Clinical trial NCT01593748
Conditions: Sarcoma
Keywords: Sarcoma Soft Tissue Sarcoma
Sponsor: Medical University of South Carolina
Start date: 2012-09-27; Completion date: 2019-04-24
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is for adult subjects with advanced tissue sarcoma. The study involves the drugs Pazopanib (Votrient), Gemcitabine (Gemzar), and Docetaxel (Taxotere). The purpose of this study is to test the effectiveness and safety of Gemcitabine and Pazopanib compared with Gemcitabine and Docetaxel in participants with soft tissue sarcoma.

Detailed description:
The purpose of this study is to test the effectiveness and safety of Gemcitabine and Pazopanib compared with Gemcitabine and Docetaxel in participants with soft tissue sarcoma. Screening tests will be done to ensure subjects are eligible to participate in this study. If the exams, tests and procedures show that subjects can be in the study, and they choose to take part, then they will be "randomized" into one of the two study groups: Group 1 or Group 2. Subjects in Group 1 will receive Gemcitabine 1000 mg/m2 intravenously (directly into a vein) on Day 1 and Day 8 and Pazopanib 800mg by mouth daily. Subjects in Group 2 will receive Gemcitabine 900 mg/m2 intravenously on Day 1 and Day 8 and Docetaxel 100 mg/m2 intravenously on Day 8. Both groups will be in 21 day cycles. Both groups will be asked to complete "quality of life" questionnaires, on their first visit, then at 6 weeks (2nd cycle), 18 weeks (6th cycle) and at the end of study treatment. Subjects will be followed for up to 2 years.

Arms: arm 1: Patients in Group 1 will get Gemcitabine 1000 mg/m2 intravenously on Day 1 and Day 8 and Pazopanib 800mg by mouth daily on a 21 day cycle. Cycles will continue until disease progression or patient withdrawal. arm 2: Patients in Group 2 will get Gemcitabine 900 mg/m2 intravenously on Day 1 and Day 8. Additionally on Day 8, patients will have Docetaxel 100 mg/m2 given intravenously. on a 21 day cycle. If disease progression occurs on this treatment, patients will have the option to receive treatment with Gemcitabine and Pazopanib (group 1).
Interventions: intervention 1: Gemcitabine and Pazopanib intervention 2: Gemcitabine and Docetaxel
Intervention descriptions: intervention 1: Gemcitabine 1000 mg/m2 by IV on day 1 and day 8 of a 21 day cycle. Pazopanib 800 mg by oral tablet daily for a 21 day cycle. intervention 2: Gemcitabine 900 mg/m2 by IV on day 1 and day 8 of a 21 day cycle. Docetaxel 100 mg/m2 by IV on day 8 of a 21 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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A Randomized, Open-label, Phase II, Multi-center Trial of Gemcitabine (G) with Pazopanib (P) or 
Gemcitabine (G) with Docetaxel (T) in Previously Treated Subjects with Advanced Soft Tissue 
Sarcoma. 
 
NCT01593748 
 
Protocol v 9.1 dated August 11, 2016  
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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NCI Protocol #: NCT01593748 
 
 
MUSC Protocol #: 101644  
Novartis Protocol #:  CPZP034BUS1T 
(GSK Protocol #:PZP115785) 
 
TITLE:  A Randomized, Open-label, Phase II, Multi-center Trial of Gemcitabine (G) with Pazopanib 
(P) or Gemcitabine (G) with Docetaxel (T) in Previously Treated Subjects with Advanced Soft 
Tissue Sarcoma.  
 
Coordinating Center: 
 
 
Medical University of South Carolina 
 
Funding:  
 
 
 
 
 
Novartis 
 
Coordinating Center Principal Investigator: Daniel Reuben, MD 
 
 
 
 
 
Medical University of South Carolina  
 
 
 
 
 
Hollings Cancer Center 
 
 
 
 
 
86 Jonathan Lucas St. 
 
 
 
 
 
Charleston, SC 29425 
 
 
 
 
 
Phone: 843-792-4271 
 
 
 
 
 
Email: reubend@musc.edu 
 
Study Contributor Principal Investigators: 
Andrew Kraft, MD 
 
 
 
 
Neeta Somaiah, MD 
University of Arizona Cancer Center  
 
 
M.D. Anderson Cancer Center  
1515 North Campbell Avenue 
 
 
 
 
1515 Holcombe Boulevard, Unit 450 
Tucson, Arizona 85724 
 
 
 
 
Houston, Texas 77030 
 
 
 
 
 
 
 
Statistician: 
       
 
 
Elizabeth Garrett-Mayer, PhD 
 
Hollings Cancer Center 
 
86 Jonathan Lucas St., Rm 118G 
 
Phone: 843-792-7764 
 
Email: garrettm@musc.edu   
 
 
 
 
  
 
Coordinating Office:   
 
 
 
 
Clinical Trials Network
Hollings Cancer Center 
86 Jonathan Lucas St  
 
Kate Anderton, MPH, CCRP 
Phone: 843-792-2708 
Fax: 843-792-5123 
Email: anderton@musc.edu 
Cameron Coggins 
Phone:  843-792-4743 
Fax:  843-792-5123 
Email:  cogginca@musc.edu 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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Study Drugs : 
Gemcitabine: commercially available 
Docetaxel: commercially available 
Pazopanib: supplied by Novartis 
 
 
Protocol Version History: 
Amendment 9.1 dated August 11, 2016 
Amendment 8 dated January 27, 2016 
Amendment 7.1 dated December 1, 2015 
Amendment 6 dated July 7, 2014 
Amendment 5 dated June 12, 2014 
Amendment 4 dated April 25, 2014 
Amendment 3 dated September 16, 2013 
Amendment 2 dated March 19, 2013 
Amendment 1 dated May 10, 2012  
Original Version 1.1 dated December 7, 2011 
Original Version 1.0 dated August 24, 2011 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
Baseline evaluations should be performed ≤ 14 days before registration except for radiological evaluation of disease, which 
should be within 4 weeks before registration. Pregnancy test when applicable should be ≤ 7 days before registration. 
 
 
Screening:  Inclusion & 
Exclusiona  
Criteria Fulfilled 
STS 
(excluding liposarcoma & GIST) 
1:1 Randomization
Stratify Leiomyosarcoma (LMS) 
(Y/N) 
Pelvic Radiation (Y/N)
Group 2:  Gemcitabine 
and Pazopanib (G+P) 
N=45 
Group 1:  Gemcitabine 
and Docetaxel (G+T) 
N=45 
Cycle =21 days 
G 900 mg/m2 iv over 90 minutes on 
days 1 & 8 
D 100 mg/m2 over 60 min on day 8 
Standard premedications 
Cycle =21 days 
G 1000 mg/m2 iv over 90 minutes on days 
1 & 8 
P 800 mg PO once daily days 1 through 21 
Standard premedications 
Optional QOL questionnaire on 
Day 1 prior to any other study 
procedures, at 6 weeks (after 
cycle 2), 18 weeks (after cycle 6) 
and at end of therapy. 
Optional blood draws  for CAF 
biomarkers and specimen 
banking prior to treatment, at 
cycle 2 and at end of  therapy 
Optional QOL questionnaire on 
Day 1 prior to any other study 
procedures, at 6 weeks (after 
cycle 2), 18 weeks (after cycle 6) 
and at end of therapy. 
Optional blood draws  for PK 
Analysis, CAF biomarkers and 
specimen banking prior to 
treatment, at cycle 2 and at end of 
therapy 
Assess disease status every 6 
weeks until progression 
Patients who progress during 
initial therapy may be given the 
option to cross over 
Disease progression, 
unacceptable toxicity, 
patient withdrawal, etc. 
Optional crossover.  Disease 
status assessments will be every 
6 weeks on the crossover arm.   
End of treatment evaluation. 
Follow patients for progression or 
survival q 3 months for a 
maximum of 24 months after the 
last patient has been registered to 
the trial.    
Disease progression, 
unacceptable toxicity, 
patient withdrawal, etc. 
Optional crossover.  Disease 
status assessments will be every 
6 weeks on the crossover arm.   
End of treatment evaluation. 
Follow patients for progression 
and survival q 3 months for a 
maximum of 24 months after the 
last patient has been registered to 
the trial.    


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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TABLE OF CONTENTS 
SCHEMA ................................................................................................................................... 4 
1 
OBJECTIVES .............................................................................................................. 9 
1.1 
Primary Objectives ....................................................................................................... 9 
1.2 
Secondary Objectives .................................................................................................. 9 
1.3 
Correlative Objectives(s) .............................................................................................. 9 
2 
BACKGROUND ..........................................................................................................10 
2.1 
Soft Tissue Sarcomas (STS) .......................................................................................10 
2.2 
Study Drug:  Pazopanib ..............................................................................................11 
2.2.1 Safety in clinical studies with monotherapy pazopanib: Integrated data from Studies 
VEG105192, VEG102616, and VEG107769 ................................................................. 12 
2.2.2 Summary of Common Toxicities ................................................................................... 14 
2.2.3 Pazopanib in soft tissue sarcoma (STS) ....................................................................... 17 
2.3 
Study Drug:  Gemcitabine ...........................................................................................18 
2.4 
Study Drug:  Docetaxel ...............................................................................................19 
2.5 
Rationale for this study ...............................................................................................19 
2.6 
Dosing rationale for the investigational arm ................................................................20 
2.7 
Correlative Studies Background ..................................................................................21 
3 
PATIENT SELECTION ...............................................................................................23 
3.1 
Inclusion Criteria .........................................................................................................23 
3.2 
Exclusion Criteria ........................................................................................................25 
3.3 
Inclusion of Women and Minorities .............................................................................27 
4 
STUDY DESIGN & REGISTRATION PROCEDURES ................................................28 
4.1 
Study Design ..............................................................................................................28 
4.2 
Registration procedure ................................................................................................28 
5 
TREATMENT PLAN ...................................................................................................29 
5.1 
Treatment schedule ....................................................................................................29 
5.2 
PAZOPANIB Instructions ............................................................................................30 
5.3 
GEMCITABINE premedications ..................................................................................30 
5.4 
TAXOTERE premedications .......................................................................................30 
5.5 
General Concomitant Medication and Supportive Care Guidelines .............................30 
5.5.1 Permitted Medications .................................................................................................. 30 
5.5.2 Permitted Medications – Use with Caution .................................................................... 31 
5.5.3 Prohibited Medications ................................................................................................. 33 
5.6 
End of Treatment ........................................................................................................34 
6 
PATIENT CROSSOVER .............................................................................................35 
6.1 
Crossover Inclusion Criteria ........................................................................................35 
6.2 
Crossover Exclusion Criteria .......................................................................................36 
6.3 
Crossover Procedures ................................................................................................38 
6.4 
Crossover Correlative Studies ....................................................................................39 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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6.5 
Crossover Therapy and Dose Level ............................................................................39 
6.6 
Duration of Follow Up .................................................................................................39 
6.7 
Crossover Criteria for removal from Study ..................................................................40 
7 
DOSING DELAYS/DOSE MODIFICATIONS ..............................................................41 
7.1 
General principles .......................................................................................................41 
Table 4:  G+P Dose Levels ..................................................................................................... 41 
Table 5:  G+T Dose Levels ..................................................................................................... 41 
7.2 
Hematologic toxicities: ................................................................................................42 
Table 6 Adjustments based on blood counts on day 1 of a treatment cycle............................. 42 
Table 7 Adjustments based on blood counts on day 8  of a treatment cycle. ........................... 42 
Table 8 Adjustments based on blood counts on Cycle 1 Day 15 of a treatment cycle 
(Pazopanib related only) ............................................................................................... 43 
7.2.1 Adjustments for febrile neutropenia and sepsis ............................................................. 43 
7.2.2 Adjustment for Anemia ................................................................................................. 43 
7.3 
Dose Interruptions/Modifications Specific for Pazopanib Related Toxicities, Excluding 
Liver Toxicities ............................................................................................................43 
Table 9 Dose Modification Algorithms for Potential Pazopanib-Related Adverse Events ......... 44 
7.4 
Dose Interruptions/Modifications for Hepatotoxicity .....................................................47 
Table 11 Guidelines for Management of Treatment Emergent Hepatotoxicity in G+T arm ...... 49 
7.5 
Dose Interruptions/Modifications Specific for Non-Hematologic Toxicities, Excluding 
Liver Toxicities ............................................................................................................49 
Table 12 Adjustments for drugs based on stomatitis, esophagitis, or dysphagia on day 1 of a 
treatment cycle ............................................................................................................. 49 
Table 13 Adjustments for drugs based on stomatitis, esophagitis, or dysphagia on day 8 of a 
treatment cycle ............................................................................................................. 50 
Table 14 Adjustments for all drugs based on dyspnea or pneumonitis on day 1 or day 8 of a 
treatment cycle ............................................................................................................. 50 
7.5.1 Hypersensitivity reaction ............................................................................................... 50 
7.5.2 Peripheral neuropathy: ................................................................................................. 50 
Table 15 Adjustments for docetaxel based on peripheral neuropathy on day 8 of a treatment 
cycle ............................................................................................................................. 50 
7.5.3 Fluid retention or Hyperlacrimation ............................................................................... 51 
7.5.4 Other treatment related non-hematologic toxicity: ......................................................... 51 
Table 16 Adjustments for G and T based on any other treatment related non-hematologic 
toxicity on day 1 or 8 of a treatment cycle (See 6.1 for exceptions) ............................... 51 
8 
STUDY AGENT INFORMATION ................................................................................52 
8.1 
Investigational agent: Pazopanib ................................................................................52 
8.1.1 Formulation, product identification, package and labeling ............................................. 52 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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8.1.2 Destruction of drug ....................................................................................................... 52 
8.1.3 Records to be kept at site, dispensing and accountability ............................................. 52 
8.1.4 Treatment of Investigational Product Overdose ............................................................ 53 
8.2 
Commercial Agent(s) ..................................................................................................54 
8.2.1 Gemcitabine ................................................................................................................. 54 
8.2.2 Docetaxel (Taxotere) .................................................................................................... 54 
9 
CORRELATIVE/SPECIAL STUDIES ..........................................................................55 
9.1 
Cytokine and Angiogenesis Factors Biomarker Studies ..............................................55 
9.2 
Specimen Banking Study ............................................................................................55 
9.3 
Pharmacokinetic Study ...............................................................................................55 
 
Quality of Life Assessment ..........................................................................................55 
9.4 
55 
10 
STUDY ASSESSMENTS ............................................................................................57 
10.1 STUDY CALENDAR- GROUP 1: GEMCITABINE + DOCETAXEL..............................58 
10.2 STUDY CALENDAR- GEMCITABINE + PAZOPANIB.................................................60 
11 
MEASURES OF EFFECT ...........................................................................................62 
11.1 Definitions ...................................................................................................................62 
11.2 Disease Parameters ...................................................................................................62 
11.3 Methods for Evaluation of Measurable Disease ..........................................................63 
11.4 Response Criteria .......................................................................................................65 
11.5 Duration of Response .................................................................................................66 
11.6 Progression-Free Survival ...........................................................................................66 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................67 
12.1 Adverse events ...........................................................................................................67 
12.2 Serious adverse events (SAE) ....................................................................................67 
12.3 Reporting of SAE's ......................................................................................................68 
12.4 Data and Safety Monitoring .........................................................................................69 
12.5 Data Collection ...........................................................................................................70 
13 
STATISTICAL CONSIDERATIONS ............................................................................71 
13.1 Primary Endpoint(s): ...................................................................................................71 
13.2 Secondary Endpoint(s): ..............................................................................................71 
13.3 Sample size justification ..............................................................................................71 
13.4 Sample Size/Accrual Rate ..........................................................................................72 
13.5 Stratification Factors ...................................................................................................72 
13.6 Analysis of Secondary Endpoints ................................................................................73 
13.7 Reporting and Exclusions ...........................................................................................73 
14 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ........................74 
14.1 Monitoring and Regulatory Compliance ......................................................................74 
14.2 Subsite Monitoring ......................................................................................................74 
14.3 Frequency of Reviews ................................................................................................75 
14.4 Data Safety Monitoring Board .....................................................................................75 
14.5 Study Initiation Requirements .....................................................................................75 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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14.6 Study Completion .......................................................................................................76 
14.7 Protocol Modifications .................................................................................................76 
14.8 Protocol Deviations and Safety Reporting ...................................................................77 
14.9 Patient Privacy ............................................................................................................77 
14.10 Publication Policy ........................................................................................................77 
15 
ETHICAL CONSIDERATIONS ...................................................................................78 
15.1 Informed Consent .......................................................................................................78 
15.2 Institutional Review Board ...........................................................................................78 
16 
DATA HANDLING AND RECORD KEEPING .............................................................79 
16.1 Data recording and quality control ...............................................................................79 
16.2 Record retention .........................................................................................................79 
17 
DATA COLLECTION ..................................................................................................80 
18 
RECRUITMENT PROCEDURE ..................................................................................81 
19 
REFERENCES ...........................................................................................................82 
APPENDIX A: PERFORMANCE STATUS CRITERIA .................................................................  84 
APPENDIX B: DETERMINATION OF CREATININE CLEARANCE (CLCR) .............................85 
APPENDIX C URINE PROTEIN CREATININE RATIO (UPC)...................................................86 
APPENDIX D:  NYHA CLASSIFICATION OF CONGESTIVE HEART FAILURE .......................87 
APPENDIX E:  SUPPORTIVE CARE GUIDELINES FOR DIARRHEA, NAUSEA AND VOMITING
 .................................................................................................................................................88 
APPENDIX F :MANAGEMENT OF ACUTE HYPERSENSITIVITY ............................................91 
APPENDIX G:MANAGEMENT OF EDEMA/FLUID RETENTION ..............................................92 
APPENDIX H:MANAGEMENT OF HYPERLACRIMATION .......................................................93 
APPENDIX I:  THE QLQ-C30 VERSION 3.0 .............................................................................94 
APPENDIX J:  EQ-5D QUESTIONNAIRE .................................................................................97 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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1 OBJECTIVES 
 
1.1 Primary Objectives 
 
 
To estimate the progression-free survival (PFS) of the combination of gemcitabine plus 
pazopanib (G+P) and to estimate the PFS of the combination of gemcitabine plus 
docetaxel (G+T) in patients with metastatic and/or locally advanced or recurrent soft 
tissue sarcoma 
 
 
To estimate the rate of grade 3 or higher toxicity with G+P and G+T and to describe the 
type and grade of toxicities. 
 
1.2 Secondary Objectives 
 
 
To estimate the hazard ratio comparing G+P vs. G+T in patients with metastatic and/or 
locally advanced or recurrent soft tissue sarcoma. 
 
 
To estimate the response rates of G+P and G+T in metastatic and/or locally advanced 
or recurrent soft tissue sarcoma patients. 
 
 
To examine quality of life (QOL) measures with both regimens (using EORTC QLQ-C30 
version 3 and EuroQol questionnaires). 
 
1.3 Correlative Objectives(s) 
 
 
An optional plasma biomarker study will be conducted for all patients randomized to 
either arm. The plasma biomarker study will evaluate circulating cytokine and 
angiogenesis factors (CAFs) that might include but are not limited to, IL-12, HGF, IL-16, 
IP-10, SDF-1α, IL-2Rα, IL-3, IFN-α2, tumor necrosis factor-related apoptosis-inducing 
ligand (TRAIL), M-CSF, and PIGF. Plasma will be collected at randomization (pre-
treatment), cycle 2 and at time of progression to examine antiangiogenic biomarkers as 
predictors of response to G+P and G+T.  
 
 
An optional PK analysis will also be conducted for patients receiving G+P (includes 
consenting patients who are initially randomized to the G+P arm and consenting 
patients who crossover to the G+P arm after G+T). A plasma sample will be collected at 
randomization (pre-treatment), cycle 2 and at time of progression for consenting 
patients receiving pazopanib to assess pazopanib concentration for correlation. 
 
 
An optional blood banking study will also be offered to patients on either arm. An 
additional blood draw at prior to treatment, Cycle 2 and at disease progression will be 
obtained from consenting patients enrolled to either arm for specimen banking and 
future studies. 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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2 BACKGROUND 
 
2.1 Soft Tissue Sarcomas (STS) 
 
STS constitutes a heterogeneous group of malignancies arising in extraskeletal connective 
tissues (muscle, fat, fibrous tissue, blood vessels, or other mesenchymally-derived tissues), 
that comprise approximately 1% of all adult malignancies, while they give rise to 2% of total 
cancer related mortality.  At present all these subtypes are usually grouped under the 
heading of STS for the purpose of treatment, although increasing options in the future 
might allow treatment directed specifically at individual subtypes.   
 
Current treatment options for patients with STS vary with clinical stage, but may include 
surgery, radiotherapy and chemotherapy [1]. For patients with resectable disease, surgery 
is the standard treatment, as it results in the greatest chance for long-term disease-free 
survival.  The addition of post-operative radiation appears to reduce the rate of local 
recurrence [2].  Radiation is also used as the primary treatment modality for inoperable 
tumors as well as for palliative purposes.  However, even optimal local treatment does not 
prevent the occurrence of distant metastasis in many patients, especially those with high-
grade tumors.  Approximately 50% of patients present with or develop advanced or 
metastatic disease. STS metastasizes primarily to the lungs, but also to bone, liver and 
other organs depending on sub-type.   
 
Chemotherapy is widely used in the treatment of non-resectable advanced disease, 
basically with palliative intent, as most initially chemotherapy sensitive patients will 
ultimately relapse.  Despite available chemotherapy, the prognosis for these patients is 
very poor, with an estimated median survival of 8 to 13 months from the start of first-line 
anthracycline-based chemotherapy, as shown in randomized studies performed over the 
last 2 decades [3-6]. In addition these patients are often debilitated by their sarcoma as 
bulky disease might result in complications such as pain, intestinal obstruction and other 
symptoms leading to end-organ failure and death. 
 
At present, initial standard chemotherapy for advanced or metastatic STS consists of an 
anthracycline (mainly doxorubicin) given as a single agent or in combination with ifosfamide 
[7].  The cumulative response rate in non-treated patients is 23% (15-30%) [8].  The use of 
doxorubicin is limited due to its risk of cumulative cardiac toxicity.  The median survival for 
patients for whom conventional chemotherapy with an anthracycline and ifosfamide has 
failed is in the range of 6 months [9-13]. 
 
The combination of gemcitabine and docetaxel is another frequently used second-line 
regimen in soft tissue sarcomas and occasionally used front-line for leiomyosarcomas, the 
histology with the highest reported response rates to this combination.  Maki et al, reported 
a phase II study in metastatic STS that suggested a survival benefit for the combination 
versus single agent gemcitabine [14]. The median progression-free survival (PFS) of 
gemcitabine therapy alone was 3 months; when combined with docetaxel, the median PFS 
increased to 6.2 months. However, the combination of gemcitabine and docetaxel is a 
relatively poorly tolerated regimen and 46% patients required at least one dose reduction 
and many of them discontinued therapy within 6 months due to toxicity.  
 
The rate of gemcitabine administration may be crucial to maximizing the antitumor activity 
of this drug. The intracellular accumulation of gemcitabine triphosphate, the active form of 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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the drug, is saturated at gemcitabine dose rates that produce plasma gemcitabine 
concentration of 10 to 20 μmol/L. A gemcitabine dose of 900 mg/m2 given over a 90-minute 
infusion remains above a 10 μmol/L threshold approximately 50% longer versus the 
standard 30 minutes bolus infusion [14]. Gemcitabine is administered iv on days 1 and 8 of 
a 21-day cycle over 90 minutes in the treatment of STS. 
 
There still remains a dearth of active agents in sarcoma and a great need to look for newer 
compounds and combinations with meaningful activity and hopefully a better toxicity profile. 
It has been reported that circulating angiogenic factor levels correlate with extent of disease 
and risk of recurrence in patients with soft tissue sarcoma [16].  Mean levels of VEGF and 
bFGF were significantly higher in patients compared to controls [17-19]. Sarcomas in 
general therefore appear to be a good target tumor type for evaluation of angiogenesis 
inhibitors, and particularly for those preventing VEGF action. In an EORTC phase II trial, 
800 mg daily of oral pazopanib showed single-agent activity in soft tissue sarcomas, 
including leiomyosarcoma and synovial sarcomas, but not in adipocytic tumors [20].  
Recently, results from PALETTE, a phase III study of pazopanib versus placebo in 
previously treated soft tissue sarcoma patients showed a statistically significant 
improvement in progression-free survival (PFS) with a median increase of 13 weeks, and 
the interim analysis for overall survival (OS) showed a trend toward improvement. [21] 
 
2.2 Study Drug:  Pazopanib 
 
Numerous growth factors and cytokines are involved in the angiogenic process, i.e., the 
process of new blood vessel formation, important in the development and progression of 
malignancy. Among these factors, vascular endothelial growth factor (VEGF) has a 
predominant role as a central mediator of tumor-related angiogenesis, and its expression has 
been shown to be an adverse prognostic factor for a number of solid tumors [22-24].  
Pazopanib, is a multi-target, small molecule inhibitor.  It is an orally-bioavailable, ATP-
competitive tyrosine kinase inhibitor of VEGFR (-1, -2, and -3), PDGFR (-α and -β), and c-Kit 
[25].  
Clinical data from more than 20 clinical Phase I, II, and III studies are presented in the current 
version of the Investigator’s Brochure (IB) (RR2002/00017/10). As of 09 September 2010, over 
5000 subjects have been enrolled in pazopanib oncology clinical studies conducted. Clinical 
data indicate that (a) pazopanib is absorbed after oral administration, (b) the 800 mg daily 
dosing regimen is an active monotherapy dose for subjects with cancer, providing optimal 
biologic and clinical effects associated with VEGFR inhibition, (c) pazopanib is generally well-
tolerated at the 800 mg daily dosing regimen, and (d) pazopanib has encouraging efficacy in 
specific tumor settings such as renal cell carcinoma (RCC), sarcoma, non-small cell lung 
cancer (NSCLC), cervical and ovarian cancer.  
 
The most common adverse events reported for pazopanib monotherapy to date are diarrhea, 
fatigue, nausea, hypertension, hair color changes (hair depigmentation), anorexia, vomiting, 
dysgeusia, headache, abdominal pain, rash, aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) increases, constipation, cough, and arthralgia. Most of these events 
were Grade 1 or 2 using the National Cancer Institute-Common Toxicity Criteria of Adverse 
Events, Version 3.0 (NCI-CTCAE, v3.0). The most frequent Grade 3 or 4 events were 
hypertension, fatigue, diarrhea, and AST and ALT increases. Less common AEs of note 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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include hand-foot syndrome, mucositis/stomatitis, proteinuria, venous thrombotic events, and 
bleeding. Intestinal perforations and arterial thromboses were uncommon.  
A review of serious adverse events (SAEs) across oncology studies revealed that the most 
frequently reported SAEs (≥50 events), regardless of causality and treatment regimen, as of 09 
September 2010 in decreasing order of frequency were alanine aminotransferase increased, 
vomiting, dyspnea, abdominal pain, diarrhea, dehydration, pyrexia, fatigue, pneumonia, 
anemia, aspartate aminotransferase increased, nausea, pleural effusion, hypertension, and 
pulmonary embolism. A number of these events are known class effects of VEGF inhibitors.  
 
2.2.1 Safety in clinical studies with monotherapy pazopanib: Integrated data from Studies 
VEG105192, VEG102616, and VEG107769 
 
The safety profile of pazopanib used in the treatment of RCC has been further defined in an 
integrated analysis of data from 593 subjects who received pazopanib across 3 RCC 
studies as of 09 January 2009.  The database supporting the safety profile of pazopanib in 
subjects with RCC includes the completed placebo-controlled Phase III study VEG105192, 
with 290 subjects treated with pazopanib, a completed supportive Phase II study 
(VEG102616) in which 225 subjects were treated with pazopanib, and the ongoing open-
label extension study VEG107769 (n=78).   
 
For the RCC studies described, the AE profile and hematology and laboratory chemistry 
abnormalities were similar to those seen for VEG105192 alone (Table 1, 2 & 3).  As of 
09 January 2009, the most common AEs reported in subjects receiving pazopanib included 
diarrhea (55%), hypertension (41%), hair color changes (40%), nausea (32%), fatigue 
(29%), anorexia (24%), vomiting (21%), and ALT increased (17%).  Most of these events 
were Grade 1 or 2 using the NCI CTCAE Version 3.0.  Commonly reported AEs with the 
most frequent Grade 3 classification were hypertension (6%), ALT increased (5%), and 
AST increased (4%).  Grade 4 and Grade 5 events were infrequently reported (9% and 4%, 
respectively). 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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Table 1: Adverse Events Reported for at Least 10% of Subjects (Safety Population) in Study 
VEG105192 
Preferred 
Term  
Number (% of subjects) 
Placebo (n=145) 
Pazopanib (n=290) 
 
Any Gradea 
Grade 3 
Grade 4 
Any Gradea 
Grade 3 
Grade 4 
Any AEa 
107 (74) 
21 (14) 
8 (6) 
268 (92) 
96 (33) 
20 (7) 
Diarrhea  
13 (9) 
1 (<1) 
0 
150 (52) 
9 (3) 
2 (<1) 
Hypertension 
15 (10) 
1 (<1) 
0 
115 (40) 
13 (4) 
0 
Hair color 
changes 
4 (3) 
0 
0 
109 (38) 
1 (<1) 
0 
Nausea  
13 (9) 
0 
0 
74 (26) 
2 (<1) 
0 
Anorexia 
14 (10) 
1 (<1) 
0 
65 (22) 
6 (2) 
0 
Vomiting 
11 (8) 
3 (2) 
0 
61 (21) 
6 (2) 
1 (<1) 
Fatigue 
11 (8) 
2 (1) 
2 (1) 
55 (19) 
7 (2) 
0 
ALT increasec 
5 (3) 
1 (<1) 
0 
53 (18) 
18 (6) 
3 (1) 
AST increasec  
5 (3) 
0 
0 
43 (15) 
13 (4) 
1 (<1) 
Asthenia 
12 (8)b 
0 
0 
41 (14) 
8 (3) 
0 
Abdominal pain 
2 (1) 
0 
0 
32 (11) 
6 (2) 
0 
Headache 
7 (5) 
0 
0 
30 (10) 
0 
0 
a. AEs are ranked by incidence in the pazopanib arm.   Any AE, any grade includes Grade 5 
(fatal) events (12 [4%] subjects in the pazopanib arm and 4 [3%] subjects in the placebo arm).  
b. One placebo subject had Grade 5 asthenia. 
c.   ALT= alanine aminotransferase; AST= aspartate aminotransferase 
 
Table 2: Summary of Worst-case Hematologic Toxicity Grade Shift from Baseline (Safety 
Population) in Study VEG105192 
 
Number (%) of subjects 
Toxicity 
Placebo  
(n=145) 
Pazopanib  
(n=290) 
  
N 
Any  
gradea 
Grade 
3 
Grade 
4 
N 
Any  
gradea 
Grade 3 
Grade 4 
Leukopenia 
144 
9 (6) 
280 
103 (37) 
 0 
Neutropenia 
144 
9 (6) 
280 
94 (34) 
3 (1) 
 1 (<1) 
Thrombocytopenia  144 
7 (5) 
(<1) 
280 
89 (32) 
2 (<1) 
 1 (<1) 
Lymphocytopenia 
144 
34 (24) 
(1) 
280 
86 (31) 
11 (4) 
 1 (<1) 
Increased PTTb 
140 
34 (24) 
(<1) 
271 
72 (27) 
4 (1) 
 0 
Anemia  
144 
44 (31) 
(1) 
(<1) 
280 
62 (22) 
5 (2) 
 2 (<1) 
INRb 
128 
25 (20) 
(2) 
246 
42 (17) 
4 (2) 
 0 
a. Any grade increase from baseline.  Subjects with missing baseline grade were assumed to have 
baseline grade of 0. 
b.   PTT= Partial thromboplastin time; INR= International Normalized ratio. 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
14 
 
Table 3: Summary of Worst-Case Toxicity Grade Shift from Baseline for Clinical Chemistry 
Parameters (Safety Population) in Study VEG105192 
Clinical 
Chemistry 
Parameter 
Number (%) of subjects 
Placebo  
(n=145) 
Pazopanib  
(n=290) 
N 
Any 
gradea 
Grade 3 
Grade 4 
N 
Any 
gradea 
Grade 3 
Grade 
4 
ALT increase 
144 
32 (22) 
2 (1) 
0 
289 
152 (53) 
30 (10) 
5 (2) 
AST increase 
144 
27 (19) 
1 (<1) 
0 
288 
152 (53) 
21 (7) 
2 (<1) 
Hyperglycemia 
144 
47 (33) 
2 (1) 
0 
280 
115 (41) 
2 (<1) 
0 
Total Bilirubin 
increase 
144 
15 (10) 
2 (1) 
1 (<1) 
280 
102 (36) 
7 (3) 
2 (<1) 
Hyponatremia 
144 
35 (24) 
6 (4) 
0 
280 
86 (31) 
11 (4) 
4 (1) 
Hypophosphatemia 
141 
16 (11) 
0 
0 
276 
95 (34) 
11 (4) 
0 
Hypocalcemia 
137 
35 (26) 
2 (1) 
1 (<1) 
272 
91 (33) 
4 (1) 
4 (1) 
Hyperkalemia 
144 
33 (23) 
7 (5) 
0 
280 
76 (27) 
12 (4) 
1 (<1) 
Alkaline  
phosphatase 
144 
50 (35) 
3 (2) 
0 
280 
75 (27) 
4 (1) 
1 (<1) 
Creatinine  
increase 
144 
36 (25) 
1 (<1) 
0 
280 
73 (26) 
0 
2 (<1) 
Hypomagnesemia 
141 
20 (14) 
0 
0 
276 
72 (26) 
2 (<1) 
4 (1) 
Hypoglycemia 
144 
4 (3) 
0 
0 
280 
47 (17) 
0 
1 (<1) 
Hypermagnesemia 
141 
13 (9) 
3 (2) 
0 
276 
31 (11) 
9 (3) 
0 
Hypernatremia 
144 
11 (8) 
0 
0 
280 
30 (11) 
2 (<1) 
0 
Hypercalcemia 
137 
25 (18) 
2 (1) 
0 
272 
29 (11) 
0 
4 (1) 
Hypokalemia 
144 
3 (2) 
0 
0 
280 
24 (9) 
3 (1) 
2 (<1) 
a. Any grade increase from baseline. 
 
2.2.2 Summary of Common Toxicities 
 
Hepatotoxicity: Liver enzyme abnormalities were noted early in pazopanib clinical 
development and have been extensively evaluated.  Close monitoring of liver markers 
(ALT, AST, bilirubin, and alkaline phosphatase) with strict stopping criteria was 
implemented in pazopanib protocols.  While approximately half of all subjects who receive 
pazopanib experience some elevations in transaminases, few subjects (4%) had increases 
to  10xULN as of 09 January 2009.  In addition, 1% subjects had concurrent ALT and 
bilirubin elevations, without significant alkaline phosphatase elevations, that might be 
predictive of possible development of hepatic functional impairment.  Elevations in 
transaminases typically occurred in the first 18 weeks of treatment.  Hepatobiliary adverse 
events that were not laboratory abnormalities were less common and liver failure and fatal 
hepatic events were rare.  Three fatal hepatic events occurred:  one in a subject for which 
an independent pathology review demonstrated massive hepatic replacement by tumor, a 
second in a subject with rapid disease progression in the liver (adjudicated as unrelated to 
study drug by an independent hepatologist), and a third in a subject with underlying 
cirrhosis who developed a fatal esophageal hemorrhage (independent hepatologist could 
not rule out contribution of study drug in the setting of underlying cirrhosis). 
 
Across the RCC database (N=593), 107 (18%) subjects had an elevation in ALT ≥ 3xULN 
as of 09 January 2009.  ALT is a more specific indicator of hepatocellular injury than AST 
and was therefore used as a single criterion for evaluating outcomes.  Liver enzyme 
elevations were reversible upon cessation of the drug and in some cases while continuing 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
15 
 
on pazopanib.  In an analysis performed across the RCC database, 96/106 (91%) subjects 
had full recovery.  Recovery was defined as any ALT < 2.5xULN after the first elevation 
including post-therapy tests.  Seven of the remaining 10 subjects had limited or no follow-
up to determine recovery and 3 died of cancer progression with no follow-up ALT data.  It 
was noted early in development that some of the subjects with elevated hepatic enzymes 
remained on study drug despite these elevations and had normalization of their 
transaminases while remaining on pazopanib (“adaptation”).  Most subjects with 
transaminase elevations in whom dosing was interrupted could be successfully re-
challenged.   
 
For purposes of this analysis, adaptation was defined as an ALT ≥ 3xULN while exposed to 
study drug followed by a return to grade 0 or baseline grade without any interruption of 
study drug.  Subjects were considered to have been re-challenged if they developed ALT ≥ 
3xULN during exposure to study drug which recovered to Grade 1 or below following 
interruption and subsequently received study drug at either the same or reduced dose.  
These subjects were evaluated for recurrence of ALT abnormalities following the re-
challenge. 
 
Adaptation: 
 
 
32 subjects remained on study drug despite elevations of ALT ≥ 3xULN and 
experienced adaptation;  
 29 (91%) without dose reduction 
 3 (9%) after a dose reduction   
 
Median time to adaptation was 57 days (range 19-188 days) 
Re-challenge: 
 
31 subjects who had a dose interruption following an ALT elevation to ≥ 3xULN 
were re-challenged; 4 (13%) at the same dose and 27 (87%) at a lower dose.  The 
dose was reduced from 800 mg to 400 mg in 24 subjects and from 400 mg to 200 
mg in 3 subjects.  
 
Median duration of interruption prior to re-challenge was 19 days (range 5-139 
days).  
 
The median duration of re-treatment among all re-challenge subjects was 194 days 
(range 2-681 days).  The maximum ALT before re-challenge and the latest ALT 
prior to interruption did not appear to correlate with the likelihood of recurrent 
elevations.  
 
20 (65%) subjects did not experience an ALT ≥3xULN following a resumption of 
study drug;  
 
10 (32%) subjects had recurrent elevations  
 
2/10 (20%) subjects with recurrent elevations were continued on study drug and 
subsequently met the criteria for adaptation as defined above. Thus, these 2 
subjects are counted both as re-challenges and as adaptations.   
 
6/10 (60%) positive re-challenges recovered.  
 
2/10 (20%) had inadequate follow-up to assess recovery.   
 
1 (3%) subject had no follow-up data on the outcome of the re-challenge.   


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
16 
 
 
The remaining 45 subjects with increases in ALT  3xULN included 10 subjects with 
inadequate or absent follow-up data to assess recovery as well as those whose 
transaminases did recover either while remaining on pazopanib (but who did not meet 
criteria for adaptation and/or re-challenge) or after discontinuation of pazopanib. 
 
Hypertension: The cumulative incidence of hypertension across the 3 primary RCC 
studies was similar to that of the pazopanib-treated subjects in the VEG105192 study.  Two 
hundred and seventy-two (47%) out of 586 subjects experienced an on-study episode of 
hypertension (defined as systolic blood pressure of ≥150 mmHg and/or diastolic blood 
pressure of ≥100 mmHg).  These subjects did not have hypertension at baseline.  By Week 
18, it was noted that 239 of these 272 subjects had at least 1 episode of hypertension, 
which was 87.9% of all occurrences of hypertension.  By Week 24, it was noted that 249 of 
272 subjects had at least 1 occurrence of hypertension, which was 91.5% of all episodes of 
hypertension that occurred on pazopanib during the RCC trials. 
 
Only 6% of the RCC pazopanib-treated subjects reported Grade 3 hypertension.  Most 
subjects had a maximum grade of 1-2 for these events.  No Grade 4 or 5 hypertension 
event was reported in the RCC studies, with the exception of the Grade 4 SAE of 
hypertensive crisis. 
 
Cardiac and Vascular Events: Cardiac and vascular events were categorized as follows: 
non-vascular cardiac events included arrhythmias and cardiac dysfunction while vascular 
events included arterial thrombotic events (myocardial infarction/ischemia, cerebral 
vascular accident and transient ischemic attack [TIA]) and venous thrombotic events (deep 
vein thrombosis, pulmonary embolus). 
 
In VEG105192, the overall incidence rate of cardiac and vascular events was higher in the 
pazopanib arm compared with placebo (10% versus 6%).  A comprehensive analysis of 
exposure-adjusted incidence rates of cardiac and vascular events (a rate of 10 per 100 
patient-years’ indicates that in a cohort of 100 patients each treated for 1 year, 10 patients 
would be expected to experience the event of interest) demonstrates a similar incidence 
across placebo and pazopanib in VEG105192 and in the integrated RCC.    
 
While the exposure-adjusted incidence rates for all cardiac and vascular events were 
similar between the 2 arms (11.99 [CI 7.55, 16.43] per 100 patient-years in the pazopanib 
arm compared with 10.22 [CI, 3.14, 17.30] in the placebo arm), the exposure-adjusted 
incidence rate for Grade 5 events was higher on placebo (1.28 versus 2.55 per 100 patient-
years).  Analysis of exposure adjusted incidence rates of arrhythmia, cardiac dysfunction 
(cardiomyopathy), and venous thrombotic events demonstrated were similar between the 
placebo and pazopanib arm of study VEG105192 and the integrated the RCC population.  
The exposure adjusted incidence rate of arterial thrombotic events was higher in the 
pazopanib arm of VEG105192 compared with placebo (3.85 [CI 1.33, 6.37] versus 0 [CI 
could not be estimated] per 100 patient years).  Subjects who experienced these events 
had underlying risk factors for arterial thrombotic events including male gender, age > 65, 
hypertension, tobacco use, diabetes and peripheral vascular disease (PVD). 
 
Overall for the RCC program, QT prolongation (>500 msec) occurred in 10/558 (1.8%) 
subjects treated with pazopanib.  Two Torsades de Pointes cases have been identified. 
[Section  5.2.8.3 of the IB [RR2002/00017/10].  


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
17 
 
  
Hemorrhagic Events: Exposure-adjusted hemorrhagic event rates were higher on the 
pazopanib arm of VEG105192 compared with placebo, but similar to those seen in the 
integrated RCC population.  The exposure-adjusted incidence rate was 15.95 (CI 10.74, 
20.96) per 100 patient-years in the pazopanib arm compared to 8.94 (CI 2.32, 15.56) in the 
placebo arm.  Hemoptysis/pulmonary hemorrhages and GI tract hemorrhages were the 
most common SAEs reported.  Association to known metastases was noted for 4 of the 5 
hemoptysis/pulmonary hemorrhagic SAEs and 3 of the 7 GI tract hemorrhagic SAEs.  The 
most common hemorrhagic event was epistaxis.  Life-threatening and fatal hemorrhagic 
events were uncommon across both the RCC and monotherapy populations. 
 
Thyroid Function Abnormalities: Increases in thyroid stimulating hormone (TSH) are 
commonly noted in RCC subjects receiving pazopanib (29%).  Most of these subjects do 
not appear to develop clinically overt hypothyroidism.  Clinical hypothyroidism manifested 
as elevated T4 was noted in 6% of subjects.  The hypothyroidism AE incidence rate was 
also low (4-7%) and similar between VEG105192 and across the RCC studies for 
pazopanib-treated subjects.  
 
Hyperthyroidism occurs infrequently (1%) and the incidence was not significantly different 
in subjects receiving pazopanib compared to those receiving placebo on study 
VEG105192. 
 
Bowel Perforation and Enteric Fistulae: In the RCC population, 5 subjects (0.9%) 
suffered SAEs related to GI perforations or fistulae.  The 5 events were described as 
follows: ileal perforation (n=1), large intestine perforation (n=2), peritonitis secondary to 
intestinal perforation (n=1), and enterocutaneous fistula (n=1).  Two of these events, large 
intestine perforation and peritonitis secondary to intestinal perforation were fatal.  One 
event of large intestinal perforation was associated with diverticulitis.  Three events of 
perforation were related to underlying tumor.   
 
Proteinuria: Proteinuria is considered a class effect of VEGF inhibitors. In the placebo-
controlled RCC study, 28 of 289 (10%) subjects treated with pazopanib with evaluable 
laboratory data had 3+ proteinuria post-baseline and 6 (2%) had 4+ proteinuria post-
baseline. 
 
2.2.3 
Pazopanib in soft tissue sarcoma (STS) 
 
2.2.3.1 Safety Profile of Pazopanib in STS 
 
Study VEG20002: Phase II Study of GW786034 in Patients with Relapsed or 
Refractory Soft Tissue Sarcoma (European Organization for Research and Treatment 
of Cancer [EORTC] Study)  
 
As of 09 September 2008, enrollment was completed with 142 adult subjects enrolled. 
Safety and efficacy analyses were completed by the European Organization for 
Research and Treatment of Cancer (EORTC) and described in a synoptic clinical 
pharmacology study report, with effective date of 24 September 2008, and published by 
Sleijfer et al [20].  
 
All 142 subjects received pazopanib 800 mg once daily. AE data were available for all 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
18 
 
142 subjects. The most frequent clinical adverse events (AEs) (≥30%), regardless of 
causality, were fatigue (70%), nausea (46%), diarrhea (46%), hypertension (45%), 
decreased appetite (39%), skin hypopigmentation (37%), vomiting (36%), weight 
decreased (31%), dyspnea (31%), cough (30%), and constipation (30%). 
 
There were 9 subjects (6.3%) who had pazopanib withdrawn due to an AE. Four of the 
9 subjects had pazopanib withdrawn for elevation in transaminase. Elevation in 
transaminase was the single most common cause of discontinuation. Other events that 
lead to discontinuation were disseminated intravascular coagulation (DIC), pulmonary 
embolism, hypertension, hemoptysis, severe back pain, and bowel perforation with 
peritonitis. 
 
2.2.3.2 Pazopanib Efficacy in Sarcoma  
 
Final efficacy data for the phase II study (VEG20002) of GW786034 in patients with 
relapsed or refractory soft tissue sarcoma study were published in 2009 [20]. Treatment 
response data are available for 138 subjects who received pazopanib 800 mg once 
daily. Ninety-nine percent of subjects had received prior chemotherapy: 35 subjects 
(25%) had received therapy in a (neo)-adjuvant setting, 83 (59%) had received therapy 
in an advanced setting, and 22 (16%) had received both. 
 
 
 The primary endpoint was the progression-free rate, using RECIST at 12 weeks after 
start of treatment. Patients with leiomyosarcoma, synovial sarcoma and “the other types 
of sarcoma” strata receiving pazopanib in VEG20002 experienced a 12-week 
progression-free rate of ≥ 40%, the pre-defined threshold indicating anti-tumor activity. 
The liposarcoma stratum did not meet its prespecified endpoint at the end of stage 1 
and did not progress to stage 2.  
 
 
 Based on the results of the VEG20002, a Phase III randomized, double blind, placebo 
controlled study (VEG110727) of pazopanib versus placebo in subjects with soft tissue 
sarcoma (study excluded patients with GIST or liposarcoma) was initiated in 2008. 
Preliminary results of this study (PALLETE) were reported at ASCO 2011. Patients on 
the pazopanib arm showed a statistically significant improvement in progression-free 
survival (PFS) with a median increase of 13 weeks, and the interim analysis for overall 
survival (OS) showed a trend toward improvement [21]. 
 
2.3 Study Drug:  Gemcitabine 
 
 
Gemcitabine is a nucleoside metabolic inhibitor used in a variety of indications. The most 
common adverse reactions for the single-agent (≥20%) are nausea, vomiting, anemia, ALT, 
AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, 
thrombocytopenia and dyspnea. Myelosuppression can be dose limiting. 
 
Pulmonary toxicity has been reported and therapy should be discontinued immediately if lung 
injury is noted. Renal function also needs to be monitored. Cases of hemolytic uremic 
syndrome (HUS) and/or renal failure, some fatal, have occurred. Serious hepatotoxicity, 
including liver failure and death, has occurred. Gemcitabine can cause fetal harm. A pattern of 
tissue injury typically associated with radiation toxicity has been reported in association with 
concurrent and non-concurrent use of gemcitabine. Analysis of the data does not indicate 
enhanced toxicity when gemcitabine is administered more than 7 days before or after radiation, 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
19 
 
other than radiation recall. 
 
 
Increased toxicity has been noted with infusion time >60 minutes or dosing more frequently 
than once weekly. However, the rate of gemcitabine administration may be crucial to 
maximizing the antitumor activity of this drug. The intracellular accumulation of gemcitabine 
triphosphate, the active form of the drug, is saturated at gemcitabine dose rates that produce 
plasma gemcitabine concentration of 10 to 20 μmol/L. A gemcitabine dose of 900 mg/m2 given 
over a 90-minute infusion remains above a 10 μmol/L threshold approximately 50% longer 
versus the standard 30 minutes bolus infusion [14]. For the treatment of sarcomas the 
gemcitabine is administered iv on days 1 and 8 of a 21-day cycle over 90 minutes as part of the 
standard gemcitabine and docetaxel regimen.  
 
2.4 Study Drug:  Docetaxel 
 
The most common adverse reactions across all docetaxel (TAXOTERE) indications are 
infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, 
neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, 
asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. 
Incidence varies depending on the indication. The most serious adverse reactions associated 
with docetaxel are toxic deaths, hepatotoxicity, neutropenia and fluid retention. In general, 
across all indications responding patients may not experience an improvement in performance 
status on therapy and may experience worsening. The relationship between changes in 
performance status, response to therapy, and treatment-related side effects has not been 
established. 
 
The combination of gemcitabine and docetaxel has shown activity in soft tissue sarcomas with 
high response rates reported in the leiomyosarcoma sub-type and is commonly used as a 
second line regimen for STS or first line for leiomyosarcomas. 
 
2.5 Rationale for this study 
 
Pazopanib is an orally-bioavailable, ATP-competitive tyrosine kinase inhibitor of VEGFR (-1, -2, 
and -3), PDGFR (-α and -β) and c-Kit [25] that is approved for the treatment of advanced renal 
cell carcinoma (RCC)  and is actively being studied in multiple other cancers. As described 
above, an EORTC phase II study and a recently reported phase III study showed activity of 
single-agent pazopanib in soft tissue sarcomas.  The 800 mg daily dosing regimen is the 
established active monotherapy dose for subjects with RCC, providing optimal biologic and 
clinical effects associated with VEGFR inhibition and is generally well tolerated.  
 
Antiangiogenic therapies such as pazopanib may work by inducing vascular normalization, 
thereby alleviating hypoxia and increasing the delivery of cytotoxic chemotherapies to cancer 
cells [Jain, 2005]. The increased penetration of drugs throughout the tumor could enhance the 
antitumor benefit of chemotherapy. This provides a rationale for combining pazopanib with 
cytotoxic chemotherapy. A phase I study of pazopanib in combination with gemcitabine has 
been completed and the recommended phase II dose was 800 mg PO of pazopanib daily with 
1000 mg/m2 of gemcitabine on days 1 and 8. [Pazopanib Investigator Brochure version 8.] 
 
The goal for this study is (1) to examine the activity of pazopanib (P) as a treatment of sarcoma 
when combining with another active agent gemcitabine (G), and (2) to examine an alternative 
regimen to commonly used gemcitabine + taxotere (G + T) with fewer side effects and 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
20 
 
increased ease of administration. The median progression-free survival (PFS) of G therapy 
when administered as a single agent was 3 months; when combined with T, the median PFS 
increased to 6.2 months  [14]. However, 46% of patients receiving the combination required at 
least one dose reduction, and many of them discontinued therapy within 6 months due to 
toxicity. This suggests that a less toxic regimen would be preferred by both patients and 
physicians.  
 
We hypothesize that G+P in combination would be a more desirable combination therapy for 
patients with soft tissue sarcoma. However, no formal statistical hypothesis will be tested. The 
primary objective is to estimate the PFS and rate of grade 3 and 4 toxicities in patients with 
advanced soft tissue sarcoma that are given G+P relative to G+T to assess whether the 
efficacy and tolerability warrants taking it forward into Phase III testing.  Sample size was 
derived based on the precision of 95% confidence intervals for reporting toxicity rates and 
median PFS in each arm. 
 
2.6 Dosing rationale for the investigational arm 
 
Pazopanib 800 mg once daily is the recommended monotherapy dose based on clinical and 
preclinical results. 
 
Pharmacodynamic data indicate that pazopanib, at a monotherapy dose of 800 mg once daily, 
results in effects consistent with inhibition of the VEGF receptors it was designed to target.  
Concentration-effect relationships were observed between trough plasma pazopanib 
concentrations and the development of hypertension in Study VEG10003 and the percent 
change from baseline in sVEGFR2 nadir in Study VEG102616.  The trough plasma pazopanib 
concentrations associated with one-half the maximal effect (EC50) in both concentration-effect 
relationships were similar (21.3 g/mL and 15.3 g/mL) and demonstrate that there is a 
consistent inhibition of VEGF receptor(s) in subjects with cancer when plasma pazopanib 
concentrations are maintained above 15 g/mL.  The plasma pazopanib EC50 values for 
biologic effects observed in the clinical studies are similar to the plasma concentration of 40 M 
(17.5 g/mL) required for optimal inhibition of VEGFR-2 phosphorylation in mice [GSK Report 
RH2003/00005/00]. 
 
Progression Free Survival (PFS) in subjects with renal cell cancer in Study VEG102616 was 
compared between subjects whose trough plasma pazopanib concentrations (Cmin) at Week 4 
were above or below selected threshold values.  The deciles of the observed Cmin values were 
selected as threshold values so that approximately equal numbers of subjects were included in 
each Cmin interval.  Subjects with a Cmin at Week 4 above the threshold values had significantly 
better PFS, compared to the remaining subjects, when the threshold concentrations were 12.6 
g/mL, 17.4 g/mL, and 20.6 g/mL.  Use of thresholds higher than 21 g/mL did not result in 
a significant improvement in PFS between patients with Cmin values above and below the 
threshold.  Patients with Cmin concentrations above 20.6 g/mL also had a significantly better 
response rate and tumor shrinkage than the remaining patients. 
 
Pazopanib C24 at steady-state was greater than 15 g/mL in 93% of subjects who received 
800 mg once daily in Study VEG10003.  Individual subjects receiving pazopanib doses below 
800 mg once daily can achieve plasma concentrations over 15 g/mL, albeit at a lower 
frequency compared with what is observed at 800 mg once daily.  Therefore, the 
pharmacokinetic and pharmacodynamic results across clinical studies demonstrate that 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
21 
 
pazopanib 800 mg once daily results in plasma concentrations that provide optimal biologic 
effects associated with VEGFR inhibition in the greatest proportion of subjects. 
 
Pazopanib in combination with gemcitabine was studied in an open-label, non-randomized, 2-
part, dose-escalation, repeat-dose study using a standard cohort 3 + 3 design. Following the 
dose-escalation phase, 6 to 9 additional subjects (to achieve a total of 12 subjects) were to be 
enrolled in the expansion cohort. Successful evaluation of this expansion phase required dose-
limiting toxicities (DLTs) in 2 of 12 subjects. 
 
In the dose-escalation phase, treatment was administered at 3 dose levels: Dose Level 0 - 
pazopanib 400 mg orally once-daily and gemcitabine 1000 mg/m2 by 30-minute infusion on 
Days 1 and 8 of a 21-day treatment cycle; Dose Level 1 - pazopanib 800 mg orally once-daily 
and gemcitabine 1000 mg/m2 by 30-minute infusion on Days 1 and 8 of a 21-day treatment 
cycle; and Dose Level 2 - pazopanib 800 mg orally once-daily and gemcitabine 1250 mg/m2 by 
30-minute infusion on Days 1 and 8 of a 21-day treatment cycle. In the cohort expansion 
phase, subjects received gemcitabine 1250 mg/m2 alone on Cycle 1, Day 1 before starting 
pazopanib 800 mg once-daily on Day 2 of a 21-day treatment cycle. The recommended phase 
II dose suggested was 800 mg PO of pazopanib daily with 1000 mg/m2 of gemcitabine on days 
1 and 8, though escalation to higher dose was possible. Two DLTs were reported in 2 subjects 
during Cycle 1: Grade 4 thrombocytopenia (Paz400/Gem1000) and Grade 3 fatigue 
(Paz800/Gem1250).  
 
2.7 Correlative Studies Background 
 
 
To date there are no validated biomarkers for response to pazopanib. Circulating angiogenic 
factor levels have been reported to correlate with extent of disease and risk of recurrence in 
patients with soft tissue sarcoma [16].  Mean levels of VEGF and bFGF were found to be 
significantly higher in patients compared to controls [17-19]. 
 
Recently, Nikolinakos and colleagues have shown that baseline levels of 11 cytokine and 
angiogenic factors (CAFs) predicted tumor response in early stage NSCLC patients treated 
with pazopanib [27]. These included IL-12, HGF, IL-16, IP-10, SDF-1α, IL-2Rα, IL-3, IFN-α2, 
tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), M-CSF, and PlGF. Plasma 
samples were collected before treatment and on the last day of therapy from 33 patients with 
early-stage NSCLC participating in a single-arm phase II trial. Levels of 31 CAFs were 
measured by suspension bead multiplex assays or ELISA and correlated with change in tumor 
volume. Pazopanib therapy was associated with significant changes of eight CAFs; sVEGFR2 
showed the largest decrease, whereas placental growth factor underwent the largest increase. 
Increases were also observed in stromal cell–derived factor-1α, IP-10, cutaneous T-cell– 
attracting chemokine, monokine induced by IFN-γ, tumor necrosis factor–related apoptosis-
inducing ligand, and IFN-α. Post-treatment changes in plasma sVEGFR2 and interleukin (IL)-4 
significantly correlated with tumor shrinkage. Baseline levels of 11 CAFs significantly correlated 
with tumor shrinkage, with IL-12 showing the strongest association. Using multivariate 
classification, a baseline CAF signature consisting of hepatocyte growth factor and IL-12 was 
associated with tumor response to pazopanib and identified responding patients with 81% 
accuracy. 
 
An optional plasma biomarker study will be conducted for all patients randomized to either arm. 
The plasma biomarker study will evaluate circulating cytokine and angiogenesis factors (CAFs) 
that might include but are not limited to, IL-12, HGF, IL-16, IP-10, SDF-1α, IL-2Rα, IL-3, IFN-


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
22 
 
α2, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), M-CSF, and PIGF. 
Plasma will be collected at randomization (pre-treatment), cycle 2 and at time of progression to 
examine antiangiogenic biomarkers as predictors of response to G+P and G+T. 
 
An optional blood banking study will also be offered to patients on either arm. An additional 
blood draw at prior to treatment, Cycle 2 and at disease progression will be obtained from 
consenting patients enrolled to either arm for specimen banking and future studies. 
 
An optional PK analysis will also be conducted for patients receiving G+P (includes consenting 
patients who are initially randomized to the G+P arm and consenting patients who crossover to 
the G+P arm after G+T). A plasma sample will be collected at randomization (pre-treatment), 
cycle 2 and at time of progression for consenting patients receiving pazopanib to assess 
pazopanib concentration for correlation.  
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
23 
 
3 PATIENT SELECTION 
 
3.1 Inclusion Criteria 
1. Subjects must provide written informed consent prior to performance of study-specific 
procedures or assessments, and must be willing to comply with treatment and follow-up. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized for 
screening or baseline purposes provided these procedures are conducted as specified in 
the protocol. 
 
2. Age ≥ 18 years or legal age of consent if greater than 18 years. 
 
3. Histologically or cytologically confirmed diagnosis of sarcoma of soft tissue. (Patients with 
liposarcoma, bone sarcoma or GIST will be excluded). 
 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
 
5. Subjects must have metastatic and/or locally advanced or locally recurrent disease that is 
not amenable to curative surgical resection.  If a patient declines surgery, they may be 
considered for this study. 
 
6. A minimum of 1 and a maximum of 3 prior chemotherapy regimens, including adjuvant and 
neo-adjuvant therapy for the treatment of sarcoma.  Patients eligible for an anthracycline 
should have received a prior anthracycline containing regimen. Patients who decline or are 
not eligible for anthracycline treatment may be considered for this protocol as a first line 
treatment. 
 
7. Patients must have measurable disease by RECIST 1.1 or cutaneous disease amenable to 
serial measurements should be present. Measurable disease (a 'target' lesion) is defined 
as at least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded). Each lesion must be ≥ 10 mm when measured by CT (CT scan 
slice thickness no greater than 5 mm); ≥ 10 mm caliper measurement by clinical exam 
(lesions which cannot be accurately measured with calipers should be recorded as non-
measurable); and ≥ 20 mm by chest x-ray. 
 
8. Able to swallow and retain oral medication. 
 
9. Adequate organ system function as defined below. 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
24 
 
Definitions for Adequate Organ Function 
System 
Laboratory Values 
Hematologic 
 
Absolute neutrophil count (ANC) 
1.5 X 109/L 
Hemoglobina 
9 g/dL (5.6 mmol/L)  
Platelets 
100 X 109/L 
Coagulation.b  Coagulation assessments should be completed according to institutional 
standards, which should include at least one of the following. 
International normalized ratio (INR)  
1.2 X ULN 
Prothrombin time (PT) 
1.2 X ULN 
Activated partial thromboplastin time (aPTT) 
1.2 X ULN 
Partial thromboplastin time (PTT)  
1.2 X ULN 
Hepatic 
 
Total bilirubin 
 ULN  
Alanine amino transferase (ALT) and  
Aspartate aminotransferase (AST)c  
2.5 X ULN 
Alkaline phosphatase 
2.5 X ULN 
Renal 
 
Serum creatinine 
1.5 mg/dL (133 µmol/L) 
Or, if serum creatinine >1.5 mg/dL: Calculated 
creatinine clearance (ClCR) (Appendix 2) 
50 mL/min   
 
Urine Protein to Creatinine Ratio (UPC; 
Appendix 3)d  
<1  
Or, 24-hour urine proteind 
<1g 
a) Subjects may not have had a transfusion within 7 days of screening assessment. 
b) Subjects receiving anticoagulant therapy are eligible if their coagulation lab values are stable 
and within the recommended range for the desired level of anticoagulation. 
c) Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are 
not permitted. 
d) If UPC 1, then a 24-hour urine protein must be assessed.  Subjects must have a 24-hour urine 
protein value <1 g to be eligible.  Use of urine dipstick for renal function assessment is not 
acceptable. 
 
10. A female is eligible to enter and participate in this study if she is of: 
 
a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), 
including any female who has had: 
 
A hysterectomy 
 
A bilateral oophorectomy (ovariectomy) 
 
A bilateral tubal ligation 
 
Is post-menopausal 
 
Subjects not using hormone replacement therapy (HRT) must have experienced total 
cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in questionable 
cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value 
< 40pg/mL (<140 pmol/L).  
 
Subjects using HRT must have experienced total cessation of menses for > 1 year and be 
greater than 45 years of age OR have had documented evidence of menopause based on 
FSH and estradiol concentrations prior to initiation of HRT. 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
25 
 
b. Childbearing potential, including any female who has had a negative serum pregnancy 
test within 7 days of registration and agrees to use adequate contraception.  Acceptable 
contraceptive methods, when used consistently and in accordance with both the 
product label and the instructions of the physician, are as follows: 
 
 
Complete abstinence from sexual intercourse for 14 days before exposure to 
investigational product, through the dosing period, and for at least 21 days after the 
last dose of investigational product 
 
Oral contraceptive, either combined or progestogen alone 
 
Injectable progestogen 
 
Implants of levonorgestrel 
 
Estrogenic vaginal ring  
 
Percutaneous contraceptive patches  
 
Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate 
of less than 1% per year 
 
Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject   
 
Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository) 
 
Female subjects who are lactating should discontinue nursing prior to the first dose of 
study drug and should refrain from nursing throughout the treatment period and for 14 
days following the last dose of study drug. 
 
3.2 Exclusion Criteria 
 
1. Prior therapy with pazopanib, gemcitabine or docetaxel.  Patients who have had prior 
treatment with gemcitabine or docetaxel for a prior malignancy are eligible if they meet the 
criteria in exclusion #3 and did not experience significant drug related toxicity. 
 
2. Any concern for hypersensitivity to pazopanib, gemcitabine or docetaxel. 
 
3. Prior malignancy.  Note: Subjects who have had another malignancy and have been 
disease-free for 3 years, or subjects with a history of completely resected non-
melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. 
 
4. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal 
carcinomatosis, except for individuals who have previously-treated CNS metastases, are 
asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 
months prior to registration.  Screening with CNS imaging studies (computed tomography 
[CT] or magnetic resonance imaging [MRI]) is required only if clinically indicated or if the 
subject has a history of CNS metastases. 
 
5. Clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding including, but not limited to: 
 
 
Active peptic ulcer disease 
 
Known intraluminal metastatic lesion/s with risk of bleeding 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
26 
 
 
Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or other 
gastrointestinal conditions with increased risk of perforation  
 
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days prior to registration. 
 
6. Clinically significant gastrointestinal abnormalities that may affect absorption of 
investigational product including, but not limited to: 
 
Malabsorption syndrome  
 
Major resection of the stomach or small bowel and experiencing the “dumping” 
syndrome. 
 
7. Presence of uncontrolled infection. 
 
8. Prior mediastinal radiation. 
 
9. Corrected QT interval (QTc) > 480 msecs using Bazett’s formula. 
 
10. History of any one or more of the following conditions within 6 months of registration: 
 
Cardiac angioplasty or stenting 
 
Myocardial infarction 
 
Unstable angina 
 
Coronary artery bypass graft surgery 
 
Symptomatic peripheral vascular disease 
 
Pneumonitis 
 
11. Class III or IV congestive heart failure, as defined by the New York Heart Association 
(NYHA) (Appendix D). 
 
12. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150 mmHg or 
diastolic blood pressure (DBP) of ≥ 90mmHg].  Note: Initiation or adjustment of 
antihypertensive medication(s) is permitted prior to study entry.  BP must be re-assessed 
on two occasions that are separated by a minimum of 1 hour; on each of these occasions, 
the mean (of 3 readings) SBP / DBP values from each BP assessment must be <150/90 
mmHg in order for a subject to be eligible for the study. 
 
13. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary 
embolism or untreated deep venous thrombosis (DVT) within 6 months of registration. 
Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating 
agents for at least 6 weeks prior to registration and are fully anti-coagulated are eligible. 
 
14. Prior major surgery or trauma within 28 days prior to registration and/or presence of any 
non-healing wound, fracture, or ulcer (procedures such as catheter placement not 
considered to be major).  If the patient has a compression fracture secondary to tumor this 
should be treated and 28 days elapsed prior to entry on the protocol.   
 
15. Evidence of active bleeding or bleeding diathesis.  
 
16. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels. 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
27 
 
17. Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of registration. 
 
18. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could 
interfere with subject’s safety, provision of informed consent, or compliance to study 
procedures.  
 
19. Unable or unwilling to discontinue use of prohibited medications listed in Section 5.2.3 for 
at least 14 days or five half-lives of a drug (whichever is longer) prior to registration and for 
the duration of the study. 
 
20. Treatment with any of the following anti-cancer or non-oncologic investigational therapies:  
 
radiation therapy, surgery or tumor embolization within 14 days prior to registration  
 
chemotherapy, immunotherapy, biologic therapy, investigational therapy or 
hormonal therapy within 14 days or 2.5 half-lives of a drug (whichever is longer) 
prior to registration. 
 
non-oncologic investigational products within 30 days or 5 half-lives prior to 
registration, whichever is longer. 
 
21. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is 
progressing in severity, except alopecia. 
 
3.3 Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
28 
 
4 STUDY DESIGN & REGISTRATION PROCEDURES 
 
4.1 Study Design 
A randomized phase II approach will be used.  Ninety patients will be randomized in a 1:1 
ratio to either receive gemcitabine 1000mg/m2 i.v. over 90 min on days 1 and 8 every 21 
days along with pazopanib 800 mg PO once daily days 1 through 21 (G+P), or gemcitabine 
900 mg/m2 i.v. over 90 min on days 1 and 8 along with docetaxel 100 mg/m2 i.v. over 60 
min on day 8 every 21 days (G+T) till disease progression. Since G+T has shown good 
activity in leiomyosarcoma patients, to ensure a balance in the treatment arms being 
compared, prior to randomization, patients will be stratified by tumor type (leiomyosarcoma 
vs. other) and whether the patient has had prior pelvic radiation.  
 
PFS and toxicity (defined as the incidence of grade 3 or 4 toxicity) will be the primary 
endpoints.  We assume that accrual will occur over 18 months and that the last patient will 
be followed for 18 months.  Interim analysis will allow early stopping in an arm for 
excessive toxicity.  Patients will be allowed to cross-over to the other treatment arm upon 
progression.  This will serve to encourage accrual and to evaluate PFS of G+P after 
exposure to G+T.  
 
4.2 Registration procedure 
The Hollings Cancer Center (HCC) Clinical Trials Network (CTN) program will provide 
centralized randomization and registration services for all patients at MUSC and 
participating multicenter sites. At a minimum, the CTN will conduct a patient eligibility audit 
review of all eligibility source documents prior to patient registration of the first three 
patients enrolled to a site. These procedures are outlined in the CTN Investigator Initiated 
Trial Multicenter Manual for this study. Upon completion of all the required baseline 
assessments, eligible subjects will be registered. They will then be stratified and randomly 
assigned to a treatment arm. A subject number will be assigned to each patient. The CTN 
will issue a patient registration confirmation email to the participating site at the time of 
registration. This confirmation will include the patient’s assigned treatment arm and study 
ID number. 
 
Once patients are randomized they should begin protocol treatment within 72 hours.  
Issues that would cause treatment delays should be discussed with the Principal 
Investigator.   
 
Participating sites are not active to study enrollment until after the CTN has received the 
site’s initial IRB approval and other start-up documents. The CTN will submit the initial 
request for study drug at the time of study activation. Any resupply orders for study drug will 
be made by the participating site per the instructions provided by Biologics, Inc. which has 
been subcontracted to handle the drug distribution for this study.  
 
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
29 
 
5 TREATMENT PLAN 
 
 
5.1 Treatment schedule 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks for pazopanib, gemcitabine and docetaxel are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
For BOTH Arms, a cycle equals 21 days. 
 
ARM 1: Gemcitabine (G) + Taxotere (T) 
 
Gemcitabine at 900 mg/m2 on DAYS 1 and 8 over 90 min (+/- 15 minutes), and 
Taxotere 100 mg/m2 on DAY 8 over 60 min (+/- 15 minutes) following the gemcitabine infusion. 
 
Premedications:  
 
Anti-emetic regimen at minimum should contain a 5-HT3 blocker i.v. and dexamethasone 
12 mg i.v or equivalent on days 1 and 8. Dexamethasone 8 mg BID or equivalent on the 
day before and day after docetaxel 
 
Growth factor support with pegfilgrastim (Neulasta TM) or filgrastim (Neupogen TM) will be 
given starting with cycle 1 per institutional guidelines. If the dose is held and not 
administered to the patient on day 1 or 8, the patient can be given growth factor support on 
day 1 or ARM 2: Gemcitabine (G) +  Pazopanib (P) 
 
Gemcitabine at 1000 mg/m2 on days 1 and 8 over 90 min (+/- 15 minutes), and 
Pazopanib at 800 mg (2x400mg or 4x200mg) once daily starting on day 1 through day 21. On 
days1 and 8 when Gemcitabine is also administered, Pazopanib can be given to the patient 
prior to gemcitabine administration. This relative timing to Gemcitabine administration is not 
required, but a recommendation. However, it is imperative that Pazopanib be taken orally per 
day without food at least one hour before or two hours after a meal. It is also important that the 
time of day Pazopanib is taken is relatively constant during study treatment. 
 
Premedications:  
 
Anti-emetic regimen at minimum should contain a 5-HT3 blocker i.v. and dexamethasone 
12 mg i.v or equivalent on days 1 and 8.  
 
If neutropenia is a problem in G+P during therapy then growth factor support with 
pegfilgrastim (Neulasta TM) or filgrastim (Neupogen TM) could be considered at the 
discretion of the treating physician.  Growth factor support should be given following 
institutional guidelines.  If the dose is held and not administered to the patient on day 1 or 
8, the patient can be given growth factor support on day 1 or 8.  
 
Patients will discontinue treatment if they have disease progression, intolerable toxicity or if 
treatment is interrupted for > 21 days. Patients may be allowed to crossover at the time of 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
30 
 
progression. 
 
5.2 PAZOPANIB Instructions  
 
Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold 
increase in area under the plasma drug concentration curve (AUC) and maximum observed 
plasma drug concentration (Cmax).  
Pazopanib should be taken orally without food at least one hour before or two hours after a 
meal. The tablets should be swallowed whole and must not be crushed or broken. The time of 
day the tablets are taken should be relatively constant.  
 
If a subject misses a dose, the subject should take the dose as soon as possible, but not less 
than 12 hours before the next dose is due.  If the next dose is due in less than 12 hours, the 
subject should skip the missed dose and take the next dose as scheduled. 
 
If a subject vomits after taking pazopanib, the subject should be instructed not to take another 
dose that day.  The subject should resume taking pazopanib at the next scheduled dose.  If 
vomiting persists, the subject should be instructed to notify the investigator. 
 
Pazopanib should be stored at room temperature between 20°C and 25°C (68°F to 77°F); 
excursions permitted to 15°C to 30°C (59°F to 86°F). 
 
Pazopanib will be supplied for the study as investigational stock. Pazopanib provided for this 
study should only be used exclusively for enrolled study patients. Appropriate patient specific 
drug accountability logs documenting the patient specific dispensing and return activity should 
be maintained by the participating institution. 
 
5.3 GEMCITABINE premedications 
 
Prophylactic anti-emetic regimen at minimum should contain a 5-HT3 blocker i.v. and 
dexamethasone 12 mg i.v or equivalent on days 1 and 8.  
 
5.4 TAXOTERE premedications 
 
All patients should be premedicated with oral corticosteroids in order to reduce the incidence 
and severity of fluid retention as well as the severity of hypersensitivity reactions. As outlined in 
5.1.,  dexamethasone 12 mg i.v or equivalent on days 1 and 8,  and dexamethasone 8 mg BID 
or equivalent may be given on the day before and day after docetaxel. Prophylactic anti-
emetics should include an i.v. 5-HT3 blocker.  
 
5.5 General Concomitant Medication and Supportive Care Guidelines 
5.5.1 Permitted Medications 
 
All subjects will be asked to provide a complete list of prescription and over-the-counter 
medications that have been taken within the 4 weeks prior to registration.  The investigator 
must be informed as soon as possible about any new medication(s) taken during screening 
from 4 weeks prior to registration until the completion of the post-treatment follow-up visit.   
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
31 
 
All concomitant medications taken during the study will be recorded in the case report form 
(CRF) with indication and dates of administration.  
 
Subjects should receive full supportive care during the study, including transfusion of blood 
and blood products, and treatment with antibiotics, analgesics, or bisphosphonates, when 
appropriate. Antiemetics (such as prochlorperazine, lorazepam, ondansetron or other 5-HT 
antagonists) may be administered prophylactically in the event of nausea.  Anti-diarrheals, 
such as loperamide, may be administered as needed in the event of diarrhea (See 
Appendix E for Supportive care guidelines for nausea/vomiting and diarrhea).  Although 
acetaminophen at doses of 2 g/day is permitted, it should be used with caution in subjects 
with impaired liver function. Glucocorticosteroids may be used as antiemetics and 
megestrol acetate may be used for appetite. 
 
Use of Growth Factors 
Prophylactic growth factor support with pegfilgrastim (Neulasta TMor filgrastim (Neupogen 
TM) will be given starting with cycle 1 in the G+T arm per institutional guidelines. 
 
If neutropenia is a problem in G+P during therapy then growth factor support with 
pegfilgrastim (Neulasta TM) or filgrastim (Neupogen TM) can be added at the discretion of 
the treating physician per institutional guidelines. 
 
If the dose is held and not administered to the patient on day 1 or 8, the patient can be 
given growth factor support on day 1 or 8. 
 
Erythropoietin may be used at the discretion of the investigator, sub-investigator, or treating 
physician but is generally discouraged. Patients could be transfused with packed red blood 
cell transfusions as necessary.   
 
5.5.2 Permitted Medications – Use with Caution 
 
  
Specific recommendations regarding Simvastatin: 
Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. 
Across monotherapy studies with pazopanib, ALT > 3 ULN was reported in 126/895 (14%) 
of patients who did not use statins, compared with 11/41 (27%) of patients who had 
concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops 
ALT elevations, follow dosing guidelines for pazopanib. Alternatively, consider 
discontinuing simvastatin. Insufficient data are available to assess the risk of concomitant 
administration of alternative statins and pazopanib. 
 
 
Specific recommendations regarding anticoagulants: 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that 
pazopanib has no effect on the metabolism of S-warfarin.  Hemorrhagic events, however, 
have been reported in clinical studies with pazopanib; therefore, pazopanib should be used 
with caution in subjects with increased risk of severe bleeding or who are receiving 
concomitant anticoagulant therapy (e.g., warfarin or its derivatives, low molecular weight 
heparin, unfractionated heparin).  Subjects taking concomitant anticoagulant therapy on 
both arms should be monitored regularly for changes in relevant coagulation parameters as 
clinically indicated, as well as for any clinical bleeding episodes. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
32 
 
 
If a patient starts on anticoagulation therapy during treatment for reasons not attributable to 
study drug (e.g., underlying disease or port closing), study treatment should be held until 
desired level of anti-coagulation is reached.  PT/INR and PTT/aPTT should be monitored 
until stable.  Once stable, the patient can be restarted at the same dose level.   
 
Specific recommendations regarding hypoglycemic therapy including insulin: 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that 
there will be no clinically relevant pharmacokinetic interaction between pazopanib and 
hypoglycemic agents.  Transient decreases in serum glucose (mainly Grade 1 and 2, rarely 
Grade 3) have been observed in clinical studies with pazopanib.  In addition, decreases in 
blood sugar have been recently reported in subjects treated with another small molecule 
tyrosine kinase inhibitor, sunitinib [26]. Such changes may require an adjustment in the 
dose of hypoglycemic and/or insulin therapy.  Subjects should be advised to report 
symptoms of hypoglycemia (e.g., confusion, visual disturbances, palpitations, sweating).  
Serum glucose should be tested during treatment as outlined in Section 10. Study calendar 
and as clinically indicated. 
 
The Effects of Pazopanib on Other Drugs 
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, CYP2C8, CYP2D6, 
CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1.  Pregnane X receptor 
transient transfection assay suggested some potential for human CYP3A4 induction at high 
concentrations.  Results from drug-drug interaction studies conducted in subjects with 
cancer suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in 
vivo, but had no clinically relevant effect on CYP1A2, CYP2C9 or CYP2C19 metabolism.  
Therefore, concomitant use of pazopanib with certain medications (substrates of CYP3A4, 
CYP2C8, and CYP2D6) with a narrow therapeutic window should be undertaken with 
CAUTION due to the potential for alterations in the pharmacologic effects of these 
medications or an increased risk for serious or life threatening adverse events associated 
with such medications (see below) secondary to the inhibition of specific CYP enzymes by 
pazopanib.  In addition, the potential for drug interaction with such medications, although 
diminished, may persist after the last dose of pazopanib due to its long half-life (i.e., mean 
30.9 hours); therefore, continue to exercise CAUTION for at least 7 days and up to 15 days 
after the last dose of pazopanib when administering these medications.  These medications 
include (but are not limited to): 
 
• 
Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine 
(potential increased risk for developing ergot toxicity that includes severe vasospasm 
leading to peripheral as well as cerebral ischemia) 
• 
Neuroleptics: pimozide (potential increased risk for QT interval prolongation, ventricular 
arrhythmia, and sudden death) 
• 
Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, quinidine, 
propafenone (potential increased risk for QT interval prolongation and Torsades de 
Pointes) 
• 
Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk for 
nephrotoxicity and neurotoxicity) 
• 
Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
33 
 
The Effects of Other Drugs on Pazopanib  
Results from in vitro studies suggest that the oxidative metabolism of pazopanib in human 
liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 
and CYP2C8.  Furthermore, in vitro data suggest that pazopanib is a substrate for p-
glycoprotein. Substances that induce or inhibit CYP3A4 may alter the pharmacologic 
effects of pazopanib and should be used with CAUTION.   
 
Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations.  
Co-administration of strong CYP3A4 inhibitors is prohibited (see Section on Prohibited 
Medications); therefore selection of an alternate concomitant medication with no or minimal 
potential to inhibit CYP3A4 is recommended. CYP3A4 inducers may decrease plasma 
pazopanib concentrations.  Selection of an alternate concomitant medication with no or 
minimal enzyme induction potential is recommended.  Drugs that induce CYP3A4 and 
may decrease pazopanib plasma concentrations include (but are not limited to): 
 
• 
Glucocorticoids:  cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10 mg), 
methylprednisolone (>8 mg), dexamethasone (>1.5 mg) 
• 
Anticonvulsants:  phenytoin, carbamazepine, phenobarbital, oxcarbazepine 
• 
HIV antivirals:  efavirenz, nevirapine 
• 
Antibiotics:  rifampin (rifampicin), rifabutin, rifapentine 
• 
Miscellaneous:  St. John’s Wort, modafinil, pioglitazone 
The Effects of Other Drugs on Docetaxel 
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of 
docetaxel may be modified by the concomitant administration of compounds that induce, 
inhibit, or are metabolized by cytochrome P450 3A4. Substances that induce or inhibit 
CYP3A4 as listed above may alter the pharmacologic effects of docetaxel also and should 
be used with CAUTION.    
5.5.3  Prohibited Medications  
 
Medications that inhibit CYP3A4 may result in increased plasma pazopanib and docetaxel 
concentrations; therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED 
beginning 14 days prior to the first dose of study drug until discontinuation from the study.  
Strong CYP3A4 inhibitors include (but are not limited to): 
 
• 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
• 
HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, lopinavir) 
• 
Antifungals:  itraconazole, ketoconazole, voriconazole 
• 
Antidepressants: nefazodone 
Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, radiation, or 
hormonal (other than leuprolide or other GnRH agonists)] not specified in the protocol while 
on treatment in this study.  Subjects should not receive any other investigational drug within 
15 days of the last dose of study therapy. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
34 
 
 
5.6 End of Treatment  
Treatment may continue on either arm until one of the following criteria applies: 
 
 
Evidence for disease progression. 
 
Inter-current illness that would, in the judgment of the investigator, affect 
assessments of clinical status to a significant degree or require discontinuation of 
study drugs. 
 
Unacceptable toxicity.   
 
Death.  
 
Patient withdraws consent.  
 
Treatment delay greater than three weeks for any toxicity  
 
Concomitant treatment with a systemic anticancer drug that is not one of the study 
drugs.  
 
Patients who do not have satisfactory compliance with study procedures.  
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
35 
 
6 Patient Crossover 
At the time that the patient is determined to have disease progression, the “At time of 
progression/At end of treatment” procedures outlined within the Section 10 study calendar should 
be completed within 7 days. Study assessments required at end of Study are outlined in Secrtion 
10 Study Calendar. However, please note that a pregnancy test is only required at this end of 
study visit if the patient is expected to crossover.   
 
All patients expected to continue with crossover study treatment must be registered with the HCC 
Clinical Trials Network (CTN).The assessments completed at the “At time of progression/At end of 
treatment” visit may be used for eligibility consideration for crossover registration. 
 
All patients who crossover must complete the following procedures prior to HCC CTN crossover 
registration and beginning any crossover study therapy. Crossover procedures must be completed 
within 14 days prior to HCC CTN study crossover registration. Patients intending to crossover, 
must be registered to crossover therapy no later than 21 days after the “At time of progression/At 
end of treatment” visit. 
 
Patients must meet the following criteria in order to continue into crossover study therapy. 
 
6.1 Crossover Inclusion Criteria 
 
1. The patient has documented disease progression after completing the initial therapy of 
this 101644 protocol.  
 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 
 
3. Subjects must have metastatic and/or locally advanced or locally recurrent disease that 
is not amenable to curative surgical resection.  
 
4. Patients must have measurable disease by RECIST 1.1. or cutaneous disease 
amenable to serial measurements should be present. Measurable disease (a 'target' 
lesion) is defined as at least one lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded). Each lesion must be ≥ 10 mm when 
measured by CT (CT scan slice thickness no greater than 5 mm); ≥ 10 mm caliper 
measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable); and ≥ 20 mm by chest x-ray. 
 
5. Able to swallow and retain oral medication. 
 
6. Adequate organ system function as defined in the table below. 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
36 
 
Definitions for Adequate Organ Function 
System 
Laboratory Values 
Hematologic 
 
Absolute neutrophil count (ANC) 
1.5 X 109/L 
Hemoglobina 
9 g/dL (5.6 mmol/L)  
Platelets 
100 X 109/L 
Coagulation Testsb Coagulation assessments should be completed according to 
institutional standards, which should at least one of the following. 
International normalized ratio (INR)    
1.2 X ULN 
Prothrombin time (PT) 
< 1.2X ULN 
Activated partial thromboplastin time 
(aPTT)  
1.2 X ULN 
Partial thromboplastin time (PTT)  
1.2 X ULN 
Hepaticc 
 
Total bilirubinc 
 ULN  
Alanine amino transferase (ALT) and 
Aspartate aminotransferase (AST)c  
2.5 X ULN 
Alkaline phosphatase 
2.5 X ULN 
Renal 
 
Serum creatinine 
1.5 mg/dL (133 µmol/L) 
Or, if serum creatinine >1.5 mg/dL: 
Calculated creatinine clearance (ClCR) 
(Appendix 2) 
50 mL/min   
 
Urine Protein to Creatinine Ratio (UPC; 
Appendix 3)d  
<1  
Or, 24-hour urine proteind 
<1g 
a) Subjects may not have had a transfusion within 7 days of screening assessment. 
b) Coagulation tests are only required for crossover registration for those patients crossing 
over into the Gem+Paz arm.  Subjects receiving anticoagulant therapy are eligible if their 
coagulation lab values are stable and within the recommended range for the desired level 
of anticoagulation.  
c) Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) 
are not permitted. 
d) If UPC 1, then a 24-hour urine protein must be assessed.  Subjects must have a 24-hour 
urine protein value <1 g to be eligible.  Use of urine dipstick for renal function assessment 
is not acceptable. UPC tests are only required for crossover registration for those patients 
crossing over into the Gem+Paz arm.   
 
6.2 Crossover Exclusion Criteria 
 
1. Patients who end initial 101644 therapy due to grade 3 or greater toxicity are not eligible to 
cross-over.   
 
2. Patients who choose to discontinue treatment on an arm (or who are removed for other 
reasons than progression such as toxicity) will not be allowed to cross over to the other 
treatment arm.   
 
3. Positive pregnancy test. 
 
4. Any concern for hypersensitivity to pazopanib, gemcitabine or docetaxel. 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
37 
 
5. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal 
carcinomatosis, except for individuals who have previously-treated CNS metastases, are 
asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 
months prior to crossover registration.  Screening prior to crossover registration with CNS 
imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is 
required only if clinically indicated or if the subject has a history of CNS metastases.  
 
6. Clinically significant gastrointestinal abnormalities that may increase the risk for 
gastrointestinal bleeding including, but not limited to: 
 
Active peptic ulcer disease 
 
Known intraluminal metastatic lesion/s with risk of bleeding 
 
Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or other 
gastrointestinal conditions with increased risk of perforation  
 
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days of crossover registration. 
 
7. Clinically significant gastrointestinal abnormalities that may affect absorption of 
investigational product including, but not limited to: 
 
Malabsorption syndrome  
 
Major resection of the stomach or small bowel and experiencing the “dumping” 
syndrome. 
 
8. Presence of uncontrolled infection. 
 
9. If crossing over to Gemcitabine + Pazopanib, corrected QT interval (QTc) > 480 msecs 
using Bazett’s formula. 
 
10. History of any one or more of the following conditions within the past 6 months of crossover 
registration: 
 
Cardiac angioplasty or stenting 
 
Myocardial infarction 
 
Unstable angina 
 
Coronary artery bypass graft surgery 
 
Symptomatic peripheral vascular disease 
 
Pneumonitis 
 
11. Class III or IV congestive heart failure, as defined by the New York Heart Association 
(NYHA) (Appendix D). 
 
12. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥150 mmHg or 
diastolic blood pressure (DBP) of ≥ 90mmHg]. 
 
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study 
entry.  BP must be re-assessed on two occasions that are separated by  a minimum of 1 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
38 
 
hour; on each of these occasions, the mean (of 3 readings) SBP/ DBP values from each 
BP assessment must be <150/90 mmHg in order for a subject to be eligible for the study. 
 
13. History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary 
embolism or untreated deep venous thrombosis (DVT) within 6 months of crossover 
registration. 
 
Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating 
agents for at least 6 weeks prior to crossover registration and are fully anti-coagulated are 
eligible. 
 
14. Prior major surgery or trauma within 28 days of crossover registration and/or presence of 
any non-healing wound, fracture, or ulcer (procedures such as catheter placement not 
considered to be major). 
 
15. Evidence of active bleeding or bleeding diathesis.  
 
16. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels. 
 
17. Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of  crossover 
registration. 
 
18. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could 
interfere with subject’s safety, provision of informed consent, or compliance to study 
procedures.  
 
6.3 Crossover Procedures 
 
At the time of screening for crossover registration, the following procedures are required within 
14 days of crossover registration. The exception is the pregnancy test for WOCBP which is 
required within 7 days of crossover registration. These assessments include: 
 
 
Medical history/Physical exam 
 
Review of concomitant medication 
 
Vital signs 
 
ECOG performance status 
 
Review of adverse events 
 
CBCD 
 
LFT 
 
Chemistries  
 
Pregnancy test for WOCBP (within 7 days) 
 
For patients who were originally randomized to the G+T arm and plan to cross over to the G+P 
arm, the following assessments must be completed in addition to the End of Treatment 
assessments.  
 
EKG 
 
Urinalysis/ UPC 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
39 
 
 
PT/INR or PTT/aPTT 
 
T4, TSH 
 
Upon completion of crossover assessments and verification of crossover eligibility, the 
following crossover registration documents should be completed and submitted to the HCC 
CTN. All documents are posted to the HCC CTN workbench. Please fax documents to 843-
792-5123. 
 
 
101644 Crossover Enrollment Packet 
 
101644 Crossover Eligibility Criteria Checklist. 
 
Radiographic assessment and RECIST source document (if applicable) of the 
patient’s last radiographic response assessment.  
 
Upon review and approval of the crossover registration, an email registration confirmation will 
be forwarded to the registering site. This confirmation should be filed within the patient 
research record. The patient should follow the assessments as outlined within the Section 10 
Study calendar for crossover therapy. 
 
6.4 Crossover Correlative Studies 
 
For patients who consented to the optional CAF biomarker, optional blood specimen banking, 
and optional quality of life assessment, these evaluations only apply to the initial study therapy. 
These studies will not be completed during the study’s crossover therapy. 
 
For patients who consented to the optional Pazopanib PK sampling and are planned to receive 
Gemcitabine and Pazopanib as part of crossover study therapy, PK draws will occur at the 
following timepoints during crossover therapy: 1) after crossover registration but prior to 
Pazopanib start, 2) at cycle two of crossover therapy, and 3) at time of progression after 
crossover therapy. 
 
6.5 Crossover Therapy and Dose Level 
 
If a Gemcitabine dose reduction was implemented during initial study therapy, the same dose 
level should be used during the crossover therapy portion of the study. The Gemcitabine dose 
level should not be increased. Please refer to Table 6.1.1 and Table 6.1.2 for description of the 
dose levels.  
 
For example, if a patient initially randomized to G+T was dose reduced to dose level -1 and 
received Gemcitabine 700 mg/m2 during initial study therapy, then the patient should continue 
at dose level -1 in the crossover therapy of G+P and receive Gemcitabine at 800 mg/m2. Thus, 
the Gemcitabine dose level used at the time that the patient ended initial therapy should 
continue when starting crossover therapy. 
 
The same dose modifications guidelines should be used for initial and crossover therapy.  
 
6.6 Duration of Follow Up 
The follow-up period begins after a patient completes initial therapy and does not continue to 
crossover therapy or after the patient completes crossover therapy. During follow-up, patients 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
40 
 
will be followed every 3 months until progression; after progression is documented, patients 
should be followed every 3 months for survival until 24 months after the last patient is enrolled 
to the study.  All attempts will be made to document progression and survival every 3 months, 
but if any of the timepoints are missed, it will not be considered a protocol deviation.   
 
6.7 Crossover Criteria for removal from Study 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The 
reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
41 
 
7 DOSING DELAYS/DOSE MODIFICATIONS  
 
7.1 General principles  
At each visit during the Treatment Period, subjects should first be evaluated for the occurrence 
of AEs and laboratory abnormalities.  The potential causes of the AEs should be thoroughly 
investigated and confounding factors identified and eliminated whenever possible.  Some AEs, 
although rare, can result in significant clinical consequence such as arterial/venous thrombosis, 
severe hemorrhage, bowel perforation and severe fatigue/asthenia, therefore should be 
promptly identified and managed. 
 
The NCI-CTCAE, v4.0 must be used to grade the severity of AEs except for hypertension and 
palmar-plantar erythrodysesthesia syndrome: grading for these events is described in the 
Table 6.3.1.  Specific recommendations for management of pazopanib related AEs along with 
guidelines for dose interruption, modification, or discontinuation are provided in Table 6.3.1.  In 
the event of treatment emergent hepatotoxicity, the guidelines for management of 
hepatotoxicity provided in Table 6.4.1 and 6.4.2 should be followed. Refer to Tables 6.2.1, 
6.2.2 and 6.2.3 for dose modifications for hematologic toxicities. Patients requiring any of the 
drug treatments to be held > 21 days must discontinue protocol treatment.  
 
Dose reductions for non- hematologic toxicities with G, P and T will be permanent with the 
following exceptions.  The investigator will be allowed to dose modify at their discretion for 
minor AEs or AEs that may be corrected by other measures. Examples of minor non-
hematological toxicities include alopecia, nausea, vomiting, fever without grade IV neutropenia, 
or metabolic imbalances that may be corrected by provision of supportive care (e.g. 
hypokalemia and provision of potassium). For minor AEs in which the patient recovers, the 
investigator will be allowed to re-escalate.  
 
Dose reductions for G, P and T for treatment related hematologic toxicities will allow re-
escalation to one level higher if the counts permit. If a second reduction is required 
subsequently this will then be a permanent reduction. 
 
Treatment will be held for all non-hematologic > grade 3 toxicities except for minor non-
hematological toxicities as described previously. Please refer to the dose level tables (6.1.1 
and 6.1.2) below for each arm to guide the dose reduction. Patients unable to tolerate dose 
level -2 or requiring treatment held beyond 3 weeks, must discontinue protocol treatment. 
 
Table 4:  G+P Dose Levels 
G+P 
Gemcitabine 
Pazopanib 
Dose level 1 (DL 1) 
1000 mg/m2 
800 mg 
Dose level -1 (DL-1) 
800 mg/m2 
600 mg 
Dose level -2 (DL-2) 
675 mg/m2 
400 mg 
 
Table 5:  G+T Dose Levels 
G+T 
Gemcitabine 
Docetaxel 
Dose level 1 (DL 1) 
900 mg/m2 
100 mg/m2 
Dose level -1 (DL-1) 
700 mg/m2 
75 mg/m2 
Dose level -2 (DL-2) 
600 mg/m2 
60 mg/m2 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
42 
 
7.2 Hematologic toxicities:  
Table 6 Adjustments based on blood counts on day 1 of a treatment cycle   
ANC 
 
Platelets 
Gemcitabine Dose 
> 1,000 
and 
> 100,000 
100% of current dose level 
<1,000 
or 
<100,000 
Hold treatment and resume at 100% of 
current dose level if counts recover to ANC 
>1,500 and platelets > 100,000 within a 
week.  Consider G-CSF or GM-CSF 
prophylaxis (per section 5.1) if not already on 
it. 
 
If a delay of >1week but less than 3 weeks is 
required for recovery of counts, then reduce 
dose of agent/s by one dose level based on 
Tables 4 & 5.  
 
Investigators’ discretion can be used to 
decide whether one or both agents need 
dose reduction. 
 
 
Table 7 Adjustments based on blood counts on day 8  of a treatment cycle. 
ANC 
 
Platelets 
Chemotherapy Dose % 
> 1,500 
and 
> 100,000 
G+T: 100% of the G dose given on day 1 
and 100% of T dose.  
 
G+P: 100% of the G dose given on day 1. P 
dose stays the same. 
750 to 1499 
or 
75,000 to 99,999 
G+T: Reduce dose by one dose level. 
 
Investigators’ discretion can be used to 
decide whether one or both agents need 
dose reduction. 
 
G+P: Reduce dose by one dose level.  
 
Investigators’ discretion can be used to 
decide whether one or both agents need 
dose reduction. 
 
Both Arms: At the discretion of the 
investigator, if patient is on dose level -2, 
hold until recovery of counts and continue 
treatment at current dose level. The patient 
will be removed from study if drug is held 
greater than 3 weeks for the recovery of 
counts.   
< 750 
or 
<75,000 
G+T: Hold G and T. Repeat counts in 1 
week and treat according to ANC and 
Platelet level. If still not recovered to higher 
level after 1 week, skip day 8 treatments 
and reduce dose of G and T in the 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
43 
 
subsequent cycles by one dose level on 
days 1 and 8. 
 
G+P: Hold G and P and repeat counts 
weekly till ANC > 750 and Platelets > 
75,000 and then re-start at the next lower 
dose level. However, if counts still not 
recovered to higher level after 1 week, skip 
day 8 treatment with G and reduce dose of 
G in the subsequent cycles by one dose 
level on days 1 and 8. Resume P at the 
lower dose when ANC > 750 and Platelets > 
75,000. 
 
Both Arms:  At the discretion of the 
investigator, if patient is on dose level -2, 
hold until recovery of counts and continue 
treatment at current dose level.  The patient 
will be removed from study if drug is held 
greater than 3 weeks for the recovery of 
counts. 
 
Table 8 Adjustments based on blood counts on Cycle 1 Day 15 of a treatment cycle 
(Pazopanib related only) 
Platelets 
Modification 
>50,000 
Continue with current dose; monitor as clinically indicated 
<50,000 
Interrupt P until toxicity resolves to < grade 2. 
 
Restart P at reduced dose level and monitor as clinically 
indicated 
 
If no recovery to < grade 2 or recurrent grade 3 or 4 platelet 
count decrease, discontinue study treatment. 
 
7.2.1 Adjustments for febrile neutropenia and sepsis 
 
If febrile neutropenia or sepsis occurs, G-CSF or GM-CSF may be instituted until the 
resolution of the febrile neutropenia or septic episode if adverse prognostic factors exist 
(according to ASCO Guidelines). Prophylactic G-CSF or GM-CSF should be strongly 
considered in G+P as per section 5.1. In the G+T arm prophylactic G-CSF or GM-CSF is 
recommended beginning with cycle 1. 
 
7.2.2 Adjustment for Anemia 
 
Erythropoietin may be used at the discretion of the investigator, sub-investigator, or treating 
physician but is generally discouraged. Patients could be transfused packed red blood cell 
transfusions as necessary.  
 
 
7.3 Dose Interruptions/Modifications Specific for Pazopanib Related Toxicities, 
Excluding Liver Toxicities 
If dose reduction is necessary, two dose reductions will be permitted in a stepwise fashion (refer 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
44 
 
to tables 6.1.1 & 6.1.2 for dose levels). 
 
Table 9 Dose Modification Algorithms for Potential Pazopanib-Related Adverse Events 
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertension 
(1)  Asymptomatic and persistent SBP of 140 
and <160 mmHg, or DBP 90 and <100 
mmHg, or a clinically significant increase in 
DBP of 20 mmHg (but still below 110 mmHg). 
Step 1.  Continue pazopanib at the current dose.  
Step 2.  Adjust current or initiate new antihypertensive 
medication(s). 
Step 3.  Titrate antihypertensive medication(s) during 
next 2 weeks as indicated to achieve well-
controlleda BP.  If BP is not well-controlled 
within 2 weeks, consider referral to a specialist 
and go to scenario (2). 
(2)  Asymptomatic SBP 160 mmHg, or DBP 
100 mmHg, or failure to achieve well-
controlleda BP within 2 weeks in scenario (A).  
Step 1.  Consider reducing or interrupting pazopanib as 
clinically indicated. 
Step 2.  Adjust current or initiate new antihypertensive 
medication(s).  
Step 3.  Titrate antihypertensive medication(s) during 
next 2 weeks as indicated to achieve well-
controlled BP.  
Step 4.  Once BP is well-controlled, restart pazopanib at 
the next lower dose level, if pazopanib was 
interrupted.   
(3)  Symptomatic hypertension or recurring SBP 
160 mmHg, or DBP 100 mmHg, despite 
modification of antihypertensive 
medication(s). 
Step 1.  Interrupt pazopanib. 
Step 2.  Adjust current or initiate new antihypertensive 
medication(s).  
Step 3.  Titrate antihypertensive medication(s) during 
next 2 weeks as indicated to achieve well-
controlled BP.  Referral to a specialist for 
further evaluation and follow-up is also 
recommended. 
Step 4.  Once BP is well-controlled, restart pazopanib 
dose-reduced to the next lower dose level.  
(4)  Refractory hypertension unresponsive to 
above interventions or < 2 dose reductions. 
Discontinue pazopanib and continue follow-up per 
protocol.  
Prolongation of QTc Interval:  
QTc   480 < 500 msec 
Continue pazopanib at the current dose; monitor as 
clinically indicated. 
QTc  500 msec 
Discontinue pazopanib and continue follow-up per 
protocol. 
Proteinuria 
 
UPC <3 
Continue pazopanib at the current dose; monitor as 
clinically indicated. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
45 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
Proteinuria 
 
UPC ≥ 3 or 24-rine protein  3g 
Step 1.  Interrupt pazopanib. 
Step 2.  Weekly UPC or 24-hr urine protein monitoring until UPC is < 
3 or 24-hr urine protein is < 3 grams.  Then restart pazopanib 
at the next lower dose level. 
Step 3.  If UPC > 3 or 24-h urine protein  3g recurs, repeat steps 1 
and 2 
Step 4.  If UPC ≥ 3 or 24-hr urine protein ≥ 3 recurs and the 
pazopanib dose can no longer be reduced, discontinue 
pazopanib and continue follow-up per protocol. 
Hemorrhage /Bleeding: Investigate and document underlying etiology of the bleeding 
Grade 1 
 
For hemoptysis, interrupt pazopanib and contact the Principal 
Investigator to discuss whether further treatment with pazopanib is 
appropriate. 
For other Grade I hemorrhage/bleeding events, continue pazopanib at 
the current dose; monitor as clinically indicated. 
Grade 2 
 
Step 1.  If pulmonary or GI bleed (other than hemorrhoidal bleeding), 
discontinue pazopanib and continue follow-up per protocol.  
Otherwise, interrupt pazopanib until the AE resolves to  
Grade 1.  
Step 2.  Restart pazopanib; consider reducing dose and monitor as 
clinically indicated. 
Grade 3 or 4, or recurrent  Grade 2 
event after dose 
interruption/reduction. 
 
Discontinue pazopanib and continue with follow-up per protocol.  
 
Venous Thrombosis (DVT, PE) 
Grade 2 
Continue pazopanib at the current dose; monitor and treat as clinically 
indicated. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
46 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
Venous Thrombosis (DVT, PE) 
Grade 3   
 
Step 1.  Interrupt pazopanib treatment. 
Step 2.  Initiate and monitor anticoagulation as clinically indicated. 
Step 3.  Resume pazopanib treatment at the same dose only if all of 
the following criteria are met:  
 
– 
The subject must have been treated with anticoagulant at the 
desired level of anticoagulation for at least one week. 
– 
No Grade 3 or 4 or clinically significant Grade 2, hemorrhagic 
events have occurred while on anticoagulation treatment. 
 
Subject should be monitored as clinically indicated during 
anticoagulation treatment and after resuming  
study treatment.  When treating with warfarin, INR should be 
monitored within three to five days after any change in pazopanib 
dosing (e.g., re-initiating, escalating/de-escalating, or discontinuing 
pazopanib), and then at least weekly until the INR is stable.  The dose 
of warfarin (or its derivatives) may need to be adjusted to maintain the 
desired level of anticoagulation. 
Grade 4 and/or PE 
Discontinue pazopanib and continue follow-up per protocol.  
Arterial Thrombosis/Ischemia 
Any Grade 
Discontinue pazopanib and continue follow-up per protocol.  
Palmar-plantar Erythrodysesthesia Syndrome 
Grade 1 
Minimal skin changes or dermatitis 
without pain (erythema, edema, 
hyperkeratosis) 
 
Step 1.  Continue pazopanib at present dose 
Step 2.  Initiate supportive care with emollient lotions 
Grade 2 
Skin changes with pain; limiting 
instrumental activities of daily living 
(ADLs) (peeling, blisters, edema, 
bleed, hyperkeratosis) 
Step 1.  Hold pazopanib  
Step 2.  Treat as clinically appropriate: emollient lotions, limiting tight 
shoes and heels 
Step 3.  Upon resolution to Grade 1 or better, restart  pazopanib at 
one lower dose level 
Step 4.  If recurrent consider a further dose reduction to dose level -2 
or discontinuation if already at dose level -2 
Grade 3 
Severe skin changes with pain and 
limiting self care ADLs 
 
Discontinue pazopanib 
Other Clinically Significant Adverse Events attributable to Pazopanibb  
Grade 1 
Continue pazopanib; monitor as clinically indicated. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
47 
 
AE Terms & Descriptions 
Dose Modification Algorithms 
Grade 2 or 3, if clinically significant  
Step 1.  Interrupt pazopanib until toxicity resolves to  Grade 1. 
Step 2.  Restart pazopanib at a lower dose level and monitor as 
clinically indicated 
Other Clinically Significant Adverse Events attributable to Pazopanibb  
Grade 4 
Discontinue pazopanib and continue follow-up per protocol.    
a. 
Well-controlled BP defined as SBP <140 mmHg and mean DBP <90 mmHg. 
b. 
AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v4)  
 
7.4  Dose Interruptions/Modifications for Hepatotoxicity  
As a general rule, since many subjects are taking multiple concurrent medications, it is critical to 
(a) do a thorough evaluation of the subject’s concurrent medications (and ensure all are 
recorded in the CRF), and (b) identify and discontinue those with known hepatotoxicity and 
replace with a non-hepatotoxic equivalent for the same indication if necessary. If hepatotoxicity 
occurs and the suspected cause is from alcohol use, this should be documented within the 
comments of the adverse event case report form.   Liver dysfunction must be fully evaluated 
even if clinical signs and symptoms indicate progression of liver tumor lesions.  Imaging studies 
must be obtained to document potential progression of malignancy. 
 
Table 10 Guidelines for Management of Treatment Emergent Hepatotoxicity in G+P arm 
Event 
Dose Modification Algorithms 
A). ALT and AST of ≤ 
3.0 x ULN 
Continue G+P at current dose with full panel LFTsa monitored as per protocol. 
Study calendar (section 10) 
B). ALT and/or AST 
>3.0 x ULN to ≤5.0 x 
ULN without bilirubin 
elevation (defined as 
total bilirubinb <2.0 x 
ULN or direct bilirubin 
≤35%) and without 
hypersensitivity 
symptoms (e.g., fever, 
rash)  
Liver Event Monitoring Criteria: 
(1) Continue G + P at current dose levels.  
(2) Monitor subject closely for clinical signs and symptoms; perform full panel 
LFTsa weekly or more frequently if clinically indicated until ALT/AST is reduced to 
Grade 1. 
C) ALT and/or AST 
>5.0 x ULN to ≤ 8 x 
ULN without bilirubin 
elevation (defined as 
total bilirubinb <2.0 x 
ULN or direct bilirubin 
≤35%) and without 
hypersensitivity 
symptoms (e.g., fever, 
rash) 
Liver Event Monitoring Criteria: 
(1) Interrupt G + P until toxicity resolves to Grade 1 or baseline.  
(2) Monitor subject closely for clinical signs and symptoms; perform full panel 
LFTsa weekly or more frequently if clinically indicated until ALT/AST is reduced 
to Grade 1. 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
48 
 
 
Event 
Dose Modification Algorithms 
 
D). ALT >8.0 x ULN 
without bilirubin 
elevation (defined as 
total bilirubinb <2.0 x 
ULN or direct bilirubin 
≤35%) and without 
hypersensitivity 
symptoms (e.g., fever, 
rash)  
1st occurrence – Liver Event Interruption Criteria: 
(1) Interrupt G + P until toxicity resolves to  Grade 1 or baseline.  Report the 
event to Novartis as an SAE within 24 hours of learning of its.  Make every 
reasonable attempt to have subjects return to the clinic within 24 to 72 hours for 
repeat liver chemistries and liver event follow up assessments. 
(2) Liver imaging and other laboratory investigations should be considered   as 
clinically appropriate. 
(3) Monitor subject closely for clinical signs and symptoms; perform full panel 
LFTsa weekly or more frequently if clinically indicated until ALT/AST is reduced 
to Grade 1 or baseline.   
(4) If the subject is benefiting from the study treatment, contact Principal 
Investigator for possible re-challenge with P.  Re-treatment may be considered if 
ALL following criteria are met:  
 
– 
ALT/AST reduced to Grade 1 or baseline 
– 
Total bilirubin <1.5 x ULN or direct bilirubin  35% 
– 
No hypersensitivity signs or symptoms 
– 
Subject is benefiting from therapy.  
 
Recurrence – Liver Event Stopping Criteria: 
Discontinue study treatment and monitor subject closely for clinical signs and 
symptoms; perform full panel LFTs a weekly or more frequently if clinically indicated 
until ALT/AST is reduced to Grade 1 or baseline.  At the time of the recurrence, 
complete the CRF liver event forms.  P should be permanently discontinued and 
further treatment off study will be at the discretion of the treating physician. 
E). ALT or AST >3.0 x 
ULN with concomitant 
elevation in bilirubinb 
(defined as total 
bilirubin 2.0 x ULN; 
with direct bilirubin 
>35%) or with 
hypersensitivity 
symptoms (e.g., fever, 
rash).  
Liver Event Stopping Criteria 
(1) Discontinue pazopanib immediately; report the event to Novartis as an 
SAE within 24 hours of learning of its occurrence. Make every reasonable 
attempt to have subjects return to the clinic for repeat liver chemistries and liver 
event follow up assessments. 
(2) Monitor subject closely for clinical signs and symptoms; record the appearance 
or worsening of clinical symptoms of hepatitis, or hypersensitivity, such as 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or 
eosinophilia as relevant on the AE report form.  Perform full panel LFTs a weekly 
or more frequently if clinically indicated until LFTs are reduced to Grade 1.   
 
For isolated total 
bilirubinb elevation 
without concurrent ALT 
/AST increases 
(defined as ALT and 
AST<3 X ULN). 
 
(1) Isolated hyperbilirubinemia (i.e., in the absence of elevated ALT/AST or other 
signs/symptoms of liver injury) does not require dose modification.  Pazopanib 
inhibits UGT1A1 and OATP1B1, which can cause elevation of indirect 
(unconjugated) bilirubin in the absence of liver injury. 
(2) If bilirubin is >1.5 x ULN in the absence of ALT elevation, fractionation of 
bilirubin elevation should be performed.  If bilirubin is >35% direct 
(conjugated), further evaluation for underlying cause of cholestasis should be 
performed. 
a. 
Full panel LFTs include: AST, ALT, alkaline phosphatase, and total bilirubin.  Coagulation tests should be performed 
as clinically indicated. 
b. 
Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject meets 
the criterion of total bilirubin >2 x ULN, then the event should be promptly reported as an SAE. 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
49 
 
Table 11 Guidelines for Management of Treatment Emergent Hepatotoxicity in G+T arm 
Bilirubin 
 
Alkaline 
phosphatase 
 
ALT/AST 
 
Dose  
>ULN 
 
AND/
OR 
>5 x ULN 
AND/
OR 
>5 x ULN 
Hold until recovered 
(recheck weekly) then 
restart treatment*:  
 
Docetaxel  
Next lower dose 
level 
Gemcitabine  
100% of current 
dose 
< ULN 
AND 
> 2.5 but < 5 x 
ULN 
AND 
> 2.5 but 
< 5 x ULN 
Hold until recovered 
(recheck weekly) then 
restart treatment*:  
 
Docetaxel  
Next lower dose 
level 
Gemcitabine  
100% of the 
current dose 
< ULN 
AND 
> 2.5 but < 5 x 
ULN 
OR 
> 2.5 but 
< 5 x ULN 
Docetaxel  
Next lower dose 
level 
Gemcitabine  
100% of the 
current dose 
* If bilirubin < ULN and alkaline phosphatase < 3 x ULN and SGOT/SGPT < 3 x ULN  
 
7.5 Dose Interruptions/Modifications Specific for Non-Hematologic Toxicities, Excluding 
Liver Toxicities  
Table 12 Adjustments for drugs based on stomatitis, esophagitis, or dysphagia on day 1 of a 
treatment cycle   
Grade 
Arm 
Dose % 
0, 1, 2 
G+P 
100% of the current dose level  
G+T 
100% of the current dose level 
3, 4 
G+P 
1st occurrence: No change in the dose of P. 
Delay G dose by 1 week, and if grade lowers 
to < 2, then resume at the next lower dose 
level. 
 
2nd occurrence or if still not recovered 
after 1 week then: reduce dose of P to the 
next lower level and reassess weekly. If 
toxicity grade < 2, then administer G at the 
next lower dose level. 
G+T 
Delay dose by 1 week, and if grade lowers to 
< 2, then administer the G at 100% of the 
current dose.  
 
If still not recovered to grade < 2 after 1 
week, reassess weekly and if toxicity grade < 
2, then administer G at the next lower dose 
level. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
50 
 
Table 13 Adjustments for drugs based on stomatitis, esophagitis, or dysphagia on day 8 of a 
treatment cycle  
Grade 
Arm 
Dose % 
1-2 
G+P 
100% of the current dose level  
G+T 
100% of the current dose level 
> 3 
G+P 
No change in the dose of P 
Delay G dose by 1 week, and if grade lowers 
to < 2, then resume at the next lower dose 
level. 
 
If still not recovered to grade < 2 after 1 
week, skip day 8 treatment and reduce dose 
in subsequent cycles by one dose level on 
days 1 and 8. 
G+T 
Delay dose of G and T by 1 week, and if 
toxicity grade < 2, then administer the G and 
T at the next lower dose level. 
 
If still not recovered to grade < 2 after 1 
week, skip day 8 treatment and reduce dose 
in subsequent cycles by one dose level on 
days 1 and 8. 
   
Table 14 Adjustments for all drugs based on dyspnea or pneumonitis on day 1 or day 8 of a 
treatment cycle  
Dyspnea Grade (due to Drug Toxicity) 
 
Dose % 
1 
All drugs 
100 
>2 
All drugs 
Discontinue Protocol 
Therapy 
Pneumonitis Grade 
 
Dose % 
1 
All drugs 
100% 
>2 
All drugs 
Discontinue protocol 
therapy 
 
7.5.1 Hypersensitivity reaction 
 
Allergic reactions may follow administration of any of the chemotherapy drugs.  See 
Appendix F for treatment of hypersensitivity reactions.  Treatment should be discontinued 
for grade 4 hypersensitivity reactions.  There are no dose reductions for hypersensitivity 
reactions.  
  
7.5.2 Peripheral neuropathy:  
 
Table 15 Adjustments for docetaxel based on peripheral neuropathy on day 8 of a treatment 
cycle  
Grade 
 
Dose  
1-2 
All drugs 
100% 
>3 
Hold until symptoms < grade 1, then restart 
as follows: 
 
Docetaxel  
Reduce by one dose level 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
51 
 
7.5.3  Fluid retention or Hyperlacrimation 
   
For patients receiving docetaxel:  See Appendix G and H. 
 
7.5.4 Other treatment related non-hematologic toxicity: 
 
Exception nausea/vomiting, alopecia, and fever without grade IV neutropenia and other 
metabolic imbalances. Please see Section 7.1 for additional detail:  
  
Table 16 Adjustments for G and T based on any other treatment related non-hematologic 
toxicity on day 1 or 8 of a treatment cycle (See 6.1 for exceptions) 
 
CTC Grade 
Chemotherapy dose (%) 
1 
100 
2 
Hold* 
3 
Hold** 
4 
Discontinue Protocol Therapy 
*   Give 100% upon improvement to grade 1 
** Reduce by one dose level upon improvement to grade 1  
 
 
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
52 
 
8 STUDY AGENT INFORMATION 
 
 
8.1 Investigational agent: Pazopanib  
8.1.1 
Formulation, product identification, package and labeling 
 
8.1.1.1 Product description 
Pazopanib monohydrochloride salt is supplied as aqueous film-coated tablets containing 
200 mg of the free base.  The tablets are oval-shaped and white in color.  Refer to the 
pazopanib IB for information regarding the physical and chemical properties of 
pazopanib and a list of excipients. 
 
8.1.1.2 Route of administration  
Pazopanib should be taken orally without food at least one hour before or two hours 
after a meal. The tablets should be swallowed whole and must not be crushed or broken. 
The time of day the tablets are taken should be relatively constant.  
 
8.1.1.3 Availability  
Pazopanib will be provided to the sites by Novartis.  The 200-mg pazopanib tablets are 
packaged 34 to a bottle.  All bottles are made of high-density polyethylene and have a 
child-resistant closure.  Each bottle will be labeled with the protocol number, dosing and 
storage instructions, sponsor name and address, and the expiration date, when required.  
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
 
Pazopanib will be dispatched to the site only after receipt of required documents in 
accordance with applicable regulatory requirements and Novartis procedures. 
 
8.1.1.4 Storage requirements 
Pazopanib must be stored in a secure, limited-access area at the study site, under the 
appropriate physical conditions for the product.  The recommended storage conditions, 
and expiration date where required, are stated on the product label.  
 
Under normal conditions of handling and administration, pazopanib is not expected to 
pose significant safety risks to site staff.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from Novartis 
upon request. 
 
8.1.2 Destruction of drug   
 
Any unused, used and expired study drug will be destroyed at the site per Institutional SOPs 
unless otherwise specified. A copy of the final drug accountability log noting the drug 
destruction must be forwarded to the HCC Clinical Trials Network. 
 
8.1.3 Records to be kept at site, dispensing and accountability 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
53 
 
Pazopanib must be dispensed or administered according to procedures described herein.  
Only subjects enrolled in the study may receive pazopanib, in accordance with all applicable 
regulatory requirements.  Only the site pharmacist, Investigator, or other authorized site 
personnel may have access to and supply or administer pazopanib.  Pazopanib will be 
dispensed to the subject after it has been confirmed that the subject meets all eligibility 
criteria and all screening assessments have been completed and the results reviewed.  
Subjects are to return to the site approximately every 3 weeks for re-supply of pazopanib, 
according to the study visit schedule. 
 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product disposition is maintained at each study site where investigational product is 
inventoried and disposed.  Records or logs must comply with applicable regulations and 
guidelines, and should include: 
 
Amount received and placed in storage area. 
 
Amount currently in storage area. 
 
 
Label ID number or batch number. 
 
Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
 
Amount dispensed to and returned by each patient, including unique patient 
identifiers. 
 
Amount transferred to another area for dispensing or storage. 
 
Non-study disposition (e.g., lost, wasted, broken). 
 
Study patients receiving Pazopanib must be instructed to complete a Pazopanib drug diary 
to document the daily administration of Pazopanib. The drug diary is available on the HCC-
CTN workbench online repository. Patients should be counseled at the beginning of and 
throughout study participation to comply with the following activities for patient safety and 
monitoring: 
 
1. Administer Pazopanib as outlined in section 8.1.1.2 Route of administration 
2. Complete the provided Pazopanib drug diary. 
3. Return the completed Pazopanib drug diary and pill bottle with any remaining study drug 
to the study site at each visit. 
 
If the treating investigator suspects a patient’s failure to comply with proper administration of 
Pazopanib, the patient should be immediately counseled and may be removed from study if 
warranted per the treating investigator’s discretion.  
 
8.1.4 Treatment of Investigational Product Overdose 
 
No maximum tolerated dose (MTD) was reached in the dose escalation study of pazopanib 
administered as a single agent at repeated doses of up to 2000 mg/day (Study VEG10003).  
Systemic exposure to pazopanib at steady-state appeared to plateau at doses greater than 
800 mg once daily.  Increases in the daily pazopanib dose above 800 mg in the fasted state 
resulted in a small or no increase in mean systemic exposure to pazopanib.     
 
In the event of pazopanib overdose (defined as administration of more than the protocol-
specified dose), the investigator should contact the Principal Investigator- Dr. Andrew Kraft.  


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
54 
 
Decisions regarding pazopanib dose modifications or interruptions will be made by the 
investigator in consultation with the Principal Investigator based on the clinical evaluation of 
the subject.  
   
Following an overdose, additional monitoring of the subject for AEs/SAEs and laboratory 
abnormalities should be considered.  A plasma sample for pharmacokinetic analysis for 
pazopanib may be requested by the Principal Investigator on a case-by-case basis.  This 
plasma sample should be collected as soon as possible, but within 7 days from the date of 
the last dose of study drug.  Information regarding the quantity of the excess dose, as well 
as the duration of overdosing, should be documented in the CRF. 
 
8.2 Commercial Agent(s) 
8.2.1 Gemcitabine 
 
Gemcitabine is commercially available. For product description and handling information, 
please refer to the package insert for Gemcitabine. 
 
 
 
Route of administration:   
In the treatment of sarcoma, gemcitabine is administered as an infusion over 90 minutes on 
Days 1 and 8 of each 21-day cycle.  
 
 
 
 
Side effects:  
The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, 
anemia, neutropenia, leukopenia, proteinuria, fever, hematuria, rash, thrombocytopenia, 
dyspnea, ALT, AST and alkaline phosphatase elevation. Please refer to the package insert 
for additional details. 
 
8.2.2 Docetaxel (Taxotere) 
 
Taxotere is commercially available. For product description and handling information, please 
refer to the package insert for taxotere. 
 
 
Route of administration:  The final TAXOTERE dilution for infusion should be administered 
intravenously as a 1-hour infusion under ambient room temperature and lighting conditions. 
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
55 
 
9 CORRELATIVE/SPECIAL STUDIES  
 
Correlative studies will be performed on all patients on either arm who give consent for the 
correlative studies outlined below.  Refer to the MUSC 101644 Correlatives Manual for processing, 
handling and shipping instructions.   
 
9.1 Cytokine and Angiogenesis Factors Biomarker Studies 
Cytokine and angiogenesis factors (CAFs) correlative studies will be performed to all patients on 
either arm who give consent for the optional biomarker study to investigate possible biomarkers 
for response or resistance. One 10 ml tube of blood will be collected after randomization (prior 
to C1D1 treatment), upon completion of cycle 2 and at the end of therapy. CAFs measured may 
include but are not limited to IL-12, HGF, IL-16, IP-10, SDF-1α, IL-2Rα, IL-3, IFN-α2, tumor 
necrosis factor-related apoptosis-inducing ligand (TRAIL), M-CSF, PIGF and sVEGFR will be 
assessed.  
 
9.2 Specimen Banking Study 
An additional blood draw will be completed for all patients on either arm who consent to the 
optional specimen banking. One 10 ml tube of blood will be collected after randomization (prior 
to C1D1 treatment), upon completion of cycle 2 and at end of therapy.  
 
9.3 Pharmacokinetic Study 
A plasma sample will also be collected after randomization (prior to C1D1treatment), upon 
completion of cycle 2 and end of therapy to assess pazopanib concentration in patients 
receiving pazopanib, who have consented for the biomarker analysis for correlation. Blood 
samples for the determination of plasma pazopanib concentrations will be collected into a 3mL 
EDTA vacutainer The study will provide all tubes for blood collection, storage, and labels with 
the visit name and time of sample collection. An initial supply of kits will be provided to the site 
at the time of study activation.. 
 
To request a resupply order of PK kits, please complete the PK materials re-order form and as 
outlined in the 101644 Correlatives Manual. Although resupply requests will be accommodated 
as expedient as possible, please monitor PK kit supplies at your site and allow 10 business 
days for processing PK kit resupply orders. Refer to the 101644 Correlative Studies Manual for 
detailed instructions. 
 
9.4 Quality of Life Assessment 
 
For patients who consent to the optional Quality of Life study, Quality of Life will be assessed 
using two questionnaires that all patients will be asked to fill out at 4 different time points. See 
section 9.2. The questionnaires are available in Appendices I and J. 
 
The European Organization for the Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) is a questionnaire with 30 questions developed to 
assess the quality of life of cancer patients. QLQ-C30 Version 3.0 is the most recent version 
that will be used. The Euroqol questionnaire (EQ-5D-3L) is a standardized instrument for use as 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
56 
 
a measure of health outcome. Applicable to a wide range of health conditions and treatments, it 
provides a simple descriptive profile and a single index value for health status. It is a descriptive 
system consisting of 5 dimensions: mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression. Each dimension has 3 levels designated simply as no problem, some 
problem, or extreme problem, and subjects are asked to check the level most descriptive of their 
current level of function or experience on each dimension. 
 
The EORTC QLQ-C30 and EQ-5D questionnaire will be completed by each patient at baseline 
(on the day of first treatment, prior to any other study specific procedures), at 6 weeks (after 2 
cycles), 18 weeks (after 6 cycles) and at the end of therapy. The questionnaires will be 
administered and collected by the study coordinator on the day of the clinic visit, prior to any 
other study specific procedure or treatment. 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
57 
 
10 Study Assessments 
 
See next page for study calendar and assessment guidelines. 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
58 
 
10.1 
STUDY CALENDAR- GROUP 1: GEMCITABINE + DOCETAXEL 
Patients receiving Gemcitabine + Docetaxel during initial or crossover therapy will follow this calendar 
 
Screeninga 
All Cycles 
Cycle 1  only 
Every 6 weeks 
(end of every 2 cycles) 
Progression/ 
End of 
Treatmenti 
Follow-up 
Day 1 
a, k 
Day 8 k 
Day 15 
Gemcitabine  
 
X 
X 
 
 
 
 
Docetaxel 
 
 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Medical History/ Physical Exam 
X 
X 
 
 
 
X 
 
Concomitant Medications 
Assessmentk 
Xk 
X 
X 
 
 
X 
 
Vitals signs 
X 
X 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
Toxicity Assessmentc 
 
X-------------------------------------------------------------------------------------------------------X 
 
CBCD, LFTs, chemistries  c, d 
X 
X 
Xc 
X 
 
X 
 
Pregnancy test (WOCBP only) 
Xa 
 
 
 
 
Xi 
 
UPC  
X 
 
 
 
 
Xi 
 
Thyroid function test (T4, TSH)  
X 
 
 
 
 
Xi 
 
Coagulation tests 
X 
Xd 
 
 
 
Xi 
 
EKG   
X 
 
 
 
 
Xi 
 
Radiographic Assessment f, k 
X 
 
 
 
Xe 
Xe 
 
Optional CAF Biomarker Blood 
Draw (initial treatment only)f 
Xf 
 
 
 
 
X f 
X 
 
Optional Blood Specimen Banking  
(initial treatment only)f 
X f 
 
 
 
X f 
X 
 
Optional QOL Assessment 
(initial treatment only)g 
X 
 
 
 
X 
X 
 
Follow uph 
 
 
 
 
 
 
Xh 
a.  Baseline evaluations are to be done within 14 days of registration, except for informed consent, radiographic disease and concomitant medication assessments that should be 
done within 4 weeks of registration, and serum pregnancy test that should be within 7 days of registration. After randomization, patients should begin treatment within 72 
hours. Screening assessments completed within 48 hours of starting Cycle 1 Day 1 treatment do not need to be repeated unless deemed appropriate by the treating 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
59 
 
physician. 
b. Toxicity will be evaluated at every clinic visit and day 1 of every cycle. Any interim toxicities requiring treatment should be reported to the study coordinator or study physician 
and documented. Use CTCAE v4.0 to grade AEs, except for hypertension and palmarplantar erythrodysesthia syndrome (See Table9). Refer to section 7 for instructions 
regarding dose modifications.  If patient is experiencing liver function toxicities (LFTs), weekly monitoring may be required depending on levels.  
c. 
On subsequent cycles after cycle 1, only CBC with differential and LFTs will be required on day 8. Repeat any other laboratory tests as necessary. Any abnormal LFTs (Total 
Bili, AST, ALT, Alkaline phosphatase) should be repeated within a week and followed thereafter per the treating physicians recommendations. Chemistries include sodium, 
potassium, chloride, bicarbonate, BUN, creatinine and glucose. Laboratory assessments may be carried out within 3 days before the actual treatment administration to allow 
flexibility in scheduling. 
d.  Coagulation test should be repeated after a week of starting therapy on any patient who is on stable therapeutic anticoagulation per institutional standards. It should be then 
followed till documentation of stabilization while on protocol therapy.  If anti-coagulation therapy is initiated on study for reasons not related to study drug, study drug should 
be held and the patient should be monitored until desired level of anti-coagulation is reached.   
e. Radiographic Assessment: CT scans to cover bodily areas in which there is disease or suspected disease. Restaging scans should be repeated every 6 weeks or 2 cycles 
until progression.  If dose holds cause a delay in the start or end of a cycle, scans should remain scheduled every 6 weeks.  Attempts should be made to obtain radiographic 
assessment at the end of treatment visit if there is no prior radiographic confirmation of disease progression. If a patient crosses study arms, radiographic assessments will 
continue to be performed according to the same schedule. MRIs may be substituted in place of CT scan for clinical reasons such as patient intolerance of intravenous 
contrast material. The same method of assessment (i.e. CT, MRI) and the same technique should be used to characterize each identified and reported lesion at baseline and 
during follow-up. Use RECIST 1.1 guidelines. Refer to Section 11. 
f. 
An additional blood draw will be collected from patients who provide informed consent to the optional biomarker and banking correlative studies and are receiving treatment 
during initial study therapy. CAF Biomarker and specimen banking samples will not be collected for patients in crossover therapy. Blood draws will occur at three time points: 
after randomization but prior to treatment, upon completion of cycle 2 (after day 15 of cycle 2 and before treatment on day 1 of cycle 3), and at the time of progression. Refer 
to 101644 Correlative Manual for processing and handling instructions.  
g. Quality of Life Questionnaires will be administered to patients who provided consent and are receiving initial study therapy at the following four time points: (1) at baseline (on 
the day of first treatment and prior to any other study specific procedures), (2) at 6 weeks (after 2 cycles), (3) 18 weeks (after 6 cycles), and (4) at the end of therapy. The 
questionnaires will be administered and collected by the study coordinator on the day of the clinic visit, prior to any other study specific procedure or treatment. Quality of life 
assessments will not be administered for patients in crossover therapy. 
h. Patients will be followed every3 months for documentation of progression and survival status for a maximum of 24 months after the last patient has been registered to the trial. 
i. 
Patients will be given the opportunity to crossover to the other treatment arm upon progression if deemed appropriate by the investigator. If the patient does crossover, the 
patient must complete the end of treatment evaluations and submit a crossover registration packet to the Hollings Cancer Center CTN. A pregnancy test, urinalysis, UPC, 
coagulation tests, EKG, T4 and TSH are only required at this end of study visit if the patient is expected to crossover to the Gem+Paz arm. Refer to Section 5.4 Patient 
Crossover for more details. 
j. 
Concomitant medications should be assessed during screening from 28 days prior to registration through completion of the end of therapy visit. Assess indication, dose 
information and dates of administration. Prohibited medications should be stopped 14 days prior to registration until discontinuation from study (Refer to Section 5.2.3).  
k. To allow for scheduling or holiday issues, patient assessments and drug administration may be done +/- 3 days. Radiographic assessments may be done +/- 7 days.  Patient 
assessments must be completed prior to administration of Gemcitabine or Docetaxel. 
10.2 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
60 
 
STUDY CALENDAR- GEMCITABINE + PAZOPANIB 
Patients receiving Gemcitabine + Pazopanib during initial or crossover therapy will follow this calendar 
 
Screeninga 
All Cyclesn 
Cycle 1 
Only 
 1st 24 weeks 
(8 cycles) 
After week 24 
(end of cycle 8) 
Progression / 
End of 
Treatmentk 
Follow-up 
Day 1a 
Day 8  
Day 15 
Every 6 weeks 
(end of every 2 cycles) 
Every 12 weeks 
(end of every 4 
cycles) 
Gemcitabine  
 
X 
X 
 
 
 
 
 
Pazopanib  
 
Xn-------------------------------------------------------------------------------------------Xn 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
History/ Physical Exam 
X 
X 
 
 
 
 
X 
 
Concomitant Medications AssessmentL 
XL 
X 
X 
 
 
 
X 
 
Vitals signs 
X 
X 
X 
Xb 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
 
 
X 
 
Toxicity Assessmentc  
 
      X-----------------------------------------------------------------------------------------------------------------X 
 
CBCD, LFTs, chemistries d 
X 
X 
Xd 
X 
 
 
X 
 
Pregnancy test (WOCBP only) 
Xa 
 
 
 
 
 
X 
 
UPC 
X 
 
 
 
X 
X 
 
 
Thyroid function test (T4, TSH) 
X 
 
 
 
X 
X 
 
 
Coagulation tests 
X 
Xf 
 
 
 
 
 
 
EKG e 
X 
 
 
 
X 
X e 
 
 
Radiographic Assessment g,n 
X 
Xg 
 
 
 
 
Xg 
 
Pazopanib Drug Diary Reviewm 
 
X 
X 
X 
 
 
X 
 
Optional CAF Biomarker Blood Draw 
(initial therapy only)h 
X h 
 
 
 
X h  
 
X 
 
Optional Blood Specimen Banking (initial 
therapy only)h  
X h 
 
 
 
X h 
 
X 
 
Optional QOL  
Assessment (initial therapy only) i 
X 
 
 
 
X 
 
X 
 
Optional Pazopanib PK Plasma Sampleh 
X h 
 
 
 
X h 
 
X 
 
Follow upj 
 
 
 
 
 
 
 
Xj 
a. 
Baseline evaluations are to be done within 14 days of  registration, except for informed consent, radiographic disease and concomitant medication assessments that 
should be done within 4 weeks of registration and serum pregnancy test that should be within 7 days of registration. After randomization, patients should begin treatment 
within 72 hours. Screening assessments completed within 48 hours of starting Cycle 1 Day 1 treatment do not need to be repeated unless deemed appropriate by the 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
61 
 
treating physician. 
b. 
Monitoring of BP:  A measurement of BP should be taken on day Cycle 1 day 15.  The BP measurement can be done in clinic or self-reported by patient.  
c. 
Toxicity will be evaluated at every clinic visit and day 1 of every cycle. Any interim toxicities requiring treatment should be reported to the study coordinator or study 
physician and documented. Use CTCAE v4.0 to grade AEs, except for hypertension and palmarplantar erythrodysesthia syndrome (See Table9). Refer to section 7 for 
instructions regarding dose modifications.  If patient is experiencing liver function toxicities (LFTs), weekly monitoring may be required depending on levels.  
d. 
On subsequent cycles after cycle 1, only CBC with differential and LFTs will be required on day 8. Repeat any other laboratory tests as necessary. Any abnormal LFTs 
(Total Bili, AST, ALT, Alkaline phosphatase) should be repeated within a week and followed thereafter per the treating physicians recommendations. Chemistries include 
sodium, potassium, chloride, bicarbonate, BUN, creatinine and glucose. Laboratory assessments may be carried out within 3 days before the actual treatment 
administration to allow flexibility in scheduling. 
e. 
After 1 year on study, ECGs will be performed every 6 months.  
f. 
Coagulation tests should be repeated after a week of starting therapy on any patient who is on stable therapeutic anticoagulation per institutional standards. It should be 
then followed till documentation of stabilization while on protocol therapy.  If anti-coagulation therapy is initiated on study for reasons not related to study drug, study drug 
should be held and the patient should be monitored until desired level of anti-coagulation is reached.  See Section 5.5.1 
g. 
Radiographic Assessment: CT scans to cover bodily areas in which there is disease or suspected disease. Restaging scans should be repeated every 6 weeks or 2 
cycles until progression.  If dose holds cause a delay in the start or end of a cycle, scans should remain scheduled every 6 weeks.  Attempts should be made to obtain 
radiographic assessment at the end of treatment visit if there is no prior radiographic confirmation of disease progression. If a patient crosses study arms, radiographic 
assessments will continue to be performed according to the same schedule. MRIs may be substituted in place of CT scan for clinical reasons such as patient intolerance 
of intravenous contrast material. The same method of assessment (i.e. CT, MRI) and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up. Use RECIST 1.1 guidelines. Refer to Section 11. 
h. 
An additional blood draw will be collected from patients who provide informed consent to the optional correlative studies and are receiving initial study treatment. The CAF 
biomarker and specimen banking do not apply to crossover therapy.  The Pazopanib PK studies will be collected from patients in the initial or crossover study phase who 
provide informed consent to the optional PK study. All blood draws will occur at three time points: after randomization but prior to treatment, upon completion of cycle 2 
(after day 15 of cycle 2 and before treatment on day 1 of cycle 3), and at the time of progression. Refer to 101644 Correlative Manual for processing and handling 
instructions.  
i. 
Quality of Life Questionnaires will be administered to patients at four time points: (1) at baseline (on the day of first treatment and prior to any other study specific 
procedures), (2) at 6 weeks (after 2 cycles), (3) 18 weeks (after 6 cycles), and (4) at the end of therapy. The questionnaires will be administered and collected by the 
study coordinator on the day of the clinic visit, prior to any other study specific procedure or treatment. Quality of life assessments will not be administered for patients in 
crossover therapy. 
j. 
Patients will be followed every3 months for documentation of progression and survival status, for a maximum of 24 months after the last patient has been registered to the 
trial. 
k. 
Patients will be given the opportunity to crossover to the other treatment arm upon progression. If the patient does crossover, the patient must complete the end of 
treatment evaluations and submit a crossover registration packet to the Hollings Cancer Center CTN. A pregnancy test is only required at this end of study visit if the 
patient is expected to crossover. Refer to Section 5.4 Patient Crossover for more details.  
L. 
 Concomitant medications should be assessed during screening from 28 days prior starting study therapy through completion of the end of therapy visit. Assess 
indication, dose information and dates of administration. Prohibited medications should be stopped 14 days prior to first dose of study drug until discontinuation from study 
(Refer to Section 5.5.3).  
m.    Pazopanib drug diaries should be collected and reviewed on Day 1 of each cycle. Patients should be instructed to bring their diaries and pill bottles with them to the each 
visit and patient compliance should be assessed. If patient non-compliance is present, the patient should be re-educated and counseled on drug compliance. Any unused 
medication should be collected and returned to the facilities pharmacy for destruction per institutional policies. 
a. 
To allow for scheduling or holiday issues, patient assessments and drug administration may be done +/- 3 days. Radiographic assessments may be done +/- 7 days.  
Patient assessments must be completed prior to administration of Gemcitabine. Patients should also continue taking Pazopanib during any scheduling delays. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
62 
 
11 MEASURES OF EFFECT 
 
Response Evaluation Criteria in Solid Tumors (RECIST)  
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria will be used for objective 
tumor response assessment.  Assessments will be performed after every two cycles of treatments. 
Attempts should be made to obtain radiographic assessment at the end of treatment visit if there is 
no prior radiographic confirmation of disease progression. If a patient crosses study arms, 
radiographic assessments will continue to be performed after every two cycles of treatments.  Once 
protocol treatment has been completed subjects will be assessed every three months or sooner as 
indicated and judged by treating physicians. 
11.1 
Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with drugs on study. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-
target disease.  The response assessment is based on the presence, absence, or unequivocal 
progression of the lesions.  
 
11.2 
Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as > 20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  Sarcomas arising in a previously irradiated site will be considered 
measurable.  Sarcoma lesions that have been treated with therapeutic intent will be considered 
measurable if they have increased in size by more than 20%. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
63 
 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up.  
 
11.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
CT and MRI  This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
64 
 
is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the same as was 
used at baseline and the lesions should be measured/assessed on the same pulse sequence.  
It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of scanner 
should be used and the image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
65 
 
11.4 
Response Criteria 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s).  
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single 
lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
Table 17 For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
66 
 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is 
evidence of a new lesion. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the 
complete response status.  
 
11.5 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 
11.6 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
67 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
 
12.1 Adverse events  
An adverse event is any unintended or undesirable experience that occurs during the course of 
the clinical investigation whether or not it is considered to be drug related.  This includes any 
newly occurring event or previous condition that has increased in severity or frequency since the 
administration of study drug.  
  
At each evaluation patients should be interviewed in a non-directed manner to elicit potential 
adverse reactions from the patient.  The occurrence of an adverse event will be based on 
changes in the patient’s physical examination, laboratory results, and/or signs and symptoms.  
  
All adverse events, regardless of causal relationship, will be recorded in the case report form 
and source documentation.  The investigator, sub-investigator, or treating physician must 
determine the intensity of any adverse events according to the NCI Common Terminology 
Criteria for Adverse Events v4.0 and their causal relationship. 
  
 
Adverse events will be followed until resolution while the patient remains on-study.  Once the 
patients is removed from study, events thought to be related to the study medication will be 
followed until resolution or until the patient starts a new treatment regimen.  
 
12.2 
Serious adverse events (SAE)  
Serious adverse events will be defined as an adverse event occurring while on study or within 
30 days of the last study drug administration that result in any of the following outcomes:  
 
 
Death.  
 
A life-threatening adverse drug experience.  
 
A persistent or significant disability/incapacity.  
 
Inpatient hospitalization or prolongation of existing hospitalization.  For the purposes 
of this study inpatient hospitalization or prolongation of existing hospitalization for the 
following reasons are not considered to be events for reporting: transfusion support, 
or other elective procedures associated with conventional medical practice, unless 
associated with other serious adverse events.  
 
A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed 
above.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
 
Any pregnancies occurring during or within 30 days of the last study drug administration should 
also be considered serious adverse events and reported to the sponsor.  
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
68 
 
In addition, any SAEs which occur as a result of protocol specific diagnostic procedures or 
interventions must also be reported. 
 
Also considered serious for the purposes of this Study: 
 
o ALT >3.0 x ULN with concomitant elevation in bilirubin (defined as total bilirubin ³2.0 
x ULN, with direct bilirubin >35%) or with hypersensitivity symptoms (e.g., fever, 
rash) – bilirubin fractionation should be performed if testing available 
 
o ALT >8.0 x ULN without bilirubin elevation (defined as total bilirubin <2.0 x ULN or 
direct bilirubin £35%) and without hypersensitivity symptoms (e.g., fever, rash) – 
bilirubin fractionation should be performed if testing available 
 
12.3 Reporting of SAE's  
Any serious adverse events which occur during the clinical study or within 30 days of receiving 
the last dose of study medication, whether or not related to the study drug, must be reported by 
the investigator.  
 
Adverse events classified as serious require expeditious handling and reporting to IRBs and 
designated IRB or ethics board policies should be followed.   
 
Sponsor Reporting: Within 24 hours of becoming aware of a SAE, the investigator must file a 
MEDWatch Form FDA 3500A (www.fda.gov/medwatch/getforms.htm) to Novartis and MUSC 
Sponsor Investigator per the information below: 
 
All serious adverse events must be reported within 24 hours to Novartis: 
US CPO DS&E 
Fax: (877)778-9739 
If unable to fax:  clinicalsafetyop.phuseh@novartis.com 
Novartis study code:  CPZP034BUS21T 
 
 
The SAE report should comprise a full written summary, detailing relevant aspects of the 
adverse events in question. Where applicable, information from relevant hospital case records 
and autopsy reports should be included. Follow-up information should be forwarded to Novartis 
within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of pazopanib and 
considered by the investigator to be related or possibly related to pazopanib must be reported to 
Novartis if and when they occur. Additionally, in order to fulfill international reporting obligations, 
SAEs that are related to study participation (e.g., procedures, invasive tests, change from 
existing therapy) or are related to a concurrent medication will be collected and recorded from 
the time the subject consents to participate in the study until he/she is discharged. 
 
Copies of the submission to Novartis must also be submitted to the Medical University of 
South Carolina 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
69 
 
ATTN: HCC CTN 
Re: CTO #101644 
Fax: 843-792-5123 
Email:  Anderton@musc.edu 
 
The following items should be included at the time of forwarding the SAE notification to the 
HCC-CTN office. 
 
 
SAE cover sheet and case report form – within case report form packet 
 
Completed MedWatch Form FDA 3500A – available online at 
www.fda.gov/medwatch/getforms.htm 
 
Novartis fax confirmation of SAE submission 
 
IRB submission, if applicable per designated IRB policies 
 
Any de-identified supporting clinical documents serving as source document of the 
SAE as deemed important by the site or as requested by the coordinating center.  
 
The site should receive confirmation from MUSC that the SAE report was received. If not, 
please contact the HCC CTN immediately.  
 
12.4 Data and Safety Monitoring  
The Principal Investigators will be responsible for monitoring the safety and efficacy of the trial, 
executing the DSM plan, and complying with all reporting requirements.   This will be 
accomplished under the oversight of the Data Safety Monitoring Committee (DSMC) of the 
Hollings Cancer Center (HCC).    
 
The HCC DSMC is responsible for monitoring data quality and patient safety for all 
interventional investigator-initiated trials (IIT's) at Hollings Cancer Center (HCC). The HCC 
DSMC will have oversight of this protocol. The HCC DSMC will meet at a minimum on an 
annual basis to discuss the investigator-initiated trial. Also, the IIT will be audited by the DSMC 
auditor or external agency (if  within 6 months of the IIT’s anniversary) at least once a year. 
 
The DSMC reviews all IRB reportable serious adverse events, monitoring/ auditing reports, and 
protocol deviations and has the authority to recommend closure and/or suspension for trials on 
which there are safety or trial conduct issues and may submit recommendations for corrective 
actions. The DSMC recommendations for modifications to the trial (if requested) are forwarded 
to the principal investigator. The principal investigator is notified of this recommendation in order 
that he/she may alert all investigators involved in the trial with regard to the potential action.  At 
this time the principal investigators may submit to the DSMC additional information that could 
affect the Committee's decision.  
 
All IRB reportable serious adverse events, monitoring/ auditing reports will be reviewed by the 
HCC DSMC for review during the DSMC monthly meetings. The HCC CTN will forward the 
event report to the HCC DSMC so that the information can be reviewed at the next available 
DSMB meeting. During the DSMB review, the DSMB can make recommendations for any 
further study action. The HCC CTN will maintain a copy of the DSMB approval letters for each 
event review within this study’s central file. 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
70 
 
12.5 
Data Collection 
Electronic and hard copy CRF’s will be provided for the recording of data.  With the exception of 
hard copy case report forms utilized for expedited reporting requirements as described in 
section 12.3 Reporting of SAE’s, the remainder of patient data will be collected and submitted 
via electronic CRFs. All data should be substantiated by clinical source documents organized 
within a patient research record. ICH Good Clinical Practices are to be followed.  
 
During the course of the study, data quality will be monitored by random inspection of the 
completed forms by a designated monitor.  Any problems detected will be discussed with the PI. 
If necessary, re-training of data collectors will be conducted.   
  
The study will be subject to a yearly internal audit via the DSMC at a minimum and audits may 
occur more frequently at the request of the DSMC.   
 
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
71 
 
13 STATISTICAL CONSIDERATIONS 
 
13.1 Primary Endpoint(s):  
 
1. Progression-free survival, defined as the time from randomization until documented 
progression or death.  For patients who are alive and progression-free upon 
discontinuing the study, their time to progression will be censored at the last clinic visit at 
which the patient was progression-free. 
2. Grade 3 or higher toxicity, defined as the occurrence of any grade 3 or higher 
hematologic or non-hematologic toxicity, felt to be related to study treatment. Adverse 
events will be classified using CTCAE v4.0. 
 
13.2 Secondary Endpoint(s):  
 
1. Tumor response defined using RECIST v1.1.  Patient will be considered to be a 
responder if s/he experiences a complete or partial response while on study. 
2. Quality of life.  Quality of life outcomes are the continuous scores from the EORTC QLQ-
C30 and EQ-5D-3L). 
 
 
 
13.3 Sample size justification   
Sample size was derived based on the precision of 95% confidence intervals for reporting 
toxicity rates and median PFS in each arm.  Hypothesis testing is not implemented due to the 
uncertainty in choosing a historical control PFS rate.  With 45 patients per arm and assuming an 
observed toxicity rate of less than 30%, the maximum half-width of the 95% confidence interval 
is <14%.  For PFS, the precision of the 95% confidence interval will depend heavily on the 
observed median PFS.  With observed median PFS of 3, 6 or 8 months, the estimated half-
widths of 95% confidence interval would be expected to be 1.4, 2.9, or 3.9 months, respectively, 
based on results from Kaplan-Meier curves and using Greenwood’s formula for variance.  
These estimates would be considered sufficiently precise for determining whether or not the 
efficacy and safety profile warrant further exploration of G+P as combined therapy. 
 
Statistical Analysis:  PFS will be analyzed in each arm by generating Kaplan-Meier curves, 
and reporting the median PFS with their 95% confidence intervals.  The proportion of patients in 
each arm with grade 3 or higher related toxicities will be reported with their 95% confidence 
intervals.  
 
Early stopping for safety: To ensure safety of patients, we will stop an arm early if there is 
significant toxicity defined as an unacceptable rate of grade 3 or higher toxicity.  Unacceptable 
toxicity is defined as any grade 3 or higher hematologic or non-hematologic toxicity (CTCAE 
v4.0) that is related to study treatment, with the following exceptions: 
1. Lymphocytopenia and anemia 
2. Grade 3 fatigue that persists for ≤ 7 days 
3. Grade 3 or 4 nausea, anorexia, vomiting, stomatitis/mucositis or diarrhea, unless 
they persist despite maximum supportive care 
4. Grade 4 neutropenia or thrombocytopenia unless it lasts for > 7 days, or is 
associated with a fever > 38.5 °C and grade > 1 bleeding, respectively 
5. Grade 3 neutropenia or thrombocytopenia, unless it is associated with a fever 
>38.5°C and grade > 1 bleeding, respectively. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
72 
 
6. Elevated AST, ALT or bilirubin < 10 x ULN. 
 
We would consider an acceptable level to be 15% (alternative hypothesis) and an unacceptable 
rate to be 30% (null hypothesis) of patients experiencing adverse events as defined above.  We 
will use a sequential probability ratio test that allows stopping for strong evidence that the rate is 
30% (vs. 15%).  The safety monitoring is based on the sequential probability ratio test and the 
threshold is defined by a likelihood ratio value of 10 or greater in favor of the null.  This 
procedure has a 74% chance of early stopping if the true rate of patients experiencing grade 3 
or higher event as described above is 0.30 and only a 6% chance of early stopping if the true 
rate of patients experiencing grade 3 or higher event as described above is 0.15 and is based 
on the binomial log-likelihood.   
 
Number of patients 
with SAE 
Total number of 
patients treated 
Point estimate of 
SAE rate 
Likelihood Ratio 
favoring H0 vs H1 
4 
4-6 
≥ 0.67 
≥ 10.9 
5 
7-10 
≥ 0.50 
≥ 12.1 
6 
11-15 
≥ 0.40 
≥ 11.2 
7 
16-20 
≥0.35 
≥ 10.3 
8 
21-24 
≥ 0.33 
≥ 11.5 
9 
25-29 
≥ 0.31 
≥ 10.5 
10 
30-33 
≥ 0.30 
≥ 11.8 
11 
34-38 
≥ 0.29 
≥ 10.8 
12 
39-42 
≥ 0.29 
≥ 12.1 
13 
43-44 
≥ 0.30 
≥ 16.4 
 
In the event of a death occurring during study treatment or within 30 days of the last dose of 
study treatment that is considered related or possibly related, the event must be reviewed by the 
HCC Data Safety Monitoring Board (DSMB) at the next available meeting. Please see section 
14.1.3 for additional DSMB reporting detail. 
 
13.4 Sample Size/Accrual Rate 
Ninety patients will participate in this study with 45 patients on each arm. We expect overall 
accrual to be approximately 5 patients per month across all sites. Accrual should be completed 
in 18 months from start of study. 
 
13.5 Stratification Factors 
Since G+T has shown good activity in leiomyosarcoma patients, to ensure a balance in the 
treatment arms being compared, we will include stratified randomization. At the time of patient 
registration, we will request information regarding sarcoma type and prior pelvic radiation 
treatment. Because there is interest in the potential for differential response by sarcoma type 
and prior pelvic radiation treatment, the above analyses will be repeated within each subtype.  
However, we do not have a large enough sample size per type to estimate parameters with 
sufficient precision.  As such, these will be considered exploratory and may yield results that are 
interesting and worth pursuing in a future study.  
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
73 
 
13.6 Analysis of Secondary Endpoints 
The hazard ratio (HR) will be estimated between the two groups for planning of future studies of 
these treatment combinations. This will be done using Cox regression.   With median PFS in the 
of G+P vs. G+T of 8 months vs. 6 months the estimated HR would be 0.75 and the expected 
95% confidence interval range from 0.48 to 1.15.  With median PFS in the of G+P vs. G+T of 6 
months vs. 3 months, the estimated HR would be 0.50 and the expected 95% confidence 
interval range from 0.32 to 0.79.  These correspond to half-widths for the 95% confidence 
intervals of 0.34 and 0.22 for these two scenarios.  
   
  
 
Response rate per arm will be estimated with its 95% confidence interval.  Overall survival will 
be described using Kaplan-Meier curves and median survival per arm with 95% confidence 
intervals.  Comparative tests will not be performed. Toxicity profiles will be described by 
estimating the SAE rate per arm and tabulating toxicities per arm by type and grade.  Quality of 
life measurements and markers of angiogenesis will be evaluated by estimating the difference 
from baseline to follow-up assessments.  These changes will be displayed graphically per arm 
and summary statistics will be used to demonstrate average change from baseline. Biomarkers 
from serum will also be analyzed by performing Cox regression, predicting PFS using biomarker 
expression as a covariate in each arm.  Graphical displays will be used to evaluate 
proportionality assumption of the proportional hazards model. 
 
13.7 Reporting and Exclusions 
Evaluation of toxicity.  All patients, who were treated on one of the two treatment groups, will 
be evaluable for toxicity from the time of their first treatment on study. 
 
Evaluation of response.  All randomized patients (intention-to-treat population) will be 
assessed for response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible. Each patient will be assigned one of the following categories:   
1) complete response  
2) partial response  
3) stable disease  
4) progressive disease  
5) early death from malignant disease 
6) early death from toxicity  
7) early death because of other cause  
8) unknown (not assessable, insufficient data)   
 
 
 
 
 [Note:  By arbitrary convention, category 9 usually designates the “unknown” status of any type 
of data in a clinical database.] 
 
All of the patients who meet the eligibility criteria and are treated with study-directed therapy will 
be included in the main analysis of the response rate.  Patients in response categories 4-9 
should be considered to have a treatment failure (disease progression).  Thus, an incorrect 
treatment schedule or drug administration does not result in exclusion from the analysis of the 
response rate.  
 
 
 


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14 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES  
 
14.1 Monitoring and Regulatory Compliance  
The Principal Investigator and the Clinical Research Coordinator assigned to the case will be 
primarily responsible for maintaining all study related documents including the clinical research 
forms.  All CRF entries will be verified with source documentation. The review of medical 
records will be done in a manner to assure that patient confidentiality is maintained.  
  
The Hollings Cancer Center Data Safety Monitoring Committee (HCC DSMC) will be reviewing 
all monitoring reports generated for the study.  
 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, Health Canada, any applicable local health authority, and 
Institutional Review Board (IRB) or Ethics Committee requirements. 
 
This study must have the approval of a properly constituted IRB or Ethics Committee.  Before 
the investigational drug is shipped to the Investigator, the Investigator or designee will provide 
Novartis with a copy of the IRB or Ethics Committee approval letter stating that the study 
protocol and any subsequent amendments and informed consent form have been reviewed and 
approved. 
 
The Investigator or designee will be responsible for obtaining annual IRB or Ethics Committee 
reapproval throughout the duration of the study.  Copies of the Investigator’s annual report to 
the IRB or Ethics Committee and copies of the IRB or Ethics Committee continuance of 
approval must be provided to Novartis. 
 
The Investigator is also responsible for notifying their IRB or Ethics Committee of any significant 
adverse events that are serious and/or unexpected. 
 
As received by Novartis, MUSC  will provide study sites with any expedited safety reports 
generated from any ongoing studies with changes to the pazopanib Investigator’s Brochure, and 
any other safety information which changes the risk/benefit profile of pazopanib during the 
conduct of the study, to allow him/her to fulfill his/her obligation for timely reporting to the 
IRB/ECs and other Investigators participating in the study. Upon completion of the trial, the 
Investigator must provide the IRB or Ethics Committee and Novartis with a summary of the 
trial’s outcome. 
 
14.2 Subsite Monitoring 
 
The Medical University of South Carolina will be responsible for the monitoring of study patient 
data and records. Monitoring will be performed centrally. All monitoring reports will be kept by 
the Hollings Cancer Center (HCC) – Clinical Trials Network (CTN) to ensure that all reports are 
contained in a central study file. The HCC - CTN manager or HCC internal auditor will be 
responsible for conducting the review of monitoring packets. A final monitoring report will be 
generated and issued to the site and will be kept in the central study file by the CTN. The HCC 
CTN will be responsible for forwarding the final monitoring reports to the HCC Data Safety 
Monitoring Committee (DSMB) for review. 


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14.3 Frequency of Reviews 
 
The first three patients at each participating center will have their eligibility criteria reviewed prior 
to enrollment by the CTN. Additional patients eligibility may be reviewed prior to enrollment at 
the discretion of the CTN.  
 
During the course of the study, each site will be selected for an audit approximately once a year. 
The number of cases reviewed will be commensurate with the site’s rate of enrollment. 
However, at a minimum, at least 10% of the patient cases enrolled at a participating center will 
be selected for random audit by the completion of the entire study period.  
 
14.4 Data Safety Monitoring Board 
 
The Hollings Cancer Center Data Safety Monitoring Board will have oversight of the protocol. 
The HCC DSMB will meet at a minimum on an annual basis to discuss the investigator-initiated 
trial. Also, the IIT will be audited by the DSMB auditor or external agency (if within 6 months of 
the IIT’s anniversary) at least once a year. 
 
In addition, all study deaths, protocol deviations and SAEs as defined above will be reviewed by 
the HCC DSMB for review during the DSMB monthly meetings. The coordinating center will 
review protocol deviation and SAE events for form completion and provide assistance in 
communicating to the subsite if more information is warranted. The HCC CTN will forward the 
event report to the HCC DSMB so that the information can be reviewed at the next available 
DSMB meeting. During the DSMB review, the DSMB can make recommendations for any 
further study action. The HCC CTN will maintain a copy of the DSMB approval letters for each 
event reviewed and will distribute to the subsite, if applicable. 
 
14.5 Study Initiation Requirements 
Participating study sites cannot begin enrollment until an initiation letter has been issued from 
the MUSC-Hollings Cancer Center. Each center is required to participate in an initiation 
conference call. 
 
Before the start of this study and the shipment of study drug to a participating study site, the 
following documents must be on file at MUSC-Hollings Cancer Center. Participating sites will be 
responsible for forwarding the initiation documents to: 
Hollings Cancer Center  
ATTN: Clinical Trials Network 
86 Jonathan Lucas Street, Suite 373 
MSC 955 
Charleston, SC 29425-9550 
 
Documents can also be submitted via email to cogginca@musc.edu or via fax at (843) 792-
5123. Please ensure that the fax cover page clearly identifies the site, study identifier and is 
addressed to ATTN: CTN.  
 
These documents are required to be submitted by each participating center:   


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1. U.S. Food and Drug Administration (FDA) Form 1572, signed by the Principal 
Investigator at the participating center. 
2. The names of any sub-investigators at the participating center must appear on this 
form.  Investigators must also complete all regulatory documentation as required by 
local regulations. This includes any required human subjects training required by the 
site’s local IRB. 
3. Current curricula vitae and documentation of professional licensure of the Principal 
Investigator and co-Investigators listed on the 1572. 
4. Resumes and human subject protections documentation (e.g. NIH, CITI) for all 
research personnel (e.g. study coordinators, data managers and other research 
personnel).  
5. A signed and dated investigator brochure acceptance form.  
6. Written documentation of IRB approval of protocol (identified by title, protocol version 
and date of approval) for each site. 
7. IRB approved study informed consent and HIPAA consent form. HIPAA consent 
language can be included within the study informed consent. Please note that all 
informed consent forms should be reviewed and approved by the HCC Clinical Trials 
Network office prior to submission to the site’s designated IRB. 
8. A signed Confidentiality Agreement.  
9. A signed Clinical Trial Agreement for each site.  
10. Laboratory certifications (CAP, CLIAs) and laboratory reference value ranges for each 
laboratory listed on the site’s 1572. 
11. The Hollings Cancer Center Clinical Trials Network site specific forms as specified in 
the 101644 investigator-initiated multicenter manual. 
 
14.6 Study Completion 
The following data and materials are required by MUSC-Hollings Cancer Center and Novartis 
before a study can be considered complete or terminated: 
 
1. Copies of protocol amendments and IRB approval/notification, if appropriate. 
2. Copies of the IRB final report, documentation of submission to the IRB.  
3. A summary of the study prepared by the Principal Investigator (Study report, 
manuscript and/or abstract). 
4. All regulatory documents (e.g., updated curriculum vitae for each Principal 
Investigator, updated U.S. FDA Form 1572 for each site). 
 
14.7 Protocol Modifications  
No modifications will be made to the protocol without the agreement of the sponsor-investigator. 
Changes that significantly affect the safety of the patients, the scope of the investigation, or the 
scientific quality of the study will require Institutional Review Board approval prior to 
implementation, except where the modification is necessary to eliminate apparent immediate 
hazard to human subjects.  Any departures from the protocol must be fully documented in the 
protocol deviation case report form and the source documentation.   
 


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14.8 Protocol Deviations and Safety Reporting 
A Protocol Deviation is any variance from the protocol involving a subject or subjects that is not 
approved by the IRB prior to its initiation or implementation, and occurs when a member of the 
study team departs from the IRB-approved protocol in any way without the investigator first 
obtaining IRB approval. 
 
Any protocol deviation or serious adverse event will be reported by the subsite within 10 days of 
notification. Protocol Deviations will be reported by completion of the hard copy Protocol 
Deviation Report form.  Serious Adverse Events will be reported by completion of a MedWatch 
3500A form and hard copy Serious Adverse Event form. For both Protocol Deviations and 
Serious Adverse Events, all required forms and any supporting clinical documentation should be 
submitted to the Clinical Trials Network office within 10 days of notification.  
 
14.9 Patient Privacy  
In order to maintain patient confidentiality, all case report forms, study reports and 
communications relating to the study will identify patients by initials and assigned patient 
numbers.  The US Food and Drug Administration (FDA) may also request access to all study 
records, including source documentation for inspection.  
 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that 
medical information be given to his/her personal physician. 
 
The Investigator/Institution will permit direct access to source data and documents by Novartis, 
its designee, the FDA and/or other applicable regulatory authority.  The access may consist of 
trial-related monitoring, audits, IRB or Ethics Committee reviews, and FDA inspections. 
 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for Privacy 
of Individually Identifiable Health Information, 45 CFR 164.508. 
 
14.10 Publication Policy  
The Investigators plan to publish and present the information obtained from the study.  
 
  
 
 


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15 ETHICAL CONSIDERATIONS  
 
15.1 Informed Consent  
The investigator will obtain written informed consent from all participating patients or their 
authorized representatives.  Obtaining informed consent must be done according to 
International Conference on Harmonization- Good Clinical Practice Guidelines (ICH GCP). 
Copies of the signed document will be given to the patient and filed in the Investigator’s study 
file, as well as the patient’s medical record if in conformance with the institution’s Standard 
Operating Procedures.  
 
15.2 Institutional Review Board  
The trial will not be initiated without approval of the appropriate Institutional Review Board (IRB).  
All administrative requirements of the governing body of the institution will be fully complied 
with.  This protocol, consent procedures, and any amendments must be approved by the IRB in 
compliance with current regulations of the Food and Drug Administration.  A letter of approval 
will be sent to the institution(s) funding the study prior to initiation of the study and when any 
subsequent modifications are made.  The IRB will be kept informed by the Investigator as to the 
progress of the study as well as to any serious or unusual adverse events.  
 
  
 
 


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16 DATA HANDLING AND RECORD KEEPING   
 
16.1 Data recording and quality control  
The Clinical Research Coordinator and Investigator will be responsible for the recording of all 
data on the Case Report Forms (CRF’s).   
  
The Investigator will provide access to his/her original records to permit a representative from 
the funding or auditing institution(s) to verify the proper transcription of data.  Data submission 
will be electronically via the REDCap database.  
  
16.2 Record retention  
Federal law requires that an Investigator maintain all study records for two years after the 
investigation is discontinued.  
  
 
 
 


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17 DATA COLLECTION 
 
Data will be reported by electronic case report forms in the REDCap database. REDCap is an 
electronic data capture system.  All data should be substantiated by clinical source documents 
organized within a patient research record. ICH Good Clinical Practices are to be followed. 
 
During the course of the study, data quality will be monitored by random inspection of the 
completed forms by a designated monitor.  Any problems detected will be discussed with the PI. If 
necessary, re-training of data collectors will be conducted.  
 
The study will be subject to a yearly internal audit via the DSMC at a minimum and audits may 
occur more frequently at the request of the DSMC. 
 
 
 
 


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18 RECRUITMENT PROCEDURE  
  
All patients referred to or seeking treatment for advanced stage soft tissue sarcoma (excluding 
GIST and liposarcoma) will be offered this trial.  
  
Women and men will be recruited, and are anticipated to be equally represented in the trial.  
  
Persons equal to or over the age of 18 are eligible for trial participation if they have a performance 
status of 0-2, thus by NIH criteria, children are eligible for trial participation.  However, the median 
age of persons with soft tissue sarcoma is 41 years, and the vast majority of participants will be 
above the age of 21.  
  
Minority participation will be especially encouraged. About 26% of patients seeking their care at 
MUSC are African American.  
 
 


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19 REFERENCES 
 
1. 
Clark, M.A. and J.M. Thomas, Delay in referral to a specialist soft-tissue sarcoma unit. European 
journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British 
Association of Surgical Oncology, 2005. 31(4): p. 443-8. 
2. 
Leibel, S.A., et al., Soft tissue sarcomas of the extremities: survival and patterns of failure with 
conservative surgery and postoperative irradiation compared to surgery alone. Cancer, 1982. 50(6): p. 1076-
83. 
3. 
Antman, K., et al., An intergroup phase III randomized study of doxorubicin and dacarbazine with or 
without ifosfamide and mesna in advanced soft tissue and bone sarcomas. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology, 1993. 11(7): p. 1276-85. 
4. 
Bramwell, V.H., Management of advanced adult soft tissue sarcoma. Sarcoma, 2003. 7(2): p. 43-55. 
5. 
Jelic, S., et al., Randomised study of high-dose epirubicin versus high-dose epirubicin-cisplatin 
chemotherapy for advanced soft tissue sarcoma. European journal of cancer, 1997. 33(2): p. 220-5. 
6. 
Le Cesne, A., et al., Randomized phase III study comparing conventional-dose doxorubicin plus 
ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage 
colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research 
and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology, 2000. 18(14): p. 2676-84. 
7. 
Verweij, J., Docetaxel: an interesting new drug for the treatment of head and neck cancers and soft 
tissue sarcomas. Anti-cancer drugs, 1995. 6 Suppl 4: p. 19-24. 
8. 
Verweij, J., et al., The absence of influence of acetylsalicylic acid (ASA) on the transient decrease in 
platelet counts observed after infusion of bleomycin and vinblastine. European journal of cancer & clinical 
oncology, 1985. 21(12): p. 1471-4. 
9. 
Hartmann, J.T., et al., An open label, non-comparative phase II study of gemcitabine as salvage 
treatment for patients with pretreated adult type soft tissue sarcoma. Investigational new drugs, 2006. 24(3): 
p. 249-53. 
10. 
Pazdur, R., M.K. Samson, and L.H. Baker, Fludarabine phosphate. Phase II evaluation in advanced 
soft-tissue sarcomas. American journal of clinical oncology, 1987. 10(4): p. 341-3. 
11. 
Reichardt, P., et al., An open label, non-comparative phase II study of topotecan as salvage 
treatment for patients with soft tissue sarcoma. Investigational new drugs, 2003. 21(4): p. 481-6. 
12. 
Rose, P.G., et al., Prolonged oral etoposide in recurrent or advanced leiomyosarcoma of the uterus: a 
gynecologic oncology group study. Gynecologic oncology, 1998. 70(2): p. 267-71. 
13. 
Woll, P.J., et al., Temozolomide in adult patients with advanced soft tissue sarcoma: a phase II study 
of the EORTC Soft Tissue and Bone Sarcoma Group. European journal of cancer, 1999. 35(3): p. 410-2. 
14. 
Maki, R.G., et al., Randomized phase II study of gemcitabine and docetaxel compared with 
gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research 
through collaboration study 002 [corrected]. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology, 2007. 25(19): p. 2755-63. 
15. 
Hensley, L.E., et al., Proinflammatory response during Ebola virus infection of primate models: 
possible involvement of the tumor necrosis factor receptor superfamily. Immunology letters, 2002. 80(3): p. 
169-79. 
16. 
Yoon, S.S., et al., Circulating angiogenic factor levels correlate with extent of disease and risk of 
recurrence in patients with soft tissue sarcoma. Annals of oncology : official journal of the European Society 
for Medical Oncology / ESMO, 2004. 15(8): p. 1261-6. 
17. 
Hayes, A.J., et al., Serum vascular endothelial growth factor as a tumour marker in soft tissue 
sarcoma. The British journal of surgery, 2004. 91(2): p. 242-7. 
18. 
Potti, A., et al., Immunohistochemical detection of HER-2/neu, c-kit (CD117) and vascular endothelial 
growth factor (VEGF) overexpression in soft tissue sarcomas. Anticancer research, 2004. 24(1): p. 333-7. 
19. 
Potti, A., et al., Determination of vascular endothelial growth factor (VEGF) overexpression in soft 
tissue sarcomas and the role of overexpression in leiomyosarcoma. Journal of cancer research and clinical 
oncology, 2004. 130(1): p. 52-6. 
20. 
Sleijfer, S., et al., Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or 
refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and 


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treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology, 2009. 27(19): p. 3126-32. 
21. 
Van Der Graaf, W.T., Blay, J., Chawla, S. P. , Kim, D. , Bui Nguyen, B. , Casali, P. G. , Schöffski, P. , 
Aglietta, M. , Staddon, A. P. , Beppu, Y. ,Le Cesne,  A. , Gelderblom, H., Judson, I. R. ,Araki,  N. ,Ouali,  M. , 
Marreaud, S. , Hodge, R. ,  Dewji, M., Dei Tos, A. P. ,Hohenberger,  P. ; Radboud University Medical Centre, 
Nijmegen, Netherlands; Centre Léon Bérard, Lyon, France; Sarcoma Oncology Center, Santa Monica, CA; 
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Institut Bergonié, 
Bordeaux, France; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of General 
Medical Oncology, University Hospitals Leuven, Leuven, Belgium; Medical Oncology, University of Torino, 
Institute for Cancer Research and Treatment, Candiolo, Italy; University of Pennsylvania, Philadelphia, PA; 
National Cancer Center Hospital, Tokyo, Japan; Institut Gustave Roussy, Villejuif, France; Department of 
Clinical Oncology, Leiden University Medical Center, Leiden, Netherlands; The Royal Marsden NHS 
Foundation Trust, London, United Kingdom; Osaka Medical Center, Osaka, Japan; European Organisation for 
Research and Treatment of Cancer Headquarters, Brussels, Belgium; EORTC Headquarters, Brussels, 
Belgium; GlaxoSmithKline Oncology, Uxbridge, United Kingdom; GlaxoSmithKline R&D, Greenford, United 
Kingdom; Azienda ULSS 9 Treviso, Treviso, Italy; Universitätsklinikum Mannheim, Mannheim, Germany 
PALETTE: A randomized, double-blind, phase III trial of pazopanib versus placebo in patients (pts) with soft-
tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy—An EORTC 
STBSG Global Network Study (EORTC 62072). in ASCO Annual Meeting. 2011. Chicago. 
22. 
Folkman, J., Tumor angiogenesis: therapeutic implications. The New England journal of medicine, 
1971. 285(21): p. 1182-6. 
23. 
Folkman, J., Angiogenesis and angiogenesis inhibition: an overview. EXS, 1997. 79: p. 1-8. 
24. 
Ferrara, F., M. Falchi, and S. Puricelli, [Angiogenesis and antitumor therapy]. Annali italiani di 
medicina interna : organo ufficiale della Societa italiana di medicina interna, 1997. 12(1): p. 26-30. 
25. 
Kumar, R., et al., Pharmacokinetic-pharmacodynamic correlation from mouse to human with 
pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Molecular 
cancer therapeutics, 2007. 6(7): p. 2012-21. 
26. 
Billemont, B., et al., Blood glucose levels in patients with metastatic renal cell carcinoma treated with 
sunitinib. British journal of cancer, 2008. 99(9): p. 1380-2. 
27.  
Nikolinakos, P.G., et al., Plasma Cytokine and Angiogenic Factor Profiling Identifies Markers 
Associated with Tumor Shrinkage in Early-Stage Non–Small Cell Lung Cancer Patients Treated with 
Pazopanib.Cancer Research, 2010. 2010 Mar 15;70(6):2171-9 
 
 
 
 
 
 


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APPENDIX A:  Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent Description 
0 
Fully active, able to carry on all 
pre-disease performance without 
restriction. 
100 
Normal, no complaints. 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
90 
Able to carry on normal activities; 
minor signs or symptoms of 
disease. 
80 
Normal activity with effort 
2 
Ambulatory and capable of all self-
care but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance but 
is able to care for most of his/her 
needs. 
3 
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours. 
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
 
Completely disabled.  Cannot 
carry on any self-care.  Totally 
confined to bed or chair. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
20 
Very sick, hospitalization indicated. 
Active supportive treatment 
necessary. 
10 
Moribund. 
5 
Dead. 
0 
Dead. 
 
http://oncologypro.esmo.org/Guidelines-Practice/Practice-Tools/Performance-Scales  
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B:  Determination of Creatinine Clearance (ClCR) 
 
Estimation of creatinine clearance using Cockroft and Gault method:  
 
ClCR for males (mL/min) =  
[140 - age (years)] X [weight (kg)] 
 
 
 
                        (72) X [Serum creatinine (mg/dL)] 
 
ClCR for females (mL/min) = 
 
(0.85) X [140 - age (years)] X [weight (kg)] 
 
 
                 (72) X [Serum creatinine (mg/dL)] 
For SI units: 
ClCR for males (mL/min) =  
 
[140 - age (years)] X [weight(kg)] X (1.23) 
 
 
 
 
                     [Serum creatinine (µmol/L)] 
 
ClCR for females (mL/min) =  
 
[140 - age(years)] X [weight(kg)] X (1.05) 
 
 
 
 
 
          [Serum creatinine (µmol/L)] 
 
Calculation of creatinine clearance based on 24-hour urinary creatinine excretion and 
concurrent serum creatinine levels: 
12 
ClCR = CU·V 
            CCR 
Here, CU is the concentration of creatinine in the urine (mg/dL or µmol/L, for SI units), V is the 
urine volume (in mL per minute of urine produced during the collection period), CCR is the serum 
creatinine concentration (mg/dL or µmol/L, for SI units), and ClCR is the creatinine clearance in 
mL per minute. 


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APPENDIX C:  Urine Protein Creatinine Ratio (UPC)  
Clinical meaning of UPC  
There is a good correlation between the ratio of protein concentration to creatinine concentration in 
a random urine sample and the amount of protein excreted over 24 hours. Creatinine excretion is 
fairly constant throughout the day regardless of changes in urine flow rate.  
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day.  
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day.  
Normal protein excretion is < 150 mg/24 hours and is similar for men and women.  
Calculating UPC  
UPC ratio = Urine protein (mg/dL) / Urine creatinine (mg/dL).  
UPC ratio ≈ equivalent to grams of protein excreted in urine over 24 hrs.  
Example: Subject has a urine protein = 90 mg/dL and urine creatinine = 30 mg/dL.  
UPC ratio= (90 mg/dL) / (30 mg/dL) = 3  
The calculated UPC ratio is 3, which correlates to roughly 3 g protein excretion in a 24-hour 
period.  
Units for UPC ratio  
Note: To calculate UPC, protein and creatinine concentrations must be expressed in the same units 
(mg/dL, g/L, or μmol/L). If, for example, protein concentration is expressed in mg/dL and creatinine 
concentration is expressed in μmol/L, conversion of one of the concentration values is required. 
Conversion factors are:  
From  
To  
Conversion Factor  
Conventional Units: mg/dL  SI Units: μmol/L  
Multiply by 88.4  
SI Units: μmol/L  
Conventional Units: mg/dL  Divide 88.4  
 
References:  
 
Xin G, Wang M, Jian L, Xu F, Wang H. Protein-to-creatinine ratio in spot urine samples as a 
predictor of quantitation of proteinuria 2004. Clinica Chimica Acta 350:35-39.  
 
NKF: NKF KDOQI Guidelines [Internet]. National Kidney Foundation; and. KDOQI Clinical Practice 
Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Available from 
http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g5.htm 
 
 
 


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APPENDIX D:  New York Heart Association (NYHA) Classification of Congestive heart failure 
 
Class I 
Subjects with no limitation of activities; they suffer no symptoms from 
ordinary activities 
Class II 
Subjects with slight, mild limitation of activity; they are comfortable with rest 
or with mild exertion. 
Class III 
Subjects with marked limitation of activity; they are comfortable only at rest. 
Class IV 
Subjects who should be at complete rest, confined to bed or chair; any 
physical activity brings on discomfort and symptoms occur at rest. 
 
 
 


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APPENDIX E:  Supportive Care Guidelines for Diarrhea, Nausea and Vomiting 
 
These general guidelines are provided to facilitate subject care in the event of diarrhea, thereby 
avoiding serious complications.  Guidelines such as these should never replace sound clinical 
judgment.  Experience thus far suggests that use of monotherapy pazopanib is associated with an 
increased incidence of diarrhea, primarily of Grade 1 or 2.  In rare cases, diarrhea can be 
debilitating and potentially life threatening, with dehydration, renal insufficiency, and electrolyte 
imbalances. 
 
Standardized and universal guidelines have been developed by an American Society of Clinical 
Oncology panel for treating chemotherapy-induced diarrhea [Benson, 2004]. 
 
Early identification and intervention is critical for the optimal management of diarrhea.  A 
subject’s baseline bowel patterns should be established so that changes in patterns while on 
treatment can be identified.  An assessment of frequency, consistency, and duration of diarrhea, as 
well as knowledge of other symptoms such as fever, cramping, abdominal pain, nausea, vomiting, 
dizziness and thirst should be taken at baseline, permitting identification of patients at high risk of 
diarrhea.  Patients should be educated on signs and symptoms of diarrhea with instructions to 
report any changes in bowel patterns to the study site physician. 
 
The NCI CTCAE Version 4.0 criteria for defining diarrhea are provided below. 
Toxicity 
Grade 
Diarrhea  
(includes diarrhea of small bowel or colonic origin and/or ostomy diarrhea) 
1 
Increase of <4 stools/day over baseline; mild increase in ostomy output compared to 
baseline 
2 
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output 
compared to baseline 
3 
Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; 
severe increase in ostomy output compared to baseline; limiting self care activities of 
daily living 
4 
Life threatening consequences, urgent intervention indicated 
5 
Death 
 
Uncomplicated diarrhea is considered mild to moderate and is defined as CTCAE Grade 1 to 2 with 
no complicating signs or symptoms. 
Complicated diarrhea is severe and defined as CTCAE Grade 3 or 4 or Grade 1 or 2 with one or 
more of the following signs or symptoms: severe cramping, ≥Grade 2 nausea/vomiting, decreased 
performance status, fever, sepsis, Grade 3 or 4 neutropenia, obvious bleeding, dehydration. 
 
Management Guidelines 
Uncomplicated diarrhea of CTCAE Grade 1 or 2: 
 
Hydration:  have subject drink 8 to 10 large glasses (approximately 2 liters) of clear 
non-caffeinated liquids a day (e.g., broth or electrolyte-containing sports drinks).  
 
If Grade 2 diarrhea, consider dose reduction of investigational products. 
 
Dietary modifications:  have subject stop all lactose-containing products and eat frequent, small 
meals 
 
Pharmacologic intervention using loperamide: 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
89 
 
 
Begin loperamide at initial dose of 4 mg followed by 2 mg every 4 hours or after every 
unformed stool. The recommended maximum daily dose of loperamide is 16 mg/day. 
 
Continuation of loperamide is suggested until diarrhea-free for 12 hours. 
 
If mild to moderate diarrhea persists for more than 24 hours, administer loperamide 2 mg 
every 2 hours and pursue evaluation for other treatable causes. 
 
If mild to moderate diarrhea persists after 48 hours total treatment with loperamide, 
discontinue study drug(s) and consider initiation of second-line agents (lomotil, octreotide). 
 
Complicated diarrhea of CTCAE Grade 3 or 4 diarrhea or Grade 1 or 2 with complicating 
features requires aggressive management: 
 
Subject must call study site physician immediately in response to any event of severe 
diarrhea with or without complications as listed above.  
 
Hospitalization may be required for subjects most at risk for life-threatening complications. 
 
Interrupt investigational products until symptoms resolve; consider reintroducing at a 
reduced dose (discuss with Sponsor-Investigator). 
 
If loperamide has not been initiated, begin loperamide usage immediately at an initial dose 
of 4 mg followed by 2 mg every 2 hours or after every unformed stool. The recommended 
maximum daily dose of loperamide is 16 mg/day. 
 
If no improvement in severity after 24-hours of maximal loperamide dosing, subject must 
visit study site and be evaluated: 
 For dehydration, use intravenous fluids as appropriate.   
 
Antibiotic therapy should be considered in patients, who present with signs and symptoms 
of bacterial diarrhea such as fever, bloody diarrhea, and presence of fecal leukocytes. 
Investigators should have a low threshold to start such treatment in patients with Grade 3 
or Grade 4 neutropenia.  
 
Before initiation of antimicrobial therapy, stool cultures should be obtained. When bacterial 
etiology for diarrhea is suspected, study-treatment and anti-motility agents (loperamide or 
others) should be held. 
 
Intervention should be continued until diarrhea free for 24 hours. 
 
Alternative Pharmacologic Intervention for Uncomplicated and Complicated Diarrhea 
 
Lomotil (dephenoxylate 2.5 mg + atropine 0.025 mg) can be used. The recommended 
dose is 2 tablets 4 times daily. When diarrhea is under control, a dose reduction should be 
attempted. 
 
The synthetic octapeptide, octreotide, has been shown to be effective in the control of 
diarrhea induced by fluoropyrimidine-based chemotherapy regimens when administered 
as an escalating dose by continuous infusion or subcutaneous injection. Octreotide can be 
administered per the current package insert and institutional guidelines.   
Nausea and Vomiting 
Every attempt should be made to control nausea and vomiting in subjects who have emesis and are 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
90 
 
unable to retain pazopanib. 
Routine pre-medication for nausea is not necessary, but symptomatic subjects should be treated 
with standard anti-nausea/anti-emetic therapy as necessary. 
If a subject vomits after taking study medication, the subject should be instructed not to take a 
replacement dose on that same day.  The subject should resume taking pazopanib at the next 
scheduled dose on the following day.  If vomiting persists, then the subject should contact their 
physician. 
To prevent or treat nausea and vomiting standard medications are recommended.  Depending upon 
approved medications in your region, these may include: 5-HT3 receptor antagonist (granisetron, 
ondansetron, dolasetron mesylate); NK-1 receptor antagonists such as aprepitant,  
metoclopramide,  phenothiazines (prochlorperazine); corticosteroids, (dexamethasones, 
prednisone); and cannibinoids (dronabinol).  
 
Reference:  
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, et al., 
Recommended Guidelines for the Treatment of Cancer-Inducted Diarrhea.  J Clin Oncol. 2004, 22; 
2918-26. 
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
91 
 
APPENDIX F :  Management of acute hypersensitivity 
  
The table below outlines the required dose modifications for these events.  Also included are 
suggested treatment guidelines; however sites may follow their institutional standards for the 
treatment of hypersensitivity.   
 
 
 
 
 
Severity of Symptoms  
Treatment Guidelines  
Mild symptoms: localized 
cutaneous reactions such as 
mild pruritus, flushing, rash  
Consider decreasing the rate of infusion until recovery from 
symptoms, stay at bedside and monitor patient.  Then, 
complete infusion at the slowed rate.  
Moderate symptoms: any 
symptom that is not listed 
above (mild symptoms) or 
below (severe symptoms) such 
as generalized pruritus, 
flushing, rash, dyspnea, 
hypotension with systolic BP > 
80 mm Hg  
Interrupt infusion.  
Give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor patient until resolution of 
symptoms.  
Resume chemotherapy infusion after recovery of symptoms; 
depending on the physician’s assessment of the patient.  
Chemotherapy infusion should be resumed at a slower rate, 
then, increased incrementally to the initial planned rate, (i.e., 
infuse at an 8-hr rate for 5 minutes, then at a 4-hr rate for 5 
minutes, then at a 2-hr rate for 5 minutes, then finally, 
resume at the 1-hr infusion rate).  
Depending on the intensity of the reaction observed, 
additional oral or IV premedication with an antihistamine 
should also be given for the next cycle of treatment, and the 
rate of infusion should be decreased initially and then 
increased back to the recommended 1-hr infusion, (i.e., 
infuse at an 8-hr rate for 5 minutes, then at a 4-hr rate for 5 
minutes, then at a 2-hr rate for 5 minutes, and finally, 
administer at the 1-hr infusion rate).  
Severe symptoms: any 
reaction such as 
bronchospasm, generalized 
urticaria, systolic BP ≤ 80mm 
Hg, angioedema  
Immediately discontinue infusion.  
Give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV and/or epinephrine as needed; 
monitor patient until resolution of symptoms.  
The same treatment guidelines outlined under moderate 
symptoms (i.e., the third and fourth bullets) should be 
followed.  
Anaphylaxis: (grade 4 
reaction)  
NO FURTHER STUDY DRUG THERAPY  
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
92 
 
APPENDIX G:  Management of edema/fluid retention  
  
No dose reduction is required.  Patients developing new onset edema, progression of existing 
edema, or another sign of fluid retention (i.e., 2 pound weight gain) are to be treated with oral 
diuretics.  Regimens found to be effective in the management of fluid retention due to docetaxel are 
listed below.  
  
Diazide (or generic equivalent) one capsule po qd up to tid.  
  
Furosemide 40 mg po daily if edema progresses despite Diazide (or equivalent) therapy.  
Potassium supplementation should be given as needed.  
  
Furosemide 20 mg po daily plus metolazone 2.5 mg po daily may be needed if, after a two-week 
trial, furosemide 40 mg po qd is ineffective.  The patient may be treated with potassium 
supplementation as needed.  
  
Further therapy should be customized depending upon the clinical situation.  The clinical tolerance 
of the patient, the overall tumor response and the medical judgment of the investigator will 
determine if it is in the patient’s best interest to continue or discontinue treatment. 
 
 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
93 
 
APPENDIX H:  Management of hyperlacrimation  
  
The excessive lacrimation (epiphora) seen in some patients receiving weekly docetaxel appears to 
be related to cumulative dose (median~300 mg/m2) and resolves rapidly after treatment cessation.  
  
Excessive lacrimation seems to be the result of a chemical conjunctivitis and/or chemical 
inflammation (with edema) of the lacrimal duct epithelium (producing a reversible lacrimal duct 
stenosis). Consequently, investigators in clinical trials have treated such patients with (a) artificial 
tears and/or (b) saline eye wash and/or (c) steroid based eye drops.  
  
It is suggested that the following approach be taken to patients experiencing clinically significant 
hyperlacrimation:  
 
 
 
 
 
 
 
 
 
 
Dose modifications will be permanent.  Only one dose reduction per patient is allowed for all 
toxicities.  
Grade 
Dose  
0 - 2 
100 
3 - 4 
Reduce by  1 dose level 
Recommend patient see 
an ophthalmologist. 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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APPENDIX I:  THE QLQ-C30 VERSION 3.0  
 
PT STUDY NUMBER: 101644 - __ __ __ __ __ - __ __ 
 
DATE COMPLETED (MM/DD/YYY):______________ 
 
WE ARE INTERESTED IN SOME THINGS ABOUT YOU AND YOUR HEALTH. PLEASE ANSWER ALL OF THE 
QUESTIONS YOURSELF BY CIRCLING THE NUMBER THAT BEST APPLIES TO YOU. THERE ARE NO “RIGHT” 
OR “WRONG” ANSWERS. THE INFORMATION THAT YOU PROVIDE WILL REMAIN STRICTLY CONFIDENTIAL. 
 
 
 
 
Not 
at all 
 
A 
little 
 
Quite 
a bit 
 
Very 
much 
 
1. Do you have any trouble doing strenuous 
activities, like carrying a heavy shopping 
bag or a suitcase? 
 
 
1 
2 
3 
4 
2. Do you have any trouble taking a long 
walk? 
 
 
1 
2 
3 
4 
3. Do you have any trouble take a short walk 
outside of the house? 
 
 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair 
during the day? 
 
 
1 
2 
3 
4 
5. Do you need help with eating, dressing, 
washing yourself or using the toilet? 
 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
During the past week: 
 
 
Not 
at all 
 
A 
little 
 
Quite 
a bit 
 
Very 
much 
 
6. Were you limited in doing either your work 
or other daily activities? 
 
 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies 
or other leisure time activities? 
 
 
1 
2 
3 
4 
8. Were you short of breath? 
 
 
1 
2 
3 
4 
9. Have you had pain? 
 
 
1 
2 
3 
4 
10. Did you need rest? 
 
 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
 
 
1 
2 
3 
4 
12. Have you felt weak? 
 
 
1 
2 
3 
4 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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During the past week: 
 
 
Not 
at all 
 
A 
little 
 
Quite 
a bit 
 
Very 
much 
 
13. Have you lacked appetite? 
 
 
1 
2 
3 
4 
14. Have you felt nauseated? 
 
 
 
1 
2 
3 
4 
15. Have you vomited? 
 
 
 
1 
2 
3 
4 
16. Have you been constipated? 
 
 
1 
2 
3 
4 
17. Have you had diarrhea? 
 
 
1 
2 
3 
4 
18. Were you tired? 
 
 
1 
2 
3 
4 
19. Did pain interfere with you daily activities? 
 
 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on 
things, like reading a newspaper or 
watching television? 
 
 
1 
2 
3 
4 
21. Did you feel tense? 
 
 
1 
2 
3 
4 
22. Did you worry? 
 
 
1 
2 
3 
4 
23. Did you feel irritable? 
 
 
1 
2 
3 
4 
24. Did you feel depressed? 
 
 
1 
2 
3 
4 
25. Have you had difficulty remembering 
things? 
 
 
1 
2 
3 
4 
26. Has your physical condition or medical 
treatment interfered with your family life? 
 
 
1 
2 
3 
4 
27. Has your physical condition or medical 
treatment interfered with your social 
activities? 
 
 
1 
2 
3 
4 
28. Has your physical condition or medical 
treatment caused you financial difficulties? 
 
 
1 
2 
3 
4 
 
 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
96 
 
 
FOR THE FOLLOWING QUESTIONS PLEASE CIRCLE THE NUMBER BETWEEN 1 AND 7 THAT BEST 
APPLIES TO YOU 
 
29. How would you rate your overall health during the past week? 
 
1 
Very poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
1 
Very poor 
2 
3 
4 
5 
6 
7 
Excellent 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
97 
 
APPENDIX J:  EQ-5D questionnaire 
 
PT STUDY NUMBER: 101644 - __ __ __ __ __ - __ __ 
 
DATE COMPLETED (MM/DD/YYY):______________ 
 


MUSC CTO 101644 (Protocol Amendment 9.1 dated August 11, 2016) 
 
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