Conditions: Renal Cell Carcinoma Soft Tissue Sarcoma Metastatic Disease
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 6
Healthy volunteers: no

Brief summary:
This phase 1 study was developed to identify recommended phase 2 doses (RP2Ds) of AR-42 and pazopanib when given in combination for subsequent clinical trials and may have potentially identified candidate pharmacodynamic and predictive biomarkers.

Detailed description:
This study was a single-arm, open-label, dose escalation phase 1 trial to determine the RP2Ds of AR-42 and pazopanib when given in combination to patients with advanced Renal Cell Carcinoma (RCC) or Soft Tissue Sarcoma (STS). Eligible patients had recurrent, unresectable, or metastatic RCC or STS for which pazopanib was an appropriate therapy.

AR-42 was taken orally once per day on 3 non-consecutive days each week during the first 3 weeks of each 4-week cycle. Pazopanib was taken by mouth once daily continuously during each cycle.

A modified 3+3 dose-escalation design was to be followed until the maximum tolerated doses (MTDs) were determined. The initial cohort of patients were assigned to an AR-42 dose of 20 mg taken once per day on 3 non-consecutive days during the first 3 weeks of each 4-week cycle and a pazopanib dose of 600 mg once daily continuously. Additional patients would be enrolled until a total of 12 patients were treated at the MTDs.

The protocol specifies a dose escalation plan that initially impacts only the pazopanib dose. The starting dose of pazopanib (600 mg) was planned to be escalated early so that the FDA-approved full dose of pazopanib (800 mg) would be reached before escalating the AR-42 dose. In subsequent dose-escalation steps, the dose of AR-42 was planned to be increased in 10-mg increments from a starting dose of 20 mg to a maximum dose of 40 mg.

If the number of Dose-Limiting Toxicities (DLT) showed that the MTD was exceeded with a pazopanib dose of 800 mg , the pazopanib dose was planned to be decreased to 600 mg and the AR-42 dose increased in 10-mg increments regardless of relationship of the DLT to one or both study medications.

Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0). The DLT evaluation period was the first treatment cycle. A minimum of 6 doses of AR-42 and 21 doses of pazopanib were required for a patient to be DLT-evaluable (if DLT was not observed with the delivered dose). DLT was defined as any ≥ grade 3 toxicity occurring during the DLT evaluation period and attributed to one or both of the study medications EXCEPT the following:

* The first incidence of grade 3 PPE at any dose level (subsequent incidences of grade 3 PPE will be considered DLT)
* Grade 3 nausea and vomiting in the absence of adequate prophylaxis and/or responsive to medical management within 48 hours
* Grade 3 diarrhea in the absence of adequate prophylaxis and/or responsive to medical management within 48 hours
* Grade 3 fatigue responsive to medical management • Grade 3 asymptomatic hypertension lasting ≤ 7 days
* Grade 3 electrolyte abnormalities that are corrected within 48 hours and, when corrected, can be maintained
* Grade 3 asymptomatic lipase elevation lasting ≤ 7 days
* Grade 3 decrease in platelet count if no clinically significant hemorrhage has occurred
* Grades 3 and 4 decrease in white blood cell count
* Grade 3 decrease in neutrophil count
* Grade 4 decrease in neutrophil count lasting ≤ 7 days
* Grades 3 and 4 decrease in lymphocyte count

Dose escalation was planned to continue until the maximum-tolerated dose (MTD), defined as one dose level below the dose in which dose-limiting toxicities (DLTs) are observed in \>1 of the participants (e.g., in at least 2 participants in a cohort of at least 3). In the cohort of 12 patients at the MTD, no more than 3 DLTs were allowed to confirm the MTD. The RP2D was defined as equal to or less than the MTD, with an allowance to consider an RP2D below the MTD given the overall tolerability of the regimen including the frequency of AEs that were not DLTs and the frequency of dose modifications.

Arms:
arm 1: Participants take 10 mg AR-42 orally per day on 3 non-consecutive days during the 1st 3 weeks of each 4-week cycle and pazopanib 600mg orally daily continuously arm 2: Participants take 20 mg AR-42 orally per day on 3 non-consecutive days during the 1st 3 weeks of each 4-week cycle and pazopanib 600mg orally daily continuously arm 3: Participants take 20 mg AR-42 orally per day on 3 non-consecutive days during the 1st 3 weeks of each 4-week cycle and pazopanib 800mg orally daily continuously arm 4: Participants take 30 mg AR-42 orally per day on 3 non-consecutive days during the 1st 3 weeks of each 4-week cycle and pazopanib 800mg orally daily continuously arm 5: Participants take 30 mg AR-42 orally per day on 3 non-consecutive days during the 1st 3 weeks of each 4-week cycle and pazopanib 600mg orally daily continuously arm 6: Participants take 40 mg AR-42 orally per day on 3 non-consecutive days during the 1st 3 weeks of each 4-week cycle and pazopanib 800mg orally daily continuously arm 7: Participants take 40 mg AR-42 orally per day on 3 non-consecutive days during the 1st 3 weeks of each 4-week cycle and pazopanib 600mg orally daily continuously

Interventions: intervention 1: AR-42 intervention 2: Pazopanib
Intervention descriptions: intervention 1: AR-42 tablets were taken orally once per day on 3 non-consecutive days during the first 3 weeks of each 4-week cycle. If treatment was interrupted during the cycle, the cycle was to be extended intervention 2: Pazopanib tablets were taken orally once daily continuously during each 4-week treatment cycle. There were no scheduled breaks in pazopanib therapy

Protocol document:
Prot_SAP_000.pdf: 
Virginia Commonwealth University Massey Cancer Center 
 
MCC Protocol #: MCC-14-10774 
FDA IND#: 129776 
Phase 1 Study of the Pan-DAC Inhibitor AR-42 and Pazopanib in Advanced Soft Tissue 
Sarcoma and Renal Cell Carcinoma  
Sponsor-Investigator 
Andrew Poklepovic, MD 
VCU Massey Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
REVISION HISTORY ................................................................................................................. 2 
LIST OF FIGURES .................................................................................................................... 6 
LIST OF TABLES ...................................................................................................................... 6 
LIST OF ABBREVIATIONS ....................................................................................................... 8 
1 
BACKGROUND .......................................................................................................... 9 
1.1 
RENAL CELL CARCINOMA AND SOFT TISSUE SARCOMAS .................................................. 9 
1.2 
PAZOPANIB IN RCC AND STS ........................................................................................10 
1.3 
AR-42 .........................................................................................................................11 
1.4 
COMBINATION OF PAZOPANIB AND HDAC INHIBITORS .....................................................13 
1.5 
RATIONALE FOR THE STUDY ..........................................................................................24 
1.6 
CORRELATIVE STUDIES .................................................................................................25 
2 
OBJECTIVES .............................................................................................................25 
2.1 
PRIMARY OBJECTIVE ....................................................................................................25 
2.2 
SECONDARY OBJECTIVES .............................................................................................25 
2.3 
EXPLORATORY OBJECTIVE ............................................................................................25 
3 
STUDY DESIGN .........................................................................................................25 
3.1 
GENERAL DESCRIPTION ................................................................................................25 
3.2 
PRIMARY ENDPOINT ......................................................................................................26 
3.3 
SECONDARY ENDPOINTS ...............................................................................................26 
3.4 
EXPLORATORY ENDPOINT .............................................................................................26 
4 
PATIENT SELECTION ...............................................................................................26 
4.1 
INCLUSION CRITERIA .....................................................................................................26 
4.2 
EXCLUSION CRITERIA ...................................................................................................27 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES ..............................................30 
5.1 
STUDY ENTRY PROCEDURES.........................................................................................30 
5.2 
STUDY WITHDRAWAL ....................................................................................................30 
6 
TREATMENT PLAN ...................................................................................................31 
6.1 
BASELINE TESTS AND PROCEDURES ..............................................................................31 
6.2 
ADMINISTRATION OF STUDY TREATMENT ........................................................................31 
6.3 
MISSED DOSES ............................................................................................................32 
6.4 
MONITORING PATIENT COMPLIANCE ..............................................................................32 
6.5 
DURATION OF THERAPY ................................................................................................32 
6.6 
AR-42 AND PAZOPANIB DOSE-ESCALATION PLAN ...........................................................33 
6.7 
DEFINITIONS OF DOSE-LIMITING TOXICITY, MAXIMUM TOLERATED DOSE, AND 
RECOMMENDED PHASE 2 DOSE ....................................................................................35 
6.8 
REQUIRED QT MONITORING AND QT INTERVAL PROLONGATION INSTRUCTIONS ...............37 
6.9 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ....................38 
6.10 
PROHIBITED/DISCOURAGED MEDICATIONS .....................................................................40 
6.11 
STUDY POCKET CARD FOR PATIENTS ............................................................................41 
6.12 
ELECTIVE SURGERY DURING STUDY PARTICIPATION ......................................................41 
6.13 
FOLLOW-UP PERIOD .....................................................................................................41 


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DOSING DELAYS/DOSING MODIFICATIONS ..........................................................41 
7.1 
RECORDING DOSE MODIFICATIONS ................................................................................41 
7.2 
TOXICITY ASSESSMENT .................................................................................................41 
7.3 
TOXICITY GRADING .......................................................................................................42 
7.4 
GENERAL INSTRUCTIONS AND GUIDELINES .....................................................................42 
7.5 
AR-42 DOSE REDUCTION GUIDELINES ...........................................................................42 
7.6 
PAZOPANIB DOSE REDUCTION GUIDELINES ....................................................................45 
7.7 
PAZOPANIB DOSE MODIFICATION INSTRUCTIONS ............................................................45 
8 
ADVERSE EVENT DEFINITIONS AND REPORTING REQUIREMENTS ..................52 
8.1 
DEFINITIONS .................................................................................................................52 
8.2 
KNOWN AES ................................................................................................................54 
8.3 
SECONDARY MALIGNANCY ............................................................................................54 
8.4 
TIME PERIOD AND GRADE OF AE CAPTURE ....................................................................54 
8.5 
PROCEDURES FOR RECORDING AES, SARS, SAES, SSARS, DLTS, AND UPS ................54 
8.6 
EXPEDITED REPORTING PROCEDURES FOR SAES, SSARS, UPS, AND DLTS ...................55 
9 
PHARMACEUTICAL INFORMATION ........................................................................57 
9.1 
AR-42 .........................................................................................................................57 
9.2 
PAZOPANIB ..................................................................................................................61 
10 
MEASUREMENT OF EFFECT ...................................................................................67 
10.1 
CRITERIA FOR TUMOR RESPONSE .................................................................................67 
10.2 
IMAGING .......................................................................................................................67 
10.3 
CRITERIA FOR TUMOR RESPONSE .................................................................................67 
10.4 
CENTRAL REVIEW FOR IMAGING INTERPRETATION ..........................................................67 
11 
CORRELATIVE STUDIES .........................................................................................67 
11.1 
PARTICIPATION IN CORRELATIVE STUDIES ......................................................................67 
11.2 
COLLECTION, IMMUNOSTAINING, AND DISTRIBUTION OF SAMPLES ....................................67 
11.3 
ARCHIVED TUMOR SAMPLES .........................................................................................68 
12 
STUDY CALENDARS ................................................................................................69 
13 
STATISTICAL CONSIDERATIONS ...........................................................................74 
13.1 
STUDY DESIGN .............................................................................................................74 
13.2 
SAMPLE SIZE/ACCRUAL RATES .....................................................................................74 
13.3 
STATISTICAL ANALYSIS FOR PRIMARY OBJECTIVE ...........................................................74 
13.4 
STATISTICAL ANALYSIS FOR SECONDARY OBJECTIVES ....................................................74 
13.5 
STATISTICAL ANALYSIS FOR EXPLORATORY OBJECTIVES ................................................74 
13.6 
EVALUABILITY FOR DLT, TOXICITY, AND RESPONSE ........................................................75 
14 
DATA AND SAFETY MONITORING PLAN ...............................................................75 
14.1 
STUDY TEAM ................................................................................................................75 
14.2 
AUDIT COMMITTEE ........................................................................................................76 
14.3 
DSMC .........................................................................................................................76 
15 
REGULATORY COMPLIANCE AND ETHICS ...........................................................76 
15.1 
ETHICAL STANDARD ......................................................................................................76 
15.2 
REGULATORY COMPLIANCE ...........................................................................................76 
15.3 
INSTITUTIONAL REVIEW BOARD .....................................................................................76 


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15.4 
INFORMED CONSENT PROCESS .....................................................................................76 
15.5 
PATIENT CONFIDENTIALITY ............................................................................................77 
16 
DATA COLLECTION AND MANAGEMENT ..............................................................77 
16.1 
DATA MANAGEMENT RESPONSIBILITIES .........................................................................77 
16.2 
CRFS AND DATA COLLECTION .......................................................................................77 
16.3 
STUDY RECORD RETENTION .........................................................................................78 
17 
REFERENCES ...........................................................................................................79 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ..............................................................81 
APPENDIX 2. COCKCROFT-GAULT FORMULA ....................................................................82 
LIST OF FIGURES 
 
Figure 1. Regulation of Autophagy by Pazopanib and Valproate ...............................................13 
Figure 2. Knockdown of Beclin1 or ATG5 Protects Cells from Pazopanib and Valproate Toxicity
 ...................................................................................................................................14 
Figure 3. Expression of Activated Akt and MEK1 Suppresses Toxicity of Pazopanib and 
Valproate ....................................................................................................................15 
Figure 4. Modulation of HSP70 NH2-terminal Detection by Pazopanib .....................................17 
Figure 5. Sildenafil Enhances the ATPase Inhibitory Effects of Regorafenib, Sorafenib, 
Pazopanib,  AR-13, and OSU-03012 ..........................................................................18 
Figure 6. Pazopanib Alters Chaperone–Chaperone Interactions Assessed after 
Immunoprecipitation ...................................................................................................19 
Figure 7. Pazopanib and Valproate Interact to Suppress the Growth of Established HT1080 
Tumors .......................................................................................................................20 
Figure 8. AR-42 and Pazopanib (1 µM) Interact to Kill Sarcoma and Kidney Cancer Cells at the  
24-Hour Time Point ....................................................................................................21 
Figure 9. AR-42 and Pazopanib (1 µM) Interact to Kill Sarcoma and Kidney Cancer Cells at the  
48-Hour Time Point ....................................................................................................22 
Figure 10. AR-42 and Pazopanib (2 µM) Interact to Kill Sarcoma and Kidney Cancer Cells at the  
24-Hour Time Point ....................................................................................................23 
Figure 11. AR-42 and Pazopanib (2 µM) Interact to Kill Sarcoma and Kidney Cancer Cells at the 
48-Hour Time Point ....................................................................................................24 
 
LIST OF TABLES 
Table 1. AR-42 and Pazopanib Dose Levels .............................................................................33 
Table 2. AR-42 and Pazopanib Dose-Escalation Guidelines .....................................................34 
Table 3. Modified 3+3 Dose Escalation .....................................................................................36 
Table 4. AR-42 Dose Reduction Steps for Toxicity Management ..............................................43 
Table 5. AR-42 Dose Modification Instructions ..........................................................................44 
Table 6. Pazopanib Dose Reduction Steps for Toxicity Management .......................................45 
Table 7. Pazopanib Dose Modification Instructions ...................................................................46 
Table 8. Dose Modification/Interruption for Pazopanib-Related Increase in ALT and/or AST ....49 
Table 9. Pazopanib Dose Modification Instructions for PPE ......................................................50 
Table 10. Pazopanib Dose Modification for Other Toxicity ........................................................51 
Table 11. Expedited Reporting Requirements ...........................................................................56 
Table 12. Summary of Related CTCAE by Worst Grade, Sorted by Frequency ........................60 


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Table 13. Adverse Reactions Occurring in ≥ 10% of Patients with RCC ....................................63 
Table 14. Adverse Reactions Occurring in < 10% of Patients with RCC ....................................63 
Table 15. Selected Laboratory Abnormalities Occurring in > 10% of Patients with RCC and 
More Commonly (≥ 5% ) in Patients Who Received Pazopanib versus Placebo .......64 
Table 16. Adverse Reactions Occurring in ≥ 10% of Patients with STS.....................................65 
Table 17. Other Adverse Reactions Occurring in ≥ 5% of Patients with STS and More 
Commonly (> 2%) in Patients Who Received Pazopanib versus Placebo .................66 
Table 18. Selected Laboratory Abnormalities Occurring in > 10% of Patients with STS and More 
Commonly (≥ 5% ) in Patients Who Received Pazopanib versus Placebo ................66 
Table 19. Study Calendar - Screening Through Treatment Cycle 1 ...........................................70 
Table 20. Study Calendar – Treatment Beginning with Cycle 2 Through Follow-Up ..................72 


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LIST OF ABBREVIATIONS 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CR 
complete response 
CrCL 
creatinine clearance 
CRF 
case report form 
CTCAE  
Common Terminology Criteria for Adverse Events  
CTRL 
Clinical and Translational Research Laboratory 
DLT 
dose-limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
HDAC 
histone deacetylase  
HR 
heart rate  
HSP 
heat shock protein 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LVEF 
left ventricular ejection fraction 
MCC 
Massey Cancer Center 
MI 
myocardial infarction 
MTD 
maximum tolerated dose 
OHRP 
Office for Human Research Protections 
Pan-DAC 
pan-deacetylase 
PBMC 
peripheral blood mononuclear cell 
PO 
by mouth (per os) 
PPE 
palmar-plantar erythrodysesthesia 
PR 
partial response 
QTc 
corrected QT interval 
RCC 
renal cell carcinoma 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors Version 1.1 
RP2D 
recommended phase 2 dose 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
SAE 
serious adverse event 
SAR 
suspected adverse reaction 
SEM 
standard error of the mean 
SSAR 
serious suspected adverse reaction 
SIIT 
Solid Tumor Investigator-Initiated Trial 
STS 
soft tissue sarcoma 
ULN 
upper limit of normal 
UP 
unanticipated problem 
VEGF 
vascular endothelial grown factor 
WCBP 
woman of childbearing potential 
WNL 
within normal limits 


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1 BACKGROUND 
1.1 Renal Cell Carcinoma and Soft Tissue Sarcomas 
This clinical trial is focused on 2 disease groups, renal cell carcinoma (RCC) and soft 
tissue sarcoma (STS). 
1.1.1 Renal Cell Carcinoma 
RCC originates within the renal cortex and is by far the most common primary renal 
neoplasm. In the United States, there are approximately 62,000 new cases and 
almost 14,000 deaths from RCC each year (1). Treatment for localized RCC 
(ie, stages IA, IB, II, and III) is surgical resection. Surgery still has a role in a small 
portion of patients with stage IV RCC. Specifically, if the tumor directly involves the 
ipsilateral adrenal gland and a radical nephrectomy (including adrenalectomy) is 
possible or if there is a solitary metastasis, metastasectomy can sometimes be 
curative. All other cases are not considered curable even with surgery. 
Treatment options for advanced RCC include high-dose interleukin-2 (IL-2) therapy, 
immune checkpoint inhibition, and molecularly-targeted therapy. IL-2 can induce 
durable long-term remissions in a minority of patients, but, due to the rigors of 
treatment, patients must have an excellent performance status and intact organ 
function (2, 3). Given the small number of patients who are eligible for IL-2 therapy 
and the small minority of eligible patients who will respond to therapy, most patients 
will receive molecularly-targeted therapy. Immune checkpoint inhibitors and 
specifically anti-PD1-based therapy have been shown to improve survival as well. 
However, durable benefit is only seen in a minority of patients (4). Outside of 
immunotherapy, treatment for RCC is either an anti-angiogenic, targeting the 
vascular endothelial growth factor (VEGF) pathway, or a mammalian target of 
rapamycin (mTOR) inhibitor (5). Additional advances in therapeutic options are 
needed. 
1.1.2 Soft Tissue Sarcoma 
Sarcomas are a rare and heterogeneous group of tumors with mesenchymal origin, 
accounting for approximately 1% of all human tumors. Sarcomas are categorized 
into 2 major groups according to primary tumor location: STS and bone sarcomas. 
The yearly incidence of STS cases in the United States is roughly 11,930, with an 
overall mortality of 4,870 deaths per year (1). 
STS can arise almost anywhere in the body. Approximately 40-60% occur in the 
extremities, 20-30% occur in and around the internal organs (eg, uterus, heart); 10% 
occur in the trunk (eg, chest, back); and 10% occur in the head and neck (6). STS 
tumors comprise more than 50 different tumor entities that can exhibit significant 
differences in terms of genetic alterations, pathogenesis, and clinical behavior. 
Local control of STS can be obtained through the use of surgery and radiotherapy. 
In approximately 30-40% of patients, disease will recur at distant sites, and of these, 
more than 90% ultimately will die from metastatic disease. Surgical resection of 


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isolated metastases can lead to cure in some patients. The probability of the tumor 
to metastasize is directly correlated with the histological grade, which is the most 
important predictive factor for distant metastases. In advanced and/or metastatic 
STS, the median overall survival of about 12 months has remained unchanged 
during the last 20 years. Only 2 agents have been approved in the past 30 years for 
progressive STS, signifying the dire need for novel therapies and combinations. In 
the vast majority of cases, both anthracyclines (epirubicin or doxorubicin) and 
ifosfamide remain the backbone of chemotherapy in patients with locally advanced 
or metastatic STS. Given the heterogeneous nature of this disease, advances in 
therapeutic options have been slower to progress compared to other cancers. New 
agents and regimens are urgently needed. 
1.2 Pazopanib in RCC and STS 
Pazopanib is an oral multikinase inhibitor approved by the Food and Drug Administration 
(FDA) for the treatment of patients with advanced (ie, unresectable or metastatic) RCC and 
patients with advanced STS who have previously received chemotherapy. 
1.2.1 Pazopanib in RCC 
In RCC, systemic treatment for many patients who have metastatic disease involves 
drugs targeting angiogenesis. High-dose interleukin 2 in the front-line setting is still 
recommended for patients with Karnofsky performance status of > 80%, and other 
immune-based therapies with immune checkpoint inhibitors are showing promise. 
However, agents targeting angiogenesis remain a cornerstone in the management 
of this disease. Two different approaches have demonstrated clinical activity in 
blocking the VEGF pathway. Clinical anticancer activity has been observed with 
small molecule tyrosine kinase inhibitors (TKIs) (eg, pazopanib, sunitinib, sorafenib, 
and axitinib) which block the intracellular domain of the VEGF receptor, as well as 
the monoclonal antibody bevacizumab which can bind circulating VEGF and prevent 
activation of the VEGF receptor. Among the TKIs, pazopanib and sunitinib are 
accepted first-line treatment options (7). 
In a randomized phase 3 study of pazopanib versus sunitinib in 1,110 previously 
untreated patients with advanced RCC, partial responses were observed in 170 
patients in the pazopanib group (31%), and one patient had a complete response 
(7). The median progression-free survival was 8.4 months with pazopanib (95% 
confidence interval [CI], 8.3 to 10.9), and the median duration of treatment was 8.0 
months (range, 0 to 40) in the pazopanib group. Regarding tolerability, 44% of 
patients treated with pazopanib had a dose interruption of 7 days or more and 44% 
of patients had a reduction in the dose. The proportion of patients who discontinued 
the study drug because of adverse events was 24%. These data demonstrate a 
favorable pazopanib safety profile compared to sunitinib, with similar efficacy. The 
results of this study established pazopanib as an acceptable front-line choice in the 
treatment of RCC with TKI-based therapy. 
1.2.2 Pazopanib in STS 
The interaction between VEGF and its receptors involved in angiogenesis plays a 
role in STS tumor progression and prognosis (8). Two studies found that high VEGF 
serum levels correlated strongly with the most poorly differentiated STS (9, 10). 


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The randomized multicenter phase 3 “PALETTE” study evaluated pazopanib 
compared to placebo in 369 patients with STS that had progressed following  
front-line therapy (11). In this study, the best overall response for patients taking 
pazopanib was a partial response in 14 of 246 (6%), stable disease in 164 (67%), 
and progressive disease in 57 (23%). Median progression-free survival was  
4.6 months (95% CI 3.7-4.8) for pazopanib compared to 1.6 months  
(95% CI 0.9-1.8) for patients who received placebo, and median overall survival was 
12.5 months (10.6-14.8) compared to 10.7 months (8.7-12.8) for the placebo arm. 
1.3 AR-42 
AR-42, the investigational agent in this study, is an orally bioavailable, small molecule, 
broad-spectrum inhibitor of histone deacetylase (HDAC) and non-histone protein 
deacetylation (pan-DAC) which has also been shown to inhibit Akt by a deacetylation- 
independent mechanism. HDAC inhibitors are a class of anticancer agents that suppress 
tumor cell growth via a broad spectrum of mechanisms including the ability to induce 
growth arrest, differentiation, and apoptosis in cancer cells (12-14). 
AR-42, a class I and class II HDAC inhibitors, belongs to a novel class of potent 
phenylbutyrate-based HDAC inhibitors possessing submicromolar HDAC-inhibitory activity. 
In addition to HDAC inhibition, AR-42 has also been shown to work via histone-
independent mechanisms including acetylation of tubulin (affects cytoskeletal integrity), 
Ku70 (inhibits DNA double-strand break repair), and Hsp90 (chaperone protein) (15-17). 
AR-42 also works via a deacetylation-independent pathway inhibiting Akt by increasing 
protein phosphatase I activity. Studies of AR-42 in a number of in vitro and in vivo models 
across a broad range of tumor types, both as a single agent and in combination, have 
shown AR-42 to be a potent HDAC inhibitor which targets multiple aspects of cancer cell 
survival including Akt signaling, mitochondrial integrity, and caspase activity. 
1.3.1 AR-42 Preclinical Data 
AR-42 has been studied in several cancer models including prostate, hepatocellular, 
and ovarian (16, 18). Antiproliferative effects via HDAC inhibition and apoptosis 
induction mechanisms were confirmed in both tumor cell lines and tumor xenograft 
studies. The effect of AR-42 on hematologic malignancies, including lymphocytic 
leukemia, mantle cell leukemia, and acute myelogenous leukemia, has also been 
studied. 
Safety studies to assess potential adverse effects on the central nervous system 
(CNS) (rats), the cardiovascular system (dogs), and the respiratory system (rats) are 
completed (19). There were no adverse effects on respiration rate or tidal volume in 
rats after oral administration of AR-42. At normal doses there were no CNS effects 
noted in rats, whereas at high doses there were mild and reversible depressive 
effects noted. There was a lower-than-expected prolongation of the QT interval in 
comparison to other HDAC inhibitors. 
In the most sensitive animal model (beagle dogs), an AR-42 dose of 1 mg/kg  
(20 mg/m2) was not toxic when given every other day PO for 7days or 28 days. 
Even at 3 mg/kg (60 mg/m2), AR-42 resulted in slight decrements in weight and 
some decrease in red and white blood cell counts, some vomiting, and some 
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1.3.2 AR-42 Clinical Data 
Two clinical studies have been conducted with AR-42: a first into man (FIM) study 
and a pharmacodynamics study in combination with decitabine (19). The FIM study 
enrolled 44 patients with multiple myeloma, chronic lymphocytic leukemia, 
lymphoma, and solid tumors. AR-42 was administered at doses of 20-70 mg/day,  
3-times-per-week for 3 weeks, followed by 7 days off treatment. Another study 
looked at AR-42 plus decitabine (20 mg/m2) in 13 adult patients with relapsed or 
refractory AML. Doses of AR-42 ranging from 10-40 mg/day administered with 
decitabine on days 6-15 were used. To date, a total of 57 patients have been 
treated with AR-42 in these 2 clinical trials. 
Of the 44 patients enrolled in the FIM study, approximately half of the  
treatment-emergent adverse events were considered to be related to  
AR-42 by the study investigator (661 events of a total of 1295 treatment-emergent 
AEs). There were 4 deaths reported within 30 days of AR-42 being discontinued. 
One death in the hematologic cancer group was considered to be related, but the 
other 3 deaths were considered to be unrelated to AR-42. The related death 
occurred at the 50 mg dose during cycle 2 in a patient with cutaneous T-cell 
lymphoma. The patient developed the following AEs: thrombocytopenia (grade 3 
during cycle 1; grade 2 during cycle 2), increased creatinine (grade 2), and 
hypotension (grade 2). AR-42 was held on day 8 of cycle 2. The patient was found 
unresponsive 2 days later, and the investigator considered the event a dose-limiting 
toxicity (DLT). 
Eight serious adverse events (SAEs) were considered to be related to AR-42. The 
SAEs included a psychiatric disorder (grade 4), lung infection (2 events, both grade 
3), a thromboembolic event (grade 3), hematuria (grade 3), increased creatinine 
(grade 1), anemia (grade 3), and decreased platelet count (grade 3). All SAEs were 
reported to be possibly related to AR-42 except for grade 3 thrombocytopenia which 
was reported with probable attribution to AR-42. Both lung infections were seen in 
patients at the 40 mg dose. The psychiatric disorder was seen in a patient at the  
80 mg dose and was considered a DLT. All other SAEs occurred in patients at the 
60 mg dose level, 4 of which occurred in the same patient (hematuria, increased 
creatinine, anemia, and thrombocytopenia). 
QTc interval was also monitored in the FIM study. Seven out of the 27 patients with 
hematologic malignancy had QTc prolongation-related events. All events were 
grade 1 with no significant cardiac toxicities. None of the patients with solid tumors 
experienced prolongation of the QTc interval. 
Three patients died within 30 days of drug being stopped in the study of AR-42 and 
decitabine combination treatment. One of these deaths was considered to be 
related to study medication. A patient with refractory AML developed febrile 
neutropenia (grade 3), dyspnea (grade 2), catheter-related infection (grade 3), 
hypoxia (grade 3), lung infection (grade 3), and gram-negative bacteremia. The 
patient expired from complications of lung infection and pseudomonas sepsis. This 
death, which occurred in cycle 1, was deemed a DLT by the data safety monitoring 
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The most common drug-related AEs were cytopenias (ie, decreased platelet, 
neutrophil, white blood cell, and lymphocyte counts), anemia, fatigue, nausea, and 
diarrhea. 
1.4 Combination of Pazopanib and HDAC Inhibitors 
1.4.1 Mechanisms of Action 
Pazopanib and HDAC inhibitors interact in an additive to a greater than additive 
fashion to kill sarcoma and kidney cancer cells in vitro. In prior studies using the 
multikinase inhibitor sorafenib, Virginia Commonwealth University (VCU) 
investigator Paul Dent, PhD and colleagues have shown that knock down of 
PDGFRβ can stimulate the number of autophagosome vesicles in cells. Pazopanib 
is an inhibitor of PDGFRβ, therefore, Dent hypothesized that autophagy plays a role 
in the survival/killing of pazopanib-treated cells (20, 21). Treatment of HT1080 cells 
with pazopanib + valproate, another HDAC inhibitor, increased the number of  
LC3-GFP and LC3-RFP vesicles, indicating increased autophagy (Figure 1) (22). 
 
Figure 1. Regulation of Autophagy by Pazopanib and Valproate 
HT1080 cells were transfected with a plasmid to express LC3-GFP-RFP. Twenty-four hours after 
transfection cells were treated with vehicle (DMSO), pazopanib (PAZ, 5.0 μM), and/or valproate 
(VAL, 500 μM). Cells were microscopically examined 6 hours and 12 hours after exposure and the 
number of GFP and RFP punctae determined in at least 40 random cells per condition (n=3, ± 
SEM). *P < 0.05 greater than the value at 6 hours (22). 
 


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Chloroquine treatment, which inhibits autophagosome fusion with lysosomes, 
decreased the numbers of LC3-RFP+ vesicles (data not shown). Collectively, these 
data demonstrate that autophagic flux was being stimulated. The multikinase 
inhibitor pazopanib increased the levels of LC3-GFP+ vesicles and in a chloroquine-
dependent and time-dependent manner to a lesser extent LC3-RFP+ vesicles, 
indicating that autophagic flux was occurring. Knock down of either Beclin1 or ATG5 
blocked drug-induced LC3-GFP+/LC3-RFP+ vesicle formation and protected cells 
from the toxic effects of treatment with pazopanib + HDAC inhibitor (Figure 2). 
 
Figure 2. Knockdown of Beclin1 or ATG5 Protects Cells from Pazopanib and Valproate Toxicity 
HT1080 cells were transfected with scrambled control siRNA (siSCR) or siRNA molecules to knock 
down expression of Beclin1 (siB1) or ATG5 (siA5). Thirty-six hours after transfection cells were 
treated with vehicle (DMSO), pazopanib (P, 5.0 μM), and/or valproate (V, 500 μM). Cells were 
isolated 24 hours after exposure and viability determined by trypan blue exclusion (n=3, ± SEM).  
#P < the corresponding value in siSCR cells (22). 
 
Autophagy data using pazopanib, which were similar to our own, were recently 
reported in bladder cancer cells (23). In addition to autophagy, the intrinsic or 
extrinsic apoptosis pathways played a role in cell killing caused by the 
pazopanib/HDAC inhibitor drug combination. Overexpression of the mitochondrial 
protective protein BCL-XL or the caspase 8 inhibitor c-FLIP-s significantly reduce 
drug combination lethality. As caspase 8 appeared to be playing a role in cell death, 
we determined whether death receptor signaling was involved. Knockdown of the 
death receptor CD95 or the death receptor/caspase 8 docking protein FADD also 
significantly reduced cell killing caused by the drug combination. Expression of both 
activated Akt and activated MEK1 was required to strongly suppress drug 
combination lethality. The drug combination inactivated mTOR, and expression of 
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Figure 3. Expression of Activated Akt and MEK1 Suppresses Toxicity of Pazopanib and Valproate 
(A) HT1080 cells were infected (50 minimum effective MOI) with empty vector control virus (CMV) or with 
viruses to express activated MEK1 (caMEK1), activated Akt (caAkt), or caMEK1 and caAkt together. 
Twenty-four hours after infection, cells were treated with vehicle (DMSO), pazopanib (PAZ, 5.0 μM), and 
valproate (VAL, 500 μM). Cells were isolated 24 hours after exposure and viability determined by trypan 
blue exclusion (n=3, ± SEM) #P < the corresponding value in CMV infected cells; ##P < the 
corresponding value in caAkt infected cells. (B) HT1080 cells were transfected with empty vector plasmid 
(CMV), with a plasmid to express activated p70 S6K (ca-p70), with a plasmid to express activated mTOR 
(ca-mTOR), or with both plasmids together. Twenty-four hours after infection, cells were treated with 
vehicle (DMSO), pazopanib (PAZ, 5.0 μM), and valproate (VAL, 500 μM). Cells were isolated 24 hours 
after exposure and viability determined by trypan blue exclusion (n=3, ± SEM) #P < the corresponding 
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1.4.2 Inhibition of Chaperone Protein Function 
In several 2015 studies conducted after publication of the initial pazopanib + HDAC 
inhibitor manuscript, we have shown that pazopanib can alter the tertiary 
conformation of chaperone proteins at their NH2-termini, as judged by occlusion of 
the antibody epitope and using in situ immunofluorescence on native proteins 
(unpublished data). Pazopanib reduced the immunofluorescence detection of 
HSP90, HSP70, and GSP78 using an NH2-terminal-specific antibody but not using 
antibodies directed against epitopes in the middle and COOH-terminal portions of 
the proteins. This altered detection effect was observed in multiple other chaperone 
proteins (Figure 4). AR-42 has also been shown to potentially disrupt heat shock 
protein 90 (HSP90) chaperone function (24). Modulation of HSP protein function has 
been explored as an anticancer therapeutic approach for years, and this approach 
has demonstrated antitumor activity in a variety of malignancies (25). 
 


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Figure 4. Modulation of HSP70 NH2-terminal Detection by Pazopanib 
Upper: GBM12 cells were treated with vehicle or pazopanib (2 µM) for 2 hours. Cells were fixed in place 
and permeabilized using 0.5% Triton X100. Immunofluorescence was performed to detect the expression 
levels of HSP70 using antibodies raised to detect the NH2-terminus; the middle; and COOH terminus of 
the protein. 
Lower: GBM14 and GBM12 cells were treated with vehicle or pazopanib (2 µM) for 2 hours. Cells were 
fixed in place and permeabilized using 0.5% Triton X100. Immunofluorescence was performed to detect 
the expression levels of the indicated chaperone proteins. 
 
 
 
 


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In agreement with the altered ability to detect chaperone NH2-termini, pazopanib (and other 
drugs) inhibited the chaperone ATPase activities of HSP90 and HSP70 (Figure 5). 
 
 
 
 
 
Figure 5. Sildenafil Enhances the ATPase Inhibitory Effects of Regorafenib, Sorafenib, Pazopanib,  
AR-13, and OSU-03012 
A. A GST-HSP90 NH2-terminal fragment containing the ATP-binding domain of the chaperone was 
synthesized in E. coli and purified from other bacterial proteins using glutathione sepharose. The  
GST-HSP90 NH2-terminal fragment protein was not eluted off the sepharose beads. Equal portions of 
beads were immediately aliquoted into individual wells in a 96-well plate. Beads were resuspended in 
kinase reaction buffer containing vehicle control; OSU-03012; sorafenib tosylate; regorafenib; pazopanib; 
AR-13; celecoxib (30 nM; 100 nM; 300 nM; 1 M) in triplicate, and incubated for 30 minutes at 37 oC. The 
reaction was started by addition of ATP-lite substrate. The plate was removed from the incubator and 
placed into a Vector 3 plate reader to determine the luminescence of the reactions under each treatment 
condition (n=3 (x 3) +/- SEM). 
B. and C. GBM12 cells were transfected with a plasmid to express HSP70-GFP or to express FLAG-
tagged HSP90. Twenty-four hours after transfection cells were treated with vehicle control or sildenafil  
(2 M) for 1 hour. Chaperone proteins were immunoprecipitated using their tags in the presence of 
phosphatase inhibitors. Equal portions of precipitate sepharose beads were immediately aliquoted into 
individual wells in a 96-well plate. Beads were resuspended in ATPase reaction buffer containing vehicle 
control; OSU-03012; sorafenib tosylate; regorafenib; pazopanib; AR-13; (30 nM; 100 nM; 300 nM; 1 M) 
in triplicate, and incubated for 30 minutes at 37 oC. The reaction was started by addition of ATP-lite 
substrate. The plate was removed from the incubator and placed into a Vector 3 plate reader to determine 
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In further agreement with pazopanib acting as a chaperone inhibitor, the association of 
chaperone proteins in complexes with other chaperone proteins was disrupted by pazopanib as 
judged after immunoprecipitation of endogenous chaperone proteins (Figure 6). 
 
 
 
Figure 6. Pazopanib Alters Chaperone–Chaperone Interactions Assessed after Immunoprecipitation 
GBM12 cells were treated with vehicle or with pazopanib (2 µM); for 10 minutes and then lysed. 
Immunoprecipitation of HSP90, GRP78, HSP27, and HSP70 was performed in the presence or absence 
of each drug individually (2 µM) for 3 hours. Cells were washed with lysis buffer in the presence or 
absence of each drug individually (3 x 1 hour, each). Immunoprecipitates were then boiled in SDS PAGE 
buffer containing glycerol and bromophenol blue. Proteins were separated on SDS PAGE (12% and 14% 
gels) and immunoblotting performed for the proteins as indicated. 
 


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1.4.3 In Vivo Data 
In vitro findings were translated into an animal model system. At the doses of drug 
used and for the treatment time, neither pazopanib nor valproate caused a large 
reduction in tumor mass. However, treatment of the animals with the drug 
combination resulted in a significantly reduced rate of tumor growth (Figure 7). 
 
 
Figure 7. Pazopanib and Valproate Interact to Suppress the Growth of Established HT1080 
Tumors 
Mice were injected in the rear flank with 1.0 × 107 HT1080 cells in 100 μl of growth medium. 
Fourteen days after tumor cell implantation when tumors had grown to ~50 mm3 (defined as 
1.00 in the graph) mice were PO administered vehicle diluent, pazopanib (25 mg/kg, QD), 
valproate (50 mg/kg BID), or the drugs in combination for 4 days. Animals were monitored daily 
and tumor volumes measured every 7 days. (Values plotted are the fold change in mean tumor 
volume at each time point; ± SEM, 8 mice per treatment condition.) (22) 
 


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1.4.4 Combination of Pazopanib and AR-42 
In multiple sarcoma and kidney cancer cell lines, at clinically achievable doses, 
pazopanib and an HDAC inhibitor (including valproate, vorinostat, and AR-42) 
interacted in an additive to greater than additive fashion to cause tumor cell death 
(Figure 8, Figure 9, Figure 10, and Figure 11). The antitumor effects seen with the 
combination of pazopanib with AR-42 was more pronounced than with the other 
HDAC inhibitors used in laboratory models. 
 
 
Figure 8. AR-42 and Pazopanib (1 µM) Interact to Kill Sarcoma and Kidney Cancer Cells at the  
24-Hour Time Point 
Tumor cells were treated with vehicle (VEH, DMSO), pazopanib (PAZ, 1.0 μM), and/or AR-42  
(600 nM) as indicated. Cells were isolated 24 hours after exposure and viability determined by 
trypan blue exclusion (n=3, ± SEM). 
 


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Figure 9. AR-42 and Pazopanib (1 µM) Interact to Kill Sarcoma and Kidney Cancer Cells at the  
48-Hour Time Point 
Tumor cells were treated with vehicle (VEH, DMSO), pazopanib (PAZ, 1.0 μM), and/or AR-42 
(600 nM) as indicated. Cells were isolated 48 hours after exposure and viability determined by 
trypan blue exclusion (n=3, ± SEM). 


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Figure 10. AR-42 and Pazopanib (2 µM) Interact to Kill Sarcoma and Kidney Cancer Cells at the  
24-Hour Time Point 
Tumor cells were treated with vehicle (VEH, DMSO), pazopanib (PAZ, 2.0 μM) and/or AR-42  
(600 nM) as indicated. Cells were isolated 24 hours after exposure and viability determined by 
trypan blue exclusion (n=3, ± SEM). 
 
 


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Figure 11. AR-42 and Pazopanib (2 µM) Interact to Kill Sarcoma and Kidney Cancer Cells at 
the 48-Hour Time Point 
Tumor cells were treated with vehicle (VEH, DMSO), pazopanib (PAZ, 2.0 μM), and/or AR-42 
(600 nM) as indicated. Cells were isolated 48 hours after exposure and viability determined by 
trypan blue exclusion (n=3, ± SEM). 
1.5 Rationale for the Study 
Most highly active cancer chemotherapy regimens involve multiple agents. Pazopanib is 
an FDA-approved agent for the treatment of both advanced RCC and STS. AR-42 is a 
broad-spectrum inhibitor of HDAC and non-histone protein deacetylation (pan-DAC 
inhibitor) which has also been shown to inhibit Akt by a deacetylation-independent 
mechanism. Preclinical studies in both tumor cell lines and animal tumor models have 
shown promising anticancer effects of the combination of AR-42 and pazopanib suggesting 
that the combination should be tested clinically. Preclinical studies also suggest that these 
promising anticancer effects may be related to modulation of tumor cell autophagy. This 
phase 1 study will identify recommended phase 2 doses (RP2Ds) of AR-42 and pazopanib 
when given in combination for subsequent clinical trials and may potentially identify 
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1.6 Correlative Studies 
Archived tumor samples from the most recent biopsy or surgery will be used to correlate 
expression of CD95 and other cellular proteins of interest with response to AR-42 and 
pazopanib exposure. 
2 OBJECTIVES 
2.1 Primary Objective 
To determine the recommended phase 2 doses (RP2Ds) of AR-42 and pazopanib when 
given in combination 
2.2 Secondary Objectives 
2.2.1 To evaluate the safety and toxicity of AR-42 and pazopanib when given in 
combination 
2.2.2 To explore the antitumor effects of the AR-42 and pazopanib treatment regimen in 
patients with advanced RCC or STS 
2.3 Exploratory Objective 
To correlate expression of CD95 and other cellular proteins of interest with response to 
AR-42 and pazopanib treatment 
3 STUDY DESIGN 
3.1 General Description 
This study is a single-arm, open-label, phase 1 trial to determine the RP2Ds of AR-42 and 
pazopanib when given in combination to patients with advanced RCC or STS. Eligible 
patients will have recurrent, unresectable, or metastatic RCC or STS for which pazopanib 
is an appropriate therapy. 
AR-42 will be taken orally once per day on 3 non-consecutive days each week during the 
first 3 weeks of each 4-week cycle. Pazopanib will be taken by mouth once daily 
continuously during each cycle. 
A modified 3+3 dose-escalation design will be followed until the maximum tolerated doses  
(MTDs) have been determined. Additional patients will be enrolled until a total of 12 
patients have been treated at the MTDs. The maximum number of patients needed is 51 
with an expected sample size of 29-35 patients enrolled over a period of about  
15-35 months. 
Correlative studies will be conducted using samples of tumor that were archived following 
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3.2 Primary Endpoint 
RP2Ds for AR-42 and pazopanib that are the same as or less than the MTDs 
3.3 Secondary Endpoints 
3.3.1 AEs characterized and graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0) to 
determine the safety and toxicity of the combination of AR-42 and pazopanib 
3.3.2 Tumor response based on Response Evaluation Criteria in Solid Tumors Version 
1.1 (RECIST v1.1) 
3.4 Exploratory Endpoint 
Expression of CD95 and other proteins of interest by immunohistochemical (IHC) analysis 
using archived tumor samples from the most recent diagnostic biopsy or surgery 
(performed before initiation of study treatment) correlated with response to study treatment 
4 PATIENT SELECTION 
4.1 Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible for this study. 
4.1.1 Recurrent, unresectable, or metastatic RCC or STS (any histologic type) for which 
pazopanib is an appropriate therapy 
4.1.2 Measurable or evaluable disease by RECIST v1.1 
4.1.3 Age ≥ 18 years 
4.1.4 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1  
(see Appendix 1) 
4.1.5 Adequate bone marrow function as defined below: 
 
Absolute neutrophil count (ANC) ≥ 1200/mm3 
 
Platelets ≥ 120,000/mm3 
 
Hemoglobin ≥ 9.5 g/dL 


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4.1.6 Adequate renal function as defined below: 
 
Creatinine ≤ 1.5 x upper limit of normal (ULN) for the laboratory or calculated or 
actual creatinine clearance ≥ 60 mL/min (see Appendix 2 for the Cockcroft-Gault 
formula for calculating creatinine clearance) 
 
Proteinuria ≤ 2+ [100 mg/dL]) using a random urine sample or < 3.0 gm using a 
24-hour sample) 
Note: If urine sample indicates ≥ 2+ [100 mg/dL]), a 24-hour urine sample must 
be collected and tested; urine protein in the 24-hour sample must be  
< 3.0 gm/24 hours. 
4.1.7 Adequate hepatic function as defined below: 
 
Total bilirubin ≤ 1.5 x ULN for the laboratory 
Note: Patients with known Gilbert’s Syndrome are not eligible for this study 
(Section 4.2.10). 
 
Aspartate aminotransferase (AST) ≤ 2.5 x ULN for the laboratory 
 
Alanine aminotransferase (ALT) ≤ 2.5 x ULN for the laboratory 
4.1.8 Non-hematologic toxicities from previous cancer therapies resolved to ≤ grade 1 
4.1.9 International normalized ratio (INR) ≤ 1.5 
4.1.10 Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN for the laboratory 
4.1.11 Left ventricular ejection fraction (LVEF) assessment (eg, echocardiogram, MUGA 
scan, first-pass technique) performed within 3 months prior to initiation of study 
treatment indicates an LVEF of ≥ 50% 
4.1.12 A woman of childbearing potential (WCBP), defined as a woman who is < 60 years 
of age and has not had a hysterectomy, must have a documented negative serum 
pregnancy test within 7 days prior to initiating study treatment 
4.1.13 A WCBP and a male patient with a partner who is a WCBP must agree to use a 
medically accepted method for preventing pregnancy for the duration of study 
treatment and for 2 months following completion of study treatment 
4.1.14 Ability to understand and willingness to sign the consent form 
4.2 Exclusion Criteria 
A patient who meets any of the following exclusion criteria is not eligible to participate in 
this study. 
4.2.1 Symptomatic or untreated brain metastasis 
4.2.2 Leptomeningeal metastasis 
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4.2.4 Previous therapy with pazopanib 
4.2.5 Inability to swallow medication 
4.2.6 Known or suspected malabsorption condition or obstruction 
4.2.7 Contraindication to antiangiogenic agents, including: 
 
Serious non-healing wound, non-healing ulcer, or bone fracture 
 
Major surgical procedure or significant traumatic injury within 4 weeks prior to 
initiating study treatment; other surgical procedures within 2 weeks prior to 
initiating study treatment 
 
Pulmonary hemorrhage/bleeding event  grade 2 within 12 weeks prior to 
initiating study treatment 
 
Any other hemorrhage/bleeding event  grade 3 within 12 weeks prior to 
initiating study treatment 
4.2.8 History of organ allograft including corneal transplant 
4.2.9 Evidence of bleeding diathesis or coagulopathy 
4.2.10 Documented Gilbert’s Syndrome 
4.2.11 Resting systolic blood pressure (BP) < 100 mmHg 
4.2.12 Hypertension defined as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg 
despite optimal medical management 
4.2.13 QTc interval > 450 ms on screening 12-lead electrocardiogram (ECG) 
 If baseline QTc on screening ECG meets exclusion criteria: 
- 
Check calcium, potassium, and magnesium serum levels. 
- 
Correct any identified hypocalcemia, hypokalemia, and/or hypomagnesemia 
and repeat ECG to confirm exclusion of patient due to prolonged QTc interval. 
 For patients with heart rate (HR) 60-100 bpm, manual read of QTc is not required. 
 For patients with a baseline HR < 60 bpm or > 100 bpm, manual read of the QT 
interval by a cardiologist is required, with Fridericia correction applied to determine 
QTc (ie, QTcF). 
4.2.14 Active or clinically significant cardiac disease including any of the following: 
 
Unstable angina (eg, anginal symptoms at rest) or onset of angina within  
3 months prior to initiating study treatment 
 
Myocardial infarction within 6 months prior to initiating study treatment 
 
Cardiac arrhythmias currently requiring anti-arrhythmic therapy other than beta 
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4.2.15 Any documented history of clinically significant thrombotic, embolic, venous, or 
arterial events, such as cerebrovascular accident, transient ischemic attack, deep 
vein thrombosis, or pulmonary embolism necessitating therapeutic anticoagulation 
within 6 months prior to initiating study treatment 
Note: Patients with a tumor-associated thrombus of locally-involved vessels should 
not be excluded from participating in the study. 
4.2.16 Active infection requiring treatment or chronic infection requiring suppressive 
therapy 
4.2.17 Chronic or active hepatitis B or C infection requiring treatment with antiviral therapy 
4.2.18 Pleural effusion or ascites that causes respiratory compromise (eg, ≥ grade 2 
dyspnea) 
4.2.19 Required ongoing treatment with other drugs thought to potentially have adverse 
interactions with either of the medications included in the study treatment; if such 
medications have been used, patients must have discontinued these agents at least 
1 week prior to initiating study treatment. Examples include: 
 
Strong CYP3A4 inhibitors and/or strong CYP3A4 inducers; the reference list of 
CYP isozymes and classification of strong, moderate, and weak interactions are 
available through the FDA website, Tables 5 and 6: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/DrugInteractionsLabeling/ucm093664.htm 
 
Strong inhibitors of P-glycoprotein (P-gp) and/or breast cancer resistance 
protein (BCRP); the reference list of strong inhibitors of P-gp and BCRP is 
available through the FDA website, Table 9: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/DrugInteractionsLabeling/ucm093664.htm 
 
Simvastatin and other HMG-CoA reductase inhibitors (ie, statins) 
 
Drugs that raise gastric pH including proton pump inhibitors and H2-blockers 
Note: Short-acting antacids, in place of PPIs and H2-blockers, are permitted. 
 
HDAC inhibitors 
4.2.20 Pregnancy or breastfeeding 
4.2.21 Medical, psychological, or social condition that, in the opinion of the investigator, 
may increase the patient’s risk or limit the patient’s adherence with study 
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5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 Study Entry Procedures 
5.1.1 Required Pre-Registration Screening Tests and Procedures 
Refer to the study calendar (Section 12) for the screening tests and procedures that 
are required prior to registration and/or treatment and for the timing of these events 
relative to the start of treatment. 
5.1.2 Registration Process 
To register a patient, the study team will provide the following items to the registrar 
at VCU Massey Cancer Center 
 
 Completed registration cover sheet 
 Completed, signed, and dated eligibility checklist 
 Signed and dated consent form 
The registrar will complete the registration process by assigning a study 
identification (ID) number and forwarding the “Confirmation of Registration” form to 
the registering study team. 
Study treatment may not begin until the Confirmation of Registration assigning a 
study ID number has been received from the registrar. The registering study team 
will enter the patient’s initial enrollment data (eg, demographics, consent, eligibility, 
on-study, treatment assignment) into the OnCore database within 24 hours of 
registration (before study treatment begins). 
5.2 Study Withdrawal 
A patient may decide to withdraw from study participation at any time. Patients must be 
withdrawn from the study when any of the following occurs: 
 
Unacceptable toxicity defined as toxicity that requires holding one or both of the study 
medications for more than 21 consecutive days 
 
Consent withdrawal for study treatment and study procedures 
 
If, in the investigator's opinion, continuation of the study requirements would be harmful 
to the patient's well-being 
 
Patient is lost to follow-up 
The reason for and date associated with study withdrawal or removal from the study must 
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6 TREATMENT PLAN 
6.1 Baseline Tests and Procedures 
Patients who are eligible and enrolled in the study but do not immediately initiate study 
treatment are expected to meet eligibility criteria until the time when treatment is initiated. 
For example, if an enrolled patient’s post-enrollment (pre-treatment) liver function tests no 
longer meet eligibility criteria, treatment should be held until the investigator can provide 
guidance to the study team. 
6.2 Administration of Study Treatment 
6.2.1 AR-42 Administration and Treatment Schedule 
 
AR-42 tablets will be taken orally once per day on 3 non-consecutive days per 
week (eg, Monday, Wednesday, and Friday) during the first 3 weeks of each  
4-week cycle (ie, a total of 9 doses). A 7-day “AR-42 rest period” during which 
AR-42 will not be taken is required at the end of each cycle (ie, AR-42 will not be 
taken by the patient during week 4 of each 4-week cycle). 
 
If treatment must be interrupted during the cycle, the cycle may be extended to a 
maximum of 5 weeks. If the cycle has been extended to 5 weeks, all doses of 
AR-42 (ie, a total of 9 doses) must be taken during the first 4 weeks of the 
extended cycle (ie, if the cycle was extended, AR-42 will not be taken by the 
patient during week 5 of the 5-week cycle). 
 
Patients will be instructed as follows: 
 
Take AR-42 once per day on 3 non-consecutive days during the first 3 
weeks of each 4-week cycle. 
 
Take AR-42 tablets with water on an empty stomach, ideally the first thing in 
the morning at least 1 hour before breakfast. If necessary, doses can be 
taken at least 1 hour before or at least 2 hours following any meal. 
 
Swallow the AR-42 tablets whole. 
6.2.2 Pazopanib Administration and Treatment Schedule 
 
Pazopanib tablets will be taken orally once daily continuously during each  
treatment cycle. There are no scheduled breaks in pazopanib therapy. 
 
Patients will be instructed as follows: 
 
Take pazopanib once daily during each 4-week cycle 
 
Take pazopanib tablets with water on an empty stomach, ideally the first 
thing in the morning at least 1 hour before breakfast. If necessary, doses can 
be taken at least 1 hour before or at least 2 hours following any meal. 
 
Swallow the pazopanib tablets whole. 


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6.3 Missed Doses 
6.3.1 AR-42 Missed Doses 
If an AR-42 dose is missed, the missed dose of AR-42 should be taken on the same 
day, as soon as the patient remembers. If the missed dose cannot be taken on the 
scheduled day, the patient should take the dose on the next day and adjust the 
schedule by one day (eg, from Monday, Wednesday, and Friday to Tuesday, 
Thursday, and Saturday) for the remainder of that cycle. The usual schedule should 
be resumed at the beginning of the next cycle as long as there has been a 7-day 
rest period. 
6.3.2 Pazopanib Missed Doses 
If a pazopanib dose of pazopanib is missed, the missed dose of pazopanib should 
be taken on the same day, as soon as the patient remembers. Two doses of 
pazopanib should not be taken on the same day to make up for doses that were 
missed on the previous day. 
6.4 Monitoring Patient Compliance 
Patients will be instructed to record the AR-42 and pazopanib doses they have taken on 
the study medication diary that will be provided. Also, patients will be instructed to bring 
their diary and any unused supply of AR-42 and pazopanib to each visit with their study 
team. 
Patient reports of self-administration, review of the study medication diary, and pill counts 
will be used to assess the patient’s compliance with the oral study treatment regimen. 
6.5 Duration of Therapy 
Treatment will continue until any of the following occurs (also see information regarding 
study withdrawal in Section 5.2): 
 
Interruption in either of the study medications due to unresolved toxicity for a period of 
more than 21 consecutive days 
 
AE that requires discontinuation of both study medications (see Section 7) 
 
Disease progression 
 
Patient decision to discontinue study treatment 
 
Investigator determination that discontinuation is in the patient’s best medical interest 
 
Withdrawal of study sponsor support 


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6.6 AR-42 and Pazopanib Dose-Escalation Plan 
The dose-escalation plan is based on the available dose levels listed on Table 1, the dose 
level instructions outlined on Table 2, and the modified 3+3 design on Table 3. 
 
The initial cohort of patients will be assigned to an AR-42 dose of 20 mg taken once 
per day on 3 non-consecutive days during the first 3 weeks of each 4-week cycle and a 
pazopanib dose of 600 mg once daily continuously. 
 
The treatment schedule as described in Section 6.2 will remain the same for all dose 
levels. 
 
The initial escalation will only affect the pazopanib dose so that the  
FDA-approved full dose of pazopanib (800 mg) is provided early in the dose-escalation 
plan. In subsequent dose-escalation steps, the dose of AR-42 will be increased in  
10-mg increments until the maximum AR-42 dose of 40 mg is reached. 
 
If the number of DLTs indicates that the MTD has been exceeded with a pazopanib 
dose of 800 mg, the pazopanib dose will be decreased to 600 mg and the AR-42 dose 
will continue to increase in 10-mg increments regardless of relationship of the DLT to 
one or both study medications. 
Table 1. AR-42 and Pazopanib Dose Levels 
AR-42 Dose 
 40 mg 
4B 
4A 
 30 mg 
3B 
3A 
 20 mg 
1 
(Starting Dose Level) 
2 
 10 mg 
-1 
N/A 
 
600 mg 
800 mg 
Pazopanib Dose 


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Table 2. AR-42 and Pazopanib Dose-Escalation Guidelines 
Dose Level 
AR-42 Dose 
(Taken orally) 
Pazopanib Dose 
(Taken orally) 
Once per day on  
3 non-consecutive days/week 
during the first 3 weeks of 
each 4-week cycle 
Once per day continuously  
during each 4-week cycle 
-1 
10 mg  
600 mg  
 If 0 or 1 DLT is observed with Dose Level -1, the MTD will be Dose Level -1. 
 If ≥ 2 DLTs are observed at Dose Level -1, the lowest possible dose level was not 
tolerated. 
1 
(Starting 
Dose Level) 
20 mg  
600 mg  
 If 0 or 1 DLT is observed with Dose Level 1, the next cohort will receive Dose Level 2. 
 If ≥ 2 DLTs are observed at Dose Level 1, the next cohort will receive Dose Level -1. 
2 
20 mg  
800 mg  
 If 0 or 1 DLT is observed with Dose Level 2, the next cohort will receive Dose Level 3A. 
 If ≥ 2 DLTs are observed at Dose Level 2, the next cohort will receive Dose Level 3B. 
3A 
30 mg  
800 mg  
3B 
30 mg  
600 mg  
 If 0 or 1 DLT is observed with Dose Level 3A, the next cohort will receive Dose Level 4A. 
 If ≥ 2 DLTs are observed at Dose Level 3A, the next cohort will receive Dose Level 3B. 
 If 0 or 1 DLT is observed with Dose Level 3B, the next cohort will receive Dose Level 4B. 
 If ≥ 2 DLTs are observed at Dose Level 3B, the highest dose level without ≥ 2 DLTs will 
be the MTD. 
4A 
40 mg  
800 mg  
4B 
40 mg  
600 mg  
 If 0 or 1 DLT is observed with Dose Level 4A, the MTD will be Dose Level 4A. 
 If ≥ 2 DLTs are observed at Dose Level 4A, the next cohort will receive Dose Level 4B. 
 If 0 or 1 DLT is observed with Dose Level 4B, the MTD will be Dose Level 4B. 
 If ≥ 2 DLTs are observed at Dose Level 4B, the MTD will be the highest dose level 
without ≥ 2 DLTs. 


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6.7 Definitions of Dose-Limiting Toxicity, Maximum Tolerated Dose, and Recommended 
Phase 2 Dose 
6.7.1 DLT-Evaluable Criteria 
The DLT evaluation period will be the first treatment cycle. Patients must have taken 
a minimum of 6 AR-42 doses and a minimum of 21 pazopanib doses during cycle 1 
to be considered evaluable for DLT, if DLT has not been observed at the delivered 
dose. 
6.7.2 DLT Definition 
DLT is defined as any ≥ grade 3 toxicity occurring during the DLT evaluation period 
and attributed to one or both of the study medications EXCEPT the following: 
 
The first incidence of grade 3 PPE at any dose level (subsequent incidences of 
grade 3 PPE will be considered DLT) 
 
Grade 3 nausea and vomiting in the absence of adequate prophylaxis and/or 
responsive to medical management within 48 hours 
 
Grade 3 diarrhea in the absence of adequate prophylaxis and/or responsive to 
medical management within 48 hours 
 
Grade 3 fatigue responsive to medical management 
 
Grade 3 asymptomatic hypertension lasting ≤ 7 days 
 
Grade 3 electrolyte abnormalities that are corrected within 48 hours and, when 
corrected, can be maintained 
 
Grade 3 asymptomatic lipase elevation lasting ≤ 7 days 
 
Grade 3 decrease in platelet count if no clinically significant hemorrhage has 
occurred 
 
Grades 3 and 4 decrease in white blood cell count 
 
Grade 3 decrease in neutrophil count 
 
Grade 4 decrease in neutrophil count lasting ≤ 7 days 
 
Grades 3 and 4 decrease in lymphocyte count 
6.7.3 MTD 
Dose escalation will follow a modified 3+3 plan (Table 3) using the dose levels listed 
in Table 1 and the guidelines in Table 2 to determine the MTDs and the RP2Ds for 
AR-42 and pazopanib. DLT is defined in Section 6.7.2. Patients will be enrolled in 
cohorts of 3 beginning at dose level 1. 


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Table 3. Modified 3+3 Dose Escalation  
Number of Patients with 
DLT at a Given Dose Level 
(Refer to Section 6.7.2 for  
DLT definition) 
Escalation Decision Rule 
(Refer to Table 1 in Section 6.6 for dose levels and Table 2 
for dose-escalation guidelines) 
0 out of 3  
Enroll 3 patients at the next dose level. 
≥ 2A  
MTD has been exceeded. No further treatment at this dose 
is allowed. Three (3) additional patients will be enrolled per 
dose levels as noted on Table 2.  
1 out of 3A 
Enroll at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, escalate doses 
to the next dose level (unless MTD has already been 
exceeded at that dose level, in which case, the current 
dose level is the MTD).B 
 If 1 or more of this group experience DLT (total of 2), 
then the MTD has been exceeded. Three (3) additional 
patients will be enrolled at the next lower dose level if 
only 3 patients were treated previously at that dose.B 
Patients enrolled to complete a total enrollment of 12 at the MTD 
≤ 3  
The MTD has been confirmed.B 
≥ 4  
The MTD has been exceeded; 3 additional patients will be 
enrolled at the next lower dose level (if available).B 
A. The first incidence of grade 3 PPE at any dose level will NOT be considered a DLT. 
(Subsequent incidences of grade 3 PPE will be considered DLT.) 
B. Confirmation that a dose level does not exceed the MTD requires evaluation of a 
minimum of 6 DLT-evaluable patients. To confirm the RP2Ds, additional patients will 
be enrolled at the MTDs until a total of 12 patients have been treated at the MTDs. 
 
6.7.4 RP2D 
The RP2D may be equal to, but may not exceed, the MTD. A RP2D below the MTD 
may be considered given the overall tolerability of the treatment regimen including 
the frequency of AEs that are not DLTs and the frequency of dose modifications. 


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6.8 Required QT Monitoring and QT Interval Prolongation Instructions 
6.8.1 Monitoring 
 
A 12-lead ECG and evaluation of QTc interval will be performed weekly in  
cycle 1, on day 1 of cycle 2, and then on day 1 of every other cycle. 
 
If the QTc is ≥ grade 2, follow instructions in Table 7 for additional observation 
and/or ECG requirements. 
 
If medically indicated, ECGs may be performed any time during treatment and 
follow-up. 
6.8.2 Requirements for Manual Read of QTc Interval 
Any time QTc is evaluated: 
 
If the HR is < 60 bpm or >100 bpm, manual read of the QT interval by a 
cardiologist is required; also the Fridericia formula for QT interval correction 
should be used (ie, QTcF). 
 
If HR is between 60-100 bpm, a manual read of QTc is NOT required. 
Any questions or concerns about ECG readings will be reviewed with a cardiologist. 
6.8.3 Concurrent Use of Drugs Known to Cause Clinically Significant QT Prolongation 
To the extent possible, concurrent use of study medications with drugs known to 
cause clinically significant QT prolongation should be avoided. Such drugs may be 
identified at the Credible Meds website (http://crediblemeds.org/login). The Credible 
Meds website requires free user registration to view the list of clinically relevant  
QT-prolonging drugs, eg, those known to carry a risk of causing Torsade de pointes. 
QT-prolonging drugs to be avoided during this trial are shown in the Credible Meds 
list of “drugs with known TdP risk.” 
When concurrent use of study treatment with any drug on the Credible Meds list of 
“drugs with known TdP risk” cannot be avoided, review QTc prior to concurrent use. 
If, prior to concurrent use, the QTc is: 
 
Grade 0 (< 450 ms), follow-up QTc evaluation should be performed at the next 
follow-up visit. 
 
Grade 1 (450-480 ms), follow-up QTc evaluation should be done within 8 days 
after concurrent use starts. 
 
Grade 2 (481-500 ms), hold study treatment until follow-up ECG at next possible 
opportunity shows QTc ≤ grade 1 (≤ 480 ms); evaluate QTc within 8 days after 
reintroduction of study treatment. 
6.8.4 Any new onset of dysrhythmia on ECG during treatment will be reviewed and 
managed with input from cardiology. 


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6.8.5 Follow instructions in Table 7 for any episode of syncope (grade 3) or  
near-syncope (pre-syncope grade 2) or QTc grade 3 (≥ 501 ms on 2 or more ECGs), 
or grade 4 (≥ 501 ms or > 60 ms change from baseline and Torsade de pointes or 
polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia). 
6.9 General Concomitant Medication and Supportive Care Guidelines 
6.9.1 Nausea/Vomiting 
Anti-emetics should be prescribed as clinically indicated. 
6.9.2 Diarrhea 
Diarrhea, a common side effect of pazopanib and AR-42, can be managed with 
loperamide. The recommended dose of loperamide is 4 mg at first onset, followed 
by 2 mg every 2 to 4 hours until diarrhea-free for 12 hours. Clinically significant 
diarrhea should be managed aggressively to prevent electrolyte abnormalities and 
dehydration. Anti-diarrheal prophylaxis should be considered in subsequent cycles. 
6.9.3 Fluid and Electrolyte Replacement 
 
Patients who develop nausea, vomiting, diarrhea, mucositis, anorexia, or other 
toxicity that can contribute to fluid loss or inadequate fluid intake should be 
carefully monitored. Fluids should be administered, as indicated, to prevent 
and/or treat dehydration and to minimize the risk of postural hypotension and 
renal failure. 
 
To reduce the risk for prolongation of the QT interval, electrolyte levels  
(ie, potassium, magnesium, and calcium) should be checked according to the 
requirements on the study calendar (Table 19 and Table 20). Replacement of 
electrolytes, if needed, is at the investigator’s discretion. Recheck serum 
potassium, magnesium, and calcium levels after replacement and consider 
chronic supplementation of potassium, magnesium, and/or calcium. 
6.9.4 Palmar-plantar Erythrodysesthesia 
PPE, also known as hand-foot skin reaction, has been reported in patients taking 
pazopanib. Biopsy specimens of patients with PPE secondary to tyrosine kinase 
inhibition show hyperkeratosis, keratinocyte necrosis, and dermal inflammation. In 
240 patients with STS, about 11% of patients who received pazopanib experienced 
PPE compared to 1% taking placebo. 
PPE, associated with pain and limitations in activities of daily living (ADL), may 
require treatment interruption and/or dose modification. Pazopanib dose 
modification instructions for PPE are provided in Table 9. 


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6.9.4.1 PPE Prevention 
 
Before initiating pazopanib treatment, check the condition of the 
patient’s hands and feet. Suggest a manicure/pedicure, when indicated. 
Recommend use of a pumice stone for callus or rough spot removal. 
During pazopanib treatment, instruct patients to avoid pressure points 
and items that rub, pinch, or create friction. 
 
Instruct the patient to apply moisturizing lotions to their hands and feet 
twice each day throughout treatment. 
6.9.4.2 PPE Treatment 
Treatment may begin at the first clinical signs of PPE. At first occurrence, 
independent of grade, supportive measures should be promptly initiated. 
 
Instruct the patient to protect tender areas as follows: 
- 
Use socks/gloves to cover moisturizing creams 
- 
Wear well-padded footwear; use insole cushions or inserts. 
- 
Soak feet in tepid water and Epson salts. 
 
Creams may be used as follows: 
- 
Non-urea-based creams may be applied liberally. 
- 
Keratolytic creams (eg, urea-based creams, salicylic acid 6%) may 
be used sparingly and only to affected (hyperkeratotic) areas. 
- 
Alpha hydroxyl acids (AHA)-based creams may be applied liberally 
twice each day. Approximately 5% to 8% strength provides gentle 
chemical exfoliation. 
- 
Topical analgesics (eg, lidocaine 2%) may be used for pain control. 
- 
Topical corticosteroids (eg, clobetasol 0.05%) should be considered 
for patients with grade 2 or grade 3 PPE. Systemic steroids should 
be avoided. 
 
Use of Celecoxib 
A meta-analysis of PPE prevention strategies concluded, with 
statistically significant results, that celecoxib was the most promising 
agent (26). Therefore, to reduce the severity of pazopanib-related PPE, 
celecoxib is recommended as follows: 
- 
Celecoxib 200 mg once daily may begin at the first clinical signs or 
symptoms of grade 2 PPE. 
- 
When PPE resolves, celecoxib 200 mg once daily throughout each 
treatment cycle, even in the absence of signs or symptoms of PPE, 
is recommended. 


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6.9.5 Hypertension 
Hypertension, including hypertensive crisis, has been observed during pazopanib 
therapy. Hypertension should be managed aggressively to prevent complications. 
Management of hypertension is at the investigator’s discretion. 
 
BP will be monitored weekly during the first 6 weeks of study treatment, at the 
beginning of every cycle beginning with cycle 3, and as clinically indicated 
throughout study treatment. 
 
Refer to Table 7 for grading definitions to be used for pazopanib dose 
modifications related to hypertension and for treatment instructions. CTCAE v4.0 
will be used to grade hypertension for AE reporting purposes. 
Note: Grade 3 hypertension will not be considered a DLT unless the patient is 
experiencing symptoms of hypertension and/or grade 3 hypertension persisted 
longer than 7 days. This guideline also applies to hypertension requiring an 
additional antihypertensive agent(s). 
6.9.6 Anemia 
Tranfusions, if necessary per the investigator, are permitted. 
6.10 Prohibited/Discouraged Medications 
 
Cancer treatment, other than the treatment specified in the protocol, is not permitted. 
 
Non-prescription nutritional and dietary supplements are discouraged but not prohibited 
unless the supplement is known to interact with or modulate drug metabolism 
pathways, eg, St. John’s wort. Supplements known to have adverse effects on the 
liver are prohibited. If nutritional and/or dietary supplements are used, the dose and 
schedule of the supplements should be documented. 
 
Hepatotoxicity is a known toxicity of pazopanib. Concomitant use of pazopanib and 
simvastatin increases the incidence of ALT elevations and should be avoided. Also, 
acetaminophen may confound interpretation of hepatotoxicity and should, therefore, be 
avoided when possible. 
 
Drugs and other substances that inhibit or induce cytochrome P450 3A enzymes. 
Refer to Section 4.2.19 for additional information regarding prohibited or discouraged 
medications. If such medications have been used, the patient must have discontinued 
these agents ≥ 1 week before starting/resuming pazopanib. 
 
Coadministration of pazopanib with strong inhibitors of CYP3A4  
(eg, ketoconazole, ritonavir, clarithromycin) should be avoided. 
 
Coadministration of CYP3A4 inducers (eg, rifampin) may decrease plasma 
pazopanib concentrations and should be avoided. 
 
Grapefruit and grapefruit juice should be avoided. 
 
Concomitant treatment with strong inhibitors of P-gp or BCRP should be avoided due 
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 
Concomitant use of pazopanib with drugs that raise gastric pH should be avoided. If 
such drugs are needed, short-acting antacids should be considered in place of proton 
pump inhibitors and H2-receptor antagonists. The antacid and pazopanib dosing 
should be separated by several hours to avoid a reduction in pazopanib exposure. 
6.11 Study Pocket Card for Patients 
A pocket card identifying the name of the study, the names of the study medications, and 
contact information including the study team and a 24-hour on-call study physician will be 
provided to each patient. The purpose of this card is to facilitate communication between 
the study team and the patient’s health care providers not involved with the study. Patients 
will be encouraged to carry the card with them at all times and to show it to their health 
care providers so that potential interactions with the study medications can be identified 
before initiating new medications. 
6.12 Elective Surgery During Study Participation 
Both study medications should be held at least 2 weeks prior to scheduled surgery. Any 
plans for elective surgery should be discussed with the Sponsor-Investigator. 
6.13 Follow-Up Period 
Patients who discontinue treatment for any reason other than consent withdrawal 
remain on study in follow-up status for a 30-day evaluation period following the last dose of 
both study medications. During this 30-day post-treatment period, resolution or stabilization 
of ongoing treatment-related AEs and evolution of new treatment-related AEs will be 
reported. Additionally, if the patient has not had tumor progression, tumor response 
assessments performed during this 30-day follow-up period will also be reported. 
Patients are off the study at the end of the 30-day follow-up period or when subsequent 
anticancer therapy begins, whichever occurs first. The primary reason(s) for a patient’s 
discontinuation of study treatment and the patient’s follow-up status will be recorded in the 
source documents and the CRFs. 
7 DOSING DELAYS/DOSING MODIFICATIONS 
7.1 Recording Dose Modifications 
All dosing interruptions and modifications will be recorded in the source documents and 
captured in the OnCore database. 
7.2 Toxicity Assessment 
Dose reduction should be limited to management of toxicity related to study treatment and 
not for management of side effects determined by the investigator to be related to 
underlying disease or other medical condition or concomitant treatment. 


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If a patient experiences more than one toxicity: 
 
Dose reduction should be according to the instructions for the toxicity with the 
higher(est) grade. 
 
In the case of 2 or more toxicities of the same grade, the investigator may dose reduce 
according to the toxicity determined to be the most likely to be related to study 
treatment. 
7.3 Toxicity Grading 
AEs will be characterized and graded according to NCI CTCAE v4.0. 
7.4 General Instructions and Guidelines 
 
If treatment delays are required, the cycle may be extended to 5 weeks; however, all 
AR-42 doses must be taken during the first 4 weeks of the 5-week cycle. Any doses 
not given within the first 4 weeks of the extended cycle will be omitted. 
 
If one or both of the study medications are held due to toxicity, a maximum of 3 
consecutive weeks is permitted for recovery. If recovery has not been sufficient to 
resume treatment 3 consecutive weeks after the decision to hold either or both of the 
study medications, both study medications must be discontinued. 
 
If AR-42 treatment must be interrupted for an AR-42-related toxicity, the patient should 
continue taking pazopanib unless dose modification instructions specifically indicate 
that pazopanib should be held or omitted. 
 
If pazopanib treatment must be interrupted due to a pazopanib-related toxicity, the 
patient should continue taking AR-42 unless dose modification instructions specifically 
indicate that AR-42 should be held or omitted.. 
7.5 AR-42 Dose Reduction Guidelines 
7.5.1 Dose Reduction Steps for AR-42 
AR-42 dose modifications, when required, will follow the predefined dose reduction 
steps outlined in Table 4. 


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Table 4. AR-42 Dose Reduction Steps for Toxicity Management 
Dose 
Reduction 
Step 
Reduced AR-42 Dose*  
When Starting 
Dose is 10 mg 
When Starting 
Dose is 20 mg 
When Starting 
Dose is 30 mg 
When Starting 
Dose is 40 mg 
- 1 
Discontinue  
AR-42 
10 mg 
20 mg 
30 mg 
- 2 
Not Applicable 
Discontinue  
AR-42 
10 mg 
20 mg 
- 3 
Not Applicable 
Discontinue  
AR-42 
10 mg 
- 4 
Not Applicable 
Discontinue 
AR-42 
*The AR-42 dose indicated on this table should be taken according to the same 
instructions and schedule outlined in Section 6.2.1. 
 
7.5.2 Dose Modification Instructions for AR-42 
In addition to the general dose modification instructions provided in Section 7.4, and 
the dose reduction steps listed on the table above, dose modification instructions for 
specific toxicities related to AR-42 are listed in Table 5. 
Note: Some pazopanib-related toxicities may result in medical reasons to also hold, 
omit, or discontinue AR-42. When AR-42 modification/discontinuation is also 
required, the pazopanib dose modification tables (Table 7, Table 8, Table 9, and 
Table 10) will also specify the required AR-42 modification. 
 


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Table 5. AR-42 Dose Modification Instructions  
Grade (CTCAE v4.0) 
AR-42 Modification 
(Refer to Table 4 for AR-42 dose reduction steps) 
Blood and Lymphatic System Disorders 
Grade 3 or 4 anemia 
Hold/omitA AR-42 until resolution to ≤ grade 2; 
transfusions are permitted. 
Grade 3 or 4 febrile neutropenia 
Hold/omitA until resolved; reduce dose by one dose 
reduction step when resuming treatment.B 
Infections and Infestations 
Grade 3 infection 
Hold/omitA until recovered to ≤ grade 2; at the 
investigator’s discretion, the dose may be reduced by 
one dose reduction step when resuming treatment.B 
Grade 4 infection  
Hold/omitA until recovered to ≤ grade 2; reduce dose by 
one dose reduction step when resuming treatment. At 
the investigator’s discretion, study treatment may be 
discontinued. 
Investigations 
Grade 3 or 4 ECG QTc interval prolonged 
Refer to Table 7 for instructions. 
Grade 3 neutrophil count decreased; 
required ≤ 7 days for recovery to ≤ grade 2 
Hold/omitA until ≤ grade 2. Dose reduction is not 
required when resuming treatment. 
Grade 3 neutrophil count decreased; > 7 
days required for recovery to ≤ grade 2 
Hold/omitA until ≤ grade 2; reduce dose by one dose 
reduction step when resuming treatment. 
Grade 4 neutrophil count decreased 
Grade 3 platelet count decreased;  
≤ 7 days required for recovery to ≤ grade 2 
Hold/omitA until ≤ grade 2. Dose reduction is not 
required when resuming treatment. 
Grade 3 platelet count decreased;  
> 7 days required for recovery to ≤ grade 2 
Hold/omitA until ≤ grade 2; reduce dose by one dose 
reduction step when resuming treatment. 
Grade 4 platelet count decreased 
Nervous System Disorders 
Grade 2 pre-syncope or grade 3 syncope 
(potentially reflecting cardiotoxicity) 
Refer to Table 7 for instructions. 
Other Toxicities Possibly Related to AR-42 (see footnote c) 
Grade 2 toxicity that is persistent, 
intolerable, or unresponsive to optimal 
management 
At the investigator’s discretion, reduce  
AR-42 by one dose reduction step.B 
Grade 3 toxicity 
Hold/omitA until resolution to ≤ grade 1, baseline, or 
tolerable grade 2; reduce dose by one dose reduction 
step when resuming treatment.B 
Grade 4 toxicity 
Discontinue study treatment. 
A. If recovery takes longer than the first 4 weeks of the cycle, any remaining doses are omitted. 
B. At the investigator’s discretion (after the DLT evaluation period [Section 6.7.1]), the dose may be 
escalated to the most recent dose taken by the patient when treatment resumes. 
C. Excludes alopecia, nausea and vomiting that improve with antiemetic therapy, lymphopenia, and 
other lab abnormalities that are asymptomatic and/or not clinically significant per investigator. 


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7.6 Pazopanib Dose Reduction Guidelines 
Treatment with pazopanib will be interrupted and/or the dose reduced for clinically 
significant toxicities that are related to pazopanib therapy. Dose modifications will follow 
predefined dose reduction steps according to the guidelines shown on the table below. 
Table 6. Pazopanib Dose Reduction Steps for Toxicity Management 
Dose 
Reduction 
Step 
Reduced Pazopanib Dose 
When Starting Dose is  
600 mg 
When Starting Dose is  
800 mg 
- 1 
400 mg 
600 mg 
- 2 
200 mg 
400 mg 
- 3 
Discontinue pazopanib 
200 mg 
- 4 
Not Applicable 
Discontinue pazopanib 
*The pazopanib dose indicated on this table should be taken according to the 
same instructions and schedule outlined in Section 6.2.2. 
 
7.7 Pazopanib Dose Modification Instructions 
In addition to the general dose modification instructions provided in Section 7.4, dose 
modification instructions for pazopanib-related toxicities are listed in Table 7,  
Table 8 (liver function abnormalities), Table 9 (PPE), and Table 10 (Other). 
Note: For some toxicities, AR-42 instructions are also included on the tables listed above. 


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Table 7. Pazopanib Dose Modification Instructions 
Toxicity 
Pazopanib Modification 
(Refer to Table 6 for pazopanib dose reduction steps) 
Cardiac 
Grade 2 heart failure 
Hold/omitA pazopanib and determine LVEF. 
 If < 15% absolute decline in LVEF compared with baseline or a 
decline in LVEF of < 10% compared with baseline and ≥ 50%: 
- When symptoms of heart failure show clinical improvement, resume 
pazopanib with reduction in dose of one dose reduction step.B 
 If ≥ 15% absolute decline in LVEF compared with baseline or a 
decline in LVEF of ≥ 10% compared with baseline and < 50%: 
- Continue holding until clinical improvement in symptoms and until 
LVEF improves to within 10% of baseline. 
- Refer patient for cardiology consult. 
- Reduce pazopanib dose by one dose reduction step when 
resuming treatment.B 
- At investigator’s discretion, pazopanib may be discontinued. 
Grade 3 or 4 heart failure 
Discontinue pazopanib (also discontinue AR-42). 
Grade 3 or 4 MI 
Discontinue pazopanib (also discontinue AR-42). 
Endocrine Disorders 
Grade 2 hypothyroidism 
Continue pazopanib (dose reduction not required); initiate 
hypothyroidism management.  
Grade 3 or 4 hypothyroidism 
Discontinue pazopanib; initiate/continue hypothyroidism management. 
Gastrointestinal Disorders 
≥ Grade 1 fistula 
Discontinue pazopanib (also discontinue AR-42). 
≥ Grade 2 perforation  
Investigations 
Grade 3 ECG QTc interval 
prolonged 
 
See Section 6.8 for 
additional instructions 
regarding QT monitoring. 
Hold/omitA pazopanib and AR-42. 
 Check potassium, magnesium, and calcium levels; immediately 
administer potassium, magnesium, and/or calcium to achieve 
potassium level of ≥ 4 mEq, magnesium level of ≥ 2 mEq, and 
calcium WNL. 
 Consider chronic supplementation for maintenance of electrolytes. 
 Review with investigator prior to patient’s next scheduled treatment, 
considering the following: 
- Hold pazopanib and AR-42 until QTc recovers to pre-study 
treatment baseline (≤ grade 1 [≤ 480ms]). 
- When QTc returns to baseline, resume pazopanib and AR-42 with 
additional QTc monitoring at earliest opportunity within 8 days after 
resuming study treatment. 
- If QTc prolongation is thought to be related to pazopanib, decrease 
pazopanib and AR-42 doses by one dose reduction step when 
resuming study treatment. 
 For recurrent grade 3 QTc thought to be related to pazopanib and/or 
AR-42 despite dose reduction, discontinue pazopanib and AR-42. 
Grade 4 ECG QTc interval 
prolonged 
Discontinue pazopanib (also discontinue AR-42). 
Elevation in AST, ALT, 
and/or bilirubin 
Refer to Table 8. 


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Table 7. Pazopanib Dose Modification Instructions (continued) 
Nervous System Disorders 
≥ Grade 2  
Reversible Posterior 
Leukoencephalopathy 
Syndrome (RPLS)  
 
An evaluation for RPLS should be performed if the patient presents 
with seizures, headache (in conjunction with other RPLS 
symptoms), visual disturbances, confusion, or altered mental 
function. 
 
If RPLS is diagnosed, discontinue pazopanib (also discontinue  
AR-42). 
Grade 2 pre-syncope or  
grade 3 syncope 
(potentially reflecting 
cardiotoxicity) 
 
 
Hold/omitA pazopanib and AR-42. 
 
Obtain 12-lead ECG for cardiology review/consultation. 
 
Check potassium, magnesium, and calcium levels; immediately 
administer potassium, magnesium, and/or calcium to achieve 
potassium level of ≥ 4 mEq, magnesium level of ≥ 2 mEq, and 
calcium WNL. If ECG shows new dysrhythmia or QTc ≥ grade 2  
(> 480ms), hospitalize for monitoring with cardiology consultation. 
 
Hold pazopanib and AR-42 until any potassium, magnesium, and 
calcium abnormalities are corrected, symptoms resolved, and QTc 
improved to ≤ grade 1 (≤ 480ms). 
 
Reintroduce pazopanib and AR-42 with input from cardiology and 
with additional QTc evaluation, either concurrent with reintroduction 
or at earliest possible opportunity within 8 days from reintroduction. 
 
If event is thought to be related to study treatment, reduce the dose 
of pazopanib and AR-42 by one dose reduction step when 
resuming study treatment.B 
 
Consider chronic supplementation for maintenance of electrolytes. 
 
For recurrent syncope or near-syncope thought to be related to 
study treatment, consider discontinuation of both pazopanib and 
AR-42. 
Renal and Urinary Disorders 
≥ Grade 2 proteinuria 
Hold/omitA pazopanib. If assessment of proteinuria was based on a 
urine dipstick reading, a 24-hour urine collection is required. Based on 
the 24-hour urine specimen: 
 
If grade 2 proteinuria, consult nephrology. 
- If urine protein is < 3.0 gm/24 hours, study treatment may be 
continued without dose modification pending nephrology consult. 
- If ≥ 3.0 gm/24 hours, hold study treatment until improvement to  
< 3.0 gm/24 hours or additional nephrology recommendations. 
 
If grade 3 proteinuria, consult nephrology and discontinue 
pazopanib.  
Respiratory, Thoracic, and Mediastinal Disorders 
≥ Grade 2 pneumonitis 
Discontinue pazopanib (also discontinue AR-42). 
Skin and Subcutaneous Disorders 
PPE (hand-foot syndrome) 
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Table 7. Pazopanib Dose Modification Instructions (continued) 
Vascular Disorders 
Grade 3 hypertension defined 
as systolic BP  
>160 mmHg and diastolic BP 
>100 mm/Hg 
 
Hold/omitA pazopanib until resolution to ≤ grade 2. 
 
Administer standard antihypertensive therapy. 
 
When resuming pazopanib, decrease pazopanib dose by one 
dose reduction step; monitor BP weekly for 4 weeks. 
 
If BP remains controlled for at least one cycle, the pazopanib 
dose may be escalated by one dose step at the investigator’s 
discretion. 
Grade 4 hypertension 
Discontinue pazopanib (also discontinue AR-42) 
A. If recovery takes longer than the first 4 weeks of the cycle, any remaining doses for that cycle are 
omitted. Refer to Section 7.4 for additional information. 
B. At the investigator’s discretion (after the DLT evaluation period [Section 6.7.1]), the dose may be 
escalated by one dose step when the toxicity has resolved and treatment can be resumed. 
 


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7.7.1 Liver Function Abnormalities 
For patients with observed worsening of serum liver tests considered to be related 
to pazopanib (ie, where no alternative cause is evident, such as post-hepatic 
cholestasis or disease progression), the dose modification and monitoring 
instructions in the table below will be followed. 
Table 8. Dose Modification/Interruption for Pazopanib-Related Increase in ALT and/or AST  
Increase in 
AST/ALT (per 
NCI CTCAE v4.0) 
First Occurrence 
Restart 
Recurrence 
Grade 2 
ALT and/or AST  
> 3-5 x ULN 
Continue study treatment with weekly monitoring of liver function until 
transaminases return to grade 1 or baseline. 
Grade 3 
ALT and/or AST  
> 5-20 x ULN  
 
Hold/omit pazopanib 
and AR-42; weekly 
monitoring until 
transaminases return to 
grade 1 or baseline.A 
If the potential benefit of 
reinitiating study 
treatment is considered to 
outweigh the risk of 
hepatotoxicity, reduce 
pazopanib and AR-42 by 
one dose reduction step.B 
Measure serum 
transaminases weekly 
for at least 4 weeks. 
Discontinue 
pazopanib and 
AR-42 
Grade 2 or 3 
with Concurrent 
Bilirubin 
Elevation 
ALT and/or AST  
> 3-20 x ULN 
and 
Bilirubin  
> 2 x ULN 
Hold/omit pazopanib 
and AR-42; weekly 
monitoring until 
transaminases return to 
grade 1 or baseline.A 
If the potential benefit of 
reinitiating study 
treatment is considered to 
outweigh the risk of 
hepatotoxicity, reduce 
pazopanib and AR-42 by 
one dose reduction step.B 
Measure serum 
transaminases and 
bilirubin weekly for at 
least 4 weeks. 
Discontinue 
pazopanib and 
AR-42 
Grade 4 
ALT and/or AST  
> 20 x ULN 
Discontinue pazopanib and AR-42.  
A. If more than a 3-week delay is required, discontinue pazopanib. 
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7.7.2 PPE 
Refer to Section 6.9.4 for supportive care instructions and recommendations for the 
prevention and treatment of PPE. Refer to the table below for study treatment 
instructions. 
Table 9. Pazopanib Dose Modification Instructions for PPE 
Grade of event 
(NCI CTCAE v4.0) 
Occurrence 
Pazopanib Dose ModificationA 
(Refer to Table 6 for pazopanib  
dose reduction steps.) 
Grade 1 
 Minimal skin changes or 
dermatitis (eg, erythema, 
edema, hyperkeratosis) 
without pain 
 Numbness, dysesthesia, 
paresthesia, tingling, 
painless swelling, or 
erythema of hands 
and/or feet 
 Does not disrupt normal 
activities 
Any 
Continue study treatment; maintain dose level.  
Grade 2 
 Skin changes  
(eg, peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with pain 
 Painful erythema and 
swelling of hands and/or 
feet 
 Limiting instrumental 
ADLB 
Any 
 If PPE is NOT interfering with instrumental ADL, 
maintain pazopanib (and AR-42) dose. 
 If PPE is interfering with instrumental ADL, reduce 
pazopanib by one dose reduction step for the 
remainder of the treatment cycle.C 
 If no improvement in spite of supportive care and 
pazopanib dose reduction, omit pazopanib for the 
remainder of the cycle. When resuming treatment, 
decrease pazopanib dose by one dose reduction 
step.C,D 
Grade 3 
 Severe skin changes  
(eg, peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with pain 
 Moist desquamation, 
ulceration, blistering, or 
severe pain of the hands 
and/or feet 
 Limiting self-care ADLE 
1st Occurrence 
 Omit pazopanib and AR-42 for a minimum of  
7 days and until toxicity resolves to ≤ grade 1.D 
 When resuming treatment, decrease pazopanib 
dose by one dose reduction step.C 
2nd Occurrence 
 Omit pazopanib and AR-42 for a minimum of  
7 days and until toxicity resolves to ≤ grade 1.D 
 When resuming treatment, decrease pazopanib 
dose by one dose reduction step.C 
3rd Occurrence 
Discontinue pazopanib and AR-42.  
A. More conservative management is permitted per investigator discretion. 
B. Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone 
managing money, etc. 
C. If toxicity returns to ≤ grade 1 after dose reduction, pazopanib escalation is permitted, up to the 
enrolled dose level, at the discretion of the investigator if the patient has completed 1 cycle at a 
reduced dose without recurrence of the event. 
D. If > 3 consecutive weeks of delay are required for recovery, discontinue pazopanib and AR-42. 
E. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications; the patient is not bedridden. 


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7.7.3 Other Toxicity 
The instructions on the table below should be followed for toxicities not addressed 
on the previous dose modification tables. 
Table 10. Pazopanib Dose Modification for Other Toxicity  
NCI 
CTCAE 
v4.0 
Initiation of 
Treatment Cycle 
Dosing Interruption 
During the CycleA 
Dose Modification If 
Treatment Resumed 
During the  
Same CycleA 
Dose for 
Subsequent 
CyclesA 
Grade 1  Start cycle on 
time 
Continue treatment 
(no interruption) 
Not Applicable 
No change 
Grade 2 
Start cycle on 
time or delay 
start of the cycle 
until ≤ grade 1 or 
baseline grade 
per investigator 
discretionB 
Continue treatment or 
interrupt dosing 
(pazopanib and  
AR-42) until resolution 
to ≤ grade 1 or 
baseline grade per 
investigator discretionB 
No change or reduce 
pazopanib dose by 
one dose reduction 
step per investigator 
discretionC 
No change or 
reduce pazopanib 
dose by one dose 
reduction step per 
investigator 
discretionC 
Grade 3 
Delay start of the 
cycle until  
≤ grade 1 or 
baseline gradeB 
Interrupt dosing until 
resolution to ≤ grade 1 
or baseline gradeB 
Reduce pazopanib 
dose by one dose 
reduction stepC 
Reduce pazopanib 
dose by one dose 
reduction stepC 
Grade 4 
Delay start of the 
cycle until  
≤ grade 1 or 
baseline gradeB 
Omit dosing for the 
remainder of the 
treatment cycle 
Reduce pazopanib 
dose by one dose 
reduction step or 
discontinue both 
pazopanib and AR-42 
per investigator’s 
discretionC 
If grade 4 toxicity 
recurs at reduced 
pazopanib dose, 
discontinue both 
pazopanib and  
AR-42 
A. Excludes alopecia, nausea and vomiting that improve with antiemetic therapy, hypersensitivity 
that improves with medical management, and laboratory abnormalities that are asymptomatic 
and/or not clinically significant in the opinion of the investigator. 
B. If treatment cannot resume after a 3-week delay, pazopanib and AR-42 must be discontinued. 
C. Refer to Table 6 for pazopanib dose reduction steps. 
 


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8 ADVERSE EVENT DEFINITIONS AND REPORTING REQUIREMENTS 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related. 
8.1.2 Suspected Adverse Reaction (SAR) 
A SAR is any AE for which there is a reasonable possibility that the drug caused the 
AE. “Reasonable possibility” means that there is evidence to suggest a causal 
relationship between the drug and the AE. 
An AE with an attribution of possible, probable, or definite (see Section 8.1.8) is a 
SAR. 
8.1.3 Serious AE (SAE) or Serious SAR (SSAR) 
An AE or SAR is considered “serious” if, in the view of the investigator, it results in 
any of the following outcomes: 
 
death, 
 
a life-threatening AE, 
An AE or SAR is considered “life-threatening” if, in the view of the investigator, 
its occurrence places the patient at immediate risk of death. It does not include 
an AE or SAR that, had it occurred in a more severe form, might have caused 
death. 
 
inpatient hospitalization or prolongation of existing hospitalization, 
Note: Planned inpatient hospitalizations (eg, for planned surgery or for logistical 
reasons such as completion of a therapy that cannot be completed due to 
outpatient clinic business hours) are exempt from SAE reporting. Events that 
prolong such hospitalizations should be considered “serious” and are still subject 
to SAE reporting requirements. 
 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 


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8.1.4 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. Expected AEs are those AEs, the specificity 
and severity of which are consistent with the listings for AR-42 and pazopanib found 
in protocol Sections 9.1 and 9.2, respectively, or in the most current version of the 
AR-42 Investigator’s Brochure or the most current FDA-approved prescribing 
information for pazopanib. 
Unexpected AEs are those AEs occurring in one or more patients participating in the 
study, the nature, severity, or frequency of which is not consistent with either: 
 
The known or foreseeable risk of AEs associated with the procedures involved 
in the research that are described in (a) protocol-related documents, such as the 
research protocol approved by the institutional review board (IRB), any 
applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as 
product labeling and package inserts; or 
 
The expected natural progression of any underlying disease, disorder, or 
condition of the patient(s) experiencing the AE and the patient’s predisposing 
risk factor profile for the AE. 
8.1.5 Unexpected SAR 
A SAR 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, as amended. 
 
“Unexpected” as used in this definition, also refers to SARs 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. 
8.1.6 Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all 
of the following criteria: 
 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
research protocol and informed consent document approved by the IRB; and  
(b) the characteristics of the patient population being studied; 
 
related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
 
suggests that the research places patients or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
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8.1.7 AE Description and Grade 
The descriptions and grading scales found in the revised CTCAE version 4.0 will be 
utilized for AE reporting. 
8.1.8 AE Attribution 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment. 
 
Unlikely – The AE is doubtfully related to the study treatment. 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.2 Known AEs 
Known AEs for AR-42 are described in protocol Section 9.1 and in the AR-42 Investigator 
Brochure. Known AEs for pazopanib are described in protocol Section 9.2 and in the 
current pazopanib (Votrient) prescribing information. 
8.3 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy. A 
secondary malignancy is not metastasis from the previous cancer. Any secondary 
malignancy should be reported via expedited reporting processes outlined on Table 11. 
8.4 Time Period and Grade of AE Capture 
All AEs regardless of grade will be recorded from the beginning of the study procedures 
through 30 days following the end of study treatment. 
8.5 Procedures for Recording AEs, SARs, SAEs, SSARs, DLTs, and UPs 
All AEs (including SAEs, SARs, and SSARs), DLTs, and UPs will be recorded in MCC’s 
OnCore Clinical Trials Management System. In most cases, it is acceptable to record in 
OnCore only the highest grade of a toxicity occurring during a particular study segment 
when an event has serial fluctuations in grade over time. 
SAEs will be entered into the OnCore SAE domain. UPs will be entered into the OnCore 
Deviations domain. An SAE that is both an SAE and a UP will be entered in both domains. 
For all SAEs, a corresponding entry should be made in the routine AE record to match the 
event entries in the SAE domain. 


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8.6 Expedited Reporting Procedures for SAEs, SSARs, UPs, and DLTs 
Refer to Table 11 for expedited reporting by investigators to the Sponsor-Investigator and 
reporting by the Sponsor-Investigator to the Data Safety and Monitoring Committee 
(DSMC), IRB, FDA, and Arno Therapeutics, Inc. 


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Table 11. Expedited Reporting Requirements  
SAEs 
UPs 
SSARs 
DLTs 
Sponsor-InvestigatorA 
Andrew Poklepovic 
Sponsor-InvestigatorA 
Andrew Poklepovic 
 
Sponsor-InvestigatorB 
Andrew Poklepovic 
 
 
Study TeamA 
Study TeamA 
 
Study TeamB 
 
 
Arno TherapeuticsC 
DSMCD 
 
 
FDAE 
 
 
IRBF 
Arno TherapeuticsC 
 
 
Arno TherapeuticsC 
 
 
A. Investigators will report event to the Sponsor-Investigator/Study Team within 1 business day of 
becoming aware of the occurrence. A PDF of a de-identified OnCore SAE or Deviation record may 
be used for expedited event reporting purposes. 
B. Investigators will report event to the Sponsor-Investigator/Study Team within 1 business day of 
becoming aware of the occurrence. Receipt of reports is confirmed. If confirmation is not received 
within 1 business day, contact the research nurse by telephone 
. 
C. The Sponsor-Investigator/Study Team will provide the de-identified OnCore SAE Record within  
24 hours of becoming aware of the occurrence to Arno Therapeutics, Inc. A de-identified OnCore 
Deviation Record will be provided to Arno Therapeutics within 2 business days of becoming aware 
of the occurrence. If FDA reporting is required (see footnote E below), a copy of the completed 
MedWatch Form 3500A will be provided by the Sponsor-Investigator/Study Team to Arno 
Therapeutics at the time of FDA submission. 
D. The Sponsor-Investigator/Study Team will report event within 1 business day of becoming aware of 
the occurrence. A PDF of a de-identified OnCore SAE or Deviation record may be used for 
expedited event reporting purposes. 
E. Using MedWatch Form 3500A, the Sponsor-Investigator will report to the FDA any: 
 AE that is all of the following: 1) possibly, probably, or definitely related to study drug (ie, the 
event is a SAR); 2) serious (ie, a SSAR); and 3) unexpected. Events meeting these criteria will 
be reported to the FDA within 15 days of determining that the event is reportable. 
 clinically important increase in the rate of SSARs within 15 days of determining that the event 
is reportable 
 unexpected fatal or life-threatening SSARs within 7 days of initial receipt of the information 
regarding the event. 
F. The Sponsor-Investigator/Study Team will report each UP to the VCU IRB within 5 business days of 
becoming aware of the occurrence.  


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9 PHARMACEUTICAL INFORMATION 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
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9.2 Pazopanib 
The following information is based on the prescribing information for Votrient (pazopanib) 
with a revision date of September 2015. 
9.2.1 Product Description 
Chemical Name: 5-[[4-[)2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-
pyrimidinyl]amino]-2-methylbenzenesulfonamide monohycrochloride 
Molecular Formula: C21H23N7O2S●HCl 
Molecular Weight: 473.99 
Mechanism of Action: Pazopanib is a tyrosine knase inhibitor 
How Supplied: 
Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble 
at pH of 1 and practically insoluble above pH of 4 in aqueous media. Pazopanib 
tablets are modified capsule-shaped, gray, film-coated tablets with GS JT debossed 
on one side. Each pazopanib 200-mg tablet contains 216.7 mg of pazopanib 
hydrochloride. The inactive ingredients in the pazopanib tablet core are magnesium 
stearate, micro crystalline cellulose, povidone sodium, and starch glycolate. In the 
coating, the inactive ingredients are hypromellose, iron oxide black, 
macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, and titanium dioxide. 
9.2.2 Route of Administration 
Pazopanib tablets are to be taken by mouth on an empty stomach, at least 1 hour 
before or 2 hours after food. Pazopanib tablets should not be crushed. 
9.2.3 Storage 
Pazopanib tablets should be stored at room temperature between 20° and 25°C 
(68° and 77°F); excursions permitted to 15-30°C (59-86°F). 
9.2.4 Stability 
When stored as directed, tablets are stable until the date indicated on the package. 
9.2.5 Availability and Ordering 
Pazopanib is commercially available. Patients or their third party payor (ie, health 
care insurance) will be responsible for the cost of pazopanib treatment. 
9.2.6 Agent Accountability 
Not applicable 


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9.2.7 Agent Destruction and Return 
Not applicable 
9.2.8 Contraindications 
None 
9.2.9 Drug Interactions 
Refer to the current Votrient (pazopanib) prescribing information and to Section 6.10 
for information and instructions regarding potential drug interactions. 
9.2.10 Warnings and Precautions 
Refer to the current Votrient (pazopanib) prescribing information for information 
regarding the following: 
 
Hepatic toxicity and hepatic impairment 
 
QT prolongation and Torsades de Pointes 
 
Cardiac dysfunction 
 
Hemorrhagic events 
 
Arterial thromboembolic events 
 
Venous thromboembolic events 
 
Thrombotic microangiopathy 
 
Gastrointestinal perforation and fistula 
 
Interstitial lung disease/pneumonitis 
 
RPLS 
 
Hypertension 
 
Wound healing 
 
Hypothyroidism 
 
Proteinuria 
 
Infection 
 
Increased toxicity with other cancer therapy 
 
Increased toxicity in developing organs 
 
Pregnancy 


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9.2.11 Adverse Events Occurring in Patients with RCC 
The most common adverse reactions in patients with advanced RCC (≥ 20%) are 
diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and 
vomiting. Adverse reactions occurring in patients with RCC are summarized in the 
following 3 tables: ≥ 10% of patients in Table 13; < 10 in Table 14; and selected 
laboratory abnormalities in > 10% of patients in Table 15. 
Table 13. Adverse Reactions Occurring in ≥ 10% of Patients with RCC  
Adverse 
Reactions 
Pazopanib 
(N = 290) 
Placebo 
(N = 145) 
All 
Grades* 
% 
Grade 3 
% 
Grade 4 
% 
All 
Grades* 
% 
Grade 3 
% 
Grade 4 
% 
Diarrhea 
52 
3 
<1 
9 
<1 
0 
Hypertension 
40 
4 
0 
10 
<1 
0 
Hair color changes 
38 
<1 
0 
3 
0 
0 
Nausea 
26 
<1 
0 
9 
0 
0 
Anorexia 
22 
2 
0 
10 
<1 
0 
Vomiting 
21 
2 
<1 
8 
2 
0 
Fatigue 
19 
2 
0 
8 
1 
1 
Asthenia 
14 
3 
0 
8 
0 
0 
Abdominal pain 
11 
2 
0 
1 
0 
0 
Headache 
10 
0 
0 
5 
0 
0 
*NCI CTCTAE v3.0 
 
Table 14. Adverse Reactions Occurring in < 10% of Patients with RCC 
Adverse Reactions 
Pazopanib 
(N = 290) 
Placebo 
(N = 145) 
All Grades* (%) 
All Grades* (%) 
Alopecia 
8 
<1 
Chest pain 
5 
1 
Dysgeusia 
8 
<1 
Dyspepsia 
5 
<1 
Dysphonia 
4 
<1 
Facial edema 
1 
0 
PPE 
6 
<1 
Proteinuria 
9 
0 
Rash 
8 
3 
Skin depigmentation 
3 
0 
Weight loss 
9 
3 
Arthralgia and muscle spasms were also reported in other clinical trials. 
*NCI CTCTAE v3.0 


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Table 15. Selected Laboratory Abnormalities Occurring in > 10% of Patients with RCC and 
More Commonly (≥ 5% ) in Patients Who Received Pazopanib versus Placebo 
Parameters 
Pazopanib 
(N = 290) 
Placebo 
(N = 145) 
All 
Grades* 
% 
Grade 3 
% 
Grade 4 
% 
All 
Grades* 
% 
Grade 3 
% 
Grade 4 
% 
Hematologic 
Leukopenia 
37 
0 
0 
6 
0 
0 
Neutropenia 
34 
1 
<1 
6 
0 
0 
Thrombocytopenia 
32 
<1 
<1 
5 
0 
<1 
Lymphocytopenia 
31 
4 
<1 
24 
1 
0 
Chemistry 
ALT increased 
53 
10 
2 
22 
1 
0 
AST increased 
53 
7 
<1 
19 
<1 
0 
Glucose increased 
41 
<1 
0 
33 
1 
0 
Total bilirubin 
increased 
36 
3 
<1 
10 
1 
<1 
Phosphorus 
decreased 
34 
4 
0 
11 
0 
0 
Sodium decreased 
31 
4 
1 
24 
4 
0 
Magnesium 
decreased 
26 
<1 
1 
14 
0 
0 
Glucose decreased 
17 
0 
<1 
3 
0 
0 
*NCI CTCTAE v3.0 
 
9.2.12 Adverse Events Occurring in Patients with STS 
The most common adverse reactions in patients with advanced STS (≥ 20%) are 
fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, hair 
color changes (depigmentation), vomiting, tumor pain, dysgeusia, headache, 
musculoskeletal pain, myalgia, gastrointestinal pain, and dyspnea. Adverse 
reactions occurring in patients with STS are summarized in Table 16, Table 17, and 
Table 18. 


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Table 16. Adverse Reactions Occurring in ≥ 10% of Patients with STS 
Adverse 
Reactions 
Pazopanib 
(N = 240) 
Placebo 
(N = 123) 
All 
GradesA 
% 
Grade 3 
% 
Grade 4 
% 
All 
GradesA 
% 
Grade 3 
% 
Grade 4 
% 
Fatigue 
65 
13 
1 
48 
4 
1 
Diarrhea 
59 
5 
0 
15 
1 
0 
Nausea 
56 
3 
0 
22 
2 
0 
Weight decreased 
48 
4 
0 
15 
0 
0 
Hypertension 
42 
7 
0 
6 
0 
0 
Appetite decreased 
40 
6 
0 
19 
0 
0 
Hair color changes 
39 
0 
0 
2 
0 
0 
Vomiting 
33 
3 
0 
11 
1 
0 
Tumor pain 
29 
8 
0 
21 
7 
2 
Dysgeusia 
28 
0 
0 
3 
0 
0 
Headache 
23 
1 
0 
8 
0 
0 
Musculoskeletal 
pain 
23 
2 
0 
20 
2 
0 
Myalgia 
23 
2 
0 
9 
0 
0 
Gastrointestinal 
pain 
23 
3 
0 
9 
4 
0 
Dyspnea 
20 
5 
<1 
17 
5 
1 
Exfoliative rash 
18 
<1 
0 
9 
0 
0 
Cough 
17 
<1 
0 
12 
<1 
0 
Peripheral edema 
14 
2 
0 
9 
2 
0 
Mucositis 
12 
2 
0 
2 
0 
0 
Alopecia 
12 
0 
0 
1 
0 
0 
Dizziness 
11 
1 
0 
4 
0 
0 
Skin disorderB 
11 
2 
0 
1 
0 
0 
Skin 
hypopigmentation 
11 
0 
0 
0 
0 
0 
Stomatitis 
11 
<1 
0 
3 
0 
0 
Chest pain 
10 
2 
0 
6 
0 
0 
A. NCI CTCTAE v3.0 
B. 27 of 28 cases of skin disorder were PPE 


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Table 17. Other Adverse Reactions Occurring in ≥ 5% of Patients with STS and 
More Commonly (> 2%) in Patients Who Received Pazopanib versus Placebo 
Adverse Reactions 
Pazopanib 
(N = 240) 
Placebo 
(N = 123) 
All Grades* (%) 
All Grades* (%) 
Insomnia 
9 
6 
Hypothyroidism 
8 
0 
Dysphonia 
8 
2 
Epistaxis 
8 
2 
Left ventricular dysfunction 
8 
4 
Dyspepsia 
7 
2 
Dry skin 
6 
<1 
Chills 
5 
1 
Vision blurred 
5 
2 
Nail disorder 
5 
0 
*NCI CTCTAE v3.0 
 
Table 18. Selected Laboratory Abnormalities Occurring in > 10% of Patients with STS and 
More Commonly (≥ 5% ) in Patients Who Received Pazopanib versus Placebo 
Parameters 
Pazopanib 
(N = 240) 
Placebo 
(N = 123) 
All 
Grades* 
% 
Grade 3 
% 
Grade 4 
% 
All 
Grades* 
% 
Grade 3 
% 
Grade 4 
% 
Hematologic 
Leukopenia 
44 
1 
0 
15 
0 
0 
Lymphocytopenia 
43 
10 
0 
36 
9 
2 
Thrombocytopenia 
36 
3 
1 
6 
0 
0 
Neutropenia 
33 
4 
0 
7 
0 
0 
Chemistry 
AST increased 
51 
5 
3 
22 
2 
0 
ALT increased 
46 
8 
2 
18 
2 
1 
Glucose increased 
45 
<1 
0 
35 
2 
0 
Albumin decreased 
34 
1 
0 
21 
0 
0 
ALP increased 
32 
3 
0 
23 
1 
0 
Sodium decreased 
31 
4 
0 
20 
3 
0 
Total bilirubin 
increased 
29 
1 
0 
7 
2 
0 
Potassium increased 
16 
1 
0 
11 
0 
0 
*NCI CTCTAE v3.0 


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10 MEASUREMENT OF EFFECT 
10.1 Criteria for Tumor Response 
Tumor response will be evaluated and recorded according to RECIST v1.1 (27) 
10.2 Imaging 
Only imaging of the initial sites of disease is required at subsequent time points to provide 
tumor measurements for assessment of antitumor effect. Brain imaging after initiation of 
study therapy is only required for patients who have a history of brain metastasis. 
The same type of imaging used at baseline should be used at each scheduled assessment 
which will be performed at the end of every other 4-week cycle (ie, approximately every 8 
weeks). At the investigator’s discretion, additional imaging may be performed when 
clinically indicated. 
10.3 Criteria for Tumor Response 
In the event of a PR or CR, the imaging used when the response was first documented 
must be repeated at the time of the next scheduled imaging, ie, in about 8 weeks, to 
confirm tumor response. (At the investigator’s discretion, confirmatory scans can be 
performed sooner, but no less than 4 weeks following the imaging indicating the PR or 
CR.) 
10.4 Central Review for Imaging Interpretation 
Centralized radiologic review for response evaluation will be conducted. 
11 CORRELATIVE STUDIES 
11.1 Participation in Correlative Studies 
Tumor samples archived following the most recent biopsy or surgery will be used for the 
correlative studies. Participation in the correlative studies using archived tumor samples, if 
available, is mandatory. 
11.2 Collection, Immunostaining, and Distribution of Samples 
 
The study team will coordinate collection of all correlative tumor samples. Additionally, 
the study team will ensure that samples are de-identified prior to distribution to the 
laboratories performing the correlative studies. 


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 
Massey Cancer Center Clinical and Translational Research Lab (CTRL) will receive, 
process, store, and/or distribute tumor samples to the laboratories performing the 
correlative studies as needed based on the plans outlined in Section 11.3. 
 
Questions regarding study requirements should be directed to the study team. The 
principal investigator should be contacted in the event that a correlative sample must be 
missed or is found to be inadequate for submission. 
 
Collection and distribution of all tumor samples will be logged by the study team in 
OnCore. 
11.3 Archived Tumor Samples 
Expression of multiple cellular proteins will be analyzed by IHC methods using samples 
from tumor archived at the time of the most recent diagnostic biopsy or surgery. 
11.3.1 Tumor Sample Requirement 
When sufficient archived tumor tissue is available: 
 
Request a tumor block from archived samples from the most recent diagnostic 
biopsy or surgical resection. 
 
If an outside hospital does not transfer blocks of tissue, request 10 unstained 
slides, each with specimen 4 microns thick. 
 
To obtain an archived biopsy specimen from an outside hospital: 
 
Request that a tissue block be sent to the study team; the study team will 
coordinate with VCU Anatomic Pathology for slide preparation. 
 
If the outside hospital does not transfer blocks of tissue, request delivery of 
10 unstained slides, each with specimen 4 microns thick. 
 
The study team should request tumor samples by the end of cycle 2 (ie, within 
about 8 weeks after initiation of study treatment). 
11.3.2 Tumor Sample Labeling 
The tumor sample should be labeled with the following information: 
 
Study number 
 
Patient study identification number 
 
Date of tumor sample collection 
11.3.3 Immunostaining of Unstained Slides 
All unstained slides will be delivered to the CTRL where immunostains for total 
CD95 expression and the expression of other proteins of interest will be performed. 
11.3.4 Interpretation of Immunostain Results 


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After staining, slides stained with validated antibodies for standard IHC will be 
returned to the VCU Anatomic Pathology for interpretation by a clinical pathologist. 
Results will be communicated to the CTRL and the study team. 
12 STUDY CALENDARS 
The schedule of tests, exams, disease assessments, collection of samples for correlative 
studies, and study treatment are listed on 2 tables: requirements during screening through 
treatment cycle 1 on Table 19 and requirements during remaining treatment beginning with 
cycle 2 and continuing through study follow-up on Table 20. 
 


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Table 19. Study Calendar - Screening Through Treatment Cycle 1 
Tests, Exams, and Other 
Requirements 
Screening 
(Days Prior to Cycle 1, Day 1) 
Study Treatment – Cycle 1 
Within  
28 Days 
Within  
14 Days 
Within  
7 Days 
Day 1A 
Day 8B 
Day 15B 
Day 22B 
Day 29B 
(If cycle was 
extended)C 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical/Surgical History  
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
X 
X 
X 
X 
Vital Signs 
 
X 
 
X 
X 
X 
X 
X 
BP 
 
X 
 
X 
X 
X 
X 
X 
Performance Status 
 
X 
 
X 
X 
X 
X 
X 
Baseline Conditions/Symptoms  
 
X 
 
 
 
 
 
 
AE Assessment  
 
 
 
 
X 
X 
X 
X 
Concurrent MedicationsD  
 
X 
 
 
X 
X 
X 
X 
Physical Exam 
 
X 
 
X 
X 
X 
X 
X 
CBC with Differential  
 
X 
 
X 
X 
X 
X 
X 
Platelet Count 
 
X 
 
X 
X 
X 
X 
X 
Serum ChemistryE 
 
X 
 
X 
XF 
XF 
XF 
XF 
aPTT and INR 
 
X 
 
 
 
 
 
 
Lipase 
 
X 
 
 
 
 
 
 
TSH and T4 
 
X 
 
 
 
 
 
 
Serum Pregnancy TestG 
 
 
X 
 
 
 
 
 
Urinalysis for protein 
 
XH 
 
 
 
 
 
 
12-Lead ECGI 
X 
 
 
 
X 
X 
X 
X 
LVEF AssessmentJ 
XK 
 
 
 
 
 
 
 
Imaging/Disease Assessment 
XL 
 
 
 
 
 
 
 
Correlative Tumor Sample Collection 
 
 
 
XM 
AR-42 PON 
 
 
 
Once daily 3 days/week during 1st 3 weeks 
XO 
Pazopanib PON 
 
 
 
Once daily continuously 
XO 
Study Med Diary Review/Pill Count 
 
 
 
X 
X 
X 
X 
X 


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Table 19 Footnotes: 
A. Except for BP and vital signs, baseline evaluations performed within 1 week prior to initiation of study treatment do not need to be 
repeated on cycle 1, day 1. 
B. Within +/- 24 hours. 
C. Day 29 requirements only apply to patients who had a treatment interruption earlier in the cycle that required extending the cycle 
beyond 28 days (up to a maximum of 35 days). 
D. Include over-the-counter medications. 
E. Serum chemistry includes the following panels and tests: basic metabolic panel (sodium, potassium, carbonate, chloride, 
glucose, calcium, BUN, and creatinine); hepatic panel (ALT, AST, ALP, total bilirubin, direct bilirubin, albumin, and total protein); 
and magnesium and phosphorous. 
F. Refer to Table 8 for instructions regarding increased frequency of liver function monitoring (weekly for at least 4 weeks) when 
pazopanib-related elevations (AST, ALT, bilirubin) occur. 
G. Only required for WCBP; see Section 4.1.12 for the definition of WCBP. 
H. If urinalysis reading for protein is ≥ 2+ (100 mg/dL), a 24-hour urine sample must be collected and tested (see Section 4.1.6 for 
related eligibility criterion). 
I. 
Refer to Section 4.2.13, Section 6.8, and Table 7 for instructions related to QTc interval prolongation. 
J. Assessment may be performed by echocardiogram or by a nuclear study (eg, MUGA scan; first-pass technique). 
K. Determination of LVEF is required within 3 months prior to cycle 1, day 1 study treatment. 
L. Baseline imaging must be contrast-enhanced and include the following: 
 
Chest CT, CT or MRI of abdomen and pelvis, and all other suspected sites of disease within 28 days prior to initiation of 
study treatment; for patients with a CT contrast allergy, the chest CT may be performed without contrast or, if the chest is 
not a known site of disease, a chest x-ray may be used 
 
Brain CT or MRI within 8 weeks prior to initiation of study treatment 
M. Collection of tumor samples archived following the most recent biopsy or surgery; tumor samples must be requested by the end 
of cycle 2 (Section 11). 
N. Refer to Sections 6.1 through 6.6 for treatment-related instructions including the AR-42 and pazopanib dose levels. 
O. If cycle has been extended to 5 weeks, AR-42 doses must be given during the 1st 4 weeks of the cycle allowing a 1-week AR-42 
rest period (Section 6.2.1); pazopanib continues daily. 
 


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Table 20. Study Calendar – Treatment Beginning with Cycle 2 Through Follow-Up 
Tests, Exams, and Other 
Requirements 
Cycle 2 
Cycle 3 
Cycle 4 
 End of 
TreatmentC 
End of  
30-Day 
Follow-Up 
Day 1A 
Day 15B 
Day 1A 
Day 1A 
Weight 
X 
 
X 
X 
X 
 
Vital Signs 
X 
 
X 
X 
X 
 
BP 
X 
X 
X 
X 
X 
 
Performance Status 
X 
 
X 
X 
X 
 
Assessment of AEs 
X 
 
X 
X 
X 
XD 
Concurrent MedicationsE 
X 
 
X 
X 
X 
 
Physical Exam 
X 
 
X 
X 
X 
 
CBC with Differential  
X 
X 
X 
X 
X 
 
Platelet Count 
X 
X 
X 
X 
X 
 
Serum ChemistryF 
XF 
XF 
XF 
XF 
X 
 
Lipase 
X 
 
X 
X 
X 
 
TSH and T4 
 
 
 
XG 
(Every 3 cycles) 
 
 
Urinalysis for Protein 
 
 
XH 
(Every 2 cycles) 
 
 
 
12-Lead ECGI 
X 
 
 
XJ 
(Every 2 cycles) 
 
 
LVEF AssessmentK  
 
 
 
XL 
(Every 3 cycles) 
 
 
Tumor Imaging/Disease 
AssessmentM 
 
 
XN 
(Every 2 cycles) 
 
XO 
Correlative Tumor Sample 
Collection 
XP 
 
 
 
 
AR-42 POQ 
Once daily 3 days/week during 1st 3 weeks of each 4-week cycleR 
 
 
Pazopanib POQ 
Once daily continuouslyR  
 
 
Study Medication Diary 
Review & Pill Count 
X 
 
X 
X 
X 
 


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Table 20 Footnotes: 
A. Within 3 days prior to or on day 1 of each treatment cycle. 
B. Within 3 days prior to or on day 15. 
C. Within 2 weeks after the end of study treatment. 
D. If the patient is unable to return for a study visit at this time, the study team may contact the patient, family member, and/or other 
care providers to get information needed to complete the AE assessment at this time point. 
E. Include over-the-counter medications. 
F. Serum chemistry includes the following panels and tests: basic metabolic panel (sodium, potassium, carbonate, chloride, 
glucose, calcium, BUN, and creatinine); hepatic panel (ALT, AST, ALP, total bilirubin, direct bilirubin, albumin, and total 
protein); and magnesium and phosphorous. (Refer to Table 8 for instructions regarding increased frequency of liver 
function monitoring [weekly for at least 4 weeks] when pazopanib-related elevations [AST, ALT, bilirubin] occur.) 
G. Following completion of 3 cycles of study treatment beginning on day 1 of cycle 4, repeating on day 1 of cycle 7, and continuing 
after every 3 cycles of treatment (ie, about every 3 months). 
H. Following completion of 2 cycles of study treatment beginning on day 1 of cycle 3, repeating on day 1 of cycle 5, and continuing 
after every 2 cycles of treatment (ie, about every 2 months). If urine protein is 2+ (100 mg/dL), a 24-hour urine sample must be 
collected and tested. 
I. 
Refer to Section 6.8 and Table 7 for instructions related to QTc interval prolongation. 
J. On day 1 (+/- 1 week) of cycles 4, 6, and continuing after every 2 cycles of treatment (ie, about every 2 months [+/- 1 week]). 
K. LVEF assessment should be performed using the same method used at baseline to determine eligibility. 
L. Following completion of 3 cycles of study treatment beginning on day 1 of cycle 4 (+/- 1 week), repeating on day 1 of cycle 7  
(+/- 1 week), and continuing after every 3 cycles of treatment (ie, about every 3 months [+/- 1 week]). 
M. Imaging may be limited to known sites of disease. Brain imaging required for patients with brain metastasis diagnosed and 
treated prior to initiation of study treatment. The imaging used at baseline should be used at each subsequent imaging time point. 
N. Following completion of 2 cycles of study treatment beginning on day 1 of cycle 3 (+/- 1 week) and continuing after every 2 cycles 
of treatment (ie, about every 2 months [+/- 1 week]); see Section 10. 
O. For patients who discontinued study treatment in the absence of disease progression: If it has been 8 or more weeks since the 
most recent disease assessment, a final on-study tumor response assessment should be performed, if possible. 
P. If not already requested during cycle 1, archived tumor samples must be requested by the end of cycle 2; see Section 11. 
Q. Refer to Section 6.2 through 6.6 for additional treatment-related instructions. 
R. Continuing until treatment is discontinued (see Section 6.5); if the cycle has been extended to 5 weeks, AR-42 doses must be 
given during the 1st 4 weeks of the cycle allowing a 1-week AR-42 rest period (Section 6.2.1); pazopanib continues daily. 
 


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13 STATISTICAL CONSIDERATIONS 
13.1 Study Design 
This is a phase 1 study of AR-42 in combination with pazopanib in patients with advanced 
RCC or STS. A modified 3+3 dose-escalation design will be conducted. Additional patients 
will be enrolled at the MTD until a total of 12 patients have been treated at the MTD. 
13.2 Sample Size/Accrual Rates 
With the 7 proposed dose levels (-1, 1, 2, 3A, 3B, 4A, and 4B) and starting at dose level 1 
(as indicated in Table 1 in Section 6.6), the number of patients needed for evaluation of 
DLT ranges from 4 to 36. To take into account the up to 20% of patients subsequently 
found to be inevaluable for DLT, the maximum number of patients required to determine 
the MTD is 45. Per the dose-escalation plan, it is likely that 4-5 dose levels will be 
explored. With an average of 4.5 patients per cohort, the likely scenarios involve 18-23 
patients and, therefore, it is expected that 23-29 patients evaluable for DLT will be enrolled 
in the study. With 6 additional patients who will be treated at the MTD, the maximum 
number of patients needed for the study is 51 with a likely sample size of 29-35 patients. 
Based on past recruitments, the recruitment rate is expected to be about 1-2 per month. 
Therefore, the anticipated enrollment period is expected to be about 15-35 months. 
13.3 Statistical Analysis for Primary Objective 
Patients’ treatment dose level, dose modification, evaluability for DLT, and DLTs will be 
listed and summarized by basic descriptive statistics such as frequency and proportion. 
The MTDs/RP2Ds will be found based on the criteria defined in Section 6.7 
13.4 Statistical Analysis for Secondary Objectives 
Patients’ demographics, AEs and SAEs, treatment status, number of patients who had 
discontinuation of study therapy, and clinical response will be listed and summary 
descriptive statistics, including frequency/proportion for discrete variables and 
mean/median/standard deviation for continuous variables, will be calculated. The clinical 
response (CR + PR) rate will also be calculated along with its 95% confidence interval. 
13.5 Statistical Analysis for Exploratory Objectives 
The study is not sufficiently powered to establish definitive outcomes for the correlative 
exploratory endpoint. Any comparison with a significant alpha, 0.05, will be deemed of 
interest to warrant further evaluation. An ordinal regression and a logistic regression will be 
used to assess the association between expression of each biomarker and clinical 
response. 


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13.6 Evaluability for DLT, Toxicity, and Response 
13.6.1 DLT-Evaluable Population 
DLT-evaluable patients are those who have taken a minimum of 6 doses of AR-42 
during the first treatment cycle and a minimum of 21 doses of pazopanib during the 
first treatment cycle, or those who have experienced a DLT with any study treatment 
during cycle 1 as described in Section 6.7.1. 
Note: Patients who for any reason are not evaluable for DLT will be replaced. 
13.6.2 Safety-Evaluable Population 
Patients who have received any study treatment will be evaluable for safety and 
toxicity analyses. 
13.6.3 Efficacy-Evaluable Population 
Efficacy-evaluable patients are those who have received any doses of AR-42 and 
pazopanib in cycle 2 (regardless of the number of doses taken during cycle 1), and 
have had at least 1 imaging assessment of response after receiving study 
treatment. 
For efficacy evaluation, patients are coded as having a response or not having a 
response as follows: 
 
Responders: Best response assessment is a PR or a CR (Section 10). 
 
Non-Responders: Best response assessment is stable disease or progressive 
disease; also included are patients who did not have assessment of tumor 
response at least once after initiation of study treatment or who were otherwise 
not evaluable for response. 
The coding of patients as responders or non-responders will be made by the 
Sponsor-Investigator with the concurrence of the Biostatistician. 
14 DATA AND SAFETY MONITORING PLAN 
The data and safety monitoring plan for this study consists of 3 elements: the study team, 
the audit committee, and the DSMC. 
14.1 Study Team 
The study team minimally consists of the Sponsor-Investigator, the research nurse, the 
clinical research associate, and the study biostatistician. While patients are on treatment, 
the Sponsor-Investigator, the research nurse, and the clinical research associate will meet 
at least monthly, and will meet at least quarterly with the study biostatistician, to review 
study status. This review will include, but not be limited to, reportable AEs and UPs and an 
update of the ongoing study summary that describes study progress in terms of the study 
schema. The appropriateness of further patient enrollment and the specific intervention for 


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a next patient enrollment are addressed. All meetings, including attendance, are 
documented. 
14.2 Audit Committee 
This study will be audited by the MCC Audit Committee. 
14.3 DSMC 
The MCC-14-10774 clinical trial will be monitored by the MCC DSMC according to the 
schedule identified by the MCC Protocol Review and Monitoring Committee. 
15 REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Patients of Research 
(US National Commission for the Protection of Human Patients of Biomedical and 
Behavioral Research, April 18, 1979). 
15.2 Regulatory Compliance 
This study will be conducted in compliance with the clinical trial protocol and with federal 
regulations, as applicable, including: 21 CFR 50 (Protection of Human Patients/Informed 
Consent); 21 CFR 56 (Institutional Review Boards); 21 CFR 312 (IND Application); and 45 
CFR 46 Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and 
Neonates), C (Prisoners), and D (Children). 
15.3 Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and 
the associated informed consent document and recruitment material by an appropriate IRB 
registered with the Office for Human Research Protections (OHRP). Any amendments to 
the protocol or consent materials must also be approved. In the United States and in other 
countries, only institutions holding a current US Federalwide Assurance issued by OHRP 
may participate. 
15.4 Informed Consent Process 
Informed consent is a process that is initiated prior to the patient’s agreeing to participate 
in the study and continues throughout the patient’s study participation. Extensive 
discussion of risks and possible benefits of this therapy will be provided to patients and 
their families. Consent forms describing in detail the study interventions/products, study 
procedures, and risks are given to the patient and written documentation of informed 
consent is required prior to starting the study intervention/administering study product. 
Consent forms will be IRB-approved and the patient will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to 
the patient and answer any questions that may arise. Patients should have the opportunity 


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to discuss the study with their surrogates and to think about it prior to agreeing to 
participate. The patient will sign the informed consent document prior to any procedures 
being done specifically for the study. Patients may withdraw consent at any time 
throughout the course of the trial. A copy of the consent form will be given to the patients 
for their records. The rights and welfare of the patients will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
15.5 Patient Confidentiality 
Patient confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to 
participating patients. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the patients 
in this study. The clinical study site will permit access to such records. 
16 DATA COLLECTION AND MANAGEMENT 
16.1 Data Management Responsibilities 
The Sponsor-Investigator is responsible for: (i) reviewing SAE reports; (ii) determining if 
SSARs need to be reported to the FDA, and if so, filing the report; (iii) filing annual IND 
reports; and (iv) filing IND amendments. 
The Sponsor-Investigator is responsible for: (i) the overall conduct of the investigation; (ii) 
ongoing review of trial data including all safety reports; and (iii) apprising participating 
investigators of any UPs. 
The Sponsor-Investigator is responsible for: (i) the data management; and (ii) reporting 
SAEs, SSARs, UPs, and DLTs as required in Section 8. 
Any laboratory conducting correlative studies must maintain the laboratory records and 
documentation. 
16.2 CRFs and Data Collection 
MCC OnCore data management will provide standard electronic CRFs (eCRFs) and create 
study-specific eCRFs to be able to capture all information required by the protocol. The 
eCRFs will be approved by the study team to ensure the most effective data acquisition. 


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The Sponsor-Investigator and other investigators and study coordinators must maintain 
source documents for each patient in the study. All information on eCRFs will be traceable 
to these source documents, which are generally maintained in the patient’s file. 
All DLT events are reported to the Sponsor-Investigator within 1 business day by email as 
indicated on Table 11. 
All eCRFs should be completed and available for collection within a timely manner, 
preferably no more than 14 days after the patient’s visit. 
16.3 Study Record Retention 
As applicable, study records will be maintained a minimum of 5 years beyond the 
publication of any abstract or manuscript reporting the results of the protocol or submission 
of a final report to clinicaltrials.gov. 


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S, Dent P. Sorafenib activates CD95 and promotes autophagy and cell death via Src 
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21. Gril B, Palmieri D, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, Andreu Z, Masana D, 
Fernandez P, Steeg PS, Vidal-Vanaclocha F. Pazopanib inhibits the activation of 
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24. Lin TY, Fenger J, Murahari S, Bear MD, Kulp SK, Wang D, Chen CS, Kisseberth WC, 
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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (eg, light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self; unable to carry on 
normal activity or to do active 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 
> 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time. 
Capable of only limited self-care, 
confined to bed or chair > 50% of 
waking hours. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 


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APPENDIX 2. COCKCROFT-GAULT FORMULA 
 
 
Calculated Creatinine Clearance (Cockcroft-Gault) 
 
Creatinine clearance (mL/min) = [(140 - Age) × Weight in kg ×G] / (Creatinine × 72) 
G=1 (males); G=0.85 (females)