to proceeding with accrual for the expansion phase. 
 
Cohort A (12 patients): Pazopanib will be given once daily as single agent from cycle 1 
day 1 to day 7.  Tumor biopsy will be done before drug administration on study 
(baseline) and on cycle 1 day 8, 8-12 hours after pazopanib administration.  After the 
tumor biopsy, patients will start to receive ARQ 197 in addition to pazopanib at the 
combination MTD.  
 
Twelve evaluable patients with both pre- and post-treatment biopsies will be treated 
initially in Cohort A.  Mean increases in MET and pMET in these 12 patients will be 
measured to assess whether or not they are statistically significant. 
 
For the purposes of final analysis of the expansion phase, only patients with paired tumor 
biopsies will be considered evaluable.  Patients with fewer than the 2 required biopsies 
will not be considered evaluable for the expansion phase and will need to be replaced in 
the accrual scheme of the expansion phase.  If a patient has a dose-limiting toxicity 
(DLT) with the single lead-in agent pazopanib in the expansion cohort, the patient will be 
taken off treatment. 
5.2 
Definition of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) is defined as an adverse event that is related (possibly, probably, or 
definitely) to administration of study drugs and fulfills one of the following criteria: 
5.2.1 Grade ≥ 3 Non-Hematological Toxicity  
Grade ≥ 3 non-hematological toxicity felt to be related to study medications will be 
considered dose-limiting with the following clarifications: 
5.2.1.1 Diarrhea Grade 3 will only be considered dose-limiting if it is refractory to 
treatment as outlined in Section 5.3.2, Supportive Care Guidelines, and 
unable to be corrected  to Grade 2 or less within 24 hours.  Bloody or 
Grade 4 diarrhea will be dose-limiting. 
5.2.1.2 Nausea and vomiting Grade 3 will only be considered dose-limiting if it is 
refractory to anti-emetic therapy and unable to be corrected to Grade 1 or 
less within 24 hours (Section 5.3.1).  
5.2.1.3 Rise in creatinine to Grade 3, not corrected to Grade 1 or less within 
48 hours with IV fluids will be considered dose-limiting.  All Grade 4 
rises in creatinine will be dose limiting. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
36 
5.2.1.4 Grade ≥ 3 metabolic toxicities unable to be corrected to Grade 2 or less 
within 48 hours (such as glucose changes, hypocalcemia or hypercalcemia, 
hypomagnesemia or hypermagnesemia, hyperuricemia, 
hypophosphatemia, and hyponatremia) will be considered dose limiting.  
For hypokalemia or hyperkalemia, grade ≥ 2 toxicities unable to be 
corrected to grade 1 or less within 48 hours will be considered dose 
limiting.  Grade 4 metabolic toxicities that are symptomatic will be 
considered dose-limiting regardless of duration or ability to correct. 
5.2.1.5 QTc prolongation to ≥ 500 msec on at least two separate EKGs (refer to 
Section 5.3) will be dose limiting. 
5.2.1.6 AST/ALT > 8 X ULN or AST/ALT > 3 X ULN and concurrent bilirubin 
elevation > 2 X ULN will be dose limiting. 
5.2.1.7 Grade ≥ 3 bleeding in any sites or grade ≥ 2 pulmonary bleeding will be 
dose limiting. 
5.2.1.8 Grade 4 venous thrombosis, pulmonary embolism, or any grade of arterial 
thrombosis will be dose limiting. 
5.2.2 Grade 4 thrombocytopenia. 
5.2.3 Grade 4 neutropenia ≥ 3 days or febrile neutropenia. 
5.2.4 Any degree of anemia, leucopenia in the absence of grade 4 neutropenia ≥ 3 days, 
or lymphopenia will not be considered dose limiting.   
5.3 
General Concomitant Medication and Supportive Care Guidelines 
All patients will be provided with the best available supportive care.  All concurrent medications 
should be documented prior to initiation of treatment, and be periodically reviewed with the 
patient.  Particular attention must be paid to medications which may prolong the QTc interval 
(Appendix C) and agents that interact with CYP450 isoenzymes (Appendix B). 
 
QTc Prolongation: 
Caution should be exercised when administering pazopanib to patients with a history of QTc 
interval prolongation, in patients taking anti-arrhythmics or other medications that may prolong 
the QTc interval, and those with relevant pre-existing cardiac disease.  A list of medications that 
may cause QTc interval prolongation are listed in Appendix C, and should be avoided by patients 
on this study.  EKG will be performed as described in Section 5.  If the QTc interval on follow-
up EKG is > 500 msec, the EKG should be repeated within 7 days and, if the QTc interval 
remains > 500 msec, the subject should be removed from the study.  Additionally, if the QTc 
interval is increased by 60 msec or more from baseline but the QTc interval remains at 
<500 msec, the EKG should be repeated within 7 days.  If the repeat EKG again shows a > 
60 msec increase in the QTc interval from baseline, consideration should be given to removing 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
37 
the subject from the study or increasing monitoring, after discussion with the principal 
investigator. 
 
CYP450 Interactions: 
In vitro and in vivo animal data indicate that the metabolism of pazopanib is primarily mediated 
by CYP3A4.  In vitro data indicate that pazopanib is a potential inhibitor for CYP2C9, CYP1A2, 
CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.  In addition, one in 
vitro study suggested that pazopanib may induce CYP3A4 at high concentrations.  Potent 
CYP3A4 inhibitors and inducers are prohibited on pazopanib trials.  In exceptional 
circumstances, medications which strongly inhibit CYP3A4 may be administered, with caution, 
if the dose of pazopanib is decreased to 50% of the dose which would otherwise be administered. 
 
Medications that strongly inhibit CYP3A4 include (but are not limited to): 
• Antibiotics:  clarithromycin, telithromycin, troleandomycin 
• HIV:  protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir) 
• Antifungals: itraconazole, ketoconazole, voriconazole 
• Antidepressant: nefazodone 
Grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib.   
 
Medications that strongly induce CYP3A4 include (but are not limited to): 
• Glucocorticoids: cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10 mg), 
methylprednisolone (>8 mg), dexamethasone (>1.5 mg) 
• Anticonvulsants: phenytoin, carbamezepine, phenobarbital, oxcarbazepine 
• HIV antivirals: efavirenz, nevirapine 
• Antibiotics: rifampin (rifampicin), rifabutin, rifapentene 
• Miscellaneous: St. John’s Wort, modafinil, pioglitazone, troglitazone   
 
Pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6.  Drugs that have narrow 
therapeutic windows and are substrates for these enzymes should be avoided and, if necessary, 
administered with caution (see Appendix B).  Because of pazopanib’s long half-life, caution 
should continue to be exercised for at least 7 days and up to 15 days after the last dose of 
pazopanib when administering these medications. 
 
Medications that are substrates for these enzymes and have narrow therapeutic windows 
medications include (but are not limited to): 
• Ergot derivatives:  dihydroergotamine, ergonovine, ergotamine, methylergonovine (potential 
increased risk for developing ergot toxicity that includes severe vasospasm leading to 
peripheral as well as cerebral ischemia) 
• Neuroleptics: pimozide (potential increased risk for QT interval prolongation, ventricular 
arrhythmia, and sudden death) 
• Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, 
propafenone (potential increased risk for QT interval prolongation and Torsade de Pointes) 
• Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for 
nephrotoxicity and neurotoxicity) 
• Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
38 
 
In vitro studies indicate ARQ 197 is metabolized by CYP2C19, and to a lesser extent CYP3A4.  
The metabolism and consequently overall pharmacokinetics of ARQ 197 could be altered by 
inhibitors and/or inducers or other substrates of CYP2C19 and CYP3A4.  In patients receiving 
any medications or substances that are inhibitors or inducers of CYP3A4 or CYP2C19, every 
attempt should be made to change the medications to another agent that does not affect the CYP 
pathway (see Appendix B). 
 
Specific recommendations regarding other oral hypoglycemics: 
Co-administration of pazopanib with some oral hypoglycemics, including glipizide, glyburide, 
(glibenclamide), glimerpiride, nateglinide, repaglinide, gliclazide, acetohexamide, carbutamide, 
glibornuride, glymidine, metahexamide, and tolazmide, (but not including tolbutamide and 
chlorpropamide, which are prohibited) may result in an increase in plasma concentrations of the 
oral hypoglycemic agents, leading to hypoglycemia.  Therefore, reducing the doses of these oral 
hypoglycemic agents should be considered when pazopanib administration starts.  The blood 
glucose should be monitored closely and patients should be instructed to measure their blood 
glucose if they experience symptoms of hypoglycemia and inform their physicians if their blood 
glucose concentrations are low.  After at least 14 days of pazopanib administration, the doses of 
oral hypoglycemic agents may be increased as necessary to maintain adequate blood glucose 
control. 
 
Specific recommendations regarding non-dihydropyridine calcium channel blockers: 
Co-administration of pazopanib with calcium channel blockers may result in increased plasma 
concentrations of the latter.  The non-dihydropyridine calcium channel blockers verapamil and 
diltiazem have potential depressive effects on cardiac conduction and contractility.  When 
pazopanib therapy is initiated, the administration of an anti-hypertensive or anti-anginal agent 
other than verapamil and diltiazem is recommended in the setting of a PR interval > 200 msec, 
sinus bradycardia (< 60 beats per minute), or second or third degree heart block, unless the 
patient has a permanent pacemaker. 
5.3.1 Nausea/Vomiting 
Anti-emetics will not be administered routinely prior to pazopanib or ARQ 197.  
However, if a patient develops nausea/vomiting, anti-emetics such as but not limited to 
prochlorperazine, metoclopramide, 5-HT3 antagonists, or aprepitant may be given.  In 
addition, if a patient develops nausea and/or vomiting that is Grade 2 or greater, anti-
emetics may be instituted prophylactically at the discretion of the investigator.  Nausea 
and vomiting will be considered refractory if it does not resolve to ≤ Grade 1 with 
treatment with a combination of at least 2 of the antiemetics within 24 hours. 
5.3.2 Diarrhea 
If diarrhea develops and does not have an identifiable cause other than study drug 
administration, anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg + atropine 
sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 4 mg po after 
the first unformed stool with 2 mg po with every 2 hours (4 mg every 4 hours while 
asleep), till resolution of episode of at least 12 hours (no more than 16 mg of loperamide 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
39 
during a 24-hour period).  This regimen can be repeated for each diarrheal episode.  
Diarrhea will be considered refractory if it does not resolve within 24 hours to ≤ Grade 2 
with the above regimen (maximum of 16 mg of loperamide in a 24-hour period).  If the 
patient develops blood or mucus in the stool, dehydration, or hemodynamic instability, or 
fever along with the diarrhea, anti-diarrheals will be discontinued and the patient will be 
treated with IV fluids and antibiotics as medically indicated.  
5.3.3 Neutropenia 
To reduce the risk of severe myelosuppression events, a complete blood count (CBC) 
should be performed weekly during cycle 1, every 2 weeks during cycle 2, and  at the 
start of each subsequent cycle (up to 3 days before start of new cycle) in the dose 
escalation phase.  In the expansion phase, CBC will be performed on D1 and D8 of cycle 
1, then at the start of each cycle (up to 3 days before start of new cycle).  Febrile 
neutropenia is a life-threatening complication requiring hospitalization and urgent broad-
spectrum antibiotics, as well as an aggressive search for the source and microbial cause 
of the episode.  Growth factors to prevent neutropenia will not be administered 
prophylactically.  If necessary, they may be administered according to accepted 
American Society of Clinical Oncology (ASCO) guidelines to allow re-treatment. 
5.3.4 Anemia 
Symptomatic anemia should be treated with red blood cell transfusion and is 
recommended if the hemoglobin falls below 8 g/dL.  The initiation of erythropoietic 
therapy for the management of chemotherapy-induced anemia follows the American 
Society of Hematology/ASCO clinical practice guidelines (http://www.asco.org/). 
5.3.5 Thrombocytopenia  
Thrombocytopenia will be treated conservatively.  In the absence of bleeding, or a 
necessary invasive procedure, platelet transfusions should be given for a platelet count 
≤10,000/mm3.  If invasive procedure(s) is (are) planned, or the patient develops bleeding, 
platelet transfusions should be administered in accordance with the standard of practice, 
usually maintaining a platelet count above 50,000/mm3. 
5.3.6 Reflux/Gastritis 
Antacids and other anti-ulcer medications such as histamine H2-receptor antagonists may 
be used if clinically indicated.  To avoid significantly altering gastric pH, when needed, 
these medications should be used 4 hours after study drug administration.  Proton pump 
inhibitors such as omeprazole and lansoprazole, which have a potential for interaction 
with ARQ 197, should be avoided. 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
40 
• Significant toxicity occurs despite 2 dose reductions as described in Section 6 or no lower 
dose level exists 
• Pregnancy 
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
5.5 
Duration of Follow Up 
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol, patient receives standard of care, or death, 
whichever comes first.  The follow-up will consist of a phone call between Days 27-30 after the 
last dose to evaluate adverse events that were ongoing and any new events that might be deemed 
related to the therapy.  Toxicities felt to be possibly, probably, or definitely related to the study 
drugs that have not resolved or stabilized by Day 30 post-treatment will be followed until 
stabilization or resolution via biweekly phone calls. 
5.6 
Criteria for Removal from Study 
Patients will be removed from study for one of the following reasons: completed 30-day follow-
up period or toxicities are unresolved but stabilized.  The reason for study removal and the date 
the patient was removed must be documented in the medical record and communicated by fax to 
Central Registration per Section 4. 
 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
Toxicities (hematologic and non-hematologic; except any grade lymphopenia, anemia, or 
alopecia) should have resolved to ≤ Grade 2 prior to starting the next cycle or receiving the next 
dose of pazopanib or ARQ 197 within a cycle.  Study drugs should be held for hypokalemia or 
hyperkalemia ≥ grade 2; hypocalcemia or hypercalcemia ≥ grade 3; hypophosphatemia ≥ grade 
3; hypomagnesemia or hypermagnesemia ≥ grade 3. These laboratory values should be corrected 
as soon as possible in a manner consistent with good medical judgment.  Study drugs may be re-
administered when hypokalemia or hyperkalemia is grade 1 or within institutional limits; 
hypocalcemia or hypercalcemia is ≤ grade 2; hypophosphatemia is ≤ grade 2; and 
hypomagnesemia or hypermagnesemia is ≤ grade 2.  Even though study drug administration is 
allowed at these lower grades, every effort should be made to correct the abnormal lab values to 
normal if possible. If the potassium level is grade 2 or greater and/or if the calcium, magnesium, 
and/or phosphate are grade 3 or higher, an EKG must be performed and appropriate action taken 
based on the results.  
 
Treatment may be delayed for a maximum of 2 weeks for toxicities.  In case toxicities do not 
resolve as stated, the patient will not receive further therapy on this protocol and will be followed 
for resolution of toxicities.  Start of next cycle may be delayed for up to 1 week to accommodate 
scheduling conflicts.  Dose modifications are intended for within-cycle and start-of-next-cycle 
changes.  If administration of study drug is interrupted for any reason, it will not be made up, and 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
41 
counting of the cycle days continues (i.e., if a patient stops pazopanib and ARQ 197 on day 15 
and resumes 2 days later, they will be considered day 17).   
 
A maximum of 2 dose reductions will be allowed before patient is taken off treatment.  Patients 
who require a dose reduction will not have the dose re-escalated.  Dose reductions may occur to 
a single compound independent of the other compound if toxicity necessitating a dose reduction 
is attributed to a single agent in the opinion of the study Principal Investigator.  One dose level 
reduction due to pazopanib-associated toxicities such as hypertension means that pazopanib dose 
should be reduced to 400 mg if an original dose is 600 mg or to 600 mg if it is 800 mg.  Similarly, 
one dose level reduction due to ARQ 197-associated toxicities means that ARQ 197 dose should 
be reduced to 120 mg bid if an original dose is 240 mg bid, or to 240 mg bid if it is 360 mg bid. 
6.1 
Dose Reduction 
6.1.1 Doses will be modified for grade 3 or greater non-hematologic toxicity with 
the following clarifications: 
• Doses will not be modified for electrolyte abnormalities, unless these are not 
correctable within 48 hours, or for alopecia.   
 
• Dose of study drugs will not be reduced for nausea, vomiting, or diarrhea unless these 
are considered refractory as defined in Section 5.3.  
 
• Dose reductions may occur to a single compound, independent of the other 
compound.  Doses of ARQ 197 will not be reduced for any grade hypertension or 
proteinuria.   
 
• For uncontrolled hypertension (as defined in Section 6.1.5), only the dose of 
pazopanib will be reduced to the next lower dose level.  
 
• For proteinuria, only the dose of pazopanib will be reduced to the next lower dose 
level (Section 6.1.6).  
6.1.2 Grade 2 drug-related toxicity: No changes will be made to the dose of either 
study drug for Grade 2 toxicities, and therapy will not be interrupted, except as 
otherwise noted (e.g., hypokalemia or hyperkalemia as described above, Grade 2 
hemorrhage or thrombosis as described in Section 6.1.10).  However, for 
persistent symptomatic skin rash or hand foot syndrome limiting instrumental 
activities of daily living that do not improve to grade 1 or less within 2 weeks 
with optimal management, doses of both pazopanib and ARQ 197 will be held 
until toxicities have resolved to ≤ Grade 1 prior to re-starting study treatment.  
Therapy will be re-initiated at the next lower dose level. 
6.1.3 Grade 3 drug-related neutropenia and/or thrombocytopenia: Doses of both 
pazopanib and ARQ 197 will be held until toxicities have resolved to ≤ Grade 2 
prior to re-starting study treatment.  Therapy will be re-initiated at the same dose 
level at the first occurrence of either event.  In the case of second occurrence of 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
42 
either event, therapy will be re-initiated at the next lower dose level.  Therapy will 
not be interrupted or doses modified for any grade lymphopenia, anemia, or 
leucopenia in the absence of grade 3 or 4 neutropenia.  
6.1.4 Grade 4 drug-related neutropenia ≥3 days and/or thrombocytopenia: Doses 
of both pazopanib and ARQ 197 will be held until toxicities have resolved to 
≤ Grade 2 prior to re-starting study treatment.  Therapy will be re-initiated at the 
next lower dose level.  
6.1.5 Hypertension toxicity 
Therapeutic BP monitoring by a health care provider will occur every 2 weeks during the 
first 2 cycles then at least every cycle for the duration of treatment in the dose escalation 
phase, and on D1 and D8 of cycle 1 then at least every cycle in the expansion phase.  All 
patients will be required to monitor their BP at least once a day (preferably BID) 
throughout the treatment and record the readings in the study diary (Appendix E).  
Table 3 will be used for the grading of pazopanib-associated hypertension, for immediate 
and long-term management, and for the determination of pazopanib dose modification.  
Suggested antihypertensive medications are listed in Table 4. 
 
Table 3: Recommended Hypertension Monitoring and Management (BP in mmHg) 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Pazopanib 
Dose Modification 
Persistent Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-90  
 
Standard       
 
No Change 
Persistent Grade 2- 
Moderate 
Systolic 140-159  
Diastolic 90-99  
   
 
Step 1)  Initiate BP treatment 
and if needed, after 24-48 hr of 
treatment,  increase dose in 
stepwise  fashion every 24-48 
hours  until BP is controlled or 
at maximum dose of medication 
 
Step 2) If BP still not controlled, 
add another anti-hypertensive 
medication, a LA DHP CCB, 
ACE1, ARB, or ABB; increase 
dose of this drug as described in 
step 1   
Step 3) If BP still not controlled, 
add 3rd drug from the list of 
antihypertensives in step 2; 
increase dose of this drug as 
described in step 1 
 
Step 4) If BP still not controlled, 
consider either 1 dose reduction 
of pazopanib or stopping 
pazopanib  
 
BP should be 
monitored as 
recommended by 
the treating 
physician  
No change except as described 
in step 4 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
43 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Pazopanib 
Dose Modification 
NOTE:  Stopping or reducing 
the dose of pazopanib is 
expected to cause a decrease in 
BP.  The treating physician 
should monitor the subject for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 
Persistent Grade 3 
Severe  
Systolic ≥160 
Diastolic ≥100  
 
 
HOLD pazopanib until systolic 
BP ≤159 and diastolic BP ≤99.  
 
BP management is identical to 
that for Grade 2 (see steps 1-4 
above) with 2 major 
exceptions:  
1)  If systolic BP >180 or 
diastolic BP >110 and the 
subject is symptomatic:  
optimal management with 
intensive IV support in ICU; 
STOP pazopanib and notify 
hospital staff that stopping 
pazopanib may result in a 
decrease in BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and the 
subject is asymptomatic, 
2 new antihypertensives must 
be given together in step 1 
(and dose escalated 
appropriately as in step 1). 
 
NOTE:  Stopping or reducing 
the dose of pazopanib is 
expected to cause a decrease in 
BP.  The treating physician 
should monitor the subject for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be 
monitored as 
recommended by 
the treating 
physician unless 
the subject is 
symptomatic with  
systolic BP >180 
or diastolic BP 
>110 in which 
case, monitoring 
should be 
intensive. 
 
 
HOLD pazopanib until systolic 
BP ≤159 and diastolic BP ≤99.  
After this, pazopanib may be re-
administered.  If BP is still 
grade 2, manage as described 
above for grade 2 hypertenison.  
 
In most circumstances, if BP 
cannot be controlled after an 
optimal trial of antihypertensive 
medications, consider either 1 
dose reduction of pazopanib 
when systolic BP ≤159 and 
diastolic BP ≤99 or stopping 
pazopanib. 
 
 
HOWEVER, 
If the subject requires 
hospitalization for 
management of symptomatic 
systolic BP >180 or diastolic 
BP >110, permanently 
discontinue pazopanib or if BP 
is controlled to systolic BP 
≤159 and diastolic BP ≤99, 
consider  re-starting pazopanib 
at 1 lower dose level after 
consultation with the study 
Principal Investigator 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management with 
intensive IV support in ICU; 
STOP pazopanib and notify 
hospital staff that stopping 
pazopanib may result in a 
decrease in BP 
Intensive 
Permanently discontinue 
pazopanib or if systolic BP 
≤159 and diastolic BP ≤99, 
consider  re-starting   pazopanib 
at 1 lower dose level after 
consultation with the study 
Principal Investigator 
Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), Angiotensin Converting 
Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB), alpha beta blocker (ABB) 
• *See table below for suggested antihypertensive medications by class 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
44 
Grade 
(CTCAE v4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Pazopanib 
Dose Modification 
• If subjects require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
• If subjects require >2 dose reductions, discontinue protocol therapy 
• Subjects may have up to 2 drugs for management of hypertension prior to any dose reduction in pazopanib 
• 24-48 hours should elapse between modifications of antihypertensive therapy 
• Hypertension should be graded using CTCAE v4 
 
Notes: 
• While patients are receiving treatment with pazopanib, the early initiation of antihypertensive 
treatment for grade 1 or 2 hypertension to minimize more severe or persistent hypertension is 
not considered a grade 3 adverse event. 
• Decisions to hold or decrease the pazopanib dose during treatment must be based on BP 
readings taken in the clinic by a medical professional. 
• Based on prior clinical experience with pazopanib, the use of calcium channel blockers 
(dihydropyridine category) and ACE inhibitors as first-line and second-line therapy is 
recommended. 
 
Table 4: Oral Antihypertensive Medications: Agents in bold characters are suggested as 
optimal choices to avoid or minimize potential drug-interactions with pazopanib through 
CYP450. 
 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-pyridine 
Calcium-Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Selective 
β Blockers 
(BB) 
metoprolol 
25 mg twice daily 
50 mg twice daily 
100 mg twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg twice daily 
200-300 mg twice 
daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
4 mg daily 
none 
8 mg daily 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
45 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Receptor 
Blockers 
(ARBs) 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
α and β 
Blocker 
labetolol 
100 mg twice daily 
200 mg twice daily 
400 mg twice daily 
CYP 2D6 substrate 
and inhibitor 
6.1.6 Proteinuria toxicity 
Evaluation of urine protein/creatinine ratio (UPC) should occur as follows: 
− Dose escalation phase: at baseline, on C1D15, then at the start of each cycle  
− Expansion phase: at baseline, on C1D8, then at the start of each cycle.   
If, at any time, a subject has a urine protein/creatinine ratio greater than 1, a 24 hour urine 
collection must be performed.  If a subject develops the nephrotic syndrome, treatment 
must be discontinued.   
Although subjects with ≥1+ proteinuria at entry are ineligible, increases in proteinuria 
may occur during treatment and should be managed as Table 5: 
 
Table 5: Pazopanib Dose Modifications for Proteinuria Toxicity 
 
UPC > 1and < 3 
Obtain 24-hr urine protein and if <3 g, continue at current dose and monitor as 
clinically indicated 
UPC ≥ 3 or 24-h urine 
protein ≥ 3 g 
Step 1. Interrupt pazopanib. 
Step 2. Weekly UPC or 24-hr urine protein monitoring until UPC is <3 or 24-hr urine 
protein is <3 grams.  Then restart pazopanib dose-reduced by 200 mg. 
Step 3.  If UPC >3 or 24-h urine protein ≥3g recurs, repeat steps 1 and 2 
Step 4.  If UPC ≥3 or 24-hr urine protein ≥3 recurs and the pazopanib dose can no 
longer be reduced, discontinue pazopanib and remove subject from study. 
Nephrotic syndrome  
Permanently discontinue pazopanib and remove subject from study 
6.1.7 Cardiac Toxicity 
1. Discontinue pazopanib in patients who develop symptomatic heart failure. 
2. Modify the pazopanib dose using the table presented in Appendix F in patients who 
develop compromised symptomatic LVEF.  The NCI developed the table in 
Appendix F using the NSABP-B31 and NCCTG9831 monitoring guidelines for 
adjuvant trastuzumab in patients with breast cancer.  These studies enrolled 
populations considered most likely to be cured; thus, the investigators used the most 
stringent and conservative monitoring. 
3. Discontinue ARQ 197 in patients who develop symptomatic bradycardia. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
46 
4. Patients with asymptomatic bradycardia will not have drug held or dose modified.  
Bradycardic patients with a heart rate < 50 beats per minute should have an EKG 
done on day 1 of every cycle, or as clinically indicated. 
5. QTc Prolongation, see Table 6. 
 
Table 6: Management of QTc Prolongation 
If EKG reveals an increase in the QTc to ≥500 msec 
or an increase in the QTc by at least 60 msec from 
baseline 
Repeat EKG before re-administration of pazopanib and/or 
ARQ 197 
If repeat EKG shows QTc interval is >500 msec 
Remove subject from study 
If on repeat EKG, QTc remains at least 60 msec 
longer than baseline but is less than 500 msec  
Consider removing subject from study 
6.1.8 Management of Subjects with Elevations in AST, ALT and/or Bilirubin 
Table 7: Management of Liver Function Test Abnormality 
AST, ALT and/or Bilirubin 
Isolated AST/ALT elevations 
between 3X ULN and 8X ULN 
Continue pazopanib, but monitor weekly until AST/ALT returns to < 2.5 or 
baseline 
AST/ALT >8 X ULN 
Hold pazopanib until AST/ALT returns to < 2.5 X ULN or baseline.   
 
If the potential benefit of reinitiating pazopanib treatment is considered to 
outweigh the risk for hepatotoxicity, then consider reintroducing  pazopanib at 
a reduced dose of 400 mg once daily and measure serum liver tests weekly for 
8 weeks only after discussion with the PI and CTEP.   
 
If AST/ALT elevations >3 X ULN recur, then pazopanib should be 
permanently discontinued. 
AST/ALT >3 X ULN and 
concurrent bilirubin elevations 
>2 X ULN 
Permanently discontinue pazopanib. 
Mild indirect 
hyperbilirubinemia, known or 
suspected Gilbert’s syndrome, 
and elevation in ALT >3 X ULN 
Continue pazopanib, but monitor weekly until ALT returns to grade 1 (NCI 
CTCAE) or baseline. 
6.1.9 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome 
RPLS or clinical syndromes related to vasogenic edema of the white matter have been 
rarely reported in association with pazopanib therapy (<3%).  Clinical presentations are 
variable and may include altered mental status, seizure, and cortical visual deficit. 
 
Hypertension is a common risk factor in patients who develop RPLS.  MRI scans are key 
to diagnosis and typically demonstrate vasogenic edema (hyperintensity in T2 and 
FLAIR images and hypointensity in T1 images) predominantly in the white matter of the 
posterior parietal and occipital lobes; less frequently, the anterior distributions and the 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
47 
gray matter may also be involved.  RPLS should be in the differential diagnosis in 
patients presenting with unexplained mental status changes, visual disturbance, seizure or 
other CNS findings.  RPLS is potentially reversible, but timely correction of the 
underlying causes, including control of blood pressure and interruption of the offending 
drug, is important in order to prevent progression to irreversible tissue damage.  
Pazopanib should be held in patients with symptoms/signs suggestive of RPLS, pending 
work-up and management, including control of blood pressure.  Pazopanib should be 
discontinued upon diagnosis of RPLS. 
 
After consultation with the study PI and CTEP, NCI, consideration of restarting the study 
drugs may be evaluated in light of any clinical benefit. 
6.1.10 Management of Other Adverse Events 
Adverse 
Event 
 
Grade 
 
Treatment Modification 
Hemorrhage/ 
Bleeding 
 
Grade 1 
No interruption in treatment until hemoptysis.  If hemoptysis, contact PI to 
determine if it is appropriate to continue pazopanib.   
Maintain current dose. 
 
 
 
Grade 2 
For non-pulmonary bleeding, hold pazopanib unless resolved to ≤ grade 1; 
reduce dose to next lower dose level, and continue treatment.  
 
For pulmonary bleeding, permanently discontinue pazopanib and remove 
subject from study. 
 
If grade 2 or greater hemorrhage/ bleeding recurs following dose reduction, 
stop pazopanib and remove subject from study. 
Grades 3 or 4 Discontinue treatment and withdraw subject from study. 
Vascular/ 
Thrombosis 
 
Grade 1 
No interruption in treatment; maintain current dose. 
 
 
 
 
Grade 2, 3  
 
Hold pazopanib until subject is receiving a stable dose of Low Molecular 
Weight Heparin (LMWH). 
Treatment  may resume during the period of full-dose anticoagulation if all of 
the following criteria are met: 
• The subject must have been treated with an anticoagulant at the desired 
level for at least one week. 
• The subject must not have had a grade 3 or 4 or significant grade 2 
hemorrhagic event while on anticoagulant. 
Subject should be monitored as clinically indicated during anticoagulation 
treatment and after resuming study treatment.  When treating with warfarin, 
international normalized ratio (INR) should be monitored within three to five 
days after any change in pazopanib dosing (e.g., re-initiating, escalating/de-
escalating, or discontinuing pazopanib), and then at least weekly until the 
INR is stable.  The dose of warfarin (or its derivatives) may need to be 
adjusted to maintain the desired level of anticoagulation. 
Grade 4 
or pulmonary 
embolus 
 
Discontinue treatment and remove subject from study. 
Arterial 
Thrombosis/ 
ischemia 
All grades  
Discontinue pazopanib and remove subject from study. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
51 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Thrombotic microangiopathy (TMA) which includes both Hemolytic uremic syndrome (HUS) and 
Thrombotic thrombocytopenic purpura (TTP) has been reported in clinical trials of GW786034. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical fistula, 
Esophageal fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL 
DISORDERS SOC.  
 
4Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC.  
 
5Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC.  
 
6Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC.  
 
7Interstitial lung disease may include, Adult respiratory distress syndrome, Pneumonitis, Pulmonary 
fibrosis, Respiratory, thoracic and mediastinal disorders - Other (Acute respiratory distress syndrome), 
Respiratory, thoracic and mediastinal disorders - Other (Aveolitis), Respiratory, thoracic and mediastinal 
disorders - Other (Bronchiolitis obliterans), Respiratory, thoracic and mediastinal disorders - Other 
(Interstitial fibrosis), Respiratory, thoracic and mediastinal disorders - Other (Interstitial pneumonia), 
Respiratory, thoracic and mediastinal disorders - Other (Interstitial pneumonitis), Respiratory, thoracic 
and mediastinal disorders - Other (Organizing pneumonia), Respiratory, thoracic and mediastinal 
disorders - Other (Pulmonary infiltrates), Respiratory, thoracic and mediastinal disorders - Other (Toxic 
pneumonitis). 
 
8These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications.  
 
9Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events also reported on Pazopanib (GW786034) trials but with the relationship to 
Pazopanib (GW786034) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac disorders - Other 
(sinus arrest); Cardiac disorders - Other (supraventricular extrasystoles); Cardiac disorders - Other 
(Takotsubo [Broken Heart Syndrome]); Cardiac disorders - Other (Torsades de Pointes); Chest pain - 
cardiac; Pericardial effusion; Supraventricular tachycardia 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
52 
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (asthenopia); Eye disorders – Other 
(eye/retinal hemorrhage); Eye disorders - Other (foreign body sensation in eyes); Eye pain; Floaters; 
Glaucoma; Photophobia; Retinal tear 
GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Duodenal obstruction; 
Dysphagia; Esophagitis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(hyperactive bowel); Gastrointestinal disorders - Other (oropharyngeal pain); Gastrointestinal disorders - 
Other (pneumatosis intestinalis); Gastrointestinal pain; Oral pain; Pancreatitis; Periodontal disease; 
Proctitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; 
Malaise; Non-cardiac chest pain; Pain 
INFECTIONS AND INFESTATIONS - Infection9 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Cardiac troponin T increased; Cholesterol high; Ejection fraction decreased; GGT 
increased; INR increased; Investigations - Other (blood lactate dehydrogenase increased); Investigations - 
Other (blood TSH increased); Lipase increased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Hypertriglyceridemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; 
Generalized muscle weakness; Head soft tissue necrosis; Muscle weakness lower limb; Muscle weakness 
upper limb; Musculoskeletal and connective tissue disorder - Other (muscle spasms); Neck pain 
NERVOUS SYSTEM DISORDERS - Extrapyramidal disorder; Intracranial hemorrhage; Ischemia 
cerebrovascular; Memory impairment; Paresthesia; Peripheral sensory neuropathy; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Hematuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Reproductive 
system and breast disorders - Other (vaginal necrosis); Vaginal discharge; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Laryngeal edema; 
Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumothorax; Postnasal drip; Sore throat; 
Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus; Purpura; 
Skin hyperpigmentation; Skin ulceration 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Vasculitis 
 
Note: Pazopanib (GW786034) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.1.2 CAEPR for ARQ 197 (NSC 750832)  
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
54 
Other (eructation [belching]); Gastrointestinal disorders - Other (peritoneal hemorrhage); 
Mucositis oral; Oral pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
limbs; Fever; Flu like symptoms; Gait disturbance; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis; Hepatic failure 
Infections and infestations – Infection2 
Injury, poisoning and procedural complications - Fracture 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; 
Aspartate aminotransferase increased; Blood bilirubin increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; INR increased; Investigations - Other 
(pancytopenia); Platelet count decreased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back 
pain; Flank pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder 
- Other (muscle spasms); Neck pain; Pain in extremity 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Treatment related 
secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia; Headache; Nervous system 
disorders - Other (spinal cord compression); Peripheral motor neuropathy; Seizure; Stroke; 
Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - 
Other (hydronephrosis); Urinary retention; Urinary tract obstruction 
Reproductive system and breast disorders - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Bronchospasm; Cough; Dyspnea; Pleural effusion; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (oropharyngeal pain) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Nail loss; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (skin 
fissures); Skin hyperpigmentation 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
Note: ARQ 197 (tivantinib) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
7.2 
Adverse Event Characteristics  
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
56 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.3 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, certain AEs/grades are exceptions to the Expedited 
Reporting Guidelines and do not require expedited reporting (i.e., CTEP-AERS).  
These are: any grade lymphopenia, grade 2 hypophosphatemia, grade 2 
hyperglycemia, any grade alopecia, grade 2 anemia, grade 2 electrolytes (sodium, 
potassium, and magnesium), grade 2 albumin, grade 2 INR, grade 2 PTT, and 
grade 2 hyperuricemia will NOT be reported through CTEP-AERS but will be 
reported in the routine data submissions. 
7.3.4 Pregnancy, Fetal Death, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy 
loss”, or 
“Neonatal loss”, the Pregnancy Information Form should be completed and faxed 
along with any additional medical information to 
.  The potential 
risk of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section of the 
CTEP-AERS report. 
 
7.3.4.1 Pregnancy 
• Because patients who become pregnant on study risk intrauterine exposure 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
57 
of the fetus to agents which may be teratogenic.  For this reason, 
pregnancy should be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal conditions 
SOC. 
• The pregnancy outcome for patients on study should be reported via 
CTEP-AERS at the time the outcome becomes known, accompanied by 
the same Pregnancy Report Form used for the initial report.  
7.3.4.2 Fetal Death 
 
• Fetal death is defined in CTCAE as “A disorder characterized by death in 
utero; failure of the product of conception to show evidence of respiration, 
heartbeat, or definite movement of a voluntary muscle after expulsion 
from the uterus, without possibility of resuscitation.” 
• Any fetal death should be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC. 
• A fetal death should NOT be reported as “Fetal death,” a Grade 5 event 
under the Pregnancy, puerperium and perinatal conditions SOC, as 
currently CTEP-AERS recognizes this event as a patient death. 
 
7.3.4.3 Death Neonatal 
 
• Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously. 
• A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration - Other (neonatal loss)” under the General 
disorders and administration SOC. 
• Neonatal death should NOT be reported as “Death neonatal” under the 
General disorders and administration SOC, a Grade 5 event.  If reported as 
such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
7.3.4 NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, 
and Deaths  
7.3.4.1 Definitions 
Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that 
occurs during the course of the clinical trial associated with the use of a drug in 
humans, whether or not the event is considered related to the treatment or 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
58 
clinically significant.  For this study, AEs will include events reported by the 
patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation.  A new illness, symptom, sign or clinically 
significant laboratory abnormality or worsening of a pre-existing condition or 
abnormality is considered an AE.  All AEs must be recorded on the AE case 
report form. 
 
All AEs, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed until satisfactory resolution.  
AEs should be reported up to 30 days following the last dose of study drug.  AEs 
that are considered treatment related, expected, continuing, but not resolvable by 
30 days after treatment completion (e.g., alopecia) will not be followed after the 
30-day period. 
 
Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the purposes of 
IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a 
causal relationship between the drug and the adverse event.  A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
 
Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application.  “Unexpected” also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
 
Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the 
definition of a Serious Adverse Event or if it compromises the safety, welfare or 
rights of subjects or others. 
 
Serious Adverse Events  
An adverse event or suspected adverse reaction is considered serious if in the 
view of the investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
59 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
 
Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 
Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, 
in the view of the investigator or sponsor, at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction that had it occurred in a 
more severe form, might have caused death. 
 
Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved research protocol. 
 
Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program 
(HRPP) policies, IRB requirements, or regulatory requirements for the protection 
of human research subjects. 
 
Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol 
and informed consent document; Investigator’s Brochure or other study 
documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized. 
7.3.4.2 Requirements 
The NCI-IRB requires that the following language be used for reporting 
events to the NCI-IRB: 
 
The Protocol PI will report to the NCI-IRB: 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
60 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All serious non-compliance 
Reports must be received by the NCI-IRB within 7 working days of PI awareness 
via iRIS. 
7.3.4.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem 
will need to be reported to the NCI IRB. 
7.4 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
7.4.1 NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing 
Review 
For reporting of adverse events at time of continuing review, the NCI-IRB requires a 
summary report of adverse events that have occurred on the protocol since the previous 
continuing review and in aggregate.  The method of presentation should provide the 
NCI-IRB with the information necessary to clearly identify risks to participants and to 
make a risk: benefit determination.  Please sort the events by the system organ class and 
by grade.  The summary report is based on the following guidance: any unexpected 
severity and/or unexpected frequency of expected events needs to be reported and 
interpreted in relation to the risk:benefit of study participants in the narrative. 
Please use the following table for reporting adverse events at time of CR: 
System 
Organ Class 
CTCAE 
Term 
Grade 
# of Events 
since last CR 
Total # 
of Events 
Attribution to 
Research 
Serious? 
Unexpected? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
61 
• All Grade 2 unexpected events that are possibly, probably or definitely 
 related to the research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to 
 the research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS.  Three options are available to describe the event:  
 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.6 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified. 
 
 
8 PHARMACEUTICAL INFORMATION 
8.1 
Pazopanib (GW786034) (NSC 737754) 
Chemical Name: 
5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-
pyrimidinyl]amino]-2-methylbenzenesulfonamide 
monohydrochloride 
Other Names: 
Pazopanib HCl, GW786034B (the suffix B denotes the 
monohydrochloride salt) 
Classification: 
VEGFR tyrosine kinase inhibitor 
Molecular Formula: 
C21H23N7O2S • HCl 
Molecular Weight: 
474.0 g/mol (monohydrochloride salt) 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
62 
437.5 g/mol (free base) 
Physical Form: 
White to slightly colored solid 
Solubility: 
Very slightly soluble in 0.1M HCl (0.65 mg/mL); practically 
insoluble in pH 7.0 phosphate buffer (0.00005 mg/mL) and in pH 
11 piperidine buffer (0.0002 mg/mL). 
Mode of Action: 
Pazopanib is a highly potent inhibitor of vascular endothelial 
growth factor (VEGF) receptor tyrosine kinases (VEGFR1, 
VEGFR2, and VEGFR3).  Vascular endothelial growth factor 
receptor inhibition may block VEGF driven angiogenesis and, as a 
consequence, constrain tumor growth. 
How Supplied: 
Pazopanib monohydrochloride is supplied as a series of aqueous 
film-coated tablets containing 200 mg and 400 mg of the free 
base: 
 
• 200 mg, oval-shaped, white, packaged in bottles containing 
34 tablets each 
 
• 400 mg, oval-shaped, white, packaged in bottles containing 
68 tablets each 
 
Tablet excipients in all tablet sizes include microcrystalline 
cellulose, povidone, sodium starch glycolate, and magnesium 
stearate.  The film-coat consists of titanium dioxide, 
hypromellose, polyethylene glycol, and polysorbate 80. 
Storage: 
The intact bottles should be stored at controlled room temperature 
[20°C-25°C, (68-77°F)].  Excursions are permitted between 15°C 
and 30°C. 
Stability: 
Stability studies are ongoing. 
Route of Administration: 
Oral pazopanib should be taken on an empty stomach either 1 
hour before or 2 hours after meals.  The tablets should be 
swallowed whole and cannot be crushed or broken. 
Potential Drug Interaction: See Section 5.3. 
Availability 
Pazopanib is an investigational agent supplied to investigators by 
the Division of Cancer Treatment and Diagnosis (DCTD), NCI.  
Pazopanib is provided to the NCI under a Collaborative 
Agreement between GlaxoSmithKline and the DCTD, NCI (see 
Section 12.3). 
8.2 
ARQ 197 (NSC 750832) 
 
Chemical Name: 
(-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-
(1H-indol-3-yl)pyrrolidine-2,5-dione 
Other Names: 
Tivantinib 
CAS Registry Number 
905854-02-06 
Classification: 
c-MET inhibitor 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
63 
Molecular Formula: 
C23H19N3O2 
Molecular Weight: 
369.43 
Solubility: 
Soluble in DMSO 
Mode of Action: 
c-MET inhibitor ARQ 197 binds to the c-MET protein and 
disrupts c-MET signal transduction pathways, which may induce 
apoptosis in tumor cells overexpressing c-MET protein or 
expressing constitutively activated c-MET protein.   
Description: 
Off-white to light to dark orange powder. 
How Supplied: 
ArQule supplies and CTEP’s Pharmaceutical Management 
Branch distributes ARQ 197 in 120 mg tablets in 50 mL high-
density polyethylene bottles with polypropylene caps.  ARQ 197 
tablets are red orange film coated and round with a diameter of 
9.2 mm. Inert ingredients include lactose monohydrate, 
croscarmellose sodium, hydroxypropyl cellulose, purified water, 
and magnesium stearate.  The film coating contains purified 
water, hypromellose, titanium dioxide, talc and ferric oxide.  
Each bottle contains 100 tablets.   
 
Storage: 
Store at controlled room temperature (20-25oC) with excursions 
allowable to 15-30oC. 
Stability: 
Stability studies of the intact bottles are ongoing. 
Route(s) of Administration: Oral 
Method of Administration: 
ARQ 197 tablets should be administered twice daily 
approximately 12 hours apart.  They should be taken with water, 
swallowed whole and cannot be crushed or broken.  ARQ 197 
should be taken with food.   
Potential Drug Interaction: 
ARQ 197 is metabolized via a drug metabolizing enzyme system 
associated with cytochrome P450 (CYP2C19 and CYP3A4).  
Interactions with drugs metabolized via the same enzyme system 
are possible.  Drugs which inhibit CYP2C19 may markedly 
increase the plasma concentration of ARQ 197.  Drugs and 
substances which inhibit CYP3A4 may increase the plasma 
concentrations of ARQ 197.  (Refer to 
http://medicine.iupui.edu/flockhart/table.htm) 
Availability: 
ARQ 197 is an investigational agent supplied to investigators by 
the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
ARQ 197 is provided to the NCI under a Collaborative 
Agreement between the Pharmaceutical Collaborator and the 
DCTD, NCI (see Section 12.3). 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
65 
biopsy date, and site of tissue biopsy will be provided.  Initial processing and shipping of 
the samples will be completed as described below.  
9.1.2 Tumor Biopsies 
9.1.2.1 Timing of tumor biopsies 
Biopsies will be collected optionally during the escalation phase:   
• before drug administration on study (baseline), and 
• on cycle 1 day 8; 8-12 hours after the Day 7 evening dose of ARQ 197 
(the morning dose of ARQ 197 will be taken 1 hour after pazopanib) 
 
Biopsies will be mandatory during the expansion phase:   
Cohort A 
• before drug administration on study (baseline), and 
• on cycle 1 day 8, 8-12 hours after pazopanib and before the first dose of 
ARQ 197 
 
The C1D8 biopsy can be collected on C1D7 for scheduling reasons.  
Tumor biopsy requires fasting during at least 8 hours after food taken with ARQ 
197.  
9.1.2.2 Biopsy Procedure 
Serial tumor biopsies will be obtained through Interventional Radiology by a 
percutaneous approach.  A maximum of 2 core biopsies 18-gauge in diameter and 
at least 1 cm in length will be obtained at each time point.  Only percutaneous 
biopsies will be performed on patients with solid tumors.   
 
It is estimated that there will be between 2-5 million cells from each biopsy.  If a 
site is deemed appropriate for biopsy with minimal risk to the participant by 
agreement between the investigators and Interventional Radiology, an attempt at 
biopsy will be made.  Determination of a disease site amenable to biopsy will be 
determined on an individual case basis after discussion with an interventional 
radiologist.  The biopsy procedure to be used in this protocol is described below; 
local anesthesia will be administered.  Such biopsies can be safely performed as 
evidenced by literature reports [31] as well as our experience at the Clinical 
Center.  Risks of the procedure include, but are not limited to, bleeding, infection, 
pain, and scarring.  We will follow Clinical Center Interventional Radiology 
SOPs for coagulant panel and platelets. 
 
• All biopsies will be by percutaneous approach  
• No biopsy by an invasive (endoscopic, laparoscopic, or surgical) procedure 
will be performed. 
• Only cutaneous, subcutaneous, or easily accessible parenchymal lesion core 
biopsies will be performed. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
68 
circulating tumor cells, hair follicles, per specific protocol) will be recorded on a PK/PD 
collection worksheet included in Appendix H. 
 
Using a computerized inventory system and a backup hardcopy process, all specimen 
collection and processing steps will be documented and the specific location of each 
specimen will be tracked.  Each new specimen collected will be assigned a unique 
barcode identifier that can be linked to the original specimen collected and other relevant 
information within the inventory system.  To ensure patient confidentiality, only 
containers used for the initial specimen collections will be labeled with patient identifiers.  
Only the barcode identifier will be applied to all subsequent specimen containers.  When 
specimens are processed and aliquoted, no patient information will be included on the 
new containers.  Original specimen containers will be discarded.  Only barcode-labeled 
specimens without patient identifiers will be shipped for analysis and/or storage.  
Specimen labels will indicate: CTEP protocol number, unique patient accession number, 
3-digit sample number (see list below), collection time, and total volume collected, as 
appropriate.  Samples from sets of at least three patients will be grouped for scientific 
analysis.   
 
Standardized 3-digit sample collection numbers: 
100 series: urine for PK 
200 series: blood for PK 
300 series: blood for PD 
400 series: blood for circulating tumor cells (CTCs) 
500 series: tumor biopsies 
600 series: skin punch biopsies 
700 series: hair follicles 
800 series: blood for pharmacogenomic analysis 
 
The inventory process contains other security provisions sufficient to safeguard patient 
privacy and confidentiality.  Access to the inventory system and associated documents 
will be restricted to appropriate individuals.  Requests to use specimens stored in the 
repository must be approved.  The only patient information available in the inventory 
system will be the patient sex, diagnosis, and level of informed consent given.  SOPs 
ensure that any changes in informed consent made by a patient and relayed to the PI will 
be reflected in the inventory system to ensure that specimens are destroyed as 
appropriate.  All laboratory personnel will be trained to adhere to SOPs and will be 
monitored for high-quality performance. 
 
Any new use of these samples will require prospective IRB review and approval.  Access 
to these samples will only be granted following IRB approval of an additional protocol, 
granting the rights to use the material. 
 
 
If at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request.  Following receipt of 
this request, the samples will be destroyed (or returned to the patient, if so requested), and 
reported as such to the IRB.  Any samples lost (in transit or by a researcher) or destroyed 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
69 
due to unknown sample integrity (i.e., broken freezer allows for extensive sample 
thawing, etc.) will be reported as such to the IRB. 
9.2 
Pharmacokinetics  
9.2.1 Blood Sample Collection 
9.2.1.1 Dose Escalation Phase 
Blood samples for PK analysis will be collected prior to drug 
administration and at multiple time points after drug administration 
beginning on D1 and D15 of cycle 1 only.  Pazopanib will be taken on an 
empty stomach 1 hour before a meal and ARQ 197 will be taken with food.   
D1: pre-dose, and 1, 2, 4, 6, and 12 hours after administration of 
pazopanib, with the morning dose of ARQ 197 administered 1 hour after 
pazopanib and the evening dose of ARQ 197 administered after the 12-
hour time point (corresponding to 1, 3, 5, and 11 hours after 
administration of ARQ 197).  The actual time of collection will be noted 
for each sample. 
D15: pre-dose, and 1, 2, 4, and 6 hours after administration of pazopanib, 
with the morning dose of ARQ 197 administered 1 hour after pazopanib 
(corresponding to 1, 3, and 5 hours after administration of ARQ 197).  The 
actual time of collection will be noted for each sample. 
9.2.1.2 Expansion Phase 
Blood samples for PK analysis will be collected prior to drug 
administration and at multiple time points after drug administration 
beginning on D1 and D7 of cycle 1 only.  Pazopanib will be taken on an 
empty stomach 1 hour before a meal and ARQ 197 will be taken with food.   
Cohort A: 
D1: pre-dose, and 1, 2, 4, 6, and 12 hours after administration of 
pazopanib. 
D7: pre-dose, and 1, 2, 4, and 6 hours after administration of pazopanib. 
 
The PK studies are mandatory and will be required for every patient.  The total volume of 
blood collected for PK studies during the initial treatment cycle is expected to be  
< 70 mL per patient.  Based on results from initial measurements, sampling times may be 
adjusted, but neither the total number of samples nor the total amount of blood drawn per 
patient will be increased.  Samples will be collected in lavender-top (EDTA) tubes with 
6 mL (3 mL for day 1 in Cohort A of the expansion phase) of blood per sample.  It is 
important to fill the Vacutainer tubes to the specified collection volume.  The tube 
containing blood for plasma preparation will be gently inverted 10 times to ensure 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
70 
thorough mixing of anticoagulant and blood, then placed in a cool box containing crushed 
ice and/or water. 
9.2.2 Blood Sample Preparation 
All samples will be centrifuged within 45 min of collection, at 1,500 x g for 10 min at 
4°C.  Immediately following centrifugation, the separated plasma for each sample will be 
divided into three aliquots at the following volume:   
1.  Aliquot #1 (for pazopanib assay): 1.0 mL 
2.  Aliquot #2 (for ARQ 197 assay): 0.5 mL 
3.  Aliquot #3 (Back up sample): Remaining volume 
Note: For samples from day 1 in Cohort A of the expansion phase, Aliquot #1 will be 
taken for analysis of single agent pazopanib. 
 
Aliquot #1 of plasma should be transferred with a plastic pipette into a 1.8 mL Nunc 
Cryovial tube (provided by GlaxoSmithKline), and Aliquots #2 and #3 should be each 
pipetted into polypropylene cryogenic sample storage vials (with screw-cap) (provided by 
Daiichi Sankyo Pharma Development, Department of Drug Metabolism and 
Pharmacokinetics [DMPK]), designated Set 1 and Set 2.  Then, they should be 
maintained being chilled before being transferred to freezer.  Within 90 min after blood 
draw, the sample storage vials will be stored, still in upright position, in a -70°C freezer.  
PPD and Covance Inc., respectively will analyze the parent drug molecules and possibly 
metabolites of pazopanib and ARQ 197 in plasma.  These facilities have extensive 
experience in the measurement of drugs and metabolites in body fluids. 
9.2.3 Shipment of Samples 
Specimens will be labeled with the following information: 
Sample type, ID number (CTEP protocol number + unique patient accession number + 3-
digit sample number), and collection time.  The shipment must contain a complete 
sample manifest (electronic or paper) containing the sample type, ID number (CTEP 
protocol number + unique patient accession number + 3-digit sample number), and  
collection time, along with the name and address, including the telephone and fax 
numbers of the person responsible for sending the samples.  No personally identifiable 
information will be sent with samples. 
 
A phone call or fax communication should precede all sample shipments.  A phone or fax 
communication must precede all HIV positive or other known infections sample 
shipments.  Detailed sample inventory information must accompany the samples.  Lack 
of paperwork or illegible information will delay sample login and project initiation.  
Samples that are unclearly or incompletely labeled may be subject to additional handling 
fees.  PPD encourages submission of sample inventory information in electronic form. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
72 
 
 
10 STUDY CALENDAR 
Baseline history and physical exam are to be conducted within 72 hours prior to start of protocol 
therapy; laboratory evaluations (including serum liver tests) and EKG must also be done within 
72 hours.  Scans, x-rays, and echocardiogram or MUGA scan must be done ≤ 4 weeks prior to 
the start of therapy.  In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy.  
The duration of a cycle will be 28 days (± 1 day for scheduling).  Start of next cycle may be 
delayed for up to 1 week to accommodate scheduling conflicts.  History and physical 
examination and laboratory evaluations can be performed up to 3 days before the start of the next 
cycle. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
73 
10.1 
Dose Escalation Phase 
Pre- 
Study 
C1 
W1 
(D1-7) 
C1 
W2 
(D8-
14) 
C1 
W3 
(D15-
21) 
C1 
W4 
(D22-
28) 
C2 
W1 
(D1-7) 
C2 
W2 
(D8-
14) 
C2 
W3 
(D15-
21) 
C2 
W4 
(D22-
28) 
C3 
W1 
on 
Off 
Treatment 
Pazopaniba 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ARQ 197a 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X-------------------------------------------------------------------X 
 
Physical examb 
X 
 
 
X 
 
X 
 
 
 
X 
X 
Vital signsc 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
 
 
 
X 
X 
Performance status 
X 
 
 
 
 
X 
 
 
 
X 
X 
CBC w/diff, pltsd 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
Serum chemistryd 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
Urine protein/creatinine 
ratio or 24-hour urine 
proteine 
X 
 
 
X 
 
X 
 
 
 
X 
X 
EKGf 
X 
 
 
X 
 
 
 
 
 
 
 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 2 cycles.  
Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
X 
B-HCGg 
X 
 
 
 
 
 
 
 
 
 
 
Tumor biopsiesh 
X 
 
X 
 
 
 
 
 
 
 
 
PD blood samplingi 
X 
X 
 
X 
 
X 
 
 
 
 
 
PG blood samplingj 
X 
 
 
 
 
 
 
 
 
 
 
PK blood samplingk 
X 
X 
 
X 
 
 
 
 
 
 
 
a: Pazopanib once daily (empty stomach) and ARQ 197 twice daily (with meals) at the assigned dose.   
b: Physical examination at Clinical Center should be performed on day 1 and day 15, and then at the start of 
each cycle (up to 3 days before start of new cycle).  For patients who have been on study for 6 or more 
cycles and are tolerating treatment well, physical exams may be performed once every 2 cycles (every 
2 months). 
c:  BP monitoring by a health care provider should be performed every 2 weeks during the first 2 cycles and 
then at the beginning of subsequent cycles.  For patients who have been on study for 6 or more cycles and 
are tolerating treatment well, BP monitoring may be performed once every 2 cycles (every 2 months).  
Mid-cycle BP check can be performed by any health care professional.  Patients should measure and 
record their blood pressure at home at least once per day for the duration of the study. 
d: Serum chemistry (albumin, alkaline phosphatase, total bilirubin, BUN, calcium, creatinine, glucose, 
phosphorus, magnesium, potassium, total protein, SGOT [AST], SGPT [ALT], sodium) and  CBC w/diff, 
platelets should be performed within 72 hours of enrollment (pre-study) and weekly during cycle 1 (D8, 
D15 and D22 ± 1 day for scheduling conflicts), every 2 weeks during cycle 2 (± 1 day for scheduling 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
74 
conflicts), and at the start of each cycle (up to 3 days before start of new cycle).  For patients who have 
been on study for 6 or more cycles and are tolerating treatment well, lab tests may be performed once 
every 2 cycles (every 2 months).  Serum liver tests (AST, ALT, serum bilirubin) will also be performed 
during weeks 3, 5, 7, and 9; thereafter, monitoring will occur at months 3 and 4, and as clinically 
indicated.  Periodic monitoring will continue after month 4. 
e:   Evaluation of urine protein/creatinine ratio should occur at baseline (within 72 hours of enrollment),  on 
C1D15 (± 1 day for scheduling conflicts), then at the start of each cycle, and as clinically indicated.  If 
patient has urine protein/creatinine ratio >1+, obtain a 24 hour urine for protein and creatinine clearance.   
f: EKG will be performed at baseline, on C1D1 (3-6 hours after the first dose of ARQ 197) and on C1D15 (3-
6 hours after the morning dose of ARQ 197) and as clinically indicated. 
g:   Serum or urine pregnancy test (women of childbearing potential) within 1 week prior to enrollment. 
h: Tumor biopsies are optional in the escalation phase: at baseline and on C1D8, 8-12 hours after the Day 7 
evening dose of ARQ 197 (taken 1 hour after pazopanib). 
i: Samples will be obtained at the following time points: at baseline, on C1D1 2, 4, and 6 hours after 
pazopanib), on C1D15 (pre-drugs), and on C2D1 (pre-drugs). 
j: A sample for PG study will be obtained at baseline. 
k: Blood samples for PK will be collected from all patients during cycle 1 only:  
D1: pre-dose, and 1, 2, 4, 6, and 12 hours after administration of pazopanib.  D15: pre-dose, and 1, 2, 4, 
and 6 hours after administration of pazopanib. 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
75 
10.2 
Expansion Phase 
Pre- 
Study 
C1 
W1 
(D1-7) 
C1 
W2 
(D8-14) 
C1 
W3 
(D15-
21) 
C1 
W4 
(D22-
28) 
C2 
W1 
(D1-7) 
C2 
W2 
(D8-
14) 
C2 
W3 
(D15-
21) 
C2 
W4 
(D22-
28) 
C3 
W1 
on 
Off 
Treatment 
Pazopaniba 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ARQ 197a 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X------------------------------------------------------------------X 
 
Physical examb 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Vital signsc 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
 
 
 
X 
X 
Performance status 
X 
 
 
 
 
X 
 
 
 
X 
X 
CBC w/diff, pltsd 
X 
 
 
X 
 
X 
 
 
 
X 
X 
Serum chemistryd 
X 
 
X 
X 
 
X 
 
X* 
 
X 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
Urine protein/creatinine 
ratio or 24-hour urine 
proteine 
X 
 
X 
 
 
X 
 
 
 
X 
X 
EKGf 
X 
 
X 
 
 
X* 
 
 
 
 
 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated every 2 cycles.  
Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
X 
B-HCGg 
X 
 
 
 
 
 
 
 
 
 
 
Tumor biopsiesh 
X 
 
X 
 
 
 
 
 
 
 
 
PD blood samplingi 
X 
X 
X 
 
 
X 
 
 
 
 
 
PG blood samplingj 
X 
 
 
 
 
 
 
 
 
 
 
PK blood samplingk 
X 
X 
 
 
 
 
 
 
 
 
 
a: Pazopanib once daily (empty stomach) and ARQ 197 twice daily (with meals) at MTD dose.  Single-agent 
pazopanib from C1D1 to D7 then the combination of ARQ 197 and pazopanib from C1D8 in Cohort A 
b: Physical examination at Clinical Center should be performed on D1 and D8 and then at the start of each 
cycle (up to 3 days before start of new cycle).  For patients who have been on study for 6 or more cycles 
and are tolerating treatment well, physical exams may be performed once every 2 cycles (every 2 
months). 
c:   BP monitoring by a health care provider should be performed on D1 and D8 of cycle 1 and then at the 
beginning of subsequent cycles.  For patients who have been on study for 6 or more cycles and are 
tolerating treatment well, BP monitoring may be performed once every 2 cycles (every 2 months).  
Patients should measure and record their blood pressure at home at least once per day for the duration of the 
study. 
d: Serum chemistry (albumin, alkaline phosphatase, total bilirubin, BUN, calcium, creatinine, glucose, 
phosphorus, magnesium, potassium, total protein, SGOT [AST], SGPT [ALT], sodium) and CBC w/diff, 
platelets should be performed within 72 hours of enrollment (pre-study) and again on D18 of cycle 1, and 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
76 
at the start of each cycle (± 1 day for scheduling conflicts).  For patients who have been on study for 6 or 
more cycles and are tolerating treatment well, lab tests may be performed once every 2 cycles (every 
2 months).  Serum liver tests (AST, ALT, serum bilirubin) will also be performed during weeks 3, 5, 7 
(*can be collected by patients’ local physician), and 9; thereafter, monitoring will occur at months 3 and 
4, and as clinically indicated.  Periodic monitoring will continue after month 4.  
e:   Evaluation of urine protein/creatinine ratio should occur at baseline, on C1D8, then at the start of each cycle 
(± 1 day for scheduling conflicts), and as clinically indicated.  If patient has urine protein/creatinine ratio 
>1+, obtain a 24 hour urine for protein and creatinine clearance.  
f: EKG will be performed at baseline, on C1D1 (3-6 hours after the morning dose of pazopanib), on C1D8 (3-
6 hours after pazopanib), on *C2D1 (3-6 hours after the morning dose of ARQ 197), and as clinically 
indicated. 
g: Serum or urine pregnancy test (women of childbearing potential) within 1 week prior to enrollment. 
h: Tumor biopsies are mandatory in the expansion phase: at baseline and on C1D8, 8-12 hours after pazopanib 
before the first dose of ARQ 197. 
i: Samples will be obtained at the following time points: at baseline, on C1D1 (2, 4, and 6 hours after 
pazopanib ), on C1D8 (pre-drugs), and on C2D1 (pre-drugs).  
j: A sample for the PG study will be obtained at baseline. 
k: Blood samples for PK will be collected from all patients during cycle 1 only on D1 and D7 as specified in 
Section 9.2.1.2. 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
77 
11 MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 2 cycles.  In 
addition to a baseline scan, confirmatory scans should also be obtained at least 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
11.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with study agents. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
11.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
78 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
11.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
79 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g., for body 
scans). 
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
80 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
  
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image. 
11.3 
Response Criteria 
11.3.1 Evaluation of Target Lesions 
Response and progression will be evaluated using RECIST version 1.1.  Changes 
in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria per Section 11.1. 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
81 
Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, which is based on the long axis for non-nodal lesions and the short 
axis for nodal lesions of target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, which is based on the long axis for non-nodal lesions and the short 
axis for nodal lesions of target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study).  In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 
11.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis).Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
11.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
82 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks.  Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks.  Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
documented at least once >4 
wks.  from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised 
11.4 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
83 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
11.5 
Confirmatory Measurement 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed at least 4 weeks after the criteria for 
response are first met.  In the case of  SD, follow-up measurements must have met the SD 
criteria at least once after study entry for a minimum interval of 8 weeks. 
 
 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1 
Data Reporting 
12.1.1 Method 
Data will be collected in the Center for Cancer Research C3D database.  This study will 
be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a 
quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are 
due January 31, April 30, July 31, and October 31.  Instructions for submitting data using 
the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html). 
 
Note:  All adverse events that have occurred on the study, including those reported 
through CTEP-AERS, must be reported via the monitoring method identified above. 
12.1.2 Responsibility for Data Submission 
N/A 
12.2 
CTEP Multicenter Guidelines 
N/A 
12.3 
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
84 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
12.3.1 Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data for Agent(s) are confidential and proprietary 
to Collaborator(s) and shall be maintained as such by the investigators.  The 
protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a 
copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  
A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
12.3.2 For a clinical protocol where there is an investigational Agent used in 
combination with (an)other Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows 
(data pertaining to such combination use shall hereinafter be referred to as "Multi-
Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
12.3.3 Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected , used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
85 
12.3.4 When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
12.3.5 Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
12.3.6 Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 
three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings.  Press releases and other media 
presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
E-mail: 
 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
 
 
13 STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Endpoints 
A primary objective of the trial is to establish the safety, tolerability, and MTD of the 
combination.  Another primary objective is to evaluate changes in MET and phospho-MET 
following treatment with pazopanib and ARQ 197. 
 
Twelve patients will be treated initially in Cohort A.  Mean increases in MET and pMET in these 
12 patients will be measured to assess whether or not it is statistically significant.   
13.2 
Sample Size/Accrual Rate 
The study is designed to have 5 dose escalation cohorts, with a standard design using 3 patients 
per cohort, unless DLT is noted, in which case up to 6 patients may be enrolled in a cohort.  With 
6 dose levels, up to 36 patients may be enrolled for determination of the MTD.  In addition, to 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
86 
characterizing the pharmacodynamics of the combination, up to an additional 12 patients will be 
enrolled in the expansion phase, for a total of 54 patients.  Only patients with paired tumor 
biopsies will be considered evaluable in the expansion phase.  To allow for a few patients who 
may not be evaluable, the accrual ceiling will be set at 56 patients. 
 
It is anticipated that 2-3 patients per month may be enrolled onto this trial.  Thus, depending on 
the number of patients needed to reach the MTD, it is expected that 18 to 27 months will be 
required to accrue the number of patients necessary to complete the trial.  
13.3 
Analysis of Secondary Endpoints 
We will assess pMET (1235/1356) reduction, MET reduction, VEGF reduction, TSP-1 increase, 
HIF1α increase, and change in EMT markers, descriptively (magnitude of change, with 2-sided 
90% CI), in blood and tumor assays (where paired samples are available), for the various dose 
combinations in the escalation and expansion phases. 
13.4 
Reporting and Exclusions 
13.4.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time of 
their first treatment with study agents. 
13.4.2 Evaluation of response – All patients included in the study will be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following categories:  
1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 9) unknown (not assessable, insufficient 
data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) will be included in the main analysis of 
the response rate.  Patients in response categories 4-9 will be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the response 
rate.  Precise definitions for categories 4-9 will be protocol specific.  
 
All conclusions will be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, 
these subanalyses may not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis will 
be clearly reported.  The 95% confidence intervals will also be provided.  
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
87 
14 HUMAN SUBJECTS PROTECTIONS 
14.1 
Justification for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race, provided that 
the aforementioned inclusion and exclusion criteria are met.  Patients for this study will be 
recruited through internal referral, our physician referral base, and through various cancer 
information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer).  To date, there is no 
information that suggests that differences in drug metabolism or effect on tumor would be 
expected in one ethnic group compared to another.  Efforts will be made to extend accrual to 
each representative population, but a balance must be struck between participant safety 
considerations and limitations on the number of individuals exposed to potentially ineffective 
treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on 
the other hand.  If differences in outcome that correlate to ethnic identity are noted, a follow-up 
study may be written to investigate those differences more fully. 
 
Due to lack of knowledge of the effects of pazopanib and ARQ 197 on the fetus or infants, as 
well as the possibility of teratogenic effects, pregnant and nursing women will be excluded from 
this trial.  Patients with unstable or serious medical conditions are excluded due to the possibility 
that pazopanib and/or ARQ 197 may worsen their condition and the likelihood that the 
underlying condition may obscure the attribution of adverse events with respect to pazopanib 
and/or ARQ 197.  HIV-positive patients on combination antiretroviral therapy are excluded from 
the study because of possible PK interactions with pazopanib and/or ARQ 197. 
14.1.1 Participation of Children   
This study includes patients 18 years of age and older.  Because insufficient dosing or 
adverse event data are currently available on the use of pazopanib and ARQ 197 in 
patients <18 years of age, children are excluded from this study, but may be eligible for 
future pediatric trials.  Studies will be performed in patients <18 years of age when it is 
appropriate to do so.  
14.2 
Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence 
of any of a range of side effects that are listed in the consent document.  The procedure for 
protecting against or minimizing risks will be to medically evaluate patients as described in 
Sections 5 and 6.  Although no compensation is available, any injury will be fully evaluated and 
treated in keeping with the benefits or care to which participants are entitled under applicable 
regulations.  
14.3 
Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
drug administration plan, research objectives, and follow-up of this trial.  The patient will be 
provided an IRB-approved consent for review and signature and his/her questions will be 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
88 
answered.  After a decision is made to enroll into the study, a signature will be obtained from the 
patient.  The original signed consent goes to Medical Records; a copy will be placed in the 
research record. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  This study may involve risks to patients, which are currently unforeseeable.  All 
patients will be monitored for side effects from taking study medication.  This research 
represents a greater than minimal risk to participants, but presents the prospect of direct benefit 
to individual subjects. 
 
The research component of this study required to obtain 2 CT tumor biopsies confers radiation 
exposure at an effective dose of 0.29 rem.  This dose is below NIH RSC guidelines and 
represents a slightly greater than minimal risk to patients.  
14.5 
Patient Advocate 
The patients’ rights representative is available to patients receiving treatment on this protocol at 
the NIH Clinical Center at 
 
, on the Bethesda NIH campus.  Patients will be informed that they can contact the study 
PI or RN at any time with questions about their medical care, and that the patients’ rights 
representative is also available to answer non-medical questions about the study.  

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
89 
REFERENCES 
 
 
1. 
Gerritsen, M.E., et al., Using gene expression profiling to identify the molecular basis of 
the synergistic actions of hepatocyte growth factor and vascular endothelial growth 
factor in human endothelial cells. British Journal of Pharmacology, 2003. 140(4): p. 595-
610. 
2. 
Xin, X., et al., Hepatocyte Growth Factor Enhances Vascular Endothelial Growth 
Factor-Induced Angiogenesis in Vitro and in Vivo. Am J Pathol, 2001. 158(3): p. 1111-
1120. 
3. 
Van Belle, E., et al., Potentiated Angiogenic Effect of Scatter Factor/Hepatocyte Growth 
Factor via Induction of Vascular Endothelial Growth Factor : The Case for Paracrine 
Amplification of Angiogenesis. Circulation, 1998. 97(4): p. 381-390. 
4. 
Zhang, Y.-W., et al., Hepatocyte growth factor/scatter factor mediates angiogenesis 
through positive VEGF and negative thrombospondin 1 regulation. Proceedings of the 
National Academy of Sciences of the United States of America, 2003. 100(22): p. 12718-
12723. 
5. 
Yamashita, J.-i., et al., Immunoreactive Hepatocyte Growth Factor Is a Strong and 
Independent Predictor of Recurrence and Survival in Human Breast Cancer. Cancer 
Research, 1994. 54(7): p. 1630-1633. 
6. 
Eder, J.P., et al., A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and 
Vascular Endothelial Growth Factor Receptor 2. Clinical Cancer Research. 16(13): p. 
3507-3516. 
7. 
Yap, T.A. and J.S. de Bono, Targeting the HGF/c-Met Axis: State of Play. Molecular 
Cancer Therapeutics. 9(5): p. 1077-1079. 
8. 
Sennino, B., et al., Reduction of tumor invasiveness and metastasis and prolongation of 
survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met by XL184 Molecular 
Cancer Therapeutics, 2009. 8(12 (suppl)). 
9. 
Pàez-Ribes, M., et al., Antiangiogenic Therapy Elicits Malignant Progression of Tumors 
to Increased Local Invasion and Distant Metastasis. Cancer Cell, 2009. 15(3): p. 220-
231. 
10. 
Ebos, J.M.L., et al., Accelerated Metastasis after Short-Term Treatment with a Potent 
Inhibitor of Tumor Angiogenesis. Cancer Cell, 2009. 15(3): p. 232-239. 
11. 
Loges, S., et al., Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis 
Revisited. Cancer Cell, 2009. 15(3): p. 167-170. 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
90 
12. 
Pennacchietti, S., et al., Hypoxia promotes invasive growth by transcriptional activation 
of the met protooncogene. Cancer Cell, 2003. 3(4): p. 347-361. 
13. 
Comoglio, P.M., S. Giordano, and L. Trusolino, Drug development of MET inhibitors: 
targeting oncogene addiction and expedience. Nat Rev Drug Discov, 2008. 7(6): p. 504-
516. 
14. 
Wang, R., et al., Activation of the Met Receptor by Cell Attachment Induces and Sustains 
Hepatocellular Carcinomas in Transgenic Mice. The Journal of Cell Biology, 2001. 
153(5): p. 1023-1034. 
15. 
Nakagawa, T., et al., E7050: A dual c-Met and VEGFR-2 tyrosine kinase inhibitor 
promotes tumor regression and prolongs survival in mouse xenograft models. Cancer 
Science. 101(1): p. 210-215. 
16. 
Qian, F., et al., Inhibition of Tumor Cell Growth, Invasion, and Metastasis by EXEL-2880 
(XL880, GSK1363089), a Novel Inhibitor of HGF and VEGF Receptor Tyrosine Kinases. 
Cancer Research, 2009. 69(20): p. 8009-8016. 
17. 
Kumar, R., et al., Pharmacokinetic-pharmacodynamic correlation from mouse to human 
with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and 
antiangiogenic activity. Mol Cancer Ther, 2007. 6(7): p. 2012-21. 
18. 
Sonpavde, G., T.E. Hutson, and C.N. Sternberg, Pazopanib, a potent orally administered 
small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert 
Opinion on Investigational Drugs, 2008. 17(2): p. 253-261. 
19. 
Podar, K., et al., The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) 
targets both tumor and endothelial cells in multiple myeloma. Proceedings of the 
National Academy of Sciences, 2006. 103(51): p. 19478-19483. 
20. 
Levy, C., M. Khaled, and D.E. Fisher, MITF: master regulator of melanocyte 
development and melanoma oncogene. Trends Mol Med, 2006. 12(9): p. 406-14. 
21. 
McGill, G.G., et al., c-Met expression is regulated by Mitf in the melanocyte lineage. J 
Biol Chem, 2006. 281(15): p. 10365-73. 
22. 
Munshi, N., et al., ARQ 197, a Novel and Selective Inhibitor of the Human c-Met 
Receptor Tyrosine Kinase with Antitumor Activity. Molecular Cancer Therapeutics. 9(6): 
p. 1544-1553. 
23. 
Bagai, R., W. Fan, and P.C. Ma, ARQ-197, an oral small-molecule inhibitor of c-Met for 
the treatment of solid tumors. IDrugs. 13(6): p. 404 - 414. 
24. 
Eathiraj, S., et al., Discovery of a Novel Mode of Protein Kinase Inhibition Characterized 
by the Mechanism of Inhibition of Human Mesenchymal-epithelial Transition Factor (c-

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
91 
Met) Protein Autophosphorylation by ARQ 197. Journal of Biological Chemistry, 2011. 
286(23): p. 20666-20676. 
25. 
Yap, T.A., et al., Phase I Trial of a Selective c-MET Inhibitor ARQ 197 Incorporating 
Proof of Mechanism Pharmacodynamic Studies. Journal of Clinical Oncology, 2011. 
29(10): p. 1271-1279. 
26. 
Srivastava, A.K., et al. Preclinical assessment of MET modulation by a VEGFR 
inhibitor/MET inhibitor combination that shows additive anti-tumor efficacy. in AACR 
Annual Meeting Abstract 3672. Chicago. 
27. 
Sennino, B., et al., Suppression of Tumor Invasion and Metastasis by Concurrent 
Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors. Cancer 
Discovery, 2012. 
28. 
Knudsen, B.S., et al., A novel multipurpose monoclonal antibody for evaluating human c-
Met expression in preclinical and clinical settings. Appl Immunohistochem Mol 
Morphol, 2009. 17(1): p. 57-67. 
29. 
Athauda, G., et al., c-Met Ectodomain Shedding Rate Correlates with Malignant 
Potential. Clinical Cancer Research, 2006. 12(14): p. 4154-4162. 
30. 
Cecchi, F., D.C. Rabe, and D.P. Bottaro, Targeting the HGF/Met signalling pathway in 
cancer. European Journal of Cancer. 46(7): p. 1260-1270. 
31. 
Dowlati, A., et al., Sequential tumor biopsies in early phase clinical trials of anticancer 
agents for pharmacodynamic evaluation. Clin Cancer Res, 2001. 7(10): p. 2971-6. 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
92 
 
APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
93 
APPENDIX B: POTENTIAL DRUG INTERACTIONS 
 
 
CYP2C19 Inhibitors 
Amiodarone 
Amitriptyline 
Amprenavir 
Aprepitant 
Azelastine 
Bortezomib 
Buprenorphine 
Cholecalciferol/Vitamin D3 
Cimetidine 
Citalopram 
Clotrimazole 
Clozapine 
Delavirdine 
Diazepam 
Dimethyl sulfoxide 
Drospirenone 
Efavirenz 
Entacapone 
Ethinyl estradiol 
Ethotoin 
Felbamate 
Fenofibrate 
Fluconazole 
Fluoxetine 
Fluvoxamine 
Fosamprenavir 
Gefitinib 
Gemfibrozil 
Imipramine 
Indinavir 
Indomethacin 
Isoniazid 
Ketoconazole 
Lansoprazole 
Letrozole 
Loratadine 
Losartan 
Mephobarbital 
Mestranol 
Methimazole 
Methoxsalen 
Methsuximide 
Miconazole 
Moclobemide 
Modafinil 
Nelfinavir 
Nicardipine 
Nilutamide 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxcarbazepine 
Paroxetine 
Pentamidine 
Pimozide 
Pioglitazone 
Probenecid 
Progesterone 
Propofol 
Rabeprazole 
Ritonavir 
Rosiglitazone 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sulconazole 
Telmisartan 
Ticlopidine 
Tioconazole 
Topiramate 
Torsemide 
Tranylcypromine 
Valdecoxib 
Valproic acid 
Voriconazole 
Warfarin 
Zafirlukast 
 
CYP2C19 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Phenytoin 
Rifampin 
 
St. John’s wort (1) 
 
CYP2C19 Substrates 
Carisoprodol 
Cilostazol 
Citalopram 
Clobazam 
Clomipramine 
Desogestrel 
Diazepam 
Escitalopram  
Esomeprazole  
Fosphenytoin 
Imipramine 
Lansoprazole 
Mephenytoin 
Mephobarbital 
Methsuximide 
Moclobemide  
Nelfinavir  
Nilutamide 
Omeprazole 
Pantoprazole 
Pentamidine 
Phenobarbital 
Phenytoin 
Progesterone  
Rabeprazole 
Sertraline 
Trimipramine 
Voriconazole 
 
When ARQ 197 is co-administered with compounds classified as ‘inhibitors’, increased plasma 
concentrations of ARQ 197 is the potential outcome.  The co-administration of ‘inducers’ would 
potentially lower plasma ARQ 197 concentrations.  When drugs classified as ‘substrates’ are co-
administered with ARQ 197, there is the potential for higher concentrations of the ‘substrate’. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers.  In: Lacy CF, 
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; 
LexiComp Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed.   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 
 
 
(1)  Wang et al. (2004). Clin Pharmacol Ther. 75:191-197 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
94 
CYP3A4 Inhibitors 
Acetaminophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice (2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort (3) 
 
CYP3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Ketoconazole 
Lansoprazole 
Letrozole 
Levomethadyl acetate 
    hydrochloride 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Quetiapine 
Quinidine 
Rabeprazole 
Repaglinide 
Rifabutin 
Rifampin 
Ritonavir 
Saquinavir 
Sertraline 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Tamsulosin 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
95 
Busulfan 
Carbamazapine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Delavirdine 
Diazepam 
Digitoxin 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fosamprenavir 
Fulvestrant 
Gefitinib 
Halofantrine 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ketamine 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pioglitazone 
Primaquine 
Progesterone 
Telithromycin 
Teniposide 
Terbinafine 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 
When pazopanib and ARQ 197 are co-administered with compounds classified as ‘inhibitors’, increased 
plasma concentrations of pazopanib and ARQ 197 are the potential outcomes.  The co-administration of 
‘inducers’ would potentially lower plasma concentrations of both study drugs.  When drugs classified as 
‘substrates’ are co-administered with pazopanib or ARQ 197, there is the potential for higher 
concentrations of the ‘substrate’.   
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers.  In: Lacy CF, 
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; 
LexiComp Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed.  Additional information for drug interactions with 
cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/. 
 
(1) Investigator’s Brochure: Pazopanib.  GlaxoSmithKline.  February 2009. 
(2) Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
(3) Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249; Frye et al. (2004). Clin Pharmacol Ther. 
76:323-329. 
 
 
 
 
 
 
 
 
 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
96 
CYP2C8/9 Inhibitors 
Amiodarone 
Amitryptiline 
Amlodipine 
Anastrozole 
Aprepitant 
Atazanavir 
Azelastine 
Bortezomib 
Candesartan 
Chloramphenicol 
Cholecalciferol (Vitamin D3) 
Cimetidine 
Clopidogrel 
Clotrimazole 
Clozapine 
Cyclosporine 
Delavirdine 
Dexmedetomidine 
Diclofenac 
Diltiazem 
Dimethyl sulfoxide 
Disulfiram 
Drospirenone 
Efavirenz 
Entacapone 
Eprosartan 
Etoposide 
Felodipine 
Fluconazole 
Fluoxetine 
Fluphenazine 
Flurbiprofen 
Fluvastatin 
Fluvoxamine 
Gemfibrozil 
Ibuprofen 
Imatinib 
Indinavir 
Indomethacin 
Irbesartan 
Isoniazid 
Ketoconazole 
Ketoprofen 
Lansoprazole 
Leflunomide 
Losartan 
Lovastatin 
Mefenamic acid 
Meloxicam 
Methimazole 
Methoxsalen 
Metronidazole 
Miconazole 
Midazolam 
Modafinil 
Montelukast 
Nateglinide 
Nelfinavir 
Nicardipine 
Nifedipine 
Olanzapine 
Omeprazole 
Ondansetron 
Orphenadrine 
Pantoprazole 
Paroxetine 
Pentamidine 
Pioglitizone 
Piroxicam 
Pravastatin 
Progesterone 
Propafenone 
Propofol 
Propoxyphene 
Pyrimethamine 
Quinidine 
Quinine 
Ritonavir 
Rosiglitazone 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Simvastatin 
Sulconazole 
Sulfadiazine 
Sulfamethoxazole 
Sulfinpyrazone 
Sulfisoxazole 
Tamoxifen 
Teniposide 
Thioridazine 
Ticlopidine 
Tioconazole 
Tolbutamide 
Tolcapone 
Tranylcypromine 
Tretinoin 
Triazolam 
Trimethoprim 
Valdecoxib 
Valproic acid 
Valsartan 
Verapamil 
Voriconazole 
Warfarin 
Zafirlukast 
 
 
CYP2C8/9 Inducers 
Carbamazepine 
Fosphenytoin 
Phenobarbital 
Phenytoin 
Primidone 
Rifampin 
Rifapentine 
Secobarbital 
 
CYP2C8/9 Substrates 
Alosetron 
Amiodarone 
Bosentan 
Carvedilol 
Fluoxetine 
Fosphenytoin 
Glimepiride 
Glipizide 
Ketamine 
Losartan 
Mephenytoin 
Mestranol 
Montelukast 
Nateglinide 
Paclitaxel 
Phenytoin 
Pioglitazone 
Propofol 
Rifampin 
Rosiglitazone 
Selegiline 
Sertraline 
Sulfadiazine 
Sulfamethoxazole 
Sulfinpyrazone 
Sulfisoxazole 
Tamoxifen 
Tolbutamide 
Torsemide 
Trimethoprim 
Voriconazole 
Warfarin 
Zafirlukast 
Zopiclone 
When drugs classified as ‘substrates’ are co-administered with pazopanib, there is the potential for higher 
concentrations of the ‘substrate’.  When pazopanib  is co-administered with compounds classified as 
‘inhibitors’, increased plasma concentrations of  pazopanib is the potential outcome.  The 
coadministration of ‘inducers’ would potentially lower plasma pazopanib concentrations. 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism.  In:  Lacy CF, Armstrong LL, Goldman MP, 
Lance LL eds. Drug Information Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.) 
 
 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
97 
 
CYP2D6 Substrates 
Amitriptyline 
Atomoxetine 
Carvedilol 
Chlorpheniramine 
Chlorpromazine 
Clomipramine 
Codeine 
Desipramine 
Dextromethorphan 
Dihydrocodeine 
Diphenhydramine 
Dolasetron 
Doxepin 
Duloxetine 
Flecainide  
Fluoxetine 
Fluvoxamine 
Haloperidol 
Hydrocodone 
Imipramine 
 
Maprotiline 
Metoclopramide 
Metoprolol 
Mexiletine 
Nortriptyline 
Palonosetron 
Paroxetine 
Perhexiline 
Promethazine 
Propafenone 
 
Propranolol 
Protriptyline 
Risperidone 
Tamoxifen 
Thioridazine 
Timolol 
Tolterodine 
Tramadol 
Trazodone 
Venlafaxine 
 
When drugs classified as ‘substrates’ are co-administered with pazopanib, there is the potential for higher 
concentrations of the ‘substrate’.   
 
 
 
 
 
 
 
 
 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
98 
APPENDIX C: MEDICATIONS THAT MAY CAUSE QTc PROLONGATION 
 
The following table presents a list of drugs that prolong, may prolong, or are unlikely to prolong the 
QTc.  Please note that this list is frequently updated.  For the most current list of medications, users 
should be directed to the following website: http://www.azcert.org/medical-pros/drug-lists/drug-
lists.cfm. 
 
Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes 
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes 
Drugs that, in some reports, have been 
weakly associated with Torsades de 
Pointes and/or QTc prolongation but that 
are unlikely to be a risk for Torsades de 
Pointes when used in usual recommended 
dosages and in subjects without other risk 
factors (e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte 
disturbances, congenital long QTc 
syndrome, concomitant drugs that inhibit 
metabolism) 
  
  
  
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Amiodarone /Cordarone® 
Alfuzosin /Uroxatral® 
Amitriptyline /Elavil® 
Amiodarone /Pacerone® 
Amantadine /Symmetrel® 
Ciprofloxacin /Cipro® 
Arsenic trioxide /Trisenox® 
Atazanavir /Reyataz® 
Citalopram /Celexa® 
Astemizole /Hismanal® 
Azithromycin /Zithromax® 
Clomipramine /Anafranil® 
Bepridil /Vascor® 
Chloral hydrate /Noctec® 
Desipramine /Pertofrane® 
Chloroquine /Aralen® 
Clozapine /Clozaril® 
Diphenhydramine /Benadryl® 
Chlorpromazine /Thorazine® 
Dolasetron /Anzemet® 
Diphenhydramine /Nytol® 
Cisapride /Propulsid® 
Dronedarone /Multaq® 
Doxepin /Sinequan® 
Clarithromycin /Biaxin® 
Felbamate /Felbatrol® 
Fluconazole /Diflucan® 
Disopyramide /Norpace® 
Flecainide /Tambocor® 
Fluoxetine /Sarafem® 
Dofetilide /Tikosyn® 
Foscarnet /Foscavir® 
Fluoxetine /Prozac® 
Domperidone /Motilium® 
Fosphenytoin /Cerebyx® 
Galantamine /Reminyl® 
Droperidol /Inapsine® 
Gatifloxacin /Tequin® 
Imipramine /Norfranil® 
Erythromycin /Erythrocin® 
Gemifloxacin /Factive® 
Itraconazole /Sporanox® 
Erythromycin /E.E.S.® 
Granisetron /Kytril® 
Ketoconazole /Nizoral® 
Halofantrine /Halfan® 
Indapamide /Lozol® 
Mexiletine /Mexitil® 
Haloperidol /Haldol® 
Isradipine /Dynacirc® 
Nortriptyline /Pamelor® 
Ibutilide /Corvert® 
Lapatinib /Tykerb® 
Paroxetine /Paxil® 
Levomethadyl /Orlaam® 
Lapatinib /Tyverb® 
Protriptyline /Vivactil® 
Mesoridazine /Serentil® 
Levofloxacin /Levaquin® 
Sertraline /Zoloft® 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
99 
 
Drugs that are generally 
accepted to have a risk of 
causing Torsades de Pointes 
 
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes 
 
Drugs that, in some reports, have been 
weakly associated with Torsades de 
Pointes and/or QTc prolongation but that 
are unlikely to be a risk for Torsades de 
Pointes when used in usual recommended 
dosages and in subjects without other risk 
factors (e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte 
disturbances, congenital long QTc 
syndrome, concomitant drugs that inhibit 
metabolism) 
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Methadone /Dolophine® 
Lithium /Lithobid® 
Solifenacin /VESIcare® 
Methadone /Methadose® 
Lithium /Eskalith® 
Trimethoprim-Sulfa /Sulfa® 
Pentamidine /Pentam® 
Moexipril/HCTZ /Uniretic® 
Trimethoprim-Sulfa /Bactrim® 
Pentamidine /NebuPent® 
Moxifloxacin /Avelox® 
Trimipramine /Surmontil® 
Pimozide /Orap® 
Nicardipine /Cardene® 
  
Probucol /Lorelco® 
Nilotinib /Tasigna® 
  
Procainamide /Pronestyl® 
Octreotide /Sandostatin® 
  
Procainamide /Procan® 
Ofloxacin /Floxin® 
  
Quinidine /Cardioquin® 
Ondansetron /Zofran® 
  
Quinidine /Quinaglute® 
Oxytocin /Pitocin® 
  
Sotalol /Betapace® 
Paliperidone /Invega® 
  
Sparfloxacin /Zagam® 
Perflutren lipid microspheres 
/Definity® 
  
Terfenadine /Seldane® 
Quetiapine /Seroquel® 
  
Thioridazine /Mellaril® 
Ranolazine /Ranexa® 
  
  
Risperidone /Risperdal® 
  
  
Roxithromycin* /Rulide® 
  
  
Sertindole /Serlect® 
  
  
Sertindole /Serdolect® 
  
  
Sunitinib /Sutent® 
  
  
Tacrolimus /Prograf® 
  
  
Tamoxifen /Nolvadex® 
  
  
Telithromycin /Ketek® 
  
  
Tizanidine /Zanaflex® 
  
  
Vardenafil /Levitra® 
  
  
Venlafaxine /Effexor® 
  
  
Voriconazole /VFend® 
  
  
Ziprasidone /Geodon® 
  
References: 
1. Physician’s Desk Reference 2002 
2. Facts and Comparisons (update to June 2005) 
3. 
The Pharmacological Basis of Therapeutics 9th Edition, 1996 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
100 
APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC 
DISEASE 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Subjects with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Subjects with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Subjects with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Subjects with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
101 
APPENDIX E: PATIENT’S MEDICATION DIARY 
 
EXPANSION PHASE, COHORT A, CYCLE 1 
 
Today’s date ____________________ 
 Agent:  Pazopanib, ARQ 197 
Patient Name___________________________ 
Patient Study ID __________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each cycle of treatment. 
2. Starting on day 1, you will take pazopanib once each day in the morning either 1 hour 
before or 2 hours after a meal with 1 cup of water.   
 
Dose:  ___________.  Take ___ 200 mg tablets and ___ 400 mg tablets every day.  You 
should swallow the tablets whole.   
Do not chew, crush, or break the tablets. 
3.     Starting on day 8, you will take ARQ 197 twice each day, about 12 hours apart, with 
food.  You should swallow the tablets whole.  Do not chew, crush, or break the tablets.  
You will not take ARQ 197 on days 1-7 of cycle 1. 
 
Morning dose: ___________.  Take ___ 120 mg tablets.  Evening dose: ___________.  
Take ___ 120 mg tablets.  
4. Record the date, the number of tablets of each size you took, and when you took them.   
5. If you have any comments or notice any side effects, please record them in the Comments 
column.   
6. Please bring this form and your bottles of pazopanib and ARQ 197 tablets when you 
return for each appointment. 
7. You should measure your own blood pressure at home at least once a day (preferably twice 
a day).  If your systolic pressure (top number) is greater than 150 or your diastolic blood 
pressure (bottom number) is greater than 90, re-measure your blood pressure 1 to 4 hours 
later.  If your systolic pressure is still greater than 150 or your diastolic blood pressure is 
still greater than 90, please contact your study team for instructions.  You should also call 
the research team if you experience any symptoms of high blood pressure, such as chest 
pain, shortness of breath, headache, blood in the urine, or double vision.

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
102 
Today’s date _____________________ 
 
 
Agent:  Pazopanib, ARQ 197 
Patient Name___________________________________  
 Patient Study ID ___________________ 
Day 
Date 
Pazopanib 
ARQ 197 
Blood 
Pressure 
AM 
Blood 
Pressure 
PM 
Comments 
Time 
of dose  
# of tablets 
taken 
Time of 
morning 
dose 
 
# of 
tablets 
taken 
Time of 
evening 
dose 
 
# of 
tablets 
taken 
200 mg 400 mg 
120 mg 
120 mg 
1 
 
 
 
 
-------- 
-------- 
-------- 
-------- 
 
 
 
2 
 
 
 
 
-------- 
-------- 
-------- 
-------- 
 
 
 
3 
 
 
 
 
-------- 
-------- 
-------- 
-------- 
 
 
 
4 
 
 
 
 
-------- 
-------- 
-------- 
-------- 
 
 
 
5 
 
 
 
 
-------- 
-------- 
-------- 
-------- 
 
 
 
6 
 
 
 
 
-------- 
-------- 
-------- 
-------- 
 
 
 
7 
 
 
 
 
-------- 
-------- 
-------- 
-------- 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
Patient’s signature  _________________________________________________________________________
 
CTEP-assigned Protocol #8880 
 
Local Protocol # ___________________ 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
103 
 
 APPENDIX F: LVEF DOSE MODIFICATION TABLE 
 
Asymptomatic Decrease in LVEF 
 
The decision to continue or hold STUDY DRUG is based on the LVEF as it relates to the institutions’s lower limit of normal (LLN) 
and change in ejection fraction from screening (LVEF as measured at registration) according to the following table: 
 
Relationship of  
LVEF to institution’s 
LLN 
LVEF Decrease  
< 10% 
LVEF Decrease   
10-15% 
LVEF Decrease  
≥ 16% 
Normal 
Continue 
Continue 
Continue and repeat 
MUGA/ECHO within 
1-2 cycles 
1-5% below LLN 
Continue and repeat 
MUGA/ECHO within 
1-2 cycles 
Continue and repeat 
MUGA/ECHO within 
1-2 cycles 
HOLD and repeat 
MUGA/ECHO within 
1-2 cycles 
≥ 6% below LLN 
Continue and repeat 
MUGA/ECHO within 
1-2 cycles 
HOLD and repeat 
MUGA/ECHO within 
1-2 cycles 
HOLD and repeat 
MUGA/ECHO within 
1-2 cycles 
 
Discontinue STUDY DRUG if: 
 
• 
Two consecutive HOLD catagories occur. 
• 
Three intermittant HOLD catagories occur (at the discretion of the investigator, STUDY DRUG may also be permanently 
discontinued prior to the occurance of 3 intermittant HOLD catagories). 
If LVEF is maintained at a “Continue and repeat MUGA/ECHO” or improves from a HOLD to a “Continue and repeat 
MUGA/ECHO” category, additonal MUGA scans/echocardiograms prior to the next scheduled MUGA/ECHO will be at the 
discretion of the investigator. 
 
Symptomatic Cardiac Events 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
104 
 
Discontinue STUDY DRUG if: 
• 
A patient has symptoms of congestive heart failure (CHF) and a diagnosis of CHF is confirmed. 
• 
A patient has a myocardial infarction. 
 
 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
105 
APPENDIX G: FACSIMILE TRANSMISSION FORM FOR SAMPLE SHIPMENT 
 
Please use this form to send notification of shipment 
 
From: 
 
Telephone: 
 
Date: 
 
Fax: 
 
 
 
 
To:  PPD 
 
 
 
Fax: 
 
Protocol Number: 
 
Number of samples shipped:  
Date Shipped: 
 
Expected date of arrival: 
 
Courier: 
 
Airway Bill No.: 
 
Number of packages: 
 
On dry ice: 
Yes / No 
(Circle one) 
Associated hazards: 
 
Shipped by: 
(Study Centre Number) 
 
 
 
 
 
 
 
 
 
 

CTEP Protocol #8880 
Clinical Center Protocol #: 12-C-0009 
 
 
106 
 
Please use this form to send notification of shipment 
 
From: 
 
Telephone: 
 
Date: 
 
Fax: 
 
 
 
 
To:  Covance Inc. 
 
Fax: 
 
Protocol Number: 
 
Number of samples shipped:  
Date Shipped: 
 
Expected date of arrival: 
 
Courier: 
 
Airway Bill No.: 
 
Number of packages: 
 
On dry ice: 
Yes / No 
(Circle one) 
Associated hazards: 
 
Shipped by: 
(Study Centre Number)