Conditions: Recurrent Thyroid Gland Carcinoma Stage III Differentiated Thyroid Gland Carcinoma AJCC v7 Stage III Thyroid Gland Medullary Carcinoma AJCC v7 Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v7 Stage IVA Thyroid Gland Anaplastic Carcinoma AJCC v7 Stage IVA Thyroid Gland Medullary Carcinoma AJCC v7 Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v7 Stage IVB Thyroid Gland Anaplastic Carcinoma AJCC v7 Stage IVB Thyroid Gland Medullary Carcinoma AJCC v7 Stage IVC Differentiated Thyroid Gland Carcinoma AJCC v7 Stage IVC Thyroid Gland Anaplastic Carcinoma AJCC v7 Stage IVC Thyroid Gland Medullary Carcinoma AJCC v7 Thyroid Gland Anaplastic Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 152
Healthy volunteers: no

Brief summary:
This phase II trial studies the side effects and how well pazopanib hydrochloride works in treating patients with advanced thyroid cancer. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by stopping blood flow to the tumor.

Detailed description:
PRIMARY OBJECTIVE:

I. To establish the safety and efficacy of GW786034 (pazopanib hydrochloride) as a therapeutic in patients afflicted with differentiated, medullary and anaplastic thyroid cancers.

CORRELATIVE OBJECTIVES:

I. Assessment of the impact of therapy with GW786034 on serum/plasma vascular endothelial growth factor (VEGF) levels.

II. To explore the potential relationship between changes in thyroglobulin levels and tumor response in patients with advanced differentiated thyroid cancer known to be thyroglobulin antibody negative.

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3 years after registration.

Arms:
arm 1: Patients with differentiated thyroid cancer (DTC) receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients with medullary thyroid cancer (MTC) receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients with anaplastic thyroid cancer (ATC) receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: Patients with confirmed, differentiated thyroid cancer (DTC) who are thyroglobulin antibody negative receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pazopanib Hydrochloride
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO

Protocol document:
Prot_SAP_000.pdf: 
NCI Protocol #: 7627 
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NCI Version Date: April 15, 2018 
i 
 
 
 
 
 
 
 
 
 
MC057H – A Phase II Trial of GW786034 in Advanced Thyroid Cancer 
 
 
P2C Addendum 25 –  
 
CTEP Request for Protocol Amendment dated February 14, 2018: 
 
# 
Section Comments 
1. 
8.1 
Novartis supplies and the PMB, DCTD, NCI distributes commercially-
labeled 200 mg pazopanib tablets (as free base). Gray, film-coated 
tablets are debossed with “GS JT” on one side and packaged in bottles 
of 120 tablets.   
 
Tablet excipients include microcrystalline cellulose, povidone, sodium 
starch glycolate, and magnesium stearate. The film-coat consists of 
titanium dioxide, hypromellose, iron oxide black, macrogol/polyethylene 
glycol 400 and polysorbate 80.  
 
Novartis supplies and the PMB, DCTD, NCI distributes pazopanib as 
aqueous, film-coated tablets according to the descriptions and availability 
below. 
 
Streng
Description 
Bottle 
Availability 
200 mg Oval-shaped, white tablets 
packaged in investigationally-
labeled HDPE induction- 
sealed bottles with white, 
l
i
hild
i
34 
Transitioning to 
commercially-
labeled supplies 
around March 
2017
200 mg Gray, tablets are debossed with 
“GS JT” on one side and 
packaged in commercially- 
labeled bottles 
120 
Transitioning 
from 
investigationally-
labeled supplies 
d M
h


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# 
Section Comments 
400 mg Oval-shaped, white tablets 
packaged in investigationally-
labeled HDPE induction- 
sealed bottles with white, 
68 
Not available after 
March 31, 2018 
or when existing 
supplies are 
 
Tablet excipients in all tablet sizes include microcrystalline 
cellulose, povidone, sodium starch glycolate, and magnesium 
stearate. The film-coat consists of titanium dioxide, hypromellose, 
macrogol/polyethylene glycol 400 and polysorbate 80.  In addition, the 
film-coat for commercially-labeled 200 mg tablets contains iron oxide 
black. 
 
 
 
 
 
 
 


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A Phase II Study of GW 786034 (Pazopanib) in Advanced Thyroid Cancer 
 
Study Chair*: Keith C. Bible, M.D., Ph.D. 
Mayo Clinic Cancer Center 
200 First Street SW 
Rochester MN 55905 
Telephone: 507-284-2511 
Fax: 507-284-5280 
bible.keith@mayo.edu 
  
Other Participating Institutions/Co-Investigators:
Robert Smallridge, M.D. 
Mayo Clinic Jacksonville 
4500 San Pablo Road 
Jacksonville FL 32224 
Telephone: 904-953-2224 
Fax: 904-953-0272 
smallridge.robert@mayo.edu  
Anne Traynor, M.D. 
University of Wisconsin 
Comprehensive Cancer Center 
600 Highland Avenue 
Madison WI 53792 
Telephone: 608-263-5389 
Fax: 608-265-8133 
amt@medicine.wisc.edu  
Nina Karlin, M.D. 
Mayo Clinic Arizona 
13400 E Shea Blvd 
Scottsdale, AZ 85259 
Telephone: 480-301-8335 
Fax: 480-301-4675 
Karlin.nina@mayo.edu 
 
Statistician: 
Hui Tang, Ph.D. 
Mayo Clinic Cancer Center 
Telephone: 507-538-4033 
h.tang@mayo.edu    
P2C Coordinating Center: 
Mayo Clinic Cancer Center 
200 First Street SW 
Rochester MN 55905 
Fax: 507-284-5280 
DCTD Supplied Investigational 
Agent(s): 
GW786034 (pazopanib; NSC 737754) 
Douglas W. Ball, M.D. 
The Sidney Kimmel Comprehensive 
Cancer Center at Johns Hopkins 
1650 Orleans St. Room 553 
Baltimore, MD, 21231-1000 
Telephone: 410-955-8506 
Fax: 410-614-9884 
dball@jhmi.edu  
Ammar Sukari, M.D. 
Barbara Ann Karmanos Cancer  
4100 John R. Road 
Detroit, MI 48201 
Telephone: 313-576-8778 
Fax: 313-993-0559 
sukaria@karmanos.org 
Jeffrey F. Moley, M.D. 
Washington University School of 
Medicine 
Campus Box 8109 
660 South Euclid Avenue 
St. Louis, MO  63110 
Telephone: 314-747-0954 
Fax 314-747-1310 
moleyj@wustl.edu 
Dr Chia-Chi (Josh) Lin, M.D., Ph.D.  
National Taiwan University Hospital  
7 Chung Shan S Rd, Taipei 100, 
Taiwan 
Tel: +886-2-23123456 ext 67680 
Fax: +886-2-23711174 
cclin1@ntu.edu.tw  
PJ Flynn, M.D. 
Minnesota Oncology Hematology, PA 
800 E 28th St, Suite 405 
Minneapolis, MN  55407 
Tel: 612-863-8585 
Fax: 612-863-8586    
patrick.flynn@usoncology.com 
 
Boon Cher Goh  
Senior Consultant  
Department of Haematology-
Oncology  
National University Hospital  
5 Lower Kent Ridge Road  
Singapore 119074  
Tel:  (65) 6772 4621  
Fax:  (65) 6777 5545  
boon_cher_goh@nuh.com.sg  
Darren Wan Teck Lim 
Department of Medical Oncology  
National Cancer Center Singapore  
11 Hospital Drive  
Singapore 169610   
Tel: (65) 6436 8174  
Fax: (65) 6227 2759  
Michael Millward  
Sir Charles Gairdner Hospital  
Hospital Avenue  
Nedlands 6009  
Australia  
Phone: +61 8 93463823  
Fax: +61 8 93462816  
Gilberto Lopes 
Johns Hopkins Singapore 
International Medical Center 
11 Jalan Tan Tock Seng 
Singapore 308433 
Tel: (65) 6880-2222 
Fax: (65) 6880-2155 


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dmolwt@nccs.com.sg  
millward@cyllene.uwa.edu.au   
glopes@imc.jhmi.edu  
 
 
 
Mohammed Milhem, MD 
University of Iowa Hospitals & Clinics 
200 Hawkins Drive, C32 GH 
Iowa City, IA 52242 
Phone:  319-356-2324 
Fax:  319-353-8383 
mohammed-milhem@uiowa.edu 
 
Brigette Ma  
The Chinese University of Hong 
Kong  
Department of Clinical Oncology  
Prince of Wales Hospital  
Shatin, Hong Kong  
Tel: (852) 2632 2118  
Fax: (852) 2648 7097  
brigette@clo.cuhk.edu.hk 
Bryan Haugen, M.D. 
University of Colorado Denver 
Anschutz Cancer Pavilion 
1665 Aurora Court, Mail Stop F704 
PO Box 6510 
Aurora, CO 80045 
Tel:  720-848-0354 
Fax:  720-848-0671 
bryanhaugen@ucdenver.edu  
 
 
 
 
 
 
* Investigator having NCI responsibility for this protocol. 
† Study contributor(s) not responsible for patient care. 
 
 
Document History 
NCI Submission: February 23, 2006 
Addendum 9 - November 4, 2009 
Addendum 19 - September 22, 2011 
Study Activation: February 22, 2008 
Addendum 10 - March 10, 2010  
Addendum 20 - November 30, 2011 
Addendum 1 - May 15, 2008 
Addendum 11 - May 26, 2010 
Addendum 21 – June 13, 2012 
Addendum 2 - July 22, 2008 
Addendum 12 - August 30, 2010 
Addendum 22 – September 6, 2012 
Addendum 3 - August 19, 2008 
Addendum 13 - October 20, 2010 
Addendum 23 - April 21, 2017 
Addendum 4 - December 9, 2008 
Addendum 14 - February 9, 2011 
Addendum 24 – April 11, 2018 
Addendum 5 - December 29, 2008 
Addendum 15 - March 15, 2011 
Addendum 25 –  
Addendum 6 - April 2, 2009 
Addendum 16 - May 16, 2011 
 
Addendum 7 - May 22, 2009 
Addendum 17 - June 16, 2011 
 
Addendum 8 - June 9, 2009 
Addendum 18 - September 22, 2011 
 
 
 


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SCHEMA 
 
 
 
Registration 
 
Advanced Thyroid Carcinoma 
(Separate cohorts for differentiated, medullary and anaplastic) 
 
 
 
 
 
 
 
 
Unacceptable toxicity 
PROG 
Patient Refusal 
Alternate therapy 
 
 
 
 
 
 
 
 
GW786034 800 mg daily (orally), 28 day cycles 
Event Monitoring per Section 16 
Drug Names/Abbreviations 
P2C Name:  GW786034 
Generic Name: Pazopanib 
Mayo Abbreviation: 786034 


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Table of Contents 
A PHASE II STUDY OF GW 786034 (PAZOPANIB) IN ADVANCED THYROID CANCER 1 
SCHEMA ........................................................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................................ 4 
1. 
OBJECTIVES .......................................................................................................................... 7 
1.1 
Primary Objectives ........................................................................................................... 7 
1.2 
Correlative Objectives ...................................................................................................... 7 
2. 
BACKGROUND ..................................................................................................................... 7 
2.1 
Thyroid Cancer ................................................................................................................. 7 
2.2 
GW786034 (pazopanib) ................................................................................................. 11 
2.3 
Background and Rationale ............................................................................................. 18 
3. 
PATIENT SELECTION ........................................................................................................ 20 
3.1 
Inclusion Criteria ............................................................................................................ 21 
3.2 
Exclusion Criteria ........................................................................................................... 22 
4. REGISTRATION PROCEDURES .......................................................................................... 25 
4.1 
Patient Registration ........................................................................................................ 25 
4.2 
Required Regulatory Documents ................................................................................... 26 
4.3 
Required Registration Documents ................................................................................. 26 
4.4 
Mandatory Translational Research ................................................................................. 26 
4.5 
Treatment Allowed Only at P2C Member Institutions .................................................. 26 
4.6 
Timing of Treatment ...................................................................................................... 27 
4.7 
 Pretreatment Tests ......................................................................................................... 27 
4.8 
Baseline Symptoms ........................................................................................................ 27 
5. 
TREATMENT PLAN............................................................................................................ 27 
5.1 
GW786034 (Pazopanib) Administration ........................................................................ 27 
5.2 
General Concomitant Medication and Supportive Care Guidelines .............................. 30 
5.3 
Duration of Therapy ....................................................................................................... 31 
5.4 
Duration of Follow Up ................................................................................................... 31 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................... 32 
6.1 
Management of Hypertension ........................................................................................ 32 
6.2 
Management of Proteinuria ............................................................................................ 35 
6.3 
Management of Other CTCAE Adverse Events ............................................................ 36 


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6.4 
Management of Other Clinically Significant Non-Hematologic Toxicities (not 
specifically addressed above) ................................................................................................... 37 
6.5 
Management of Potassium, Calcium, Phosphorus and Magnesium. ............................. 38 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................................ 39 
7.1 
CAEPR for Pazopanib .................................................................................................... 39 
7.2 
Adverse Event Characteristics ....................................................................................... 42 
7.3 
Expedited Adverse Event Reporting .............................................................................. 43 
7.4 
Routine Adverse Event Reporting .................................................................................. 46 
7.5 
Secondary AML/MDS ................................................................................................... 46 
8. 
PHARMACEUTICAL INFORMATION ............................................................................. 46 
8.1 
Nursing Guidelines ......................................................................................................... 50 
9. 
CORRELATIVE/SPECIAL STUDIES ................................................................................. 51 
9.1 
Hypothesis 1 ................................................................................................................... 51 
9.2 
Hypothesis 2: .................................................................................................................. 51 
9.3 
Sample Instructions for Hypothesis 1 & 2: .................................................................... 51 
10. 
STUDY CALENDAR ....................................................................................................... 53 
11. 
MEASUREMENT OF EFFECT........................................................................................ 54 
11.1 
Schedule of Evaluations ............................................................................................. 54 
11.2 
Treatment evaluation for patients (MTC or DTC) with measurable disease using 
RECIST1 Criteria ...................................................................................................................... 54 
11.3 
Measurement of Effect ............................................................................................... 55 
11.4 
Formal Statistical Definitions of Analysis Variables ................................................. 58 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS ....................................... 58 
12.1 
Data Reporting ............................................................................................................ 58 
12.2 
CTEP Multicenter Guidelines .................................................................................... 58 
12.3 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) ..................................................................................................................... 59 
13. 
STATISTICAL CONSIDERATIONS............................................................................... 61 
13.1 
Study Design/Endpoints ............................................................................................. 61 
13.2 
Sample Size/Accrual Rate .......................................................................................... 62 
13.3   
Statistical Design to be used for the ATC, DTC, and MTC Patient Groups .............. 63 
13.4 
Analysis Plans ............................................................................................................ 66 
13.5 
Monitoring .................................................................................................................. 68 


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13.6 
Data Reporting ............................................................................................................ 68 
13.7 
Subset Analyses for Minorities: ................................................................................. 68 
14.0 DESCRIPTIVE FACTORS ............................................................................................... 69 
14.1    Baseline Calcitonin Levels ............................................................................................ 69 
15.0 PATHOLOGY CONSIDERATIONS ............................................................................... 69 
16. 
DATA SUBMISSION TO COORDINATING CENTER ................................................. 69 
16.1 
Data Collection ........................................................................................................... 69 
16.2 
Cancels........................................................................................................................ 69 
16.3 
Ineligible ..................................................................................................................... 69 
16.4 
Treatment Discontinuation ......................................................................................... 70 
16.5 
Data Entry/Submission Timetable .............................................................................. 71 
17.   FUNDING CONSIDERATIONS ...................................................................................... 72 
17.1 
Costs Charged to Patient............................................................................................. 72 
17.2 
Other Budget Concerns .............................................................................................. 72 
17.3 
Manufacturer to Supply Drug ..................................................................................... 72 
REFERENCES ............................................................................................................................. 72 
APPENDIX A: PERFORMANCE STATUS CRITERIA ............................................................ 77 
APPENDIX B: DRUGS KNOWN TO BE METABOLIZED BY SELECTED CYP450 
ISOENZYMES ............................................................................................................................. 78 
APPENDIX C: NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC 
DISEASE ...................................................................................................................................... 83 
APPENDIX D: PATIENT’S MEDICATION DIARY ................................................................. 84 
APPENDIX E: PATIENT’S BLOOD PRESSURE DIARY ........................................................ 85 
APPENDIX F: BLOOD PRESSURE – RECOMMENDATIONSFOR DATA 
COLLECTION/RECORDING AND EVENT MANAGEMENT ............................................... 87 
APPENDIX G: MANAGEMENT OF GW786034 (PAZOPANIB)-INDUCED 
HYPERTENSION* ...................................................................................................................... 88 
APPENDIX H: CTEP MULTICENTER GUIDELINES ............................................................. 89 
APPENDIX I: MEDICATIONS THAT MAY CAUSE QTC PROLONGATION ..................... 91 
 
  


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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.11 
The primary objectives of this trial are to establish the safety and efficacy 
of GW786034 (pazopanib) as a therapeutic in patients afflicted with 
differentiated, medullary and anaplastic thyroid cancers.  Efficacy will be 
assessed via the primary endpoint of the proportion of patients who incur 
clinical responses based upon RECIST criteria, and the secondary 
endpoint of progression free survival (proportion of patients without 
progression at 6 months for differentiated and medullary, 3 months for 
anaplastic). Tertiary clinical endpoints include time to treatment failure, 
overall survival, duration of response, time to subsequent therapy, and 
biomarker-based measures of response and time to progression.  
 
1.2 
Correlative Objectives 
 
1.21 
Correlative objectives of the trial include assessment of the impact of 
therapy with GW786034 on serum/plasma VEGF levels.  
 
1.22 
To explore the potential relationship between changes in thyroglobulin 
levels and tumor response in patients with advanced differentiated thyroid 
cancer known to be thyroglobulin antibody negative. 
 
2. 
BACKGROUND 
 
2.1 
Thyroid Cancer 
 
Differentiated thyroid carcinoma is the most common endocrine malignancy, with 
an estimated 25,000 new cases annually, accounting for approximately 1500 
deaths each year in the United States (Jemal, Murray et al. 2005) The disease is 
classified histologically into 5 major groups: Papillary (PTC - representing 80 – 
85% of all differentiated thyroid cancer); Follicular (FTC - 5 – 10%) and its 
Hurthle Cell variant (HCC - 3 – 5%); Medullary carcinoma (MTC - ~5%); and 
Anaplastic carcinoma (ATC - ~1%) (Hay, Bergstralh et al. 1993).  
 
Papillary, Follicular and Hurthle cell carcinoma. 
These three major groups of tumors arise from the thyroid follicular cell, and 
typically retain some differentiated cell functions, including production of 
thyroglobulin and some capacity for iodine concentration (Kinder 2003). 
Amongst older patients and those with more advanced disease at diagnosis, the 
capacity for iodine concentration is less pronounced and may be absent, which 
has important implications for treatment, as discussed below (Fernandes, Day et 
al. 2005). Continued production of thyroglobulin provides a clinically useful 
marker for disease recurrence, correlating with disease burden, within an 
individual (Hay, Thompson et al. 2002). 


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Overall survival for these cancer types is good, with a combined 5-year survival 
of ~95% at 1 year and 85% at 5 years (Tseng, Lee et al. 1996). However, non-
papillary histotypes carry a less favorable prognosis that PTC.  Moreover, 
advanced stage of disease also impacts on survival, with overall 5-year mortality 
for metastatic FTC and HCC about 50% (Chow, Law et al. 2003).  Even amongst 
PTC patients, 10 year mortality is ~20% in stage III (node positive disease in 
patients over 45 years), and 5-year mortality approaches 80% in stage IV disease 
(Hay, Thompson et al. 2002). 
 
Treatment of differentiated thyroid carcinoma of all types relies on surgical 
resection of the disease along with the normal thyroid gland and any involved 
cervical lymph nodes, followed by radioactive iodine therapy, administered both 
to eliminate the normal thyroid remnant and in an effort to eradicate residual or 
metastatic disease (D'Avanzo, Ituarte et al. 2004). Postoperative suppression of 
thyrotropin (TSH) may also decrease the risk for recurrence and cause-specific 
mortality in high-risk patients (Cooper, Specker et al. 1998).  
 
Radioactive iodine is an effective treatment for metastatic thyroid cancer, 
particularly amongst young patients, in whom control or effective cure, 
particularly of pulmonary metastases, can sometimes be achieved (Brink, van 
Heerden et al. 2000). However, not all thyroid cancers concentrate iodine, making 
this group of tumors unresponsive to radioactive iodine treatment, while some 
tumors lose iodine avidity over time to become iodine-refractory (Caplan, Wickus 
et al. 2005).  This problem of radioiodine refractory disease affects an estimated 
20% of PTC amongst young patients (<45 years), but as many as 70 – 80% of 
FTC, HCC and PTC amongst older patients. For patients experiencing locally 
recurrent disease in the neck, following primary surgery and radioactive iodine 
treatment, external beam irradiation may provide effective control of the disease 
when further surgical exploration is not a suitable option (Kim, Yang et al. 2003). 
 
Currently, no effective systemic treatment options are available for radioiodine 
refractory metastatic disease.  Palliative intervention may be used to treat 
symptomatic or pre-symptomatic metastases, including surgical resection and 
external beam irradiation. Response rates of 10 – 20% have been reported in small 
series of chemotherapy trials, using doxorubicin and/or cisplatin (Gimm 2001), 
but no responses were seen in a trial of etoposide treatment in differentiated 
thyroid cancer of all types (Leaf, Wolf et al. 2000). Occasional patients may 
exhibit some inhibition of tumor growth in response to octreotide, though this 
may be restricted to the minority of patients with octreotide-avid disease, and the 
impact on tumor spread and on survival is, at best, marginal (Alhamarneh, 
Murphy et al. 2004). Consequently, there is no standard single-agent or 
combined-agent therapy in routine clinical use at the current time. 
 
In contrast to the lack of effective systemic therapies for differentiated thyroid 
carcinoma, our understanding of their molecular and genetic underpinnings has 


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progressed dramatically in the last decade. Identification of activating mutations 
of ras and B-Raf, and activating rearrangements of the RET proto-oncogene, 
implicate the ras/raf/MAP-kinase pathway in the pathogenesis of PTC (Salvatore, 
Giannini et al. 2004). Animal models have confirmed the oncogenic potential of 
at least some of these identified mutations (Capen and Sagartz 1998). There is 
also a recognized role in PTC and FTC/HCC of the receptor protein-kinase 
systems (PKA and PKC) (Fagin 2004), while between 30% and 50% of FTC 
express an oncoprotein that inhibits PPAR pathways, which has been implicated 
in oncogenesis (Sahin, Allard et al. 2005). A number of growth factor receptors, 
including EGF-R, IGF-α, and IGF-1 are also expressed in thyroid cancers (Duh 
and Grossman 1995), which also exhibit increased telomerase activity, and 
hTERT gene expression (Zeiger, Smallridge et al. 1999). 
 
Development of novel targeted drugs affecting each of these pathways offers 
promise of new therapies for patients with advanced thyroid carcinoma, which is 
currently otherwise untreatable.  
 
Medullary Thyroid Cancer (MTC) 
MTC arises from the C-cells of the thyroid gland, of neural crest lineage 
(Clayman and el-Baradie 2003).  These tumors retain the capacity to secrete 
calcitonin, providing a reliable marker for disease recurrence, progression and 
response to treatment. MTC occurs either sporadically (~80%) or as one 
manifestation of a familial cancer predisposition syndrome (~20%). In familial 
MTC (FMTC) the only phenotype is MTC arising typically in early to mid-adult 
life (Quayle and Moley 2005). Presentation of MTC typically occurs earlier, and 
may be more aggressive, in the multiple endocrine neoplasia (MEN) syndromes. 
In MEN type 2A, MTC is accompanied by a high incidence of 
pheochromocytoma and hyperparathyroidism, while MEN-2B is associated also 
with developmental anomalies and multiple benign neurofibromata (Quayle and 
Moley 2005). The penetrance of MTC in each of these familial syndromes 
approaches 100% and presentation is earlier and more aggressive in MEN2B than 
MEN2A, with nodal and distant metastatic spread being the rule, unless these 
patients are detected by genetic screening.  
 
Treatment of MTC consists of surgical resection of the disease and the disease-
bearing thyroid gland, with cervical lymph node dissection.  However, nodal 
metastatic spread affects up to 60% of cases, and the majority of these cases 
suffer either residual or recurrent disease, which may require further surgical 
debulking (Cohen and Moley 2003).  
 
Because MTC arises from the C-cell lineage, these tumors do not express the 
sodium-iodide transporter and do not exhibit iodine-concentrating activity. 
Consequently, radioactive iodine is not effective in treating this disease.  
Similarly, the response of MTC to radiation therapy has proven disappointing, 
though it may prove useful to palliate symptomatic metastases.  
 


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Metastatic MTC may cause symptoms directly, by local compression and 
invasion, or indirectly through the secretion of calcitonin and other neuroactive 
substances, which cause flushing, diarrhea, anorexia and malaise. Some useful 
control of these symptoms can be achieved by use of octreotide, which may also 
slow the growth, at least of octreotide-avid disease. Octreotide is the only 
accepted standard treatment for metastatic MTC, but its impact on survival is 
marginal and unproven (Traugott and Moley 2005). Chemotherapeutic 
combinations have had only limited success in a small number of case reports and 
consequently, there is no currently accepted systemic therapy for metastatic MTC. 
 
Activating mutations of the RET proto-oncogene, a receptor tyrosine kinase 
involved in signaling for cell growth and differentiation, are responsible for the 
familial MTC syndromes, and are also detectable in 50 – 80% of sporadic MTC 
(Jindrichova, Kodet et al. 2003).  Novel agents directed at this and other 
intracellular signaling cascades offer hope for modulation of this disease.  
 
Anaplastic Thyroid Cancer (ATC) 
ATC is a highly aggressive and rapidly progressive form of thyroid cancer, 
accounting for half of all thyroid cancer deaths despite comprising only 2% of all 
thyroid cancers (Jemal, Murray et al. 2005).  Mortality from ATC exceeds 90% at 
1 year, and approaches 95% at 5 years, with a median life expectancy from the 
time of diagnosis of ~3 months (McIver, Hay et al. 2001).  
 
Although ATC may arise spontaneously in some cases, a majority of cases exhibit 
co-existing differentiated thyroid cancer, suggesting that ATC may reflect “de-
differentiation” of a pre-existing differentiated thyroid cancer (McIver, Hay et al. 
2001).  Mutations of the p53 tumor suppressor gene may play a role in the 
aggressive phenotype and chemoresistance of this tumor (Quiros, Ding et al. 
2005). 
 
Initial treatment for localized ATC includes primary surgery and lymph node 
dissection, with consideration given to adjuvant radiotherapy and/or 
chemotherapy due to its highly aggressive nature.  Often, however, the disease 
presents at a locally advanced stage, precluding surgical resection and requiring 
radiotherapy, with palliative tracheostomy and gastrostomy tube placement, 
because of rapidly progressive disease in the neck. Metastatic disease is present at 
the time of diagnosis in over 50% of all patients and becomes evident in the 
majority of the remaining patients rapidly thereafter (McIver, Hay et al. 2001). 
 
Palliative therapies in use for advanced or metastatic disease include single agent 
doxorubicin or paclitaxel, with transient responses to paclitaxel observed in up to 
50% of treated patients (Ain, Egorin et al. 2000).  However, there is no evidence 
that such treatment alters the outcome of this near-universally fatal disease 
(McIver, Hay et al. 2001), for which no effective therapy is currently available.  
 


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2.2 
GW786034 (pazopanib) 
 
GW786034 (pazopanib) is a potent and selective, orally available, small molecule 
inhibitor of VEGFR-1, -2, and -3, PDGF-α, PDGF-β, and c-kit tyrosine kinases 
(TKs) [Pazopanib (GW786034) Investigator’s Brochure, 2005].  The agent 
selectively inhibits proliferation of endothelial cells stimulated with VEGF but not 
with basic fibroblast growth factor.  In non-clinical angiogenesis models, 
GW786034 (pazopanib) inhibited VEGF-dependent angiogenesis in a dose-
dependent manner and in xenograft tumor models, twice-daily administration of 
GW786034 (pazopanib) significantly inhibited tumor growth in mice implanted 
with various human tumor cells.  Upon chronic oral dosing, GW786034 
(pazopanib) is expected to inhibit VEGF-driven angiogenesis and as a 
consequence, limit solid tumor growth.  Because angiogenesis is necessary for the 
growth and metastasis of solid tumors, and VEGF is believed to have a pivotal 
role in this process, GW786034 (pazopanib) treatment may have broad-spectrum 
clinical utility.   
 
Mechanism of Action 
Tumor VEGF expression has been associated clinically with disease prognosis in 
many different types of malignancies.  Expression of VEGF is elevated by diverse 
stimuli, including proto-oncogene activation and hypoxia, the latter effect 
frequently arising in solid tumors because of inadequate perfusion.  In addition to 
its angiogenic role, VEGF also profoundly increases the permeability of the 
vasculature, an effect that can also contribute to tumor progression.  A leaky 
tumor endothelium enhances nutrient and catabolite exchange and represents less 
of a barrier to tumor cell intravasation during metastasis.  Two high-affinity 
receptors for VEGF with associated TK activity have been identified on human 
vascular endothelium, VEGFR-1 (fms-like TK-1, or Flt-1) and VEGFR-2 (kinase 
insert domain-containing receptor, or KDR).  Although the relative contributions 
of VEGFR-1 and VEGFR-2 signaling in mediating tumor progression have not 
been elucidated, a number of studies suggest that VEGFR-2 performs a 
predominant role. 
 
In addition to VEGF receptor signaling, increasing evidence implicates platelet-
derived growth factor receptor (PDGFR) signaling in tumor angiogenesis.  PDGF 
is a critical regulator of pericyte recruitment to tumor vessels.  Pericytes surround 
the endothelial cells and play a key role in vascular development, stabilization, 
maturation, and remodeling.  Pericytes express PDGFR-, and pericyte 
abnormalities in tumors are consistent with alterations in PDGF signaling 
pathways.  Recent nonclinical evidence suggests that inhibition of PDGFR 
signaling augments the antitumor and antiangiogenic effects of VEGFR inhibitors 
by destabilizing pericytes.  In addition, PDGF signaling is implicated in the 
autocrine growth of tumor cells, and in the recruitment and regulation of tumor 
fibroblasts. 
 
In vitro experiments have shown that GW786034 (pazopanib) inhibited the TK 


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activity of human VEGFR-1, -2, and -3 with IC50 values of 10, 30, and 47 nM, 
respectively.  The agent also potently inhibited mouse, rat, and dog VEGFR-2 
with IC50 values of 42, 17, and 17 nM, respectively.  Compared to 23 other tested 
kinases, GW786034 (pazopanib) was 3- to 400-fold more selective for VEGF 
receptors.  These studies also demonstrated that the agent inhibited PDGFR- and 
-, and c-kit TKs with IC50 values of 71, 84, and 74 nM, respectively. 
 
In addition to its ability to inhibit TK activity, GW786034 (pazopanib) selectively 
inhibited proliferation of human umbilical vein endothelial cells (HUVEC) 
stimulated with VEGF (IC50=21 nM) compared to its effect on HUVEC 
proliferation stimulated by basic fibroblast growth factor (bFGF; IC50=721 nM).  
Further evidence of the agent’s potential effect on angiogenic activity is shown by 
its inhibition of VEGF-induced tyrosine phosphorylation of VEGFR-2 in HUVEC 
in a dose-dependent manner (IC50=7 nM).  GW786034 (pazopanib) does not act 
directly on tumor cell proliferation as shown by its failure to inhibit the 
proliferation of human cell lines HT-29 (colon), MDA-MB-468 (breast), PC3 
(prostate), or A375P (melanoma).  However, when the experiment evaluated the 
agent’s effect on angiogenic processes, GW786034 (pazopanib) was >1400-fold 
selective for VEGF-induced HUVEC proliferation relative to all four tumor cell 
lines and 48-fold more selective relative to human foreskin fibroblast (HFF) 
proliferation. 
 
Nonclinical Efficacy 
In contrast to in vitro proliferation studies, in vivo administration of GW786034 
(pazopanib) produced marked growth inhibition of a variety of human tumor 
xenografts in mice.  When GW786034 (pazopanib) was administered at 100 
mg/kg twice daily for 21 days to mice bearing HT29 (colon) or HN5 (head and 
neck carcinoma) xenografts, tumor growth was inhibited by 82% and 101%, 
respectively.  A375P and PC3 xenografts were less sensitive to GW786034 
(pazopanib). 
 
The inhibitory effect of GW786034 (pazopanib) on bFGF- and VEGF-induced 
angiogenesis has been demonstrated in two different mouse models of 
angiogenesis, the Matrigel™ plug assay, and the cornea micropocket model.  In 
the Matrigel™ plug assay, a Matrigel™ plug containing bFGF is implanted 
subcutaneously in female Swiss nu/nu mice, resulting in new blood vessel growth 
into the plug that is highly dependent on VEGFR-2 signaling.  When GW786034 
(pazopanib) was administered either once or twice daily for 5 days in this model 
system, a dose-dependent inhibition of angiogenesis resulted:  82-86% (100-200 
mg/kg per day), 57-58% (30-60 mg/kg per day), and 32% (10 mg/kg administered 
twice daily).  A once-daily dose of 10 mg/kg was ineffective.  The ED50 (dose 
producing 50% of the maximal effect) values were 29.4 mg/kg for once-daily 
dosing and 20.3 mg/kg for twice-daily dosing.  In the cornea micropocket model, 
VEGF or bFGF is formulated into sucralsulfate micropellets, then implanted in 
the normally avascular cornea of female Swiss nu/nu mice.  Angiogenic endpoints 
are quantified by measuring the degree of vascularization at the cornea-limbus 


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interface (clock hours) and maximum blood vessel length.  Using this model, 
administration of oral GW786034 (pazopanib) at 100 mg/kg twice daily for 5 
days inhibited vascularization by 71% (bFGF) and 100% (VEGF), and the 
maximum blood vessel length was reduced by 97% (bFGF) and 135% (VEGF).   
 
GW786034 (pazopanib) has been evaluated in combination with other TK 
inhibitors and with various chemotherapeutic agents.  The combined antitumor 
activity of GW786034 (pazopanib) and lapatanib (an EGFR/ErbB2 TK inhibitor) 
was examined in breast adenocarcinoma BT474 and in nonsmall cell lung cancer 
NCI-H322 tumor xenografts in SCID mice.  GW786034 (pazopanib) administered 
alone at 30 or 100 mg/kg/day produced dose-dependent inhibition of both tumor 
xenografts.  When combined with lapatanib, there was a modest increase in 
antitumor activity against both tumor xenografts compared to either agent alone; 
however, the differences were not statistically significant.  GW786034 
(pazopanib) has also been evaluated in combination with various other 
chemotherapeutic agents (topotecan, irinotecan, 5-fluorouracil, oxaliplatin, or 
docetaxel) against HT29 tumor xenografts.  While GW786034 (pazopanib) alone 
administered at 30 or 100 mg/kg/day produced dose-dependent inhibition of 
HT29 tumor growth and all of the chemotherapeutic agents  
alone have demonstrated activity against this xenograft model, the effect of any of 
the combinations on tumor growth was not significantly different from that of 
either agent alone.    
 
Follow up studies were done with GW786034 (pazopanib) and docetaxel with an 
endpoint of time to reach 2 tumor doublings.  GW786034 (pazopanib) was 
administered orally (PO) at 100 mg/kg daily and docetaxel was administered 
intraperitoneally (IP) at 50 mg/kg once weekly (Q7D) for three weeks.  In two 
independent experiments, the median time to reach two tumor doublings was 
longest in mice treated with both GW786034 (pazopanib) and docetaxel 
concomitantly.  These results clearly show an advantage of combining 
GW786034 (pazopanib) with docetaxel (and likely other chemotherapeutic 
agents) for better tumor control.   
 
Nonclinical Pharmacology and Toxicology  
In safety pharmacology studies, there were no GW876034 (pazopanib)-related 
central and peripheral nervous system, respiratory, or cardiovascular effects in 
rats or monkeys given single oral doses of up to 300 mg/kg and 500 mg/kg, 
respectively.  There were also no treatment-related effects on action-potential 
duration or other action-potential parameters when dog Purkinje fibers were 
incubated with up to 80 nM GW786034 (pazopanib).  There was no detectable 
effect on -andrenergic control of the cardiovascular system in the rat following 
IV treatment with up to 10 mg/kg GW786034 (pazopanib).  In rats, drug-related 
effects after 1 month of dosing were limited to slight liver enzyme increases and 
pharmacologically mediated changes due to VEGFR-2 inhibition in bone and 
bone marrow (doses ≥ 100 mg/kg/day) and in teeth (incisors; doses ≥ 30 
mg/kg/day).  All drug-related effects had reversed or were resolving by the end of 


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a 10-week recovery period.  After 6 months of GW786034 (pazopanib) dosing at 
3 mg/kg/day in rats where systemic exposure (AUC) was approximately 90 
mcg•hour/mL, there were significant agent-related findings in the trachea, kidney, 
adrenals, and pituitary glands.  Additional target organ effects occurred in the 
pancreas and nail and nail bed in rats given 30 mg/kg/day. 
 
Extended dosing in monkeys resulted in severe gastrointestinal signs in some 
animals, which may have been secondary to precipitation of the drug in the 
intestinal lamina propia.  These events resulted in termination of the animals in 
the 500 mg/kg/day dose group after 9 months of dosing.  The 12-month no 
observed adverse effect level (NOAEL) in the monkey has not been determined; 
however, a dose of 50 mg/kg/day (AUC 100 mcg•hour/mL in the 1-month study) 
was well tolerated. 
 
Nonclinical reproductive toxicology studies indicate reduced female fertility, fetal 
teratogenic effects, and reduced fetal body weight in pregnant rats and/or rabbits 
given GW786034 (pazopanib).  In rats, GW786034 (pazopanib) caused a 
reduction in the number of stage I-V round spermatids at ≥ 300 mg/kg/day, 
resulted in female reproductive tract target organs effects at 300 mg/kg/day, and 
caused early embryo resorptions.  The agent was found to be non-mutagenic and 
non-clastogenic in a range of genetic toxicity tests. 
 
Nonclinical Pharmacokinetics and Drug Metabolism 
GW786034 (pazopanib) has good oral bioavailability in both rodent and non-
rodent species.  Following oral administration of radiolabeled GW786034 
(pazopanib) to rats and monkeys, excretion of drug-related material was rapid and 
essentially complete.  The majority of the dose was excreted via feces in both 
species with lesser amounts in the urine.  Biliary excretion accounted for a 
significant portion of the radioactivity ultimately found in the feces.  GW786034 
(pazopanib) is highly (>99.9%) protein bound in mouse, rat, dog, monkey, and 
human plasma.  Preliminary in vitro data indicate that GW786034 (pazopanib) is 
highly permeable across membranes and is a substrate for the P-glycoprotein 
(Pgp) transporter.   
 
Clinical Experience 
The company-sponsored phase 1 dose-escalation study of orally administered 
GW786034 (pazopanib) has completed enrollment of 63 patients with a variety of 
solid tumor types.  Doses administered ranged from 50 mg three times per week 
to 2000 mg once daily.  The maximally tolerated dose was not defined in this 
trial.  Tumor shrinkage (1 partial and 4 minimal responses) or stable disease (2 
cases) has been observed in all seven patients with renal cell carcinoma (RCC) 
treated at ≥ 800 mg once daily (n=5) and 300 mg bid (n=2).  Tumor shrinkage 
was also seen in patients with Hurthel cell and neuroendocrine tumors, as well as 
chondrosarcoma.  In all, 15 patients, including those with RCC, Hurthel cell, 
carcinoid, GIST, neuroendocrine, sarcoma, melanoma, and lung cancer tumors, 
have remained on study for 6 months or longer.   


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Safety  
The most common adverse events (AEs) seen in this phase 1 trial regardless of 
causality were all grade 1 or 2 (except as noted).  These AEs (in decreasing order 
of frequency) include nausea (49%), diarrhea (45%), hypertension (35%), fatigue 
(33%), anorexia (29%) and vomiting (27%).  One of three patients treated with 
2000 mg daily of GW786034 (pazopanib) developed dose-limiting toxicity of 
grade 3 fatigue (Hurwitz et al., 2005).  Hair depigmentation (indicative of c-kit 
and, potentially, VEGFR modulation) was seen in 12 patients, all of whom were 
treated at doses ≥ 800 mg.  One of three patients dosed at 2000 mg once daily 
experienced grade 3 fatigue that resolved upon dose reduction to 800 mg.   
 
As seen with many of the other agents that block VEGF signaling, grade 1-3 
hypertension that could be controlled with antihypertensive medication as well as 
proteinuria have been observed in this ongoing GW786034 (pazopanib) 
monotherapy phase 1 study.  In addition, there have been single events of 
gastrointestinal bleeding, pulmonary thrombosis, and deep vein thrombosis.  No 
effect of GW786034 (pazopanib) on QTc has been seen.  Grade 3 hemoptysis, 
coagulopathy, thrombosis, and hemorrhage have been reported with other 
angiogenesis inhibitors and could potentially occur with GW786034 (pazopanib).  
The use of GW786034 (pazopanib) in pediatric patients is contraindicated due to 
the potential effect on epiphyseal growth plates. 
 
The pathogenesis of hypertension induced by angiogenesis inhibitors is likely to 
be multifactorial.  VEGF and VEGFR-2 are involved in the proper maintenance, 
differentiation, and function of endothelial cells.  Arterial hypertension is 
characterized by reduced nitric oxide (NO) biosynthesis, activation of the Renin-
Angiotensin-Aldosterone-System (RAAS), increased vasoconstriction, and 
microvascular rarefaction of arterioles and capillaries.  Microvascular rarefaction 
in hypertension is partly due to impaired angiogenesis.   
 
Hypertension observed with angiogenesis inhibitors is thought to be due to 
reduced endothelium-derived NO bioavailability.  This situation would effectively 
lead to NO deficiency, which would limit NO-dependent signal transduction 
pathways to the detriment of normal cellular function.  In addition to being a 
potent vasodilator, NO is required for angiogenesis, although the cellular 
signaling mechanisms by which NO affects angiogenesis are not yet well 
characterized.  Angiogenic growth factors such as VEGF and FGF induce NO.  
NO upregulates VEGF leading to increased vascular permeability and 
angiogenesis. The RAAS also affects angiogenesis.  Angiotensin II (Ang II), a 
main effector molecule of the RAAS, acts as an angiogenic factor.  Ang II induces 
targeted migration of endothelial cells and pericytes.  However, the exact 
mechanisms by which Ang II induces angiogenesis are not fully elucidated yet.  
 
Clinical Pharmacokinetics and Pharmacology 
Pharmacokinetic (PK) data have been collected on 51 patients who received oral 


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GW786034 (pazopanib) at doses ranging from 50 mg 3 times weekly to 2000 mg 
daily while enrolled in the company-sponsored phase 1 trial.  In a preliminary 
report on results from 43 patients, data showed a mean t1/2 of 35 hours (Hurwitz et 
al., 2005).  Mean Cmax and AUC0-24 values increased after single doses of 50-800 
mg, but the increases in these parameters were neither consistent nor proportional 
to the increase in dose at all dose levels.  Maximal exposure (trough 
concentrations >18 mcg/mL) was observed at doses ≥ 800 mg daily.  Daily 
administration resulted in an approximate 1.5- to 3-fold accumulation of 
GW786034 (pazopanib) in the plasma in most patients across all dose cohorts, 
and there were no obvious time-dependent changes in GW786034 (pazopanib) PK 
values.  Updated PK information from this trial indicates that the greatest mean 
AUC0-24 and mean C24 (plasma concentration at 24 hr) values on Day 22 were 
observed in the 800 mg and 1000 mg/day cohorts (Company Communication).  
Cohorts with daily doses greater than 1000 mg had similar or lower mean Cmax, 
AUC0-24, and C24 values compared to those of the 800 mg cohort.   GW786034 
(pazopanib) administered at 300 mg or 400 mg twice daily (BID) resulted in an 
approximately 4- to 7-fold accumulation in plasma [based on AUC0-12] on Day 22 
in most patients.  Mean Cmax values on Day 22 in the 300 mg BID and 400 mg 
BID dose groups were similar, and both values were less than the mean Cmax 
values in the 800 mg and 1000 mg once daily cohorts.  However, mean C24 values 
on Day 22 were similar all 4 dosing regimens.  There were no obvious time-
dependent changes in GW786034 (pazopanib) PK after 22 days of 300 mg BID or 
400 mg BID dosing. 
 
Potential Drug Interactions 
In vitro data indicate that GW786034 (pazopanib) causes a marked to moderate 
inhibition of cytochrome P450 enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, 
and 2E1.  Due to the early phase of development, human experience with 
GW786034 (pazopanib) is limited, and definitive information on the metabolism 
and drug interaction profile of GW786034 (pazopanib) is not available.  However, 
GW786034 (pazopanib) has the potential to alter the metabolism of medications 
which are substrates for cytochrome P450 enzymes.  GW786034 (pazopanib) 
should not be coadministered with medications which are substrates for 
cytochrome P450 enzymes (i.e., CYP2C9) and which have the potential to cause 
serious and/or life-threatening adverse events.  Because the in vitro data also 
suggest that GW786034 (pazopanib) is a substrate for CYP3A4, medications that 
induce or inhibit CYP3A4 may alter the pharmacologic effects of GW786034 
(pazopanib).  Due to the potential for drug interactions with certain anti-
hypertensive therapies and other frequently used medications, the prohibited and 
cautionary medications list should be reviewed prior to initiating treatment (see 
Section 8).   
 
Dose Selection 
The 800 mg daily dose of oral GW786034 (pazopanib) to be tested in this study is 
supported by both nonclinical and clinical data.  Animal models (mice with 
human tumor xenografts and the Matrigel plug model of angiogenesis) using an 


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osmotic pump to maintain a steady-state plasma concentration of GW786034 
(pazopanib) suggest that a concentration of > 40 mcM (> 17,500 ng/mL) was 
required for optimal in vivo activity.  These results were further supported by 
studies showing that the inhibition of VEGF-stimulated receptor phosphorylation 
in mouse lungs also required similar plasma GW786034 (pazopanib) 
concentrations for reproducible activity.  The activity of GW786034 (pazopanib) 
against human and mouse VEGFR-2 kinase is similar (IC50 of 23 and 9 nM 
against human and mouse VEGFR-2, respectively); therefore, similar effective 
concentrations are expected in humans.  In vitro and in vivo results, taken 
together, suggest that steady-state plasma GW786034 (pazopanib) concentrations 
of at least 17,500 – 22,000 ng/mL (40 to 50 mcM) were required to optimally 
inhibit VEGFR-2 activity. 
 
Doses ranging from 50 mg three times weekly to 2000 mg QD were evaluated 
clinically in the phase 1 dose-escalation study (VEG10003).  Mean plasma 
GW786034 (pazopanib) concentrations were maintained above 20,000 ng/mL (46 
mcM) over the entire dosing interval with 800 mg QD dosing (geometric mean 
C24 ~ 33,000 ng/mL [75 mcM]) or 300 mg BID dosing (geometric mean C24 ~ 
27,000 ng/mL [62 mcM]). These results suggest that GW786034 (pazopanib) 800 
mg QD or 300 mg BID dosing is required to maintain plasma GW786034 
(pazopanib) concentrations at levels required for optimal activity in preclinical 
models for the entire dosing interval. 
 
Evidence of biological activity associated with VEGFR inhibition was observed 
in cancer subjects in study VEG10003 at plasma GW786034 (pazopanib) 
concentrations similar to those required for optimal biologic effect in preclinical 
models.  The probability of an increase in blood pressure requiring a modification 
of antihypertensive therapy increased markedly when plasma GW786034 
(pazopanib) concentrations were maintained above 20,000 ng/mL (46 mcM) over 
the entire dosing interval.  Preliminary DCE-MRI data indicate that doses of 800 
mg QD or 300 mg BID affect the IAUGC60, which is consistent with a decrease in 
tumor perfusion.  In addition, preliminary data indicate inhibition of phospho-
VEGFR2 in the over-biopsy samples of the wound healing assay at doses  800 
mg QD. 
 
Evidence of clinical activity after GW786034 (pazopanib) treatment has been 
observed in subjects with metastatic RCC.  In study VEG10003, twelve subjects 
with metastatic RCC who had failed prior treatments were enrolled into the study.  
Tumor reductions, as assessed by RECIST criteria, were observed in all 7 subjects 
in whom the trough concentrations were  40 mcM (300mg BID, n=2;  800mg 
QD, n=5).  One of these seven subjects achieved a PR, and the other six had 
tumor reductions that were less than a PR.  In contrast, no tumor reductions were 
observed in the 5 RCC subjects dosed at 400 mg or less (100mg three times a 
week, n=1; 50mg QD, n=2; 400mg QD, n=2), and all of these 5 subjects had 
trough plasma GW786034 (pazopanib) concentrations of <40 mcM.  
 


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In the phase 1 study (VEG10003), 800mg daily dosing was relatively well 
tolerated and C24 concentrations were maintained above 40 mcM in subjects who 
were treated at this dose.  No consistent increase in exposure was observed when 
the dose was increased from 800 mg daily up to 2000 mg daily, and no MTD was 
established in this study.  Data from definitive studies comparing 800mg daily 
and 300mg twice daily dosing will not be available in a time frame that can affect 
dose selection in this trial.  Thus, a dose of GW786034 (pazopanib) of 800 mg 
daily was selected as the dose to be tested in this trial. 
 
2.3 
Background and Rationale    
 
TUMOR ANGIOGENESIS 
Tumor angiogenesis is the result of a complex sequence of events triggered by 
several seminal upstream mediators.  Activation occurs via vascular endothelial 
growth factors (VEGFs), fibroblast growth factors (FGFs), and TGF  and –ß-- 
while inhibition is mediated via thrombospondins, angiostatins, endostatins, and 
others.  The VEGF gene family appears to play a fundamental role in 
neoangiogenesis (Leung 1989) by inducing proliferation of endothelial cells, 
stimulating angiogenesis, and increasing vascular permeability.  The expression of 
VEGF is controlled by differentiation, transformation, and oxygen supply. 
 
ANGIOGENESIS IN THYROID CANCER 
In the thyroid gland, neoangiogenesis occurs in hyperplastic goiters, Graves 
disease, thyroiditis, and cancer.  Further, Bunone et al. (Bunone 1999) reported 
overexpression of VEGF in thyroid cancers, compared with normal tissue.  The 
authors suggested that factors inducing neoangiogenesis are involved in the 
neoplastic growth and aggressiveness of thyroid cancers-- and that VEGF might 
be an initial angiogenic signal, inducing tumor growth and local invasiveness.  
Recently, it was shown that the intensity of VEGF expression is associated with 
an increased risk of recurrence and decreased disease-free survival in papillary 
thyroid carcinomas (Lennard 2001).  Mounting evidence demonstrates that VEGF 
plays a role in thyroid cancer proliferation, as demonstrated by 1) increasing 
VEGF levels in differentiated thyroid cancer in comparison to control benign 
thyroid tissue, and 2) the fact that increased VEGF levels in sera/plasma from 
thyroid cancer patients is a negative prognostic indicator associated with 
increased risk of distant metastases and disease recurrence (Lin 2003).  
Furthermore, increased VEGF immunohistochemical staining in tumor specimens 
is similarly associated with worse patient outcome (Klein 2001; Lennard 2001; 
Kilicarslan 2003), and interventions targeting VEGF attenuate tumor growth in 
xenograft models of both differentiated (Soh 2000; Bauer 2003) and anaplastic 
thyroid cancers (Bauer 2002; Schiff 2004).   Collectively, available data therefore 
implicate VEGF as a potentially important therapeutic molecular target in thyroid 
cancer.  
 
GW786034 (Pazopanib) 


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GW786034 (pazopanib) is a novel, orally active small molecule targeting multiple 
tyrosine kinases including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha and –
beta, and c-kit.  An antitumor effect due to inhibiting of the VEGF driven 
angiogenic pathway is well established (package insert).  In addition to its effects 
on VEGF receptors, GW786034 targets additional tyrosine kinases, including 
PDGF receptors and c-kit that also have established roles in tumorigenesis and 
oncogenic mutations (Shibuya 1990).  Preliminary data from a phase I study of 
GW786034 in patients with solid tumors demonstrated early evidence of 
antitumor activity (Terman 1992).  Among 43 patients enrolled, a minimal 
response occurred in 4 patients and stable disease > 6 months was observed in an 
additional 6 patients.  GW786034 was well tolerated at doses up to 2000 mg 
daily.   
 
DIFFERENTIATION STATUS AND RESPONSE TO RADIOACTIVE IODINE 
Differentiated thyroid carcinomas of the follicular and papillary type have an 
overall excellent prognosis because of their high grade of differentiation and the 
effective use of therapeutic radioiodine. However, there is a small but significant 
fraction of patients who ultimately develop radioiodine-resistant cancer and die of 
their disease.  The reason for this appears to be at least partially attributable to 
progressive dedifferentiation with loss of tumor expression of sodium-iodine 
symporters.  Effective therapeutic options for such patients are presently 
unavailable.  Therefore, new approaches to the treatment of poorly or 
dedifferentiated thyroid tumors and tumors without iodine uptake are necessary.  
Various agents including retinoids, inhibitors of histone deacetylation and anti-
retrovirals have been tested with promising preclinical effects (Landriscina 2005).  
However, despite their activity in vitro, retinoids, the most study agents in this 
group, did not show sufficient clinical activity in human trials (Cohelo 2005). 
 
TYROSINE KINASE INHIBITORS IN THYROID CANCER 
In xenograft models of several human carcinomas (pancreas, renal cell and colon 
cancer), VEGF receptor blockade with the tyrosine kinase inhibitor PTK/ZK 
induced significant inhibition of tumor growth (Drebs 2202; Baker 2002; Ellis 
2000; Wood 2000).  Similarly, blockade of VEGF receptors by PTK/ZK inhibited 
growth of xenografts from human thyroid tumor cells of the ML-1 cell line 
implanted into nude mice, with mean xenograft tumor volume significantly 
reduced in PTK/ZK-treated mice, compared to control animals. 
 
Based upon these data, we hypothesized that blockade of VEGF function may be 
a promising target for the treatment of poorly or dedifferentiated thyroid 
carcinomas.  We also hypothesized that protein kinase inhibitor-mediated 
blockade of the VEGF/VEGF receptor system may result in re-differentiation of 
thyroid tissue, with re-expression of the NIS gene resulting in induction of iodine 
uptake ability in the tumor cells-- hopefully thereby leading to restored sensitivity 
to therapeutic radioiodine.  
 


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Hypothesis 1:GW786034 treatment of patients with thyroid cancers will lead to 
attenuated tumor growth or tumor regression, as well as to stabilization or 
reductions in patient tumor markers (e.g. thyroglobulin, calcitonin).  Tumor 
burden will be serially assessed via patient-appropriate imaging, and relevant 
tumor markers will be serially evaluated in plasma, to assess the effects of 
GW786034 on tumor extent and growth rate.  In particular, tumor extent will be 
formally evaluated using standard response criteria (RECIST) and changes in 
tumor status on treatment will be compared to tumor measurements prior to study 
entry to capture not only GW786034-induced tumor regression, but also 
GW786034-induced disease stability.  This will be accomplished by requiring that 
all enrolled patients have evidence of tumor progression in the 6 month period 
prior to GW786034 initiation, making it possible to compare tumor growth pre- 
and on-study.  Similarly, rates of change of relevant tumor markers (e.g. 
thyroglobulin, calcitonin, CEA) of patients will be evaluated pre- and on-study to 
determine whether GW786034 therapy may lead to either reductions, or 
stabilizations, of these markers.  This will be critical, because substantial data 
suggest that VEGF-targeted agents will likely lead more to disease stabilization 
than regression.   
 
Hypothesis 2:  GW786034 will affect decreased levels of angiogenic markers 
(over time and in response to treatment), consequently impacting downstream 
targets of the pathway.  Levels of free VEGF and PDGF will be explored in a 
graphical manner in pre-treatment and multiple on-treatment samples.  Results of 
these assays of circulating VEGF and PDGF, will be used to identify candidate 
markers of response to pazopanib. 
 
Hypothesis 3: GW786034-induced changes in thyroglobulin levels in patients 
with advanced differentiated thyroid cancers who are thyroglobulin antibody 
negative will be predictive of patient objective response and disease progression.   
 
Rationale: Anecdotal experience of investigators enrolling patients on the initial 
cohort of differentiated thyroid cancer patients on MC057H suggested that 
induced changes in thyroglobulin seen in thyroglobulin antibody negative patients 
might be predictive of patient response.  Formal retrospective analysis indeed 
demonstrated that the proportion of patients with at least a 50% decrease in Tg 
values from pre-treatment levels was 0.50 among the 12 patients with stable or 
progressive disease and 0.80 among the 6 patients with a PR, suggesting that such 
an association may exist.  We therefore now propose to more rigorously and 
prospectively examine this association in an expanded DTC patient cohort.  This 
analysis will be important in the design of future pazopanib clinical trials in 
differentiated thyroid cancer, given its apparent promising clinical activity in 
DTC, so as to allow optimal use of tumor markers and imaging in the evaluation 
of further patients receiving the agent. 
 
3. 
PATIENT SELECTION 
 


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3.1 
Inclusion Criteria 
 
3.11 
Histologically or cytologically confirmed differentiated, medullary or 
anaplastic thyroid cancer that is now advanced or metastatic.  NOTE: 
Patients with thyroid lymphomas or sarcomas are specifically excluded, as 
are patients with metastatic disease from other sites of origin to thyroid. 
 
3.111   As of P2C Addendum 6, patients with confirmed differentiated 
thyroid cancer to be enrolled in the expanded/additional DTC 
cohort must be thyroglobulin antibody negative. 
 
3.11a Zero, one or two prior therapeutic regimens (this includes cytotoxic plus 
non-cytotoxic therapeutic regimens). 
 
3.12 
Absence of sensitivity to therapeutic radioiodine (differentiated only). 
 
3.13 
Measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as 
>20 mm with conventional techniques or as >10 mm with spiral CT scan.  
See section 11.2 for the evaluation of measurable disease.  NOTE: Disease 
that is measurable by physical examination only is not eligible.  
 
3.14 
Age >18 years.  NOTE: GW786034 (pazopanib) is contraindicated in the 
pediatric population due to the potential effect on the epiphyseal growth 
plates. 
 
3.15 
Life expectancy >3 months. 
 
3.16 
ECOG performance status (PS) 0, 1 or 2 (Karnofsky ≥60%; see Appendix 
A). 
 
3.17 
Normal/acceptable organ and marrow function as defined below and 
obtained ≤ 7 days prior to registration: 
 
• Leukocytes > 3,000/mcL 
• Absolute neutrophil count > 1,500/mcL 
• Platelets >1 00,000/mcL 
 
• Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN)  
(If there is reason to believe that the patient has Gilbert’s 
Syndrome, the bilirubin can be fractionated.  If the fractionated 
bilirubin is consistent with Gilbert’s Syndrome and there is no 
other possible explanation for the elevated indirect bilirubin, 
the patient may be eligible for the study if and only if the direct 
bilirubin is ≤ 1.5 X institutional ULN) 
 
 


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• AST(SGOT) < 2 .5 X institutional ULN 
• Creatinine ≤ 1.5 X ULN 
• Proteinuria ≤ + on urinalysis (may re-check per exclusion criteria 
3.25) 
• INR ≤ 1.2 X the ULN 
 
3.18 
Blood pressure (BP) <140 mmHg (systolic) and <90 mmHg (diastolic).  
Initiation or adjustment of BP medication is permitted prior to registration 
provided that the average of three BP readings at a visit prior to 
registration is <140/90 mmHg.   
 
3.19a Objective evidence of tumor progression in the 6 month period prior to 
GW786034 initiation as assessed by unequivocal progression of 
objectively measured disease on successive appropriate imaging (e.g. CT 
scan).  In cases of uncertainty of tumor progression, the Principal 
Investigator of the study will be available to assist in decisions. 
 
3.19b Women of child-bearing potential must have a negative serum pregnancy 
test ≤7 days prior to registration.  NOTE: The effects of GW786034 
(pazopanib) on the developing human fetus are unknown.  However, 
teratogenic effects and reduced fetal body weight have been seen in 
pregnant rats and/or rabbits given GW786034 (pazopanib).  For this 
reason and because antiangiogenic agents as well as other therapeutic 
agents used in this trial are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study 
entry and for the duration of study participation.    Should a woman 
become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately.  Effective 
contraception is required for all fertile participants in the trial. 
 
3.19c Ability to understand and the willingness to sign a written informed 
consent document. 
 
3.19d Willingness to comply with the requirement of the study. 
 
3.19e Willingness to donate blood for correlative marker studies. (Only 
applicable to sites within the United States) 
 
3.2 
Exclusion Criteria 
 
3.21 
Anaplastic, Differentiated, Medullary: a total of > 2 prior therapeutic 
regimens (this total includes cytotoxic plus non-cytotoxic regimens).  
Note: Enrollment of anaplastic, differentiated, and medullary patients who 
have had zero, one or two prior therapeutic regimens (cytotoxic plus non-


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cytotoxic regimens) is allowed - provided therapy ceased > 21 days prior 
to registration. 
 
NOTE: The Principal Investigator of the study should be contacted in the 
event of uncertainty related patient eligibility based upon prior therapies. 
 
3.21b Disease that is measurable by physical examination only. 
 
3.22    Any of the following: 
• Radiotherapy ≤ 4 weeks prior to registration. 
• Major surgery ≤4 weeks prior to registration 
• Radiotherapy to ≥25% of bone marrow   
• Concurrent therapy with octreotide unless tumor progression on 
this therapy has been demonstrated. 
 
3.23 
Any other ongoing investigational agents. 
 
3.24 
History of allergic reactions attributed to compounds of similar chemical 
or biologic composition to GW786034 (pazopanib) or other agents used in 
the study. 
 
3.25 
> +1 proteinuria (<30 mg/dL) on two consecutive dipstick or other urine 
assessments taken at least 1 week apart.  NOTE: (In cases where questions 
arise related to disparate proteinuria measurements, the study PI should be 
consulted for assistance in determining patient study eligibility.)  
 
3.26 
QTc prolongation (defined as a QTc interval ≥480 msecs) or other 
significant ECG abnormalities (e.g. frequent ventricular ectopy, evidence 
of ongoing myocardial ischemia).  NOTE: The Principal Investigator of 
the study should be contacted in the event of uncertainty related patient 
eligibility based upon ECG changes.    
 
3.27 
Receiving CYP interactive concomitant medications. 
 
Certain medications that act through the CYP450 system are specifically 
prohibited in patients receiving GW786034 (pazopanib) because in vitro 
data indicate that the agent has the potential to interact with the 
cytochrome P450 isoenzymes CYP2C9 and CYP3A4.  Certain other 
agents should be used with caution.  A list of medications that are 
specifically prohibited or that should be used with caution during this trial 
of GW786034 (pazopanib) can be found in Section 8.  Comprehensive 
lists of agents that could affect GW786034 (pazopanib) through the 
cytochrome P450 system can be found in Appendix B. 
 
3.28 
Any condition (e.g., gastrointestinal tract disease resulting in an inability 
to take oral medication or a requirement for IV alimentation, prior surgical 


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procedures affecting absorption, or active peptic ulcer disease) that 
impairs their ability to swallow and retain GSK786034 (pazopanib). 
 
3.29a Any of the following conditions: 
• Serious or non-healing wound, ulcer, or bone fracture 
• History of abdominal fistula, gastrointestinal perforation, active 
diverticulitis, intra-abdominal abscess or gastrointestinal tract 
bleeding ≤ 28 days of registration 
• Any history of cerebrovascular accident (CVA) ≤6 months 
• Current use of therapeutic warfarin.  Note: Low molecular weight 
heparin and prophylactic low-dose warfarin (INR<1.2 X ULN) are 
permitted.  PT/PTT must meet the inclusion criteria (Section 3.17) 
• History of myocardial infarction, cardiac arrhythmia, admission for 
unstable angina, cardiac angioplasty or stenting within the last 12 
weeks 
• History of venous thrombosis in last 12 weeks 
• Class III or IV heart failure as defined by the NYHA functional 
classification system (see Appendix C).  NOTE: A patient who has 
a history of Class II heart failure and is asymptomatic on treatment 
may be considered eligible 
• History of bleeding disorder, including patients afflicted with 
hemophilia, disseminated intravascular coagulation, or any other 
abnormality of coagulation potentially predisposing patients to 
bleeding  
• Poorly controlled depression or anxiety disorder, or recent (≤6 
months) suicidal ideation 
 
3.29b Known active and/or untreated brain metastases and/or brain metastases 
requiring ongoing therapy (e.g. corticosteroids).  NOTE: (Because of the 
poor prognosis often associated with brain metastases and because of the 
potential risk of bleeding in active brain metastases associated with multi-
targeted tyrosine kinase inhibitor therapy, patients with active and/or 
untreated brain metastases and/or those with brain metastases requiring 
ongoing therapy - e.g. corticosteroids - are excluded from trial 
enrollment.  Enrollment will, however, be permitted in cases of patients 
with longstanding treated and inactive brain metastases not requiring 
ongoing therapy, providing that stability of brain metastases has 
been demonstrated for a  period of 3 months or greater as assessed by 
intracranial imaging - and providing that there is no indication of 
increased vascularity of the treated metastases by MRI  imaging conducted 
≤14 days prior to registration.  When questions arise related to these 
criteria, the PI of the trial, Dr. Keith Bible, should be contacted for 
assistance on eligibility.) 
 


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3.29c Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection or psychiatric illness/social situations that would or might 
reasonably be expected to limit compliance with study requirements.  
 
3.29d Pregnant women.  NOTE: (Because GW786034/pazopanib is an 
antiangiogenic agent which has produced teratogenic effects and reduced 
fetal body weight in pregnant rats and/or rabbits, and therefore has the 
potential for teratogenic or abortifacient effects in humans.  Because there 
is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with GW786034/pazopanib, 
breastfeeding should be discontinued if the mother is treated with 
GW786034/pazopanib.  These potential risks may also apply to other 
agents used in this study.) 
 
3.29e HIV-positive patients on combination antiretroviral therapy. NOTE: 
(Because of the potential for pharmacokinetic interactions with 
GW786034/pazopanib.  In addition, these patients are at increased risk of 
lethal infections when treated with marrow-suppressive therapy.  
Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated.) 
 
3.29f Receiving any medications or substances known to affect or with the 
potential to affect the activity or pharmacokinetics of GW786034 
(pazopanib).  NOTE: The eligibility of patients will be determined 
following review of their case by the Principal Investigator (see Section 
3.27 for further information).  Efforts should be made to switch patients 
who are taking enzyme-inducing anticonvulsant agents to other 
medications.  
 
3.29g Receiving any concomitant medications that are associated with a risk of 
QTc prolongation and/or Torsades de Pointes. (Appendix I)  NOTE:  
These medications should be discontinued or replaced with drugs that do 
not carry these risks, if possible.  
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Patient Registration 
To register a patient, access the Phase 2 Consortium (P2C) web page and enter the 
remote registration/randomization application.  The remote 
registration/randomization application is available 24 hours a day, 7 days a week.  
Back up is available between 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday) by phone at (507) 284-2753 or by fax at (507) 284-0885.  
 
The instructions for remote registration are available on the P2C web page and 
detail the process for completing and confirming patient registration.  Prior to 


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initiation of protocol treatment, this process must be completed in its entirety and 
a P2C subject ID number must be available as noted in the instructions.  It is the 
responsibility of the individual and institution registering the patient to confirm 
the process has been successfully completed prior to release of the study agent.  
Patient registration via the remote system can be confirmed in any of the 
following ways:  
 
• Contact the P2C Registration Office (507)-284-2753.  If the patient was 
fully registered, the Registration Office staff can access the information 
from the centralized database and confirm the registration.  
• In the remote registration application, select the Show Subject button to 
verify that the patient registration data is retrievable. 
• Enter the remote data entry system and, using the P2C subject ID, confirm 
the patient appears in the data entry system. 
 
4.2 
Required Regulatory Documents 
A signed HHS 310 form, documenting current approval by the investigator’s 
Institutional Review Board), must be on file in the P2C Registration Office before 
an investigator may register patients.  In order to assure timely processing, this 
documentation must be faxed directly to the P2C Registration Office at 
(507) 284-0885. 
 
In addition to submitting initial IRB approval documents, ongoing approval 
documentation must be submitted (no less than annually) to the P2C Registration 
Office.  If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not 
be enrolled in the protocol until the situation is resolved. 
 
4.3 
Required Registration Documents 
Prior to accepting the registration/randomization, the remote 
registration/randomization application will verify the following: 
• IRB approval at the registering institution 
• Patient eligibility 
• Existence of a signed consent form 
• Existence of a signed authorization for use and disclosure of protected 
health information (USA institutions only) 
 
4.4 
Mandatory Translational Research 
A mandatory translational research component for blood is part of this study, the 
Randomization Center will automatically register patients separately to the 
mandatory translational component of this study (see Section 9.0). (Only 
applicable to sites within the United States).   
 
 
4.5 
Treatment Allowed Only at P2C Member Institutions 
Treatment on this protocol must commence at a P2C member institution under the 
supervision of a physician, endocrine surgeon, endocrinologist, and/or medical 


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oncologist investigator registered with NCI Pharmaceutical Management Branch 
(PMB) and the P2C Coordinating Center. 
 
4.6 
Timing of Treatment 
Treatment cannot begin prior to registration and must begin 7 days after 
registration. 
 
4.7 
 Pretreatment Tests  
Pretreatment tests must be completed within the guidelines specified on the test 
schedule. 
 
4.8 
Baseline Symptoms 
All required baseline symptoms (see Section 7.34) must be documented and 
graded. 
 
5. 
TREATMENT PLAN 
 
5.1 
GW786034 (Pazopanib) Administration 
 
 
5.11 
Treatment Regimen – One Cycle = 28 days 
 
Agent 
Dose 
Route  
Schedule 
Cycle Length 
GW786034 
800 mg 
PO (orally) 
Once 
daily 
28 days+ 
+Cycle length can be altered in the range of 21 to 35 days on an occasional basis 
with the specific approval of the study PI so as to accommodate holidays, 
inclement weather, and other scheduling issues if a particular patient is tolerating 
the study drug well.  Cycle length can also be extended to 56+7 days (8 weeks + 1 
week) at treating MD discretion after a patient has been on study >12 cycle/1 
year. 
 
• Grouping Factor: DTC, MTC, or ATC 
Patients will be divided into three cohorts based upon the nature of their 
thyroid cancer: Cohort 1, differentiated thyroid cancers; Cohort 2, 
medullary thyroid cancer; Cohort 3, anaplastic thyroid cancer.  These three 
cohorts will be evaluated independently for efficacy and toxicity end 
points. 
 
• Treatment will be administered on an outpatient basis.  Reported adverse 
events and potential risks are described in Section 7.  Appropriate dose 
modifications for GW786034 (pazopanib) 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. 
 
• Patients receive GW786034 (pazopanib) on an outpatient basis at a dose 


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of 800 mg/day (two 400-mg tablets; dose modification will be 
accomplished by combining 400-mg and 200-mg tablets as necessary).  
Patients are instructed to swallow tablets once a day (preferably in the 
morning) on an empty stomach either 1 hour before or 2 hours after meals.  
Tablets should be swallowed whole; they must not be chewed, broken, or 
crushed.  Treatment continues until one of the criteria in Section 5.4 
applies, provided that the retreatment criteria in Section 5.3 have been 
met.  Missed and/ or withheld doses of pazopanib (whether intentional or 
unintended) are to be reported in the Medication Diary below, but not 
made up.  Patients will be provided with a Medication Diary for 
GW786034/pazopanib (Appendix D), instructed in its use, and asked to 
bring the diary with them to each appointment.  A new copy of the 
Medication Diary will be given to patients whose dose is reduced due to 
adverse events. 
 
• TSH will be monitored each cycle, and if > 0.1 mIU/L, differentiated 
thyroid cancer patient’s dosage of levothyroxine ( Synthroid ) should be 
increased by 0.05 mg (50 micrograms) per day.  Dosage of l-thyroxine 
should not be increased more frequently than every 8 weeks.   
 
 
5.12 
Precautions/Warnings 
 
Medical personnel must refer to the list of prohibited and “use with 
caution” agents in Section 8 prior to administering treatment.   
 
Substances that are prohibited cannot be taken from prior to the 
administration of the first dose of GW786034 (pazopanib) until 1-2 weeks 
after discontinuation from the study.  The length of the pre-study 
prohibition will be at the discretion of the clinician based on the 
pharmacokinetic properties of the agents involved.   
 
Patients taking medications that are listed as “use with caution” should be 
closely monitored for adverse events.  In some instances of treatment for 
hypertension, a lower dose of the medication may be sufficient to provide 
the required antihypertensive control.  In other instances, the standard dose 
of such a medication may be associated with adverse events because of 
increased exposure.  Alternatively, the investigator may choose to replace 
the medication with another in the same pharmacologic class that is less 
likely to interact with GW786034 (pazopanib).  If such a medication is 
discontinued and replaced, the transition period should occur no less than 
7 days prior to the first dose of GW786034 (pazopanib).  Based on prior 
clinical experience with GW786034 (pazopanib), the use of calcium 
channel blockers (dihydropyridine category) and ACE inhibitors as first-
line and second-line antihypertensive therapy is recommended.   
 


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Frequent blood pressure (BP) monitoring is important in patients 
receiving GW786034 (pazopanib) starting on day 8 and continuing until 
patient is off study.  Experience to date suggests that increases in BP may 
occur following dosing with GW786034 (pazopanib) for a number of 
weeks and that these increases may occur relatively quickly.  It is 
imperative that the investigator institute appropriate measures to control 
BP.  This may necessitate changes to existing antihypertensive 
medication, addition of new medication(s) and/or interruption/withdrawal 
of GW786034 (pazopanib).  Section 6 includes specific guidelines on the 
management and, if appropriate, dose modifications for treatment-
emergent hypertension.   
 
Patients will be provided with a diary in which to record their twice-daily 
BP readings (see Appendix E).  The two daily readings should be taken at 
least 1 to 4 hours apart.  If two successive systolic readings are >140 
mmHg OR two successive diastolic readings are >90 mmHg OR any 
combination of elevated systolic and diastolic readings, patients will be 
instructed to contact their physician as soon as possible.  Patients should 
seek medical advice if their BP exceeds 180 mmHg (systolic) or 105 
mmHg (diastolic) at any time and should also be encouraged to contact 
their physician if they are concerned about any symptoms that may be 
associated with high BP (e.g., headache).  Recommendations for the 
monitoring and recording of BP readings as well as a flow chart for event 
management are presented in Appendix F.  Home blood pressure monitors 
can be obtained free of charge from GlaxoSmithKline (GSK)(See Section 
17.1).   
 
Renal function (creatinine and urinary protein) should be frequently 
monitored as suggested by the pathologic changes noted in animal studies 
and evidence from studies of other antiangiogenic agents.  Specific 
guidelines for management of proteinuria and elevated creatinine are 
presented in Section 6. 
 
The risks of diverticular disease and/or intestinal perforation and/or 
bleeding appear to be increased in patients receiving pazopanib and 
related agents.  On this basis, patients with active diverticulitis, 
gastrointestinal tract bleeding and other potentially serious underlying GI 
conditions within 28 days of enrollment will be specifically excluded from 
the trial.  Moreover, patients receiving pazopanib should be closely 
monitored and treated aggressively in response to any symptoms deemed 
suspicious for evolving GI tract pathology.  In particular, abdominal pain - 
especially when accompanied by fever - should be promptly evaluated 
with CT scan and treated aggressively with empiric antibiotics, with 
strong consideration of discontinuation of pazopanib.  Similarly, any 
patient presenting with gastrointestinal tract bleeding should be promptly 
evaluated with endoscopies, with strong consideration given to cessation 


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of pazopanib.   Further, any patient suspected of having GI tract 
perforation should be subject to prompt surgical evaluation, with cessation 
of pazopanib until perforation is absolutely excluded. 
 
5.13 
Criteria for Continuing Treatment 
 
Patients will be evaluated at each clinic visit during the treatment period to 
determine if continued treatment is appropriate.  If, at any time during 
treatment the evaluation criteria are not met, GW786034 (pazopanib) will 
be held or the dose adjusted according to the dose modification criteria 
stated in Section 6.  To continue therapy, subjects must meet the following 
criteria: 
 
o Absolute neutrophil count (ANC) ≥ 1,000/mm3 (1 X 109/L). 
o Platelet count ≥ 50,000/mm3 (50 X 109/L). 
o Blood pressure, if elevated, should be controlled with 
antihypertensive medication(s).  
o Urine protein < 1+ (30 mg/dL). 
o No clinically significant non-hematologic toxicity ≥ grade 2. 
o No indication of new or active gastrointestinal tract pathology (see 
section 5.12 above). 
 
Medical judgment should be exercised in deciding whether an adverse 
event of greater than or equal to grade 2 requires dose interruption or 
modification (see Section 6 for Dose Modification guidelines). 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because GW786034 (pazopanib) is known to interact with other concomitantly 
administered drugs through the cytochrome P450 (CYP450) system, the CRF 
must capture the concurrent use of all other drugs, over-the-counter medications, 
or alternative therapies. 
 
Because of the risk of prolonged QTc, Caution should be exercised when 
administering pazopanib to patients with a history of QTc interval prolongation, 
in patients taking anti-arrhythmics or other medications that may prolong the QTc 
interval, and those with relevant pre-existing cardiac disease.  
 
Section 8 provides lists of agents and substances specifically prohibited during 
GW786034 (pazopanib) administration as well as those which are to be used with 
caution.  Appendix B provides comprehensive lists of agents and substances that 
are known or which may have the potential to interact with GW786034 
(pazopanib) through CYP450 isoenzymes.  The Principal Investigator should be 
alerted if the patient is taking any agent on these lists. 
 
Patients should receive full supportive care during the study, including transfusion 


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of blood and blood products, treatment with antibiotics, anti-emetics, anti-
diarrheals, analgesics, erythropoietin, or bisphosphonates, when appropriate. 
 
Patients with new gastrointestinal tract pathology and/or symptoms should be 
managed in accord of the guideline provided above in section 5.12. 
 
Repeat EKG must be performed during the week 4, cycle 1 visit.  If the QTc 
interval at 4 weeks is > 500 msec, the EKG should be repeated within 7 days and, 
if the QTc interval remains ≥500 msec, the patient should be removed from the 
study.  Additionally, if the QTc interval is increased by 60 msec or more from 
baseline but the QTc interval remains at < 500 msec, an EKG should be repeated 
within 7 days.  If the repeat EKG again shows a ≥ 60 msec increase in the QTc 
interval from baseline, consideration should be given to removing the patient from 
the study or increasing monitoring, after discussion with the principal 
investigator. 
 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may 
continue indefinitely or until one of the following criteria applies: 
 
• Disease progression, 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• Unacceptable adverse event(s), 
 
• Patient goes on to alternate therapy,  
 
• Patient decides to withdraw from the study, or 
 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
5.4 
Duration of Follow Up 
 
▪ If a patient discontinues treatment due to progression within 3 years of registration, 
submission of an event monitoring form is required every 6 months thereafter until 
death or a maximum of 3 years post-registration.   
 
▪ If a patient discontinues treatment due reasons other than progression or death within 
3 years of registration, submission of an event monitoring form is required every 3 
months until progression then every 6 months thereafter until death or a maximum of 
3 years post-registration. 
 


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▪ If a patient discontinues treatment more than 3 years after registration, 
submission of an event monitoring report is required 6 months after 
treatment discontinuation. 
 
   
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Appropriate dose modifications for GW786034 (pazopanib)-related adverse events are 
outlined in the following subsections.  If treatment has been held for more than 21 days to 
allow for resolution of an adverse event, the investigator should contact the sponsor 
(DCTD, NCI) to review the subject’s condition prior to resuming the patient’s treatment 
except for delays due to hypertension (see Section 6.1 below).  Dose level reductions 
follow: 
 
Dose level 
GW786034 (pazopanib)* 
-3 
200 mg daily 
-2 
400 mg daily 
-1 
600 mg daily 
1 
800 mg daily 
 
 
 
*If doses are held, do not make up doses. 
 
6.1 
Management of Hypertension 
 
Increases in blood pressure (BP) and cases of hypertension have been associated 
with many drugs acting on the VEGF pathway.  The proposed mechanism for this 
increase is through inhibition of VEGF-induced peripheral vasodilation.  
Hypertension following GW786034 (pazopanib) treatment has been seen in 
animal studies as well as clinical trials.  Specific guidelines for management of 
this adverse event are provided below; additional suggestions for BP management 
can be found in the flow chart in Appendix F. 
 
• While patients are receiving treatment with GW786034 (pazopanib), the 
early initiation of antihypertensive treatment for grade 1 or 2 hypertension 
to minimize more severe or persistent hypertension is not considered a 
grade 3 adverse event. 
 
• Decisions to hold or decrease the GW786034 (pazopanib) dose during 
treatment must be based on BP readings taken in the clinic by a medical 
professional. 
 
Hypertension Monitoring and Management* 
 
Systolic and Diastolic 
Categories 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
GW786034 (pazopanib) 
Dose Modification 
Category A 
< 140 mmHg Systolic 
< 90   mmHg Diastolic 
• None 
• Baseline 
• Standard monitoring 
(BID) 
•  
• No Change 


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Category B 
140-159 mmHg Systolic 
90-94   mmHg Diastolic 
 
• Initiate BB or 
 Initiate DHP CCB  
 
• Increase doses of 
existing medications 
until BP controlled 
or at maximum dose 
• Increased frequency 
of BP monitoring 
until stabilized 
• No Change 
Category C 
160-179 mmHg Systolic 
95-104 mmHg Diastolic 
 
• Initiate BB or 
preferably 
 DHP CCB (may use  
 ACEI or 
 Vasodilator if DHP 
CCB ineffective) 
 
• Increase dosages or 
number of 
medications until BP 
controlled or at 
maximum dosages 
• Increased frequency 
of BP monitoring 
(e.g., every 4-6 hours) 
until stabilized 
 
• Supervised by 
healthcare 
professional 
• If partial or no control and 
BP still in a moderate range 
for 24-48 hours, hold 
GW786034 (pazopanib) and 
add additional 
antihypertensive drugs, 
increasing to a maximum 
dose until hypertension 
controlled; monitor for 
hypotension.  
 
• Decrease GW786034 
(pazopanib) by 1 dose level 
Category D 
> 180 mmHg Systolic 
> 105 mmHg Diastolic 
• Start immediate 
therapy with 2 drug 
combination 
including at least a 
DHP CCB 
 
• Escalate dosages to 
achieve optimal 
control of BP, up to 
the maximum dose 
 
• If partial or no BP 
control, add 
additional drugs up 
to 4; increase to 
optimal or maximum 
dosages of all drugs 
 
• Increased frequency 
of BP monitoring 
(e.g., every 4-6 hours) 
until stabilized 
 
• Supervised by 
healthcare 
professional 
• Hold GW786034 
(pazopanib); if control of 
BP in the Mild range, restart 
GW786034 (pazopanib) at 
the next lower dose level 
 
• If partial or no control, 
decrease GW786034 
(pazopanib) by another dose 
level or discontinue therapy 
per investigator  
 
• Stop GW786034 
(pazopanib) if hypertension 
is symptomatic, and 
hospitalize patient for 
management of BP 
Category E 
Hypertensive Crisis 
• Optimal 
management with 
intensive IV support 
in ICU 
• Hospitalize patient 
for management 
• Off protocol therapy, 
discontinue GW786034 
(pazopanib), and monitor 
closely for hypotension 
Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), Angiotensin 
Converting Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB) 
 
• 
*See table below for suggested antihypertensive medications by class 
• 
If patients require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
• 
If patients require >2 dose reductions, discontinue protocol therapy 
• 
Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in GW786034 
(pazopanib) 
• 
24-48 hours should elapse between modifications of antihypertensive therapy 
• 
Hypertension should be graded using the NCI CTCAEv4.0 
                       
 Oral Antihypertensive Medications 
Agents in bold characters are suggested as optimal choices to avoid or minimize 
potential drug-interactions with GW786034 (pazopanib) through CYP450. 
Agent  
 
Initial 
Intermediate 
Maximum 
Hepatic 


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34 
 
 
 
 
class 
Agent 
dose 
dose 
dose 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Selective 
 Blockers 
(BB) 
metoprolol 
25 mg  
twice daily 
50 mg 
twice daily 
100 mg  
twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg  
twice daily 
200-300 mg 
twice daily 
400 mg  
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used:       
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely used:       
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
 and   
Blocker 
labetolol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 substrate 
and inhibitor 
 
 


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6.2 
Management of Proteinuria 
 
Although patients with persistently >1+ (30 mg/dL) proteinuria at entry are 
ineligible, increases in proteinuria may occur during treatment and should be 
managed as follows: 
 
 


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Management of Proteinuria 
 
Proteinuria value 
Monitoring 
Dose modification 
>1+ (30 mg/dL, dipstick 
or equivalent routine 
laboratory analysis) 
Perform the following tests: 
• 24-hour urine collection for total protein 
and creatinine 
• microscopic examination of fresh urine 
• urine protein electrophoresis at first 
occurrence of >1+ (30 mg/dL) proteinuria 
only 
See below 
Based on results of the 24-hour urine collection: 
<1g protein 
(24-hour collection) 
Continue dipstick or equivalent routine 
laboratory analysis 
Continue planned dose 
>1 g but < 2g protein 
(24-hour collection) 
Perform 24-hour urine collection (total 
protein, creatinine) prior to day 1 of each 
subsequent cycle of therapy (q4w) until total 
protein is <500 mg/24 hours 
Decrease one dose level; 
continue treatment 
>2 g protein 
(24-hour collection) 
Perform 24-hour urine collection (total 
protein, creatinine) weekly until proteinuria is 
<2 g  
 
Hold GW786034 
(pazopanib) 
 
When protein is <2 g/24 
hours, resume treatment at 
one lower dose level 
Perform 24-hour urine collection (total 
protein, creatinine) prior to day 1 of each 
subsequent cycle of therapy (q4w) 
Continue until patient is off 
treatment 
 
 
6.3 
Management of Other CTCAE Adverse Events 
 
Adverse Event/ 
CTCAE v3.0 
Category 
 
Grade 
 
Treatment Modification 
 
Follow Up 
Gastrointestinal 
Perforation, GI 
Grade >1 
Discontinue treatment and go to event 
monitoring 
Monitor and treat as clinically 
indicated. 
Diverticulitis/colitis 
Typhlitis 
Grade >1 
Hold Pazopanib therapy until resolved, 
resume at discretion of treating 
physician after complete resolution 
Hold Pazopanib therapy until 
resolved, treat aggressively 
with antibiotics and supportive 
care; hospitalize if fever >101 F 
or if otherwise clinically 
indicated. 
Hemorrhage/ 
Bleeding/ 
Coagulopathy 
Grade 1 
No interruption in treatment; maintain 
current dose. 
Monitor as clinically indicated. 
 
 
 
Grade 2 
Hold GW786034 (pazopanib) until 
resolved to < grade 1; reduce dose to 
next lower dose level, and continue 
treatment.  
 
Monitor as clinically indicated.   
 
 
Follow up per protocol (Section 
5.4) if patient is removed from 


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If grade 2 or greater hemorrhage/ 
bleeding recurs following dose 
reduction, stop GW786034 
(pazopanib) and remove patient from 
study. 1 
the study. 
 
Grades 
3 or 4 
Discontinue treatment go to event 
monitoring. 1 
Follow up per protocol (see 
Section 5.4). 
Vascular/ 
Thrombosis 
Grade 2 
No interruption in treatment; maintain 
current dose. 
Monitor as clinically indicated. 
 
 
 
 
Grade 3 or 
asymptomatic 
Grade 4 
Hold GW786034 (pazopanib) until 
patient is receiving a stable dose of 
Low Molecular Weight Heparin 
(LMWH). (Coumadin® is a prohibited 
medication.) 
Treatment  may resume during the 
period of full-dose anticoagulation if 
all of the following criteria are met: 
• The subject must be on a stable 
dose of LMWH for treatment. 
• The subject must not have had a    
>grade 2 hemorrhagic event while 
on anticoagulation. 
Monitor as clinically indicated. 
Symptomatic 
Grade 4 
Discontinue treatment and go to event 
monitoring. 
Follow up per protocol (see 
Section 5.4 
Thrombocytopenia/ 
Neutropenia/Anemia 2 
Grades  
1 or 2 
No interruption in treatment; maintain 
current dose. 
Monitor as clinically indicated. 
Grade 
3 or 4 
Interrupt treatment until toxicity is ≤ 
Grade 2; reduce dose to 400 mg.   
 
If event recurs following dose 
reduction, discontinue treatment and 
remove patient from study. 
 
If patient is benefiting from therapy, 
contact the sponsor (DCTD, NCI) to 
discuss course of action. 
Monitor as clinically indicated.  
 
 
If subject is withdrawn from 
study, follow up per protocol 
(see Section 5.4). 
1 If recurrent event has no clearly associated clinical consequences, consult with the sponsor (DCTD, NCI) about 
continued treatment at 200 mg per day for patients who are benefiting from GW786034 (pazopanib). 
2 Patients with anemia due to hemorrhage/bleeding should be managed according to 
Hemorrhage/Bleeding/Coagulopathy section of this table. 
 
 
6.4 
Management of Other Clinically Significant Non-Hematologic Toxicities (not 
specifically addressed above) 
 
Observation 
Action 
AE resolves promptly with supportive care 
Maintain dose level 
1. Grade 3 or higher (non-hematologic or grade 4 (hematologic) 
AE related to GW786034 (pazopanib) and lasting >5 days that 
does not resolve to grade 2 or below despite maximum 
 
 
Reduce one dose level* 


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38 
 
 
 
 
supportive care for < 48 hours. 
2. Lower grade but related AEs (e.g., abdominal pain) 
AE does not resolve to grade 2 or below after treating patient at the 
lowest (i.e., 200 mg daily) reduced dose level. 
In general, move patient to event 
monitoring** 
* 
Alternatively and if medically appropriate, investigators may choose to hold dose for up to 21 days 
or withdraw patient from study.   
** After consultation with study PI, Dr. Keith Bible, a dose of 200 mg daily may be considered for 
patients on study > 3 months who are benefiting from the agent.  
 
6.5 
Management of Potassium, Calcium, Phosphorus and Magnesium. 
 
 
If, according to CTCAE version 4 criteria, the potassium level is grade 2 or greater and/or if 
the calcium, magnesium and/or phosphorous are grade 3 or higher, an EKG must be 
performed and appropriate action taken based on the results (see below). 
 
 
Adverse Event 
 
Grade 
 
Treatment Modification 
 
Follow Up 
Hypokalemia (< LLN) or  
Hyperkalemia 
(>5.5mmol/L) 
 
Grade ≥ 2 
Hold Pazopanib therapy until 
hypokalemia or hyperkalemia is grade 
1 or within institutional limits 
 
 
 
 
 
 
 
 
 
Even though pazopanib 
administration is allowed at these 
lower grades, every effort should 
be made to correct the abnormal 
lab values to normal if possible.   
 
Hypocalcemia  (<7.0 
mg/dL; <1.75 mmol/L; 
Ionized calcium 
<0.9mmol/L;) 
or  
Hypercalcemia (>12.5 
mg/dL; > 3.1 mmol/L; 
Ionized calcium > 1.6 
mmol/L) 
 
 
 
Grade  ≥ 3 
 
 
 
 
Hold Pazopanib therapy until 
hypokalemia or hyperkalemia is grade 
2 
Hypophosphatemia (<2.0 
mg/dL; <0.6 mmol/L)  
Hypomagnesemia (<0.9-
mg/dL; <0.4 mmol/L)  
or  
Hypermagnesemia (>3.0 
mg/dL; >1.23 mmol/L) 
 
 


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7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 
7.2) will determine whether the event requires expedited (via AdEERS) reporting in 
addition to routine (via CDUS) reporting.   
 
7.1 
CAEPR for Pazopanib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Pazopanib (GW786034, NSC 737754) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI via AdEERS (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification.  Frequency is provided based on 1568 patients. Below is the CAEPR for pazopanib 
(GW786034). 
NOTE:  Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.4, April 11, 20121 
 
 Adverse Events with Possible  
 Relationship to GW786034 (pazopanib) 
 (CTCAE 4.0 Term) 
[n= 1568] 
 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
 
 Sinus bradycardia 
 
  
ENDOCRINE DISORDERS 
  
 
 Hypothyroidism 
 L 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3)  
 
 Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
 
Gastrointestinal fistula2 
 Gastrointestinal fistula2 (Gr 1) 
 
 
Gastrointestinal hemorrhage3 
  
 
Gastrointestinal pain 
 
  
 
 
Gastrointestinal perforation4 
 Gastrointestinal perforation4 (Gr 1) 
 
 Mucositis oral 
 
  


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Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
 Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
 Fever 
 
  
 
 Non-cardiac chest pain 
 
  
INVESTIGATIONS 
  
 
Activated partial 
thromboplastin time 
prolonged 
 
  
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased (Gr 3) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase increased 
(Gr 3) 
Blood bilirubin increased 
 
 
 Blood bilirubin increased (Gr 3) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
 Ejection fraction 
decreased 
 
  
 
 
Electrocardiogram QT corrected 
interval prolonged (accompanied 
by Torsades de pointes) 
  
 
INR increased 
 
  
 
Lipase increased 
 
  
Lymphocyte count 
decreased 
 
 
 Lymphocyte count decreased (Gr 3) 
Neutrophil count decreased  
 
 Neutrophil count decreased (Gr 3) 
 
Platelet count decreased  
 Platelet count decreased (Gr 3) 
 
Serum amylase 
increased 
 
  
 
 Weight loss 
 
 Weight loss (Gr 2) 
White blood cell decreased  
 
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 3) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
Hypernatremia 
 
  
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 3) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr 3) 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Back pain 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
Tumor pain 
 
  
NERVOUS SYSTEM DISORDERS 
  


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Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Proteinuria 
 
 Proteinuria (Gr 3) 
 
 
Urinary fistula 
 Urinary fistula (Gr 1) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
 
Female genital tract fistula 
 Female genital tract fistula (Gr 1) 
 
 
Uterine fistula 
 Uterine fistula (Gr 1) 
 
 
Vaginal fistula 
 Vaginal fistula (Gr 1) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
Respiratory hemorrhage5  
 Respiratory hemorrhage5 (Gr 1) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 1) 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
Skin and subcutaneous 
tissue disorders - Other 
(hair color change/hair 
depigmentation) 
 
 
 Skin and subcutaneous tissue 
disorders - Other (hair color 
change/hair depigmentation) (Gr 3) 
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 1) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event 
(venous)6 
  
 
 
Vascular disorders - Other 
(arterial thromboembolic event)6 
  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical fistula, 
Esophageal fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 


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5Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC. 
 
6These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 
Also reported on pazopanib (GW786034) trials but with the relationship to pazopanib (GW786034) 
still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac disorders - Other (sinus 
arrest); Cardiac disorders - Other (supraventricular extra systoles); Pericardial effusion; Supraventricular 
tachycardia 
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Eye disorders - Other (asthenopia); Eye disorders - Other (eye/retinal 
hemorrhage); Eye pain; Floaters; Glaucoma 
GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Dyspepsia; Dysphagia; 
Esophagitis; Flatulence; Gastrointestinal disorders - Other (pneumatosis intestinalis); Oral pain; 
Pancreatitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Malaise; 
Pain 
INFECTIONS AND INFESTATIONS - Infection7 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Cholesterol high; GGT increased; Investigations - Other (blood TSH increased) 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hypermagnesemia; Hypertriglyceridemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Chest wall pain; Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder -  Other (muscle spasms); Neck pain; Pain in 
extremity 
NERVOUS SYSTEM DISORDERS - Extrapyramidal disorder; Intracranial hemorrhage; Ischemia 
cerebrovascular; Paresthesia; Peripheral sensory neuropathy; Stroke; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Confusion; Depression; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Hematuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pharyngolaryngeal pain; Pleuritic pain; 
Pneumonitis; Pneumothorax; Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus; Skin ulceration 
VASCULAR DISORDERS - Flushing; Hot flashes 
Note: Pazopanib (GW786034) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.2 
Adverse Event Characteristics  
 
CTCAE term (AE description) and grade:  CTCAE term (AE description) 
and grade:  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will 
be utilized until September 30, 2010 for AE reporting.  CTCAE v4.0 will be 
utilized for expedited adverse event reporting only, beginning October 1, 
2010.All appropriate treatment areas should have access to a copy of the 


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43 
 
 
 
 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site (http://ctep.cancer.gov). 
 
“Expectedness”:  AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) 
are bold and italicized in the CAEPR (Section 7.1.1). 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.31 
Expedited AE reporting for this study must use AdEERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page 
(http://ctep.cancer.gov).  The reporting procedures to be followed are 
presented in the “CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements” which can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the 
table below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, an AE report may 
be submitted using CTEP's Adverse Event Expedited Report-Single 
Agent.  A 24-hour notification is to be made to CTEP by telephone at 301-
897-7497, only when Internet connectivity is disrupted.  Once Internet 
connectivity is restored, an AE report must be entered electronically into 
AdEERS by the original submitter at the site. 
 
Effective with Addendum 12, and beginning October 1, 2010, expedited 
AdEERS reporting for this protocol has been updated by the NCI/CTEP to 
use CTCAE v4.0.  Therefore; 
 
1) Events requiring expedited reporting through AdEERS must be 
reported through the AdEERS system in CTCAE v4.0.  
 
2) The events reported via AdEERS must ALSO be reported through 
routine reporting (i.e., Case Report Forms) using CTCAE v3.0.   
 
3) Routine data collection via Case Report Forms, including the 
"Notification Form: Grade 4 or 5 Non-AER Reportable 
Events/Hospitalization Form", will remain using CTCAE v3.0 for this 
study. 
 


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7.32 
AdEERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  AdEERS provides a copy feature 
for other e-mail recipients.  
 
7.33 
Expedited Reporting Guidelines – AdEERS Reporting Requirements for 
Adverse Events that occur within 30 Days1 of the Last Dose of the Investigational 
Agent on Phase 2 and 3 Trials 
 
Phase 2 and 3 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
AdEERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report is 
required as outlined in the table. 
December 15, 2004 
Note:  All deaths on study require both routine and expedited reporting regardless 
of causality.  Attribution to treatment or other cause must be provided. 
 
Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
AdEERS within 24 hours of learning of the event followed by a complete AdEERS 
report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete AdEERS report on the AE must be submitted within 
10 calendar days of the investigator learning of the event.  
 
Any medical event equivalent to CTCAE v4.0 grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported regardless of 
attribution and designation as expected or unexpected with the exception of any events 
identified as protocol-specific expedited adverse event reporting exclusions.   
 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via AdEERS if the event occurs following 
treatment with an agent under a CTEP IND. 
 
SECONDARY MALIGNANCIES (defined as “cancer caused by treatment for previous 
malignancy,” e.g., treatment with radiation or chemotherapy) are to be reported through 
Addenda 12, 13 


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AdEERS, as noted in Section 10.22.  Secondary malignancies are not considered 
metastasis of the initial neoplasm.  Secondary malignancy is unrelated to the first cancer 
that was treated, and may occur months or even years after initial treatment. 
 
Note:  Second Primary malignancy (malignancy not due prior to treatment) should not be 
reported through AdEERS. 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
7.34 
Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per Common Terminology 
Criteria for Adverse Events (CTCAE) v3.0 grading unless otherwise stated in the 
table below: 
 
Category  
(CTCAE v3.0) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Cardiac General 
Hypertension 
X 
X 
Constitutional 
Symptoms 
Fatigue (lethargy, malaise, asthenia) 
X 
X 
Dermatology/ 
Skin  
Hypopigmentation (Hair and or skin 
pigmentation change) 
X 
X 
Neurology 
Mood alteration – select 
- Agitation 
- Anxiety 
- Depression 
- Euphoria 
X 
X 
Neuropathy, sensory 
X 
X 
Gastrointestinal 
Anorexia 
X 
X 
(# of stools per day) 
X 
 
Diarrhea 
 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Blood/Bone Marrow 
Hemoglobin 
X 
X 
Leukocytes (total WBC) 
X 
X 
Platelets 
X 
X 
Neutrophils/granulocytes 
(ANC/AGC) 
X 
X 
Hemorrhage/ 
Bleeding  
Hemorrhage, GI (select) 
Abdomen NOS 
 
X 
Lower GI NOS 
 
X 
Oral Cavity 
 
X 
Upper GI NOS 
 
X 
Metabolic/ 
Laboratory 
AST, SGOT (serum glutamic 
oxaloacetic transaminase) 
X 
 
X 
 


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Proteinuria 
X 
X 
 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine (CDUS) study data submissions.  
AEs reported through AdEERS must also be reported in routine study data 
submissions. 
 
7.41  Submit to the P2C Research Base via the Nadir/AE Log the following AEs 
experienced by a patient and not specified in Section 7.34: 
 
7.411  Grade 2 AEs deemed possibly, probably, or definitely related to 
the study treatment or procedure. 
 
7.412  Grade 3 and 4 AEs regardless of attribution to the study treatment 
or procedure. 
 
7.413  Grade 5 AEs (Deaths) 
 
7.4131 Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
7.4132 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly treatment 
related must also be submitted as a Grade 5 AE, with a CTCAE 
type and attribution assigned. 
 
7.42  Refer to the instructions in the Forms Packet (or electronic data entry 
screens, as applicable) regarding the submission of late occurring AEs 
following completion of the Active Monitoring Phase (i.e., compliance 
with Study Calendar in Section 10.0). 
 
7.5 
Secondary AML/MDS 
 
Beginning October 1, 2010, AdEERS will only accept CTCAE v4.0 for this 
study:  Report these events using “Neoplasms benign, malignant and unspecified 
(incl. cysts and polyps) – Other (Specify, _____).” 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1.   
 
8.1 
GW786034 (NSC 737754)   
 


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Other Names: Pazopanib HCl, GW786034B (the suffix B denotes the monohydrochloride 
salt). 
 
Classification: VEGFR tyrosine kinase inhibitor 
 
Mechanism of Action: GW786034 is a highly potent inhibitor of vascular endothelial 
growth factor (VEGF) receptor tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3). 
Vascular endothelial growth factor receptor inhibition may block VEGF driven angiogenesis 
and, as a consequence, constrain tumor growth.  
 
Molecular Formula: C21H23N7O2S-HCl 
 
M.W.: 474.0 (monohydrate  salt) 437.5 (free base) 
 
Chemical Name: 5-[[4-[(2, 3-Dimethyl-2H-indazol-6-yl) methylamino]-2 pyrimidinyl] 
amino]-2-methylbenzenesulfonamide monohydrochloride 
 
Approximate Solubility: The monohydrochloride salt is very slightly soluble in 0.1 M HCl 
(0.65 mg/mL), and is practically insoluble in pH 7.0 phosphate buffer (0.00005 mg/mL), 
and in pH 11 piperidine buffer  (0.0002 mg/mL).  
 
How Supplied:  
 
Novartis supplies and the PMB, DCTD, NCI distributes commercially-labeled 200 mg 
pazopanib tablets (as free base). Gray, film-coated tablets are debossed with “GS JT” on one 
side and packaged in bottles of 120 tablets.   
 
Tablet excipients include microcrystalline cellulose, povidone, sodium starch glycolate, and 
magnesium stearate. The film-coat consists of titanium dioxide, hypromellose, iron oxide 
black, macrogol/polyethylene glycol 400 and polysorbate 80.  
 
 
Storage: The intact bottles should be stored at controlled room temperature [20°C - 25°C 
(68°F - 77°F)].  Excursions are permitted between 15°C and 30°C.  
 
Stability: Refer to package label for expiration date of commercially-labeled supplies.   
Repackaging is not allowed and tablets must be dispensed in the original container.  If 
exact quantity must be dispensed, then extra tablets should be removed, documented as 
waste and destroyed immediately. 
 
Route of Administration: Oral.  GW786034 should be taken on an empty stomach either 1 
hour before or 2 hours after meals.  The tablets should be swallowed whole and cannot be 
crushed or broken. 
 
Potential Drug Interactions: 
 
 
In vitro data indicate that GW786034 is an inhibitor for CYP2C9, CYP1A2, CYP2B6, 


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CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.  In animal studies, there were 
no GW786034-related effects on the activities of CYP1A, CYP2B, CYP2E, CYP3A, 
and CYP4A. 
 
In vitro, the most potent inhibition was seen for the isoenzyme CYP2C9.  Accordingly, 
the following medications which are substrates for CYP2C9 are PROHIBITED in 
subjects receiving GW786034 (the washout period is at the discretion of the clinician 
based on the pharmacokinetic properties of each individual agent): 
 
• Anticoagulants:  warfarin (therapeutic doses only) 
• Oral hypoglycemics:  glipizide, glyburide, tolbutamide, glimepiride, nateglinide 
• Ergot derivatives:  dihydroergotamine, ergonovine, ergotamine, 
methylergonovine 
• Neuroleptic:  pimozide 
• Erectile dysfunction agents:  sildenafil, tadalafil, vardenafil 
• Antiarrhythmics:  bepridil, flecainide, lidocaine, mexilitine, amiodarone, 
quinidine, propafenone 
• Immune modulators:  cyclosporine, tacrolimus, sirolimus 
• Miscellaneous:  theophylline, quetiapine, risperidone, tacrine, cloazapine, 
atomoxetine 
 
Certain medications should be used with CAUTION due to the potential for alterations 
in the pharmacologic effects or increased adverse events secondary to the inhibition of 
multiple CYP enzymes by GW786034.  These medications include (but are not limited 
to): 
 
• Antidepressants: amitriptyline, buproprion, fluoxetine, fluvoxamine, imipramine 
• HMG co-reductase inhibitors:  atorvastatin, fluvastatin, lovastatin, simvastatin 
• Benzodiazepines:  alprazolam, midazolam, triazolam, clorazepate, diazepam, 
flurazepam 
• Calcium channel blockers:  diltiazem, felodipine, nifedipine, nicardipine, 
nimodipine, nitrendipine, verapamil, amlodipine, nisoldipine, isradipine 
• Angiotensin II blockers:  losartan, irbesartan 
• Beta blockers:  carvedilol, metoprolol, propanolol, timolol 
• Anticonvulsants:  phenobarbital, phenytoin, primadone, carbamazepine 
• Miscellaneous:  codeine, methadone, mifepristone, estrogens and progestins 
(including oral contraceptives) 
• Oral hypoglycemics: pioglitazone, rosiglitazone 
 
In vitro data also suggest that GW786034 is a substrate for CYP3A4.  Therefore, 
substances that induce or inhibit CYP3A4 may alter the pharmacologic effects of 
GW786034 and should be used with CAUTION.  These medications include (but are 
not limited to):   
 
Inhibitors of CYP3A4: 


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• Antibiotics:  clarithromycin, erythromycin, troleandomycin 
• HIV:  anti-retrovirals (delaviridine),  protease inhibitors (ritonavir, indinavir, 
saquinavir, nelfinavir, amprenavir, lopinavir) 
• Antifungals:  itraconazole, ketoconazole, voriconazole, fluconazole 
• Antidepressants:  nefazodone, fluvoxaine 
• Calcium channel blockers:  verapamil, diltiazem 
• GI:  cimetidine, aprepitant 
 
Miscellaneous:  grapefruit or its juice 
 
Inducers of CYP3A4: 
•  Glucocorticoids:  cortisone (> 50 mg), hydrocortisone (> 40 mg), prednisone (> 
10 mg),, methylprednisolone (> 8 mg), dexamethasone (> 1.5 
mg)Anticonvulsants:  phenytoin, carbamazepine, Phenobarbital, oxcarbazepine 
• HIV:  efavirenz, nevirapine 
• Antibiotics:  rifampin, rifabutin, rifapentine 
• Miscellaneous:  St. John’s wort, modafinil 
 
 
Availability: Pazopanib is supplied by Novartis Pharmaceuticals and distributed  by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Agent Ordering: NCI-supplied agents may be requested by the Principal Investigator (or 
their authorized designees) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that the agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time. Refer to the PMB’s 
website for specific policies and guidelines related to agent management. 
 
Agent Accountability: The Investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing  and final 


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disposition of all agents received from the PMB using the NCI Investigational Agent 
(Drug) Accountability Record Form (DARF) available on the CTEP forms page.  Store 
and maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol. 
   
Investigator Brochure Availability: The current versions of the IBs for the agents 
will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password. Questions 
about IB access may be directed to the PMB IB coordinator via email. 
 
Useful Links and Contacts: 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• PMB Online Agent Order Processing (OAOP) application: 
https://eappsctep.nci.nih.gov/OAOP/pages/login.jspx 
• CTEP Identity and Access Management (IAM) account: 
https://eappsctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help: 
ctepreghelp@ctep.nci.nih.gov 
• PMB email: PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• IB Coordinator: IBCoordinator@mail.nih.gov 
 
 
Nursing Guidelines 
 
• Due to the early investigation nature of this drug, not all adverse effects can be 
known at this time.  Monitor patients closely and report side effects to the MD. 
 
• Hypertension is the most commonly reported side effect. Monitor blood pressure 
closely per study guidelines.  Administer antihypertensives as ordered by MD. 
 
• Nausea and vomiting were also frequently reported in early studies.  Administer 
antiemetics as ordered and assess for the effectiveness. 
 
• Diarrhea was seen in all phase I dosing groups.  Assess hydration status, and 
administer antidiarrheals as ordered. Instruct patient to report an increase in the 
number of stools or nocturnal diarrhea to the study team. 
 


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• Due to the similarity in nature of this agent to other VEGF inhibitors 
(bevacizumab, VEGF-trap, etc.) monitor for signs of thrombosis and PE.  Instruct 
patient to report any calf tenderness, shortness of breath or chest pain 
immediately. 
 
 
9. 
CORRELATIVE/SPECIAL STUDIES  
(Mandatory unless otherwise noted) 
 
Only applicable to sites within the United States 
 
9.1 
Hypothesis 1 
 GW786034 treatment of patients with thyroid cancers will lead to reductions in 
patient blood tumor markers (e.g. thyroglobulin, calcitonin, CEA).  Rates of 
change of relevant blood tumor markers (thyroglobulin, calcitonin, CEA) of 
patients will be evaluated pre- and on-study to determine whether GW786034 
therapy may lead to either reductions, or stabilizations, of these markers.  This 
will be critical, because substantial data suggest that VEGF-targeted agents will 
likely lead more to disease stabilization than regression.  Relevant markers will be 
assessed as proscribed in the Section 10. 
 
9.2 
Hypothesis 2:   
GW786034 will affect decreased levels of angiogenic markers (over time and in 
response to treatment), consequently impacting downstream targets of the 
pathway.  Levels of free VEGF, free GW786034, and GW786034/VEGF will be 
explored in a graphical manner in pre and post-treatment samples. Results of 
these assays, in addition to effects on circulating VEGF, PDGF and other 
angiogenic marker levels, will be used to identify markers of response in 
responders versus non-responders.  Times of collection of samples for 
VEGF/PDGF/angiogenic markers assessment are indicated in Section 10.  
Weekly assessment of VEGF/PDGF/ angiogenic markers will be accomplished 
cycle 1 only to capture non-sustained/transient induced changes. 
 
9.3 
Sample Instructions for Hypothesis 1 & 2: 
 
PLASMA PK SPECIMENS 
 
Blood should be drawn at the following timepoints: 
• Pretherapy 
• Cycle 1, Week 1 
• Cycle 1, Week 2 
• Cycle 1, Week 3 
• Cycle 1, Week 4 
• Retreatment Week 4 
• Retreatment Week 8 
• Retreatment Week 12 
• Retreatment Week 16 


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• End of treatment 
------------------------------------------------------------------------------------------------------ 
COLLECT:          (Lavender)EDTA 3.0 mL 
 
COAGULATE:  MIN. 30'/MAX. 60' 
 
PREPARE: 
CENTRIFUGE AT 4°C MIN. 10' MAX. 15'AT 3000 RPM 
(approx. 1,000 x g) 
 
 
 
TRANSFER WITH A PIPETTE 
 
RETURN: 
 
PLASMA (1.8 NuncCryovial) 
 
 
1.0 mL 
 
 
PK STORAGE 
 
Do not fill tube completely as liquid will expand when frozen. 
 
STORE IN AN UPRIGHT POSITION AT –20°C ON SITE AND SEND ON 
DRY ICE ON THE DAY OF COLLECTION. 
 
Kit ordering:  Participating site Principal Investigators will be sent starter kits 
(after confirmation of local IRB approval) directly from Quest Diagnostics with 
complete instructions on how to order future kits (the protocol identification for 
Quest is listed under: (Dr. Keith Bible-NCI-7627).  Please use the patient 
number with the “PH” removed when identifying the patient study number.   
 
Shipping information:  Quest Diagnostics Clinical Trials, Attn: Specimen Processing 
for NCI Protocol #7627, 7600 Tyrone Avenue, Van Nuys, CA 91405 


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10. 
STUDY CALENDAR   
This schedule is based on currently available information regarding the study regimen and specifies the 
minimum procedures, exams, testing, etc., necessary to determine eligibility (baseline) and to evaluate 
safety and plan dose adjustments at subsequent cycles.  The frequency of procedures may be increased or 
additional procedures performed as clinically indicated at physician discretion. 
 
 
 
 
 
 
Tests and procedures 
7 days prior to 
registration 
Prior to 
subsequent cycles 
 End of Treatment  
History10 and exam, wt, PS or Karnofsky score, concomitant 
medications11 
X 
X 
X 
Blood Pressure 
X 
X6 
 
BP and Medication Diaries 
 
X6 
 
Height 
X 
 
 
Hematology group 
WBC, ANC, Hgb, PLT 
X 
X3 
X 
Chemistry group (fasting) 12: glucose, total and direct 
bilirubin, creatinine, alkaline phosphatase, AST (SGOT), 
ALT (SGPT), Na, K, Ca, Mg, phosphorus,  cholesterol, 
triglycerides, lactate, TSH 
X 
X 
X 
Tumor Markers (e.g. thyroglobulin, calcitonin, CEA), TSH; 
as appropriate for involved cancer7 
X 
X 
X 
INR 
X 
 
 
VEGF, PDGF, Angiogenic Markers 5, R  
X9 
X4 
X 
Tumor Measurement/ 
Evaluation of indicator lesion (CT, MRI, etc.)2,8,  
X 
X2 
 
ECG 
X 
X13 
 
Urinalysis 
X 
X 
 
Serum pregnancy test1 
X 
 
 
1. 
For women of childbearing potential only. 
2. 
Baseline assessment may be 21 days prior to registration.  Use the same method throughout the study.  Followup 
scans to be performed every other cycle (8 weeks) for differentiated and medullary cancers, but every cycle (4 
weeks) for anaplastic thyroid cancer.  If tumor measurement made by physical examination, must document prior 
to each cycle.  Repeat measurements are required 4 weeks following a PR or CR to document sustained response. 
See Section 11.0 for full RECIST criteria. 
3. 
To be performed weekly (+/- 1 day).  Weekly CBC's are optional (physician discretion) after cycle 2. 
4. 
To be performed weekly (+/- 1 day), cycle 1 weeks 1-4, retreatment weeks 4, 8, 12, 16 and End of Treatment. 
5. 
To be assayed off-site by GlaxoSmithKline.  
6. 
Twice daily blood pressure monitoring beginning Day 8 until off treatment (See Section 5.12 & Appendix E-1).  
Home Blood Pressure monitors can be obtained free of charge from GlaxoSmithKline (See Section 17.1). 
7. 
Papillary, follicular, Hurthle cell: TSH, anti-thyroglobulin antibody and thyroglobulin should be tested, with l-
thyroxin dosage adjusted to maintain TSH< 0.1 mIU/L; medullary: CEA and calcitonin should be tested; 
anaplastic: no specific tumor marker testing required. 
8. 
Baseline imaging of brain metastases, if known, should be accomplished ≤14 days prior to registration using MRI 
with gadolinium enhancement (see Section 3.29b). 
9. 
Plasma PK samples can be drawn after registration but prior to Day 1 therapy.   
10. To be performed ≤28 days prior to study drug administration, patient history of heart disease, prolonged QTc, 
family history of prolonged QTc and medications associated with prolonged QTc (Appendix I) must be obtain 
11 Any concomitant medications that are associated with a risk of QTc prolongation and/or Torsades de Pointes 
should be discontinued or replaced with drugs that do not carry these risks, if possible.  Patients who must take 
medications with a risk or possible risk of Torsades de Pointes should be watched carefully for symptoms of QTc 
prolongation, such as syncope.  Performing additional EKGs on patients who must take one or more of these 
medications is not required; however, additional investigations, including EKGs, may be performed as per the 
treating physician’s judgment. 
12.  If, according to CTCAE version 4 criteria, the potassium level is grade 2 or greater and/or if the calcium, 
magnesium and/or phosphorous are grade 3 or higher, an EKG must be performed and appropriate action taken.  
(see section 16.5) and footnote 14 for EKG monitoring 
13. Repeat EKG must be performed during the week 4, cycle 1 visit.  If the QTc interval at 4 weeks is > 500 msec, the 
EKG should be repeated within 7 days and, if the QTc interval remains ≥500 msec, the patient should be removed 
from the study.  Additionally, if the QTc interval is increased by 60 msec or more from baseline but the QTc 


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interval remains at < 500 msec, an EKG should be repeated within 7 days.  If the repeat EKG again shows a ≥ 60 
msec increase in the QTc interval from baseline, consideration should be given to removing the patient from the 
study or increasing monitoring, after discussion with the principal investigator. 
R. 
Research funded.  
 
11. 
MEASUREMENT OF EFFECT    
 
11.1 
Schedule of Evaluations  
For the purposes of this study, patients should be reevaluated by tumor 
measurement (i.e. scan) every 2 cycles (Differentiated, Medullary), versus every 
cycle (Anaplastic) (see Section 10.0 for more details).  
 
11.2 
Treatment evaluation for patients (MTC or DTC) with measurable disease using 
RECIST1 Criteria 
 
11.21 Definitions of Measurable and Non-Measurable Disease 
 
11.211 Measurable disease is defined as at least one lesion whose 
longest diameter can be accurately measured as 2.0 cm with 
conventional techniques or as 1.0 cm with spiral CT.  Clinical 
lesions will only be considered measurable when they are 
superficial (e.g., skin nodules, palpable lymph nodes).  Lesions 
on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, 
CT is preferable. 
 
11.212 All other lesions (or sites of disease), including small lesions 
(longest diameter <2.0 cm with conventional techniques or as 
1.0 cm with spiral CT) are considered non-measurable disease.  
Bone lesions leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (not followed by CR or MRI), and 
cystic lesions are all non-measurable. 
 
11.22 Guidelines for Evaluation of Measurable Disease 
 
11.221 Measurement Methods:  All measurements should be recorded in 
metric notation (i.e., decimal fractions of centimeters) using a 
ruler or calipers.  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.  For patients 
having only lesions measuring at least 1 cm to less than 2 cm 
must use spiral CT imaging for both pre- and post-treatment 
tumor assessments.  Imaging-based evaluation is preferred to 
evaluation by clinical examination when both methods have been 
used at the same evaluation to assess the antitumor effect of a 
treatment.  


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11.222 Acceptable imaging modalities for measurable disease: CT scan 
(conventional and spiral), MRI, chest x-ray.   
 
• Conventional CT and MRI should be performed with cuts of 
1.0 cm or less in slice thickness contiguously. 
 
• Spiral CT must be performed using a 5 mm contiguous 
reconstruction algorithm.  This specification applies to 
tumors of the chest, abdomen, and pelvis, while head and 
neck tumors and those of the extremities require specific 
procedures.   
 
• Ultrasound (US): is not acceptable to measure tumor lesions 
that are clinically not easily accessible. 
 
• Color Photography: In the case of skin lesions, 
documentation by color photography including a ruler to 
estimate the size of the lesion is recommended. 
 
11.223 Measurement at Follow-up Evaluation:   
 
• A subsequent scan must be obtained 4 weeks following 
initial documentation of an objective status of either 
complete response (CR) or partial response (PR). 
 
• In the case of stable disease (SD), follow-up measurements 
must have met the SD criteria at least once after study entry 
at a minimum interval of 6 weeks (see Section 11.44). 
 
• The cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the 
treatment) and progressive disease. 
 
• Cytologic and histologic techniques can be used to 
differentiate between PR and CR in rare cases (e.g., residual 
lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain.) 
 
11.3 
Measurement of Effect 
 
11.31 Target Lesions 
 


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All measurable lesions (as defined in Section 11.311) up to a maximum of 
10 lesions representative of all involved organs should be identified as 
target lesions and recorded and measured at baseline.  If the protocol 
specified studies are performed, and there are fewer than 10 lesions 
identified (as there often will be), there is no reason to perform additional 
studies beyond those specified in the protocol to discover new lesions.  For 
any one organ, no more than 5 lesions need to be measured. Target lesions 
should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repetitive measurements (either 
by imaging techniques or clinically). 
 
A sum of the longest diameter (LD) for all target lesions will be calculated 
and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference to further characterize the objective tumor response of the 
measurable dimension of the disease. 
 
11.32 Non-Target Lesions 
 
All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not 
required, and these lesions should be followed in accord with 11.33. 
 
11.33 Response Criteria 
 
All identified sites of disease must be followed on re-evaluation.  
Specifically, a change in objective status to either a PR or CR cannot be 
done without rechecking all identified sites (i.e., target and non-target 
lesions) of pre-existing disease. 
 
Evaluation of Target Lesions 
 
• 
Complete Response (CR): Disappearance of all target lesions. 
 
• 
Partial Response (PR): At least a 30% decrease in the sum of the 
LD of target lesions taking as reference the baseline sum LD. 
 
• 
Progression (PD): At least a 20% increase in the sum of LD of 
target lesions taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more new 
lesions. 
 
• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD taking as references the 
smallest sum LD. 
 
Evaluation of Non-Target Lesions 


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• 
Complete Response (CR): Disappearance of all non-target lesions. 
 
• 
Stable Disease (SD): Persistence of one or more non-target lesions. 
 
• 
Progression (PD): Appearance of one or more new lesions.  
Unequivocal progression of existing non-target lesions. 
 
NOTE:  Although a clear progression of “non-target” lesions only is 
exceptional, in such circumstances, the opinion of the treating physician 
will prevail, and the progression status will be confirmed at a later time 
by the study chair or a review panel. 
 
11.34 Overall objective status 
 
The overall objective status for an evaluation is determined by combining 
the patient’s status on target lesions, non-target lesions, and new disease 
as defined in the following table. 
 
Target 
Lesions 
Non-Target 
Lesions 
New  
Lesions 
Overall 
Objective Status 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
11.35 
Residual Disease: 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. 
 
11.36 
Symptomatic Deterioration:  Patients with global deterioration of health 
status requiring discontinuation of treatment without objective evidence 
of disease progression at that time, and not either related to study 
treatment or other medical conditions, should be reported as PD due to 
“symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment due to 
symptomatic deterioration: 
• Weight loss >10% of body weight 
• Worsening of tumor-related symptoms 
• Decline in performance status of >1 level on ECOG scale or > 
20% on the Karnofsky scale 


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11.4 
Formal Statistical Definitions of Analysis Variables  
Formal statistical definition of analysis variables involving response and disease 
progression are contained in Section 13.0. 
 
12. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.11 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) 
version 3.0.  Cumulative CDUS data will be submitted quarterly to CTEP 
by electronic means.  Reports are due January 31, April 30, July 31, and 
October 31.  Instructions for submitting data using the CDUS can be 
found on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
12.12 Responsibility for Submissions 
 
Study participants are responsible for submitting CDUS data and/or data 
forms to the Coordinating Center quarterly to allow time for Coordinating 
Center compilation, Principal Investigator review, and timely submission 
to CTEP (see Section 12.11.).  For trials monitored by CTMS, the monthly 
data submission to CTEP from Theradex should be copied to the 
Coordinating Center. 
 
The Coordinating Center is responsible for compiling and submitting 
CDUS data to CTEP for all participants and for providing the data to the 
Principal Investigator for review.   
 
12.2 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP 
Multicenter Guidelines.  The specific responsibilities of the Principal Investigator 
and the Coordinating Center (Study Coordinator) and the procedures for auditing 
are presented in Appendix H. 
 
• The Principal Investigator/Coordinating Center is responsible for 
distributing all IND Action Letters or Safety Reports received from CTEP 
to all participating institutions for submission to their individual IRBs for 
action as required. 
 


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• Except in very unusual circumstances, each participating institution will 
order DCTD-supplied agents directly from CTEP.  Agents may be ordered 
by a participating site only after the initial IRB approval for the site has 
been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
12.3 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
 
The agent(s), supplied by CTEP, DCTD, NCI, used in this protocol is/are 
provided to the NCI under a Collaborative Agreement (CRADA, CTA) between 
the Pharmaceutical Company(ies) [hereinafter referred to as Collaborator(s)] and 
the NCI Division of Cancer Treatment and Diagnosis.  Therefore, the following 
obligations/guidelines, in addition to the provisions in the Intellectual Property 
Option to Collaborator@ (http://ctep.cancer.gov/industry) contained within the 
terms of award, apply to the use of Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this 
protocol, nor can Agent(s) be transferred or licensed to any party not 
participating in the clinical study.  Collaborator(s) data for Agent(s) are 
confidential and proprietary to Collaborator(s) and shall be maintained as 
such by the investigators.  The protocol documents for studies utilizing 
investigational agents contain confidential information and should not be 
shared or distributed without the permission of the NCI.  If a copy of this 
protocol is requested by a patient participating on the study or patient’s 
family member, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in 
combination with (an)other investigational Agent(s), each the subject of 
different collaborative agreements, the access to and use of data by each 
Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”.): 
 
a. NCI must provide all Collaborators with prior written notice 
regarding the existence and nature of any agreements governing 
their collaboration with NIH, the design of the proposed 
combination protocol, and the existence of any obligations that 
would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data 
from the clinical trial by any other Collaborator solely to the extent 
necessary to allow said other Collaborator to develop, obtain 
regulatory approval, or commercialize its own investigational 
agent. 


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c. Any Collaborator having the right to use the Multi-Party Data from 
these trials must agree in writing prior to the commencement of the 
trials that it will use the Multi-Party Data solely for development, 
regulatory approval, and commercialization of its own 
investigational agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a 
collaborative agreement will be made available exclusively to 
Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order.  Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for 
the protection of human subjects, including, if applicable, the Standards 
for Privacy of Individually Identifiable Health Information set forth in 45 
C.F.R. Part 164.   
 
4. When a Collaborator wishes to initiate a data request, the request should 
first be sent to the NCI, who will then notify the appropriate investigators 
(Group Chair for Cooperative Group studies, or PI for other studies) of 
Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for phase 3 studies must be in 
accordance with the guidelines and policies of the responsible Data 
Monitoring Committee (DMC), if there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be 
provided to CTEP for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) 
will have 30 days from the date of receipt for review.  Collaborator shall 
have the right to request that publication be delayed for up to an additional 
30 days in order to ensure that Collaborator’s confidential and proprietary 
data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding 
to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP 
prior to release.  Copies of any manuscript, abstract, and/or press release/ 
media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
 
 
 
 
6130 Executive Boulevard, Suite 7111 
Rockville, MD  20892 
 
 
 
FAX 301-402-1584 
 
 
 
E-mail: anshers@ctep.nci.nih.gov 


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The Regulatory Affairs Branch will then distribute them to 
Collaborator(s).  No publication, manuscript or other form of public 
disclosure shall contain any of Collaborator’s confidential/proprietary 
information. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
 
13.1 
Study Design/Endpoints 
 
13.11   Study Overview: The primary goal of this phase-II study is to evaluate the 
efficacy and biological effects of GW786034 treatment in patients with 
thyroid cancer.  Evaluating this treatment regimen in patients with 
differentiated thyroid carcinoma (DTC) is of primary interest; however, as 
noted above, we are also interested in evaluating this treatment in 
medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma 
(ATC). Therefore, we propose to assess clinical and biologic responses as 
well as tolerability of GW786034 treatment simultaneously and 
independently in each of these three patient cohorts.  Specifically, a one-
stage phase-II study design with an interim analysis based on the 
proportion of patients who have a clinical response (based on RECIST 
criteria) will be applied to the DTC, ATC, and MTC group to assess 
efficacy.  This study will also assess toxicity, the proportion of patients 
who have not failed treatment by 6 months (3 months for ATC patients), 
survival, time to progression, and several biochemical and genetic 
correlates in each of the groups.   
 
An expanded/additional cohort of 75 patients with confirmed 
differentiated thyroid cancer who are thyroglobulin antibody negative will 
be added to the original cohort of DTC patients enrolled on trial in order to 
prospectively examine a potential/hypothesized correlation between 
induced changes in thyroglobulin levels and patient response.  Rationale: 
Anecdotal experience of investigators enrolling patients on the initial 
cohort of differentiated thyroid cancer patients on MC057H suggested that 
induced changes in thyroglobulin seen in thyroglobulin antibody negative 
patients might be predictive of patient response.  Formal retrospective 
analysis undertaken in response indeed demonstrated that the proportion 
of patients with at least a 50% decrease in Tg values from pre-treatment 
levels was 0.50 among the 12 patients with stable or progressive disease 
and 0.80 among the 6 patients with a PR, suggesting that such an 
association may exist.  We therefore now propose to more rigorously and 
prospectively examine this association in an expanded DTC patient cohort.  
This analysis will be important in the design of future pazopanib clinical 
trials in differentiated thyroid cancer, given its apparent promising clinical 
activity in DTC, so as to allow optimal use of tumor markers and imaging 
in the evaluation of further patients receiving the agent. 


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13.12   Primary Endpoint: The primary efficacy endpoint for each of the groups 
evaluated in this trial is the proportion of patients who have achieved an 
objective response to the study agent (RECIST criteria). 
 
13.13   Secondary Endpoints: The secondary efficacy endpoints for each of the 
groups evaluated in this trial is the proportion of patients who have not 
failed treatment at 6 months (3 months for ATC), the proportion of 
patients in which the radioactive iodine scan have changed from “no 
uptake” to “any uptake”, and the proportion of patients achieving a 
biochemical response in appropriate tumor markers. Any patients who 
have progressive disease within 6/3 months of study entry will be 
considered treatment failures and will be included in the denominator of 
the proportion for efficacy analyses.  Note that each of the groups will be 
using radiographic (i.e. RECIST) criteria only to document progression.  
In addition, radioactive iodine scan will be used to determine response to 
GW786034, as will tumor markers. Any patients who discontinue 
treatment due to adverse reactions, refusal, or who go on to receive 
alternate therapy within 6/3 months of study entry will be considered 
treatment failures and will be analyzed in a similar manner.  For this 
measure we will evaluate those patients who are not treatment failures at 
6/3 months; i.e. those patients who are progression-free and have not gone 
off treatment due to adverse reactions, refusal, or have not gone on to 
receive further alternate therapy and those patients in which the 
radioactive iodine scan has changed from “negative” to “any uptake”. 
 
13.2 
Sample Size/Accrual Rate 
  
13.21   Sample Size: The single arm, one stage design with an interim analysis to 
be used for each patient group (i.e. DTC, MTC, and ATC) is fully 
described below.  The efficacy decision rules require 33 evaluable patients 
for each patient group.  To accommodate potential losses due to 
ineligibility, cancellation, or major violations, 3 additional patients will be 
accrued to each group.  Thus, a total of 36 patients will be accrued to each 
group for a maximum of 108 patients overall to this trial, unless undue 
toxicity is encountered or accrual is stopped early based on the results of 
the planned interim analysis.   An interim analysis will be performed in 
each patient group (as described below) after the first 14 eligible patients 
have been accrued to each of the DTC, MTC, and ATC patient groups, 
have begun treatment, and have been observed for at least 6/3 months.  
Accrual will not be suspended prior to the interim analysis.  We recognize 
that additional patients will be accrued by the time of these interim 
analyses; however, given the paucity of treatments available for these 
patients as well as the relatively small overall sample size for each group, 
these analyses can be used for interim reporting of results as appropriate.  
 


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13.22   Accrual Time and Study Duration: Based upon ongoing accrual to the 
currently active Mayo P2C thyroid trial, the anticipated accrual rate for the 
proposed trial is about 1 to 2 patients per month in the cohort of patients 
with differentiated thyroid cancer (Cohort A).  At this accrual rate, it will 
take approximately 9 months to enroll the 14 patients needed for the 
interim analysis for Cohort A.   Overall accrual to Cohort A is expected to 
take 24 months.  Note that these accrual estimates also include the 
anticipated over accrual.  Accrual to Cohorts B (medullary thyroid cancer) 
and C (anaplastic thyroid cancer) are expected to be somewhat slower.  If 
accrual is slower than expected, then the study can be opened to accrual at 
other Phase 2 Consortia. 
 
13.3   Statistical Design to be used for the ATC, DTC, and MTC Patient Groups 
 
13.31  Primary endpoint: This study is designed to also look at the proportion of 
patients who have a clinical response to treatment as defined by the 
RECIST criteria. Few prospective clinical studies have been done in these 
patient populations and little published data exist in these relatively rare 
patient groups for these kinds of trials, especially for the MTC and ATC 
groups.  Given that this study is focusing on (and hence requiring) patients 
who have documented disease progression within the 6 months prior to 
study entry, this translates to a cohort of patients who have more 
aggressive disease.  Therefore, we can assume that only 5% of patients 
will achieve a response if this therapeutic regimen is not effective in this 
patient population. If this single agent therapy of GW786034 is truly 
promising, we would expect that the true response rate would be at least 
20% for each of these patient populations.  In other words, the fact that we 
are requiring patients to have documentation of progressive disease within 
the 6 months prior to study entry (ATC patients excepted), we can assume 
that the same response rates would be of interest for all three thyroid 
carcinoma subtype populations.  
 
13.32   Definition of success: As discussed above, a treatment success in this trial 
will be considered the event that a patient has a clinical response (i.e. a PR 
or CR by the RECIST criteria).  This same definition for success will be 
used for all three patient groups.  
 
13.33   Decision rule: This decision rule will be applied independently and 
individually for each of the patient cohorts. The largest success proportion 
where the proposed treatment regimen would be considered ineffective in 
this patient population is 5%, and the smallest success proportion that 
would warrant subsequent studies with the proposed regimen in this 
patient population is 20%.  The following Three-Outcome Phase II study 
design44 is a modification of the Simon Optimal design and uses a 
maximum of 33 evaluable patients to test the null hypothesis that the true 
success proportion in the patient population is at most 5%. The following 


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decision rule will be used for each patient cohort: 
 
“Not promising”: This regimen will be classified as not promising with 
respect to the success rate in this patient population if at most 1 
success is observed in a total of 33 evaluable patients. 
 
“Inconclusive”:  The results of this study will be classified as 
inconclusive with respect to this regimen demonstrating an improved 
success rate if 2-3 successes are observed in 33 evaluable patients.  In 
this case, the proportion of patients who have not failed treatment at 6 
months (or 3 months for the ATC group), toxicity, and time to 
progression observed in this study will be used in addition to the rate 
of patients who responded to treatment in order to make the final 
determination as to whether or not this treatment is considered 
promising and worthy of further study in this patient population. 
 
“Promising”:  This regimen will be classified as promising with 
respect to increasing the success rate in this patient population if at 
least 4 successes are observed in 33 evaluable patients.  Subsequent 
larger confirmatory studies may be recommended. 
 
13.34   Interim analyses:  
Efficacy: An interim analysis will be performed in each patient group after 
14 evaluable patients have been observed for at least 6 months.  If 
in the interim analysis no patients have responded to treatment, we 
will consider this regimen insufficiently active and accrual may be 
terminated in this group at this point.  It should be noted that unless 
we observe an unexpected toxicity rate or rapid accrual, we will 
not suspend accrual between stages to wait to perform the interim 
analysis.   
 
Toxicity Stopping Rule: The following toxicity stopping rule will be 
applied independently to each of the patient cohorts in this trial. If 
at any time 30 % or more patients in a patient group develop 
grade 4 non-hematologic toxicity (including febrile neutropenia), 
accrual to that patient group will be suspended to allow for 
investigation. After consideration by the study team (study 
chair[s], statistician, P2C Operations Office, etc.) and consultation 
with CTEP and the primary IRB affiliated with the P2C Operations 
Office, a decision will be made as to whether accrual can be 
resumed.  CTCAE v3.0 will be used to determine grading for these 
stopping rules. 
 
13.35   Power and significance level: Assuming that the number of successes is 
binomially distributed, the significance level for this study design is 0.07.  
This decision rule has 90% power to detect an effective treatment given 


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that the true response rate is at least 20% using this treatment.  
 
13.36   Other considerations: Toxicity, incidence and duration of response, and 
other considerations will be taken into account in any decision process at 
each step.  If more than 33 evaluable patients are accrued, only the first 33 
will be used for decision purposes, but the additional patients will be 
included in the analyses described above.  
 
13.37   Statistical Design to be used for the expanded cohort of patients with DTC 
who are thyroglobulin antibody negative:  
13.371    Primary endpoint:  The primary endpoint of this trial is a 
confirmed tumor response defined as a CR or PR (by the 
RECIST criteria) noted as the objective status on 2 consecutive 
evaluations at least 8 weeks apart. 
13.372    Overview: The goal of this extended cohort of differentiated 
thyroid carcinoma (DTC) patients is to examine whether the 
proportion of patients whose tumor size decreases (PR or CR by 
the RECIST criteria) tend in parallel to have greater decreases in 
serum thyroglobulin levels (Tg levels). This analysis will be 
important in the design of future pazopanib clinical trials, so as 
to allow optimal use of tumor markers and imaging in evaluation 
of patients receiving the agent.  Among the patients with DTC 
initially enrolled on MC057H, the proportion of patients with at 
least a 50% decrease in Tg values from pre-treatment levels was 
0.50 among the 12 patients with stable or progressive disease and 
0.80 among the 6 patients with a PR, suggesting that such an 
association may exist. 
 
13.373 Study design:  We expect a 2:1 ratio between the number of 
patients in the stable or progressive disease and the PR groups. A 
one stage clinical trial design will be used to assess whether the 
difference in the proportion of patients with at least a 50% 
decrease in Tg values from pre-treatment levels between patients 
who response to treatment and those who do not differs by at 
least 30%.  With 45 patients in the stable or progressive disease 
group and 23 patients in the PR group, a one-sided two sample 
test of proportions will have a significance level 0.05 and a 80% 
chance of detecting that difference in the proportion of patients 
with at least a 50% decrease in Tg values from pre-treatment 
levels between patients who respond to treatment and those who 
do not is at least 0.30, when the proportion of patients with at 
least a 50% decrease in Tg values from pre-treatment levels 
among patients with stable or progressive disease is 0.50. 
 
To account for ineligibility, cancellation, major treatment 
violation, or other reasons, we will additionally accrue 7 


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additional patients - for a total of 75 required.  We therefore 
propose an extended cohort of 75 additional patients to test our 
hypothesis.  Since a phase II trial has been conducted just prior to 
this extended study, there will be no interim analysis for this 
cohort, but patients will be closely monitored for toxicity, AE, 
etc.  
 
Final analysis decision rule: after full accrual, we will conduct a 
two-sample test for proportions as specified in the design. 
 
13.4 
Analysis Plans 
The following analyses will be performed for each patient group.  All evaluable 
patients in that group will be used. 
 
13.41   Primary Efficacy Endpoint 
Patient evaluability: All patients meeting the eligibility criteria who have 
signed a consent form and begun treatment will be considered evaluable 
for estimation of response to treatment 
 
Success probability: The proportion of successes will be estimated by (a) 
the standard binomial estimator, i.e., the number of successes divided by 
the total number of evaluable patients, and (b) 90% binomial confidence 
intervals. 
 
13.42 Analysis of Secondary Endpoints for all 4 Patient Cohorts 
 
Definitions and Analyses of Secondary Endpoints: 
 
Toxicity: As per NCI CTCAE Version 3.0, the term toxicity is defined as 
adverse events that are classified as either possibly, probably, or definitely 
related to study treatment.  The maximum grade for each type of toxicity 
will be recorded for each patient, and frequency tables will be reviewed to 
determine toxicity patterns.  In addition, we will review all adverse event 
data that is graded as 3, 4, or 5 and classified as either “unrelated or 
unlikely to be related” to study treatment in the event of an actual 
relationship developing. 
 
Proportion of patients who fail treatment at 6 months (3 months for ATC 
patients): The proportion of patients who have not failed treatment due to 
disease progression, adverse reactions, refusal for further participation, or 
who went on to alternate therapy at 6 months (3 months for ATC patients) 
will be calculated and summarized independently within each of the 
patient groups.  Assuming that the incidence of response is binomially 
distributed, 90% binomial confidence intervals will also be calculated.  
 
Times to progression and death:  The overall survival time is defined as 


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the time from registration to date of last follow-up or death due to any 
cause.  Similarly, the time to progression is defined as the time from 
registration to the date of progression or last follow-up, whichever comes 
first.  The distributions of overall survival time and time to progression 
will be estimated using the method of Kaplan-Meier. In addition, the 6-
month progression-free rate will be evaluated using the 6-month rates and 
associated confidence intervals. In addition, competing risk analyses may 
be done to evaluate time to progression, allowing for going on to alternate 
treatment or death prior to progression as competing risks. 
 
Time to treatment failure and time to subsequent therapy: The time to 
treatment failure is defined as the time from registration to the date the 
patient discontinues treatment, and its distribution will be estimated using 
the method of Kaplan-Meier.  In addition, the time to subsequent therapy 
will also be evaluated using a similar approach.  
 
Duration of response: Duration of response will be calculated from the 
date of documentation of response (PR or CR) until the date of 
progression or last follow-up (whichever comes first) in the subset of 
patients with confirmed response. 
 
Biomarker-based response and progression-free survival: Response and 
progression-free rates based on biomarker-based definitions alone will 
also be evaluated in each of these patient groups and summarized 
independently.  Specifically, calcitonin-based progression alone will be 
evaluated for the MTC group and changes in thyroglobulin levels will be 
evaluated for the DTC group.  These rates will be summarized assuming 
they are binomially distributed, and the biomarker levels themselves will 
be explored both quantitatively and graphically before and after treatment. 
 
Correlative assay analyses: Given the limited sample sizes available for 
each of the patient cohorts evaluated in this trial, the following correlative 
endpoint analyses for each of the groups will be done in an exploratory 
manner.  In addition, we will also evaluate differences between groups and 
may analyze these endpoints across all three thyroid carcinoma subtypes.  
In this case, we may also be able to evaluate these relationships 
quantitatively in addition to the summarization and primary graphical 
analyses described below.  
 
Blood markers for angiogenesis including levels of free VEGF, free 
GW786034, and GW786034/VEGF complexes will be evaluated before 
and during therapy.  Changes in these levels will largely be explored in a 
graphical manner as well as exploring any potential relationships between 
these levels and clinical outcome such as response or progression-free rate 
and toxicity incidence.  
 


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13.5 
Monitoring 
The principal investigator and the study statistician will review the study 
periodically to identify accrual, toxicity, and any endpoint problems that might be 
developing. In addition, this study will be monitored according to the Mayo Clinic 
Cancer Center (MCCC) Data Safety Monitoring Plan that is currently in place.  
The MCCC Data Safety Monitoring Board (DSMB) is responsible for reviewing 
safety data for this trial at least twice a year, based on reports provided by the 
MCCC Statistical Office. 
 
13.6 
Data Reporting 
This study will be monitored by the Clinical Data Update System (CDUS) version 
2.0.  The coordinating center will submit cumulative CDUS data quarterly to 
CTEP by electronic means.  Reports are due January 31, April 30, July 31, and 
October 31. 
 
At the time CTCAE v4.0 became available, this study involved collection of 
adverse events using CTCAE v3.0.  The study continues to collect all routine AE 
data using CTCAE v3.0; however, all adverse event data submitted via CDUS must 
use CTCAE v4.0 terminology.  CTEP provided mappings will be used to convert 
v3.0 data to v4.0 prior to submission to CTEP, as agreed upon by NCI and the 
Mayo Clinic Cancer Center. 
 
13.7 
Subset Analyses for Minorities: 
This study will be available to all eligible patients, regardless of sex, race or 
ethnic origin.  The planned analyses will look for difference in treatment effect 
based on racial groupings.  The current percentage of ethnic minorities accrued to 
studies at the P2C sites is approximately 7%.  Therefore, it is not expected that 
more than 5 ethnic minority patients will be accrued to this study.  Since there is 
no evidence currently available that suggests that the effects of therapies studied 
in this trial would be related to gender or ethnic status, the sample sizes are not 
increased in order to provide additional power for subset analyses. 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
2 
2 
0 
4 
Not Hispanic or Latino 
92 
92 
0 
184 
Ethnic Category: Total of all subjects* 
94 
94 
0 
188* 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
1 
1 
0 
2 
Black or African American 
2 
2 
0 
4 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
91 
91 
0 
182 
Racial Category: Total of all subjects* 
94 
94 
0 
188 
*These totals must agree.   Enter actual estimates (not percentages) 
 


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Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, or other 
Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used in addition to 
“Hispanic or Latino.” 
Not Hispanic or Latino 
 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original peoples of North, 
Central, or South America, and who maintains tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, or the 
Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, 
the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have been 
recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial groups of Africa. Terms 
such as “Haitian” or “Negro” can be used in addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original peoples of 
Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or North 
Africa. 
 
14.0 
DESCRIPTIVE FACTORS 
 
14.1    Baseline Calcitonin Levels 
 Baseline Thyroglobulin levels 
 
15.0 
PATHOLOGY CONSIDERATIONS  
 
Histologic or cytologic confirmation of disease will be the responsibility of each center 
independently without central review.  A copy of the pathology reports is to be sent to the 
P2C Coordinating Center ≤2 weeks of study entry (see Section 16.5).  NOTE: At Mayo 
enrollment sites, molecular markers of thyroid cancer will be assessed to complete 
histological/cytological studies. (This is normal standard practice at Mayo Clinic).  
 
16. 
Data SUBMISSION To Coordinating Center 
 
16.1 
Data Collection 
Data will be collected using protocol-specific forms and the P2C web-based 
remote data entry system.  Data is to be submitted ≤ 2 weeks following each 
evaluation of the patient and according to the schedule in Section 16.5.   
After the patient discontinues treatment, follow–up will continue as specified in 
the following section(s): 
 
16.2 
Cancels 
Those patients who cancel participation prior to the start of treatment must 
provide On-study material and the End of Active Treatment/Cancel Notification 
Form must be submitted. No further follow-up is required. 
 
 16.3 Ineligible 
A patient is deemed ineligible if at the time of registration, the patient did not 
satisfy each and every eligibility criteria for study entry.  
 
▪ If the patient received treatment, all data up until the point of confirmation 


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of ineligibility must be submitted.  Event monitoring will be required per 
Section 16.5 of the protocol.  
 
▪ If the patient never received treatment, On-study materials and the End of 
Active Treatment/Cancel Notification Form must be submitted. No further 
follow-up is required. 
 
16.4 
Treatment Discontinuation 
After a patient discontinues treatment, follow-up data will be collected and 
entered via the remote data entry system according to schedule outlined below 
(also see Section 16.5). 
   
▪ If a patient discontinues treatment due to progression within 3 years of 
registration, submission of an event monitoring form is required every 6 
months thereafter until death or a maximum of 3 years post-registration.   
 
▪ If a patient discontinues treatment due reasons other than progression or 
death within 3 years of registration, submission of an event monitoring 
form is required every 3 months until progression then every 6 months 
thereafter until death or a maximum of 3 years post-registration. 
 
▪ If a patient discontinues treatment more than 3 years after registration, 
submission of an event monitoring report is required 6 months after 
treatment discontinuation.  
 
Follow-up data will be collected and entered via the remote data entry system 
according to the schedule in Section 16.5.   
 


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71 
 
 
 
16.5 
Data Entry/Submission Timetable 
 
Forms/Other 
Active-Monitoring Phase 
(Compliance with Test Schedule) 
Event-Monitoring Phase2 
(Completion of Active-Monitoring Phase) 
PD = Progression (see Section 11.0) 
At Each Occurrence 
Initial Material 
Subsequent material 
2 weeks after 
registration 
At each 
evaluation 
At end of 
treatment 
q. 3 
months 
until PD2 
At PD2 
After PD q. 
6 mos.2 
Death 
All Grade 4/5 AEs 
All Hospitalizations During 
Treatment Secondary AML/MDS 
New 
Primary 
Late 
Adverse 
Event 
On-Study Form 
X 
 
 
 
 
 
 
 
 
 
Baseline Adverse Events 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Form 
X 
X 
X 
 
 
 
 
 
 
 
Measurement Form4 
X 
X4 
X4 
 
 
 
 
 
 
 
Pathology Report 
 
Submission1 
X 
 
 
 
 
 
 
 
 
 
Event-Monitoring  
 
Form 
 
 
 
X 
X4 
X 
X 
 
X 
X 
Evaluation/Treatment  
 
Form 
 
X 
X 
 
 
 
 
 
 
 
Nadir/Adverse Event 
 
Form 
 
X 
X 
 
 
 
 
 
 
 
Endocrine Lab Form 
X 
X 
 
 
 
 
 
 
 
 
Specimen Submission Form 
(Blood) 
X 
X6 
 
 
 
 
 
 
 
 
End of Active 
Treatment/Cancel 
Notification Form 
X5 
 
X 
 
 
 
 
 
 
 
AE Reporting per Section 7.0 
 
 
 
 
 
 
 
X3 
X3 
 
CTEP Report 
    Variables Form 
X 
 
 
 
 
 
 
 
 
 
Notification Form, Grade 4/5 
 
 
 
 
 
 
 
X 
 
 
1. 
Submit copy of pathology reports via fax or mail to the P2C Coordinating Center, (Attention: QCS for MC057H), 200 First Street SW, Rochester, MN 55905, Fax: (507) 266-7240. 
2.  
 If a patient discontinues treatment due to progression within 3 years of registration, submission of an event monitoring form is required every 6 months thereafter until death or a maximum 
of 3 years post-registration.  If a patient discontinues treatment due reasons other than progression or death within 3 years of registration, submission of an event monitoring form is required 
every 3 months until progression then every 6 months thereafter until death or a maximum of 3 years post-registration.  If a patient discontinues treatment more than 3 years after 
registration, submission of an event monitoring report is required 6 months after treatment discontinuation. 
3. 
Reminder: Adverse events that necessitate expedited reporting are also to be reported via the routine clinical data (i.e. Nadir/Adverse Event Form, etc.) submitted with each evaluation. 
4. 
Submit copy of documentation of response, recurrence, or progression to the P2C Coordinating Center, Attention: QCS for MC057H, Fax (507) 266-7240. 
5. 
Submit this form only if withdrawal/refusal prior to beginning protocol therapy occurs. 
6. 
To be performed (+/-) 1 day.  Cycles 1 weeks 1-4, retreatment weeks, 4, 8, 12, and 16 and End of Treatment.


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17.   
FUNDING CONSIDERATIONS 
 
 17.1 Costs Charged to Patient  
All routine clinical care.  GW786034 will be provided by the NCI.  The patient or the 
patient’s health plan/insurer will be responsible for charges associated with supplies and 
procedures necessary for administration of the study drug(s), as well as all other drugs or 
treatment given to help control adverse events as well as the cost of tests or exams to 
evaluate possible adverse events.  Blood pressure monitors will be provided free of 
charge and can be obtained by contacting Graham Arnold (garnold@theradex.com), 
telephone 609-799-7580 Ext 3001.   
 
17.2 
Other Budget Concerns  
This study is supported by the Phase 2 Consortium (P2C) through its N01 contract with 
the National Cancer Institute. 
 
17.3 
Manufacturer to Supply Drug 
The manufacturer of GW786034 will accomplish all VEGF and PDGF analyses at the 
site of their specification and at their expense. 
 
 
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Kilicarslan AB, Ogus M, Arici C, Pestereli HE, Cakir M, Karpuzoglu G.  Clinical importance of 
vascular endothelial growth factor (VEGF) for papillary thyroid carcinomas.  APMIS. 2003 
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Kim, T. H., D. S. Yang, et al. (2003). "Value of external irradiation for locally advanced papillary 
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Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in 
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Landriscina M, Fabiano A, Altamura S, Bagala C, Piscazzi A, Cassano A, Spadafora C, Giorgino F, 
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vivo and Restore TSH Signaling and Iodine Uptake in Human Thyroid Anaplastic Carcinoma.  J Clin 
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Leaf, A. N., B. C. Wolf, et al. (2000). "Phase II study of etoposide (VP-16) in patients with thyroid 
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Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence 
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APPENDIX A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 


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APPENDIX B: Drugs Known to be Metabolized by Selected CYP450 Isoenzymes 
 
Selected drugs known to be metabolized by CYP450 isoenzymes 
 
CYP2C8/9 
 
 
SUBSTRATES 
 
INHIBITORS 
 
INDUCERS 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Antibiotics: e.g. 
    Rifampin 
    Sulfadiazine 
 
Rifadin 
-- 
 
Antifungals: e.g. 
    Fluconazole 
    Ketoconazole 
    Miconazole 
    Tioconazole 
 
Diflucan 
Nizoral 
Lotramin  
Monistat 
Sedatives: e.g. 
    Phenobarbiatl 
    Primidone 
 
Luminal 
Mysoline 
Misc. CV agents: e.g. 
    Amiodarone 
    Carvedilol 
 
Cordarone 
Coreg 
Antimalarials: e.g. 
    Pyrimethamine 
    Quinine     
 
Daraprim 
Legatrin 
Anticonvulsants: e.g.  
    Carbamazapine 
    Phenobarbital 
    Phenytoin 
 
Tegretol 
Luminal 
Dilantin 
Anti-asthmatics: e.g. 
    Montelukast 
    Zafirlukast 
 
Singulair 
Accolate 
Anti-hyperlipidemics: e.g. 
     Fluvastatin 
    Gemfibrozil 
 
Lescol 
Lopid 
Antibiotics: e.g. 
    Rifapentine 
    Rifampin 
 
Priftin 
Rifadin 
Antidepressants: e.g. 
    Fluoxetine 
    Sertraline 
 
Prozac 
Zoloft 
Antibiotics: e.g. 
    Isoniazid 
    Sulfadiazine 
    Sulfamethoxazole 
    Trimethoprim 
 
INH, Nydrazid 
-- 
Bactrim, Septra 
Primsol 
 
 
Anticonvulsants: e.g. 
    Fosphenytoin 
    Phenytoin 
 
Cerebyx 
Dilantin 
Analgesics: e.g. 
    Flurbiprofen 
    Ibuprofen 
    Indomethacin 
    Mefenamic acid 
 
Ansaid 
Advil, Motrin 
Indocin 
Ponstel 
 
 
Anesthetics: e.g. 
    Ketamine 
    Propofol 
 
Ketalar 
Diprivan 
Anti-ulceratives: e.g. 
    Omeprazole 
    Pantoprazole 
 
Prilosec 
Pantoloc 
 
 
Anti-diabetics: e.g. 
     Glimepiride 
     Rosiglitazone 
 
Amaryl 
Avandia 
Antihypertensives: e.g. 
    Irbesartan 
    Losartan 
    Nicardipine 
 
Avapro 
Cozaar 
Cardene 
 
 
Antihypertensives: e.g. 
    Losartan 
    Bosentan 
 
Cozaar 
Tracleer 
 
 
 
 
Paclitaxel 
Taxol 
Anti-diabetics: e.g. 
    Pioglitazone 
    Rosiglitazone 
 
Actos 
Avandia 
 
 
Alosetron 
Lotronex 
Amiodarone 
Cordarone 
 
 
Torsemide 
Demadex 
Delavirdine 
Rescriptor 
 
 
 
 
Piroxicam 
Feldene 
 
 
 
 
Warfarin 
Coumadin 
 
 
 
 
Zafirlukast 
Accolate 
 
 
 
When drugs classified as ‘substrates’ are co-administered with (Study Agent), there is the potential for higher concentrations of the ‘substrate’. When  (Study Agent)  is 
co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of  (Study Agent) is the potential outcome. The coadministration of 
‘inducers’ would potentially lower plasma   (Study Agent) concentrations. 
 


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


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Selected Potential Cytochrome P450 (CYP) Drug Interactions 
 
CYP3A4 
 
 
SUBSTRATES 
 
INHIBITORS 
 
INDUCERS 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Anti-neoplastics: e.g. 
    Docetaxel 
    Gefitinib 
    Irinotecan 
 
Taxotere 
Iressa 
Camptosar 
Anti-arrhythmics: e.g. 
    Amiodarone 
    Diltiazem 
    Quinidine 
 
Cordarone, Pacerone 
Cardizem, Dilacor XR 
Cardioquin 
Aminoglutethimide 
Cytadren 
Anti-virals: e.g. 
    Amprenivir 
    Rifampin 
 
Agenerase 
Rifadin 
 
 
Anti-virals: e.g. 
    Amprenavir 
    Indinavir 
    Nelfinavir 
    Ritonavir 
 
Agenerase 
Crixivan 
Viracept 
Norvir 
Antibiotics: e.g. 
    Rifabutin 
    Rifampin 
 
Rifadin 
Mycobutin 
 
 
Anxiolytics: e.g. 
    Diazepam 
    Sertraline 
 
Valium 
Zoloft 
Cimetadine 
Tagamet 
Anticonvulsants: e.g.   
    Carbamazapine 
    Phenytoin 
    Pentobarbital 
    Phenobarbital 
 
Tegretol 
Dilantin 
Nembutal 
Luminal 
Cyclosporine 
Sandimmune 
Cyclosporine 
Sandimmune 
Hypericum perforatum (2) 
St. John’s Wort 
Anti-infectives: e.g. 
    Erythromycin 
    Tetracycline 
 
Erythrocin 
Sumycin 
Antibiotics: e.g. 
    Ciprofloxacin 
    Clarithromycin 
    Doxycycline 
    Enoxacin 
    Isoniazid 
    Telithromycin 
 
Cipro, Ciloxan 
Biaxin 
Adoxa, Periostat 
Penetrex 
Nydrazid, INH 
Ketek 
 
 
Steroids: e.g. 
    Estrogens, conjugated 
    Estradiol 
    Progesterone 
 
Premarin 
Climara 
Crinone 
Imatinib 
Gleevec 
  
 
Haloperidol 
Haldol 
Haloperidol 
Haldol 
 
 
Cardiovascular agents: e.g. 
    Digitoxin 
    Quinidine 
 
Crystodigin 
Cardioquin 
Diclofenac 
Cataflam, Voltaren 
 
 
Anti-hypertensives: e.g. 
    Nicardipine 
    Verapamil 
 
Cardene 
Calan, Chronovera 
Vasodilators: e.g. 
    Nicardipine 
    Verapamil 
 
Cardene 
Calan, Chronovera 
 
 
Anesthetics: e.g. 
    Ketamine 
    Lidocaine 
 
Xylocaine 
Diprivan 
Anesthetics: e.g. 
    Lidocaine 
    Propofol 
 
Xylocaine 
Diprivan 
 
 
Nefazodone 
     
Serzone 
Anti-depressants: e.g. 
    Nefazodone 
    Sertraline 
 
Serzone 
Zoloft 
 
 
Cocaine 
 
Anti-fungals: e.g. 
    Itraconazole 
    Ketoconazole 
   Miconazole 
 
Sporanox 
Nizoral 
Lotrimin, Monistat 
 
 
Ketoconazole 
Nizoral 
Caffeine 
 
 
 
Sildenafil 
Viagra 
Grapefruit juice (1) 
 
 
 
Albuterol 
Ventolin 
 
 
 
 
Carbamazapine 
Tegretol 
 
 
 
 
Lovastatin 
Mevacor 
 
 
 
 
 
When drugs classified as ‘substrates’ are co-administered with (Study Agent), there is the potential for higher concentrations of the ‘substrate’. When  (Study Agent)  
is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of  (Study Agent) is the potential outcome. The coadministration of 
‘inducers’ would potentially lower plasma   (Study Agent) concentrations. 
 
 
 


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Comprehensive List of Drugs That May Have Potential Interactions 
 
CYP3A4 
 
Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazapine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Delavirdine 
Diazepam 
Digitoxin 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fosamprenavir 
Fulvestrant 
Gefitinib 
Halofantrine 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ketamine 
Ketoconazole 
Lansoprazole 
Letrozole 
Levomethadyl acetate 
    hydrochloride 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pioglitazone 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole 
Repaglinide 
Rifabutin 
Rifampin 
Ritonavir 
Saquinavir 
Sertraline 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Terbinafine 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 
 
 
 


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CYP3A4 
 
Inhibitors 
Acetominophen 
Acetazolamide 
Amioderone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffiene 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetadine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Cyclophosphamide 
Cyclosporine 
Danazol 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradapine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan 
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nitrendipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapimil 
Vinblastine 
Vincristine 
Vinorelbine 
Zafirlukast 
Ziprasidone 
 
 
 
Inducers 
Aminoglutethimide 
Carbamazapine 
Fosphenytoin 
St. John’s wort 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 
12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.) 
 
(1)  Malhorta et al. (2000). Clin Pharmacol Ther. 69:14-23 
 
(2)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329 
 
 
 
 
 
 
 
 


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APPENDIX C: New York Heart Association Classification of Cardiac Disease 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 
 
 
 
 


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APPENDIX D: Patient’s Medication Diary 
PATIENT’S MEDICATION DIARY - GW786034 (pazopanib) 
 
     Today’s date _______________________________ 
Agent __________________GW786034 (pazopanib)________ 
     Patient Name_________________________ (initials acceptable) Patient Study ID _____________________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each month. 
2. 
Take your dose of GW786034 (pazopanib) each day.  You should take GW786034 on an empty stomach either 1 hour before or 2 hours 
after meals.  The tablets should be taken with about 1 cup (240mL) of water.  You will take ___200 mg tablets and ___ 400 mg tablets 
every day.  You should swallow the tablets whole.  Do not chew, crush, or break the tablets. 
3. 
Record the date, the number of tablets of each size you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please return the forms to your physician when you go for your next appointment. 
 
Day 
 
Date 
What time was 
dose taken? 
# of tablets taken 
Comments 
200 mg 
400 mg 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
29 
 
 
 
 
 
30 
 
 
 
 
 
31 
 
 
 
 
 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment____________________________________________________________________ 
2. 
Date patient was removed from study_____________________________________________________________________ 
3. 
Patient’s planned total daily dose________________________________________________________________________ 
4. 
Total number of pills taken this month (each size)___________________________________________________________ 
5. 
Physician/Nurse/Data Manager’s Signature ________________________________________________________________ 
 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 


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    Patient’s signature:__________________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
APPENDIX E: Patient’s Blood Pressure Diary 
Today’s date ________________________________ 
Patient Name________________________________  Patient Study ID ________________________________ 
(initials acceptable) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Your blood pressure readings have two numbers.  The first number is the pressure in your blood vessels during a heart beat 
(systolic), and the second number is the pressure in the vessels when the heart rests in between beats (diastolic).  These 
numbers are usually written with a slash in between them (for example, 110/85). 
2. 
Record the date, then record your blood pressure twice each day using a home blood pressure monitor: 
• 
each morning while you are resting or reading (not while you are active:  dressing, making breakfast, etc.) 
• 
each evening at bedtime or while you are relaxing during the evening 
3. 
If you take your blood pressure at other times of the day, please record the numbers and time under “Other readings”. 
4. 
Normal blood pressure is usually considered to be 120/80 mmHg.  If your systolic pressure is greater than 140 or your 
diastolic blood pressure is greater than 90 when you measure your blood pressure two times at least 1 to 4 hours apart on 
the same day, please contact your doctor’s office at _______________________________ for instructions. 
5. 
Please bring this form to every clinic visit or appointment. 
Date 
AM 
readings 
PM 
readings 
Other readings (include 
time of day) 
Date 
AM 
readings 
PM 
readings 
Other readings (include 
time of day) 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
Patient’s Signature: _____________________________________________  Date: ____________________________________ 
 
CTEP-assigned Protocol # _____________ 
 
Local Protocol # ______________________ 


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Physician’s Office will complete this section: 
 _________________________________ 
____________________________________________________________ 
 
Date of this clinic visit 
Physician/Nurse/Data Manager’s Signature    


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APPENDIX F: Blood Pressure – Recommendations for Data Collection/Recording and Event Management 
 
Collection/Recording of Blood Pressure Information 
1.0 
General Guidelines 
1.1 
Frequency of monitoring.  Blood pressure (BP) should be monitored at least every 2 weeks for the duration of treatment.  
More frequent monitoring should be considered on a study by study basis, particularly during the first two cycles of 
GW786034 (pazopanib) therapy. 
 
1.2 
Data recording.  All required data should be recorded in the appropriate CRF or on the patient’s blood pressure monitoring 
diary, as appropriate.  The following data are required at baseline and at each subsequent assessment: 
• 
Assessment date and time 
• 
Pulse 
• 
Systolic and diastolic BP (2 readings/assessment taken 5 minutes apart while patient sitting) 
 
1.3 
Risk factors for hypertension (assess and record data in baseline history/physical CRF) 
• 
Diabetes (type 1 or type 2) 
• 
Renal disease (specify on CRF) 
• 
Endocrine condition associated with HTN (specify on CRF) 
• 
Use of steroids or NSAIDs (specify all concomitant meds) 
• 
Underlying cardiovascular condition – specify (i.e., ischemic heart disease) 
 
2.0 
Baseline data collection  (at study entry) 
2.1 
All patients 
• 
Current BP 
• 
Proteinuria, if present 
 
2.2 
Patients with preexisting hypertension (i.e., those for whom “hypertension” is entered as a concomitant condition at study 
entry, or those who are currently receiving therapy with antihypertensive medication) – also record: 
• 
Date of HTN diagnosis (original) 
• 
Type HTN (essential or secondary) 
• 
CTCAE v3.0 grade of HTN (at time of study entry) 
• 
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following: 
- 
Antihypertensive agents taken at study entry 
- 
Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of efficacy) 
 
3.0 
Follow up BP data collection (during study) 
3.1 
All patients (at each clinic visit) 
• 
Current BP 
• 
Proteinuria, if present 
 
3.2 
Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg (diastolic) OR BP >150/100 (if 
previously within normal limits)] – record at time of hypertension diagnosis and at all subsequent clinic visits: 
• 
BP changes from baseline (or from previous assessment) (specify CTCAE v3.0 grade changes) 
• 
Hypertension-related symptoms as reported by patient (e.g., headache) 
• 
Other relevant changes associated with development of hypertension (e.g., ECG abnormalities) 
• 
Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently prescribed antihypertensive 
agents 
 
3.3 
Patients with preexisting hypertension at study entry – record at each clinic visit 
• 
BP changes from previous clinic visit (specify CTCAE v3.0 grade changes) 
• 
Hypertension-related symptoms reported by patient (e.g., headache) 
• 
Other relevant changes associated with development of hypertension (e.g., ECG abnormalities) 
• 
Changes in antihypertensive medications since last assessment (e.g., dose change, add/discontinue drug) 
 
Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, beta blockers, diuretics, angiotension 
II receptor antagonists.


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APPENDIX G: Management of GW786034 (Pazopanib)-Induced Hypertension* 
 
 
Persistent Mild Hypertension 
140-149 / 90-99   
Persistent Moderate Hypertension 
150-179 / 100-109 
Persistent Severe Hypertension 
>180 / >110 
Consider long-acting DHP CCB at initial 
dose. 
→  partial or no control, ↑  dose in 
stepwise fashion until BP control 
Start/add a long-acting DHP CCB at intermediate 
dose.  If partial or no control,, ↑ to maximum dose 
until BP control (at least down to mild 
hypertension) 
WORSENS 
No Control 
WORSENS 
Asymptomatic 
SYMPTOMATIC 
Add 2nd /additional drug (BB, ACEI, ARB, or ABB) 
→  partial or no control, ↑  dose in stepwise fashion 
until BP control. 
No Control 
WORSENS 
• Hold GW786034 (pazopanib) 
• Start / add 2-drug combination (DHP CCB, 
BB, ACEI, or ARB) 
• ↑  dose(s) in stepwise fashion until BP control 
• When BP controlled, may start GW786034 
(pazopanib) per protocol 
No Control and 
Asymptomatic 
No Control AND 
SYMPTOMATIC 
Add 3rd drug at initial dose 
↑ dose(s) in stepwise fashion 
until BP control 
Add 3rd / additional drug (BB, ACEI, ARB, or ABB) 
→  partial or no control, ↑ dose in stepwise fashion until BP control 
OR 
Hold GW786034 (pazopanib) and restart when BP controlled per 
No Control and 
Asymptomatic 
No Control 
WORSENS 
↓ GW786034 (pazopanib) by 
one further dose level 
OR 
Stop GW786034 (pazopanib) 
↓ GW786034 (pazopanib) by 
one dose level 
OR 
Stop GW786034 (pazopanib) 
• Stop GW786034 (pazopanib) 
• Consider hospitalization for 
close monitoring and IV 
therapy 
• Treat as hypertensive crisis. 
PLEASE NOTE: 
• These are guidelines only 
• Investigators should use them  at their 
own discretion 
• 24-48 hrs are suggested as an elapsed 
time between decision steps unless 
persistent severe hypertension occurs. 
DHP CCB (Dihydropyridine Calcium-Channel Blockers); BB (selective Beta blockers); ACEIs (Angiotensin Converting Enzyme Inhibitors); ARBs (Angiotensin II Receptor Blockers);  ABB (alpha and beta blocker) 
* Refer to Section 6.1for 
additional information on 
hypertension management and a 
list of oral antihypertensive 
medications 


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APPENDIX H: CTEP Multicenter Guidelines 
 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
•  Prior to the activation of the protocol at each participating institution, an OHRP form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research  
• G-2 
• records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 


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IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
 
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.  
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO.  
 
 
 
 
 


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


NCI Protocol #: 7627 
Local Protocol #: MC057H 
NCI Version Date: April 15, 2018 
92 
 
 
 
 
 
Drugs that are generally 
accepted to have a risk of 
causing Torsades de 
Pointes 
 
Drugs that in some reports have been 
associated with Torsades de Pointes 
and/or QTc prolongation but at this 
time lack substantial evidence for 
causing Torsades de Pointes 
 
Drugs that, in some reports, 
have been weakly associated 
with Torsades de Pointes and/or 
QTc prolongation but that are 
unlikely to be a risk for Torsades 
de Pointes when used in usual 
recommended dosages and in 
patients without other risk 
factors (e.g., concomitant QTc 
prolonging drugs, bradycardia, 
electrolyte disturbances, 
congenital long QTc syndrome, 
concomitant drugs that inhibit 
metabolism). 
  
  
  
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Methadone /Dolophine® 
Lithium /Lithobid® 
Solifenacin /VESIcare® 
Methadone /Methadose® 
Lithium /Eskalith® 
Trimethoprim-Sulfa /Sulfa® 
Pentamidine /Pentam® 
Moexipril/HCTZ /Uniretic® 
Trimethoprim-Sulfa /Bactrim® 
Pentamidine /NebuPent® 
Moxifloxacin /Avelox® 
Trimipramine /Surmontil® 
Pimozide /Orap® 
Nicardipine /Cardene® 
  
Probucol /Lorelco® 
Nilotinib /Tasigna® 
  
Procainamide /Pronestyl® 
Octreotide /Sandostatin® 
  
Procainamide /Procan® 
Ofloxacin /Floxin® 
  
Quinidine /Cardioquin® 
Ondansetron /Zofran® 
  
Quinidine /Quinaglute® 
Oxytocin /Pitocin® 
  
Sotalol /Betapace® 
Paliperidone /Invega® 
  
Sparfloxacin /Zagam® 
Perflutren lipid microspheres 
/Definity® 
  
Terfenadine /Seldane® 
Quetiapine /Seroquel® 
  
Thioridazine /Mellaril® 
Ranolazine /Ranexa® 
  
  
Risperidone /Risperdal® 
  
  
Roxithromycin* /Rulide® 
  
  
Sertindole /Serlect® 
  
  
Sertindole /Serdolect® 
  
  
Sunitinib /Sutent® 
  
  
Tacrolimus /Prograf® 
  
  
Tamoxifen /Nolvadex® 
  
  
Telithromycin /Ketek® 
  
  
Tizanidine /Zanaflex® 
  
  
Vardenafil /Levitra® 
  
  
Venlafaxine /Effexor® 
  
  
Voriconazole /VFend® 
  


NCI Protocol #: 7627 
Local Protocol #: MC057H 
NCI Version Date: April 15, 2018 
93 
 
 
 
 
  
Ziprasidone /Geodon®