Conditions: Thyroid Gland Anaplastic Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 123
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies the side effects and how well intensity-modulated radiation therapy (IMRT) and paclitaxel with or without pazopanib hydrochloride works in treating patients with anaplastic thyroid cancer. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy and paclitaxel are more effective when given with pazopanib hydrochloride in treating thyroid cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety of IMRT, paclitaxel, and pazopanib (pazopanib hydrochloride) suspension. (Run-in component) II. To evaluate and compare overall survival at 1 year from study registration. (Phase II component)

SECONDARY OBJECTIVES:

I. To evaluate local-regional control at 6 and 12 months. (Phase II component) II. To evaluate the rate of grade 4 (Common Terminology Criteria for Adverse Events version 4.0 \[CTCAE, v. 4.0\]) hemorrhage, grade 4 febrile neutropenia, or any grade 5 adverse event assessed to be definitely, probably, or possibly related to the induction or concurrent treatment components of the protocol regimen. (Phase II component) III. To evaluate the rates of other adverse events (CTCAE, v. 4.0) assessed to be definitely, probably, or possibly related to the induction or concurrent treatment components of the protocol regimen. (Phase II component) IV. To evaluate the rate of treatment discontinuation due to toxicity during the induction or concurrent treatment components of the protocol regimen. (Phase II component) V. To evaluate response (as per Response Evaluation Criteria in Solid Tumors \[RECIST\]) of the primary site following the treatment component in subjects with measurable disease prior to chemoradiation. (Phase II component)

OUTLINE:

RUN-IN COMPONENT: Patients receive paclitaxel intravenously (IV) over 1 hour once weekly and pazopanib hydrochloride orally (PO) once daily (QD) for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and intensity-modulated radiotherapy (IMRT) 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

RANDOMIZED PHASE II COMPONENT: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

ARM II: Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 1 year, and then annually thereafter.

Arms:
arm 1: Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease). arm 2: Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats every 3 weeks for 4 cycles (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

Interventions: intervention 1: Intensity-Modulated Radiation Therapy intervention 2: Paclitaxel intervention 3: Pazopanib Hydrochloride intervention 4: Placebo Administration
Intervention descriptions: intervention 1: Undergo IMRT intervention 2: Given IV intervention 3: Given PO intervention 4: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
 
For Protocol Amendment 14 of RTOG 0912, A Randomized Phase II Study of Concurrent Intensity 
Modulated Radiation Therapy (IMRT), Paclitaxel, and Pazopanib (NSC 737754)/Placebo for the 
Treatment of Anaplastic Thyroid Cancer 
 
NCI/Local Protocol #: RTOG 0912 
 
NCI Protocol Version Date: March 6, 2020 
 
Section 
Change 
Cover page 
Amendment 14 was added to the Document History Table. 
5.3.1 
 
Protocol Specific Requirements for RTOG 0912 Site Registration was updated per 
standard NCI language since the RT Facilities Inventory form is no longer used.  
13.5.5 
The statement, “This change was done in a blinded fashion regarding the clinical 
outcomes” was added for clarification to the final analysis. 
Informed 
Consent 
No changes to the text of the sample consent; the version date of the consent was 
changed to be consistent with the amended protocol. 
 
 


 
1            RTOG 0912, Version Date: March 6, 2020 
NRG ONCOLOGY 
 
RTOG 0912 
 
A RANDOMIZED PHASE II STUDY OF CONCURRENT INTENSITY MODULATED 
RADIATION THERAPY (IMRT), PACLITAXEL AND PAZOPANIB (NSC 
737754)/PLACEBO, FOR THE TREATMENT OF ANAPLASTIC THYROID CANCER 
CTEP Drug: Pazopanib (NSC 737754) 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the 
National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network 
of NCTN organizations: the Alliance for Clinical Trials in Oncology; ECOG-ACRIN Medical Research 
Foundation, Inc.; and SWOG. 
 
Study Team (24-FEB-2020) 
 
Co-Principal Investigator/Medical Oncology 
Medical Physics Co-Chair 
Eric Sherman, MD 
Ping Xia, PhD 
Memorial Sloan-Kettering Cancer Center 
Cleveland Clinic 
300 East 66th Street 
9500 Euclid Avenue 
New York, NY 10065 
Cleveland, OH 44195 
646-888-4324/FAX 646-888-4269 
216-444-1938/FAX 216-444-8934 
shermane@mskcc.org 
xiap@ccf.org 
 
 
Co-Principal Investigator/Radiation Oncology 
Pathology Co-Chair 
Nancy Lee, MD 
Ronald A. Ghossein, MD 
Memorial Sloan-Kettering Cancer Center 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
1250 First Avenue, Box 36 
New York, NY 10065 
New York, NY 10065 
212-639-3341/FAX 212-639-2417 
212-639-2701/FAX 212-794-3186 
leen2@mskcc.org  
ghosseir@mskcc.org 
 
 
Medical Oncology Co-Chair 
Translational Science Co-Chair 
Keith Bible, MD, PhD 
Christine Chung, MD 
Mayo Clinic 
Moffitt Cancer Center 
200  First Street SW 
12902 USF Magnolia Drive 
Rochester, MN 55905 
Tampa, FL 33612 
507-266-0029/FAX 507-284-1803 
 813-745-4673/FAX 813-449-8210  
bible.keith@mayo.edu 
Christine.Chung@Moffitt.Org 
 
 
 
Senior Statistician 
 
Pedro A. Torres-Saavedra, PhD 
 
NRG Oncology 
 
50 South 16th St, Suite 2800 
 
Philadelphia, PA 19102 
 
215-717-7085/FAX 215-928-0153 
 
torresp@nrgoncology.org 
 
 
 
 
 
 


 
2            RTOG 0912, Version Date: March 6, 2020 
NRG ONCOLOGY  
 
RTOG 0912 
 
A RANDOMIZED PHASE II STUDY OF CONCURRENT INTENSITY MODULATED 
RADIATION THERAPY (IMRT), PACLITAXEL AND PAZOPANIB (NSC 
737754)/PLACEBO, FOR THE TREATMENT OF ANAPLASTIC THYROID CANCER 
CTEP Drug: Pazopanib (NSC 737754) 
 
 
Protocol Agents (6/5/14) 
 
Agent 
Supply 
NSC # 
IND # 
Pazopanib 
NCI 
737754 
75648 
Paclitaxel 
Commercial 
673089 
N/A 
 
 
Participating Sites (6/5/14) 
 US Only 
 Canada Only 
 US and Canada 
Approved International Member Sites 
 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 14 
March 6, 2020 
N/A 
Amendment 13 
February 24, 2020 
N/A 
Closure with 
Amendment 12 
October 21, 2016 
December 30, 2016 
Amendment 12 
October 21, 2016 
November 14, 2016 
Amendment 11 
September 13, 2016 
 November 14, 2016 
Amendment 10 
March 8, 2016 
March 28, 2016 
Amendment 9 
September 30, 2015 
October 19, 2015 
Amendment 8 
March 11, 2015 
March 26, 2015 
Amendment 7 
February 10, 2015 
March 2, 2015 
Amendment 6 
June 5, 2014 
June 23, 2014 
Update 
March 25, 2014 
March 25, 2014 
Update 
July 31, 2013 
July 31, 2013 
Amendment 5 
July 15, 2013 
July 31, 2013 
Amendment 4 
May 3, 2012 
June 11, 2012 
Update 
April 18, 2012 
April 18, 2012 
Update 
March 8, 2012 
March 8, 2012 
Amendment 3 
February 27, 2012 
March 8, 2012 
Amendment 2 
August 24, 2011 
September 22, 2011 
Amendment 1 
April 19, 2011 
May 5, 2011 
Update 
March 4, 2011 
March  4, 2011 
Update 
October 28, 2010 
October 28, 2010 
Activation 
October 28, 2010 
October 28, 2010 
 
 
 
 


 
3            RTOG 0912, Version Date: March 6, 2020 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
 
  
This protocol was designed and developed by NRG Oncology.  It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  
No other use or reproduction is authorized by NRG Oncology nor does NRG 
Oncology assume any responsibility for unauthorized use of this protocol. 


 
4            RTOG 0912, Version Date: March 6, 2020 
NRG ONCOLOGY 
 
RTOG 0912 
 
A RANDOMIZED PHASE II STUDY OF CONCURRENT INTENSITY MODULATED 
RADIATION THERAPY (IMRT), PACLITAXEL AND PAZOPANIB (NSC 
737754)/PLACEBO, FOR THE TREATMENT OF ANAPLASTIC THYROID CANCER 
CTEP Drug: Pazopanib (NSC 737754) 
 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION (24-FEB-2020) 
For regulatory 
requirements: 
For patient enrollments:  
For study data submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
(Sign in at www.ctsu.org, 
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to 
use the Portal should alert 
the CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
 
Contact the CTSU 
Regulatory Help Desk at 1-
866-651-2r878 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network 
(OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN
_SYSTEM/ or 
https://OPEN.ctsu.org 
 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com. 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
 
Submit data electronically via the NRG 
Oncology/RTOG web site, www.rtog.org 
 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy the 
CTSU on data submissions.   
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ web site is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For clinical questions (i.e. patient eligibility or treatment-related) 
For eligibility questions, contact the Study Data Manager For other clinical questions, contact the Study 
PI of the Lead Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission)  
Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU web site is located at   https://www.ctsu.org 
 


 
5            RTOG 0912, Version Date: March 6, 2020 
 
TABLE OF CONTENTS 
 
SCHEMA  ...................................................................................................................................................... 7 
ELIGIBILITY CHECKLIST  ............................................................................................................................ 9 
1.0 
INTRODUCTION ........................................................................................................................ 13 
1.1  
Anaplastic Thyroid Cancer .......................................................................................................... 13 
1.2  
Anaplastic Thyroid Cancer and Surgery ..................................................................................... 13 
1.3  
Anaplastic Thyroid Cancer and Radiation Therapy/Chemotherapy............................................ 13 
1.4  
Anaplastic Thyroid Cancer and Angiogenesis inhibition ............................................................. 13 
1.5 
Pazopanib ................................................................................................................................... 14 
1.6  
Rationale to Use Paclitaxel, Pazopanib, and Radiation Therapy To Treat Anaplastic Thyroid 
Cancer ........................................................................................................................................ 19 
1.7  
Current Experience of the Use of Paclitaxel, Pazopanib, and Radiation Therapy to Treat 
Anaplastic Thyroid Cancer .......................................................................................................... 20 
2.0 
OBJECTIVES .............................................................................................................................. 20 
2.1  
Primary Objective for Run-In Components ................................................................................. 20 
2.2 
Primary Objective for Phase II Component ................................................................................. 20 
2.3 
Secondary Objectives for Phase II Component .......................................................................... 20 
3.0 
PATIENT SELECTION ............................................................................................................... 21 
3.1 
Conditions for Patient Eligibility ................................................................................................... 21 
3.2 
Conditions for Patient Ineligibility ................................................................................................ 22 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT ................................................................. 23 
4.1 
Required Evaluations/Management ............................................................................................ 23 
4.2 
Highly Recommended Evaluations/Management ....................................................................... 23 
5.0 
REGISTRATION PROCEDURES  ............................................................................................. 24 
5.1 
Pre-Registration Requirements for IMRT Treatment Approach .................................................. 25 
5.2 
Digital RT Data Submission to NRG Using TRIAD ..................................................................... 25 
5.3        Regulatory Pre-Registration Requirements ................................................................................ 26 
5.4 
Registration   ............................................................................................................................... 27 
6.0 
RADIATION THERAPY .............................................................................................................. 28 
6.1 
Dose Specifications ..................................................................................................................... 28 
6.2 
Technical Factors ........................................................................................................................ 28 
6.3 
Treatment Planning, Imaging and Localization Requirements ................................................... 28 
6.4 
Treatment Planning/Target Volumes .......................................................................................... 29 
6.5 
Critical Structures ........................................................................................................................ 30 
6.6 
Compliance Criteria ..................................................................................................................... 31 
6.7 
R.T. Quality Assurance Reviews................................................................................................. 32 
6.8 
Radiation Therapy Adverse Event Reporting .............................................................................. 33 
7.0 
DRUG THERAPY ....................................................................................................................... 33 
7.1 
Treatment .................................................................................................................................... 33 
7.2 
Prior to Radiation Therapy: Treatment Details ............................................................................ 33 
7.3 
During Radiation Therapy: Treatment Details ............................................................................. 34 
7.4 
Study Agents ............................................................................................................................... 35 
7.5 
Clinical Trials Agreement ............................................................................................................ 43 
7.6 
Dose Modifications ...................................................................................................................... 44 
7.7 
Modality Review .......................................................................................................................... 58 
7.8 
Adverse Events ........................................................................................................................... 58 
7.9 
CTEP-AERS Adverse Event Reporting Requirements ............................................................... 59 
8.0 
SURGERY .................................................................................................................................. 61 
9.0 
OTHER THERAPY ..................................................................................................................... 61 
9.1 
Permitted Supportive Therapy .................................................................................................... 61 
9.2 
Non-permitted Supportive Therapy ............................................................................................. 61 
10.0 
TISSUE/SPECIMEN SUBMISSION ........................................................................................... 62 
10.1 
Tissue/Specimen Submission  .................................................................................................... 62 
10.2 
Tissue Collection for Central Review – Mandatory ..................................................................... 62 


 
6            RTOG 0912, Version Date: March 6, 2020 
10.3 
Specimen Collection for Banking – Recommended.................................................................... 63 
10.4 
Reimbursement ........................................................................................................................... 64 
10.5 
Confidentiality/Storage  ............................................................................................................... 65 
11.0 
PATIENT ASSESSMENTS ......................................................................................................... 65 
11.1 
Study Parameters ....................................................................................................................... 65 
11.2 
Pre-Treatment Evaluations ......................................................................................................... 65 
11.3 
Evaluations During Pre-Radiation Treatment ............................................................................. 66 
11.4 
Evaluations During Concurrent Treatment .................................................................................. 66 
11.5 
Imaging After Completion of Radiation Therapy ......................................................................... 66 
11.6 
Long-Term Follow up .................................................................................................................. 66 
11.7 
Measurement of Response ......................................................................................................... 67 
11.8 
Criteria for Discontinuation of Protocol Treatment  ..................................................................... 67 
12.0 
DATA COLLECTION .................................................................................................................. 68 
12.1 
Summary of Data Submission  ................................................................................................... 68 
12.2 
Summary of Dosimetry Digital Data Submission ........................................................................ 68 
13.0 
STATISTICAL CONSIDERATIONS ............................................................................................ 69 
13.1 
Endpoints .................................................................................................................................... 69 
13.2 
Background and Sample Size Determination ............................................................................. 69 
13.3 
Patient Accrual ............................................................................................................................ 70 
13.4 
Randomization ............................................................................................................................ 70 
13.5 
Analysis Plan ............................................................................................................................... 70 
13.6 
Gender and Minorities  ................................................................................................................ 72 
REFERENCES ............................................................................................................................................ 73 
APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS ................................. 76 
APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT .......................... 77 
APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP ...................................... 78 
APPENDIX II: ZUBROD PERFORMANCE SCALE AND CLASSIFICATION OF CARDIAC DISEASE .... 79 
APPENDIX III: AJCC STAGING SYSTEM  ................................................................................................ 80 
APPENDIX IV: MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED PATIENTS ......................... 81 
APPENDIX V: ORAL ANTIHYPERTENSIVE MEDICATIONS ................................................................... 83 
APPENDIX VI: DRUGS THAT PROLONG, MAY PROLONG, OR ARE UNLIKELY TO PROLONG THE 
QTC ............................................................................................................................................ 84 
APPENDIX VII: DRUGS KNOWN TO BE METABOLIZED BY SELECTED CYP450 ISOENZYMES ....... 87 
APPENDIX VIII: NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS  ............................... 92 
APPENDIX IX: NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS  .................................... 93 
APPENDIX X: PREPARATION OF 50 MG/ML OF PAZOPANIB ORAL SUSPENSION ........................... 96 
 
 
 
  


 
7            RTOG 0912, Version Date: March 6, 2020 
NRG ONCOLOGY  
RTOG 0912 
 
A Randomized Phase II Study of Concurrent Intensity Modulated Radiation Therapy (IMRT),  
Paclitaxel, and Pazopanib (NSC 737754)/Placebo for the Treatment of Anaplastic Thyroid Cancer 
 
SCHEMA (6/5/14) 
 
 
1st RUN-IN COMPONENT-Completed   
 
Pre-IMRT: Paclitaxel weekly + Pazopanib daily for 2-3 weeks 
R 
 
E 
Concurrent Therapy: IMRT, 66 Gy, in 33 fractions for 6.5 weeks 
G 
Paclitaxel weekly for 6 weeks (6 doses) 
I 
+ Pazopanib daily for 6 weeks or until the end of radiation 
S 
 
T 
Post-Concurrent Therapy: (Begins 25-31 days after the completion of IMRT) 
E 
Paclitaxel weekly + Pazopanib daily 
R 
 
 
If measurable disease remains: Continue Paclitaxel + Pazopanib until disease progression or  
 
significant toxicity requires that treatment be stopped. 
 
 
 
If no measurable disease: Paclitaxel + Pazopanib for 4 cycles (12 weeks) or until disease  
 
progression or significant toxicity, whichever is first. 
 
Note: Accrual will be suspended after 11 patients have been accrued to the run-in component; the study 
will remain closed until these 11 patients complete radiation therapy and a safety analysis performed. See 
Section 13.2.1 for further details. 
 
 
 
 
2nd RUN-IN COMPONENT-Completed  
 
Pre-IMRT: Paclitaxel (80 mg/m2) weekly + Pazopanib (600 mg suspension) daily for 2-3 weeks 
R 
 
E 
Concurrent Therapy: IMRT, 66 Gy, in 33 fractions for 6.5 weeks 
G 
+ Paclitaxel, 50 mg/m2, weekly for 6-7 weeks    
I 
+ Pazopanib 300 mg suspension daily for 6-7 weeks or until the end of RT 
S 
 
T 
 
E 
Note: Accrual will be suspended after 11 patients have been accrued to this 2nd run-in  
R 
component. 
 
 
 
The study will remain closed until these 11 patients complete radiation therapy and a safety  
 
analysis performed. See Section 13.2.1 for further details. 
 
IMRT is required for this study. See the pre-registration requirements for IMRT in Section 5.1.   
 
 
 
Schema continued on next page 
 


 
8            RTOG 0912, Version Date: March 6, 2020 
NRG ONCOLOGY  
 
RTOG 0912 
 
A Randomized Phase II Study of Concurrent Intensity Modulated Radiation Therapy (IMRT),  
Paclitaxel, and Pazopanib (NSC 737754)/Placebo for the Treatment of Anaplastic Thyroid Cancer 
 
SCHEMA (Continued) (6/5/14) 
 
 
3rd  RUN-IN COMPONENT-Completed  
 
Pre-IMRT: Paclitaxel (80 mg/m2) weekly + Pazopanib (400 mg suspension) daily for 2-3 weeks 
R 
 
E 
Concurrent Therapy: IMRT, 66 Gy, in 33 fractions for 6.5 weeks 
G 
+ Paclitaxel, 50 mg/m2, weekly for 6-7 weeks    
I 
+ Pazopanib 300 mg suspension daily for 6-7 weeks or until the end of RT 
S 
 
T 
 
E 
Note: Accrual will be suspended after 11 patients have been accrued to this 3rd run-in  
R 
component. The study will remain closed until these 11 patients complete radiation therapy and  
 
a safety analysis performed. See Section 13.2.1 for further details. 
 
 
 
 
RANDOMIZED PHASE II COMPONENT  
 
 
 
 
 
 
 
Pre-IMRT: 
S 
Presence of Metastatic 
R 
 Paclitaxel, 80 mg/m2, weekly  
T 
Disease 
A 
+ Pazopanib/placebo, 400 mg suspension,  
R 
1. M0 
N 
daily for 2-3 weeks 
A 
2. M1 
D 
 
T 
3. Mx 
O 
 
I 
 
M 
Concurrent Therapy 
F 
 
I 
 IMRT, 66 Gy, in 33 fractions for 6.5 weeks  
Y 
 
Z 
+ Paclitaxel, 50 mg/m2, weekly for 6-7 weeks    
 
 
E 
+ Pazopanib/placebo, 300 mg suspension,  
 
 
 
daily for 6-7 weeks or until the end of RT 
 
 
 
 
IMRT is required for this study. See the pre-registration requirements for IMRT in Section 5.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Pathologically (histologically or cytologically) proven diagnosis of anaplastic thyroid cancer (a diagnosis 
that is noted to be “consistent with anaplastic thyroid cancer” with the presence of a thyroid mass is 
acceptable) 
 
Required Sample Size: Each Run-In Component: 11 patients; Phase II Component: 88 patients 


 
9            RTOG 0912, Version Date: March 6, 2020 
ELIGIBILITY CHECKLIST (3/8/16) 
(page 1 of 4) 
NRG Oncology Institution #   
 
RTOG 0912 
 
 
 
 
  
Case #  
 
 
 
 
     
 
 
(Y)  1.  Does the patient have pathologically (histologically or cytologically) proven diagnosis of 
anaplastic thyroid cancer? (A diagnosis that is noted to be “consistent with anaplastic 
thyroid cancer” with the presence of a thyroid mass is acceptable.) 
 
          (Y/NA)   2.  If there was a total or partial thyroidectomy completed within 3 months of enrollment, is 
the surgical specimen showing anaplastic thyroid cancer at least 1 cm in greatest 
dimension? 
 
                (Y)   3.    Was a history/physical examination done within 2 weeks prior to registration? 
 
                (Y)  4.   Was imaging of the neck and brain (CT scan or MRI) and chest/abdominal imaging 
(chest x-ray, chest CT scan, or full body PET/CT are acceptable) done within 4 weeks 
prior to registration and as described in Section  3.1.3? 
 
                (Y)    5.   Was an electrocardiogram done within 10 days prior to registration? 
 
                (Y)    6.   Is the patient’s Zubrod Performance Status 0-2? 
 
                (Y)    7.   Is the patient at least 18 years of age? 
 
                (Y)    8.   Does the patient have adequate bone marrow, hepatic, and renal function as specified 
in Section 3.1? 
 
                (Y)    9.   Were the serum electrolytes done within 10 days prior to registration? 
 
                (Y)    10.  Was the patient’s history of QTc prolongation, family history of prolonged QTc, and 
relevant cardiac disease documented within 10 days of registration? 
 
                (Y)    11.  Were the patient’s medications evaluated within 10 days of registration, with attempt 
to change any medication that affects CYP3A4? 
  
                (Y)    12.  Was the patient’s blood pressure taken and recorded by a health care professional 
within 10 days of registration?   
 
                (Y) 
 
If yes, was the patient’s blood pressure < 140/90? 
 
                (Y) 
If the patient’s systolic blood pressure was > 140 and/or diastolic blood pressure 
was > 90, does the treating physician believe it is feasible to control the patient’s 
blood pressure to < 140/90 prior to treatment? 
 
                (Y)   13.   Did the patient have a PT/INR/PTT as specified in Section 3.1 within 10 days prior to 
registration? 
 
          (Y/NA)   14.   For women of child bearing potential, was a serum or urine pregnancy test completed 
within 10 days of registration? 
 
_______(Y) 
 
If yes, was the pregnancy test negative? 
 
 
 
 
 
 
 
 
 
 
Continued on next page 


 
10            RTOG 0912, Version Date: March 6, 2020 
ELIGIBILITY CHECKLIST  
(page 2 of 4) 
NRG Oncology Institution #   
 
RTOG 0912 
 
 
 
 
  
Case #  
 
 
 
 
  
 
           (Y/NA)   15.  If a woman of child bearing potential or sexually active male, is the patient willing to 
use medically acceptable forms of contraception while on treatment and for 6 months 
post-treatment?  
 
                (N)   16.   Does the patient have any other known active invasive malignancy? (except non-
melanomatous skin cancer or differentiated thyroid cancer; the presence of prostate 
cancer confined to the prostate with a PSA < 1 for more than 6 months also is 
allowed) 
 
                (N)   17.   Did the patient have prior systemic chemotherapy for anaplastic thyroid cancer?  
 
                (N)   18. Did the patient have chemotherapy or radiotherapy within 4 weeks of registration (6 
weeks for nitrosoureas or mitomycin C) or has the patient not recovered from 
adverse events due to agents administered > 4 weeks previously? 
 
                (N)   19.   Did the patient have prior radiotherapy to the region of the study cancer that would 
result in overlap of radiation therapy fields? 
 
                (N)   20.   Does the patient have any of the cardiovascular conditions specified in Section 3.2.4? 
 
             (Y/N)   21.   Is the patient taking medications associated with a risk or QTc prolongation and/or 
Torsades de Pointes (see Section 3.2.5)?  
 
_______(Y) 
If yes, can these medications be avoided or replaced with medications that do 
not carry these risks? 
 
 
                (N)   22.   Does the patient require heparin? (other than low-molecular weight heparin)   
 
                (N)   23.   Does the patient have any condition that may impair the ability to absorb oral 
medications/investigational product, as specified in Section 3.2? 
 
                (N)   24.   Does the patient have any condition that may increase the risk of gastrointestinal 
bleeding or gastrointestinal perforation, as specified in Section 3.2?  
 
               (N)   25.    Did the patient have a history of hemoptysis within 30 days of registration? (patients 
who have minimal bleeding from the mouth, which is clearly not related to a source in 
the lungs, are eligible only after good hemostasis has been documented). 
 
                 (N)  26. Does the patient have uncontrolled intercurrent illness or psychiatric illness/social 
situations that would limit compliance with study requirements? 
 
                (N)   27.   Does the patient have a history of prior allergic reaction to the study drug(s) involved 
in this protocol? 
 
 
 
 
 
 
 
 
 
 
Continued on next page 


 
11            RTOG 0912, Version Date: March 6, 2020 
ELIGIBILITY CHECKLIST (7/31/13) 
(page 3 of 4) 
NRG Oncology Institution #   
 
RTOG 0912 
 
 
 
 
  
Case #  
 
 
 
  
 
                (N)   28.   Does the patient have QTc prolongation, defined as a QTc interval ≥ 480 msecs or 
other significant EKG abnormalities? 
 
               (N)   29.   Does the patient have known brain metastasis? 
 
                (N)   30. Is the patient HIV-positive and on combination antiretroviral therapy? 
 
            (N/Y)   31.  Is the patient receiving prohibited medications that act through the CYP450 system 
per Section 7.4.1?   
 
                 (Y) 
If yes, has Dr. Sherman or Dr. Bible been contacted to discuss the patient’s 
medications? 
 
The following questions will be asked at Study Registration:  
IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION. 
 
 
         
1. 
Institutional person randomizing this case? 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials (First Middle Last) [May 2003; If no middle initial, use hyphen] 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at VA or military hospital? 
 
 
         
16. 
Calendar base date 
 
 
 
 
 
 
 
Continued on next page 


 
12            RTOG 0912, Version Date: March 6, 2020 
ELIGIBILITY CHECKLIST (3/25/14) 
(page 4 of 4) 
NRG Oncology Institution #   
 
RTOG 0912 
 
 
 
 
  
Case #  
 
 
  
 
 
         
17. 
Randomization date 
 
 
         
18. 
Medical Oncologist’s name 
 
              (Y/N) 19. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 20.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
              (Y/N) 22. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's 
disease, or heart disease).  
 
              (Y/N) 23. 
Have you obtained the patient's consent to allow someone from this institution to  
 
 
 
contact him or her in the future to take part in more research?  
 
              (Y/N) 24. 
Does the site require expedited drug service for the patient? 
 
 
 
 
If yes, select one of the following couriers and provide the account number. 
 
_____United Parcel Service (UPS)    Account number:_____________________ 
 
 
 
 
_____ Federal Express (FedEx)        Account number:_____________________ 
 
         _________ 25.      Presence of Distant Metastatic Disease (M0, M1, MX) 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, 
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated 
during an institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
13 
             RTOG 0912, Version Date: March 6, 2020 
1.0 INTRODUCTION 
1.1  
Anaplastic Thyroid Cancer 
There are approximately 37,000 new cases of thyroid cancer annually in the U.S. alone, resulting in 1600 
deaths. Of the 37,000 cases, 1-2% are anaplastic thyroid cancer. While differentiated thyroid cancers are 
typically curable, anaplastic thyroid cancer (ATC) is one of the most aggressive and deadly solid tumors, 
with a 1-year survival rate of only approximately 10% and with very few long-term survivors (Goutsouliak 
2005). 
 
ATC often presents with a rapidly growing neck mass. Other common symptoms include hoarseness and 
neck pain. Because airway and esophageal compromise are of major concern, obtaining local control of 
this disease in the neck is crucial, as it is essential for patient quality of life, particularly in preventing 
asphyxiation and allowing maintenance of oral nutrition.  Improving local control also is thought to 
improve overall survival (Haigh 2001). Historical methods to improve local control in ATC have included 
surgery and/or radiation therapy.  
 
1.2  
Anaplastic Thyroid Cancer and Surgery  
 
The role of surgery is limited in ATC for the following reasons: 1) These tumors are rarely resectable at 
diagnosis due to their ill-defined borders, as well as their attachment to surrounding vital structures in the 
neck; and 2) Systemic disease is almost uniformly present, at least at the microscopic level, even upon 
initial diagnosis. However, there has been some evidence that surgery followed by post-operative 
radiation therapy and chemotherapy can result in better patient outcomes than radiotherapy alone (Haigh 
2001).  
 
1.3  
Anaplastic Thyroid Cancer and Radiation Therapy/Chemotherapy 
 
Non-surgical treatment approaches, such as the use of hyperfractionated radiation therapy with weekly 
doxorubicin, can improve median survival to 12 months. Eventually, most patients succumb to distant 
metastatic disease (Unpublished data, Memorial Sloan-Kettering). Data from Princess Margaret Hospital 
have suggested that patients who underwent radical radiotherapy had significantly higher local 
progression-free rate versus those who underwent palliative radiotherapy, with median survival greater in 
patients with radical (11.1 months), versus palliative (3.2 months) radiotherapy (p<0.0001).  However, 
there has been no significant difference in the median overall survival in patients undergoing 
hyperfractionation versus once-daily radiotherapy (Wang 2006). A range of doses was used in this study, 
and 60 Gy given over 40 fractions in 1.5 Gy per fraction was typically used when patients underwent a 
hyperfractionated regimen. 
 
 
Delivering high dose radiation to the tumor when treating anaplastic thyroid cancer is limited by the 
presence of the spinal cord and lung, which lie in close proximity to the tumor target. Intensity modulated 
radiation therapy (IMRT) improved tumor coverage when compared to conventional radiotherapy 
techniques while significantly reducing the dose to these surrounding normal tissues (Nutting 2001; Lee 
2003).  At the University of California-San Francisco Medical Center, IMRT has been used for the 
treatment of anaplastic thyroid cancer in combination with chemotherapy (Posner 2000). This treatment 
strategy has been shown to prolong survival with a median survival as high as 43 months in patients who 
also had complete surgical resection. Treatments are typically given in once a day rather than twice daily 
fractionation. 
 
 
 
While doxorubicin often has been considered the “standard” agent for treating ATC patients with 
advanced disease, many preclinical studies have shown very limited activity (Ain 1996). Ain, et al. (2000) 
have shown significant activity with paclitaxel in 6 human ATC cell lines, and a subsequent, small multi-
institutional phase II study using single agent paclitaxel in advanced ATC demonstrated a promising 
response rate of 53%. 
 
1.4  
Anaplastic Thyroid Cancer and Angiogenesis inhibition 
Vascular Endothelial Growth Factor (VEGF) receptor (r) inhibitors have shown promise in anaplastic and 
differentiated thyroid cancers. In nude mice, Bauer, et al. (2002) demonstrated significant response of 
ATC to monoclonal antibodies to VEGFr. In the treatment of differentiated thyroid cancers, phase II 
studies with multiple agents that act as angiogenesis inhibitors (e.g., xatinib, sorafinib, sutinib, pazopanib, 
lenalidomide) also have shown activity (Adjei 2008; Gupta-Abramson 2008). 
 


 
 
 
 
 
 
14 
             RTOG 0912, Version Date: March 6, 2020 
Oxygen free radicals formed by radiation are essential for the induction of radiation-induced DNA-
damage. One might predict that inhibition of angiogenesis would decrease oxygen delivery to the tumor, 
thereby attenuating the antitumor activity of radiation. However, both preclinical and clinical models have 
shown that antiangiogenic agents improve response to radiotherapy (Gorski 1998; Nieder 2007; Hess 
2001). To explain these results, several researchers invoke the pathologic nature of tumor neovessels, 
which are dilated, tortuous, and highly permeable. These characteristics of tumor vasculature result in 
increased interstitial fluid pressure (IFP), a hallmark of solid tumors. In theory, pretreatment with 
antiangiogenic agents reduces the number of inefficient vessels and improves tumor perfusion. In support 
of this ‘vascular normalization’ hypothesis, antibody to VEGF-A reduces tumor vascular density and IFP. 
Another theoretical premise holds that antiangiogenic therapy sensitizes tumor cells to radiation-induced 
apoptosis by interfering with autocrine loops. Many solid tumor types, including head and neck squamous 
cell carcinoma (HNSCC), express VEGF receptors. VEGF-A produced by tumor cells may promote tumor 
cell survival by an autocrine loop. As such, VEGF-A blockade may sensitize tumor cells to the radiation-
induced apoptosis. The 2 theoretical mechanisms of vascular normalization and tumor sensitization may 
coexist. 
 
1.5 
Pazopanib 
 
Pazopanib is a second-generation, multi-targeted tyrosine kinase inhibitor against VEGFR-1, 2, and 3, 
platelet-derived growth factor receptor, c-kit, Ret and other kinases. Preclinical data suggests synergy 
with radiation therapy when started 1 week prior to the start of radiation therapy (Confidential Information, 
GlaxoSmithKline). Currently, pazopanib is undergoing a phase II study in differentiated, medullary, and 
anaplastic thyroid cancers at the Mayo Clinic, with evidence of activity in all 3 tumor types (Bible 2009). 
Phase I studies have shown that pazopanib also can be safely administered with paclitaxel (Tan 2008). 
Moreover, in non-small cell lung cancer, it has been shown to be safely given 1 week after surgery, 
making its use in the immediately post-operative period feasible. 
 
 
 
 
1.5.1   
Nonclinical Pharmacokinetics and Drug Metabolism 
Mean bioavailability ranged from 47% in dogs to 72% in rats.  There was a 4- to 5-fold 
decrease in exposure in fed compared to fasting dogs, but in monkeys the exposure did not 
change substantially on feeding. Pazopanib is highly (>98.8%) plasma protein bound in mouse, 
rat, dog, monkey, and human plasma.  In vitro data indicate that pazopanib is highly permeable 
across membranes and is a substrate for the P-glycoprotein (P-gp) transporter and breast 
cancer resistant protein (BCRP). Following oral administration of radiolabeled pazopanib, 
excretion of drug-related material was rapid and essentially complete. Circulating metabolites 
observed in humans were minor and were also noted in the nonclinical species.  Metabolism 
appeared to be predominantly mediated by CYP3A4 and to a lesser extent by CYP1A2 and 
CYP2C8.  The majority of the dose was excreted via feces in humans, rats, and monkeys. 
1.5.2 
Clinical Experience of Pazopanib 
Approximately 3000 subjects with cancer have been enrolled in clinical studies of pazopanib as 
of September 2009.  In October 2009, the FDA approved pazopanib tablets for the treatment of 
subjects with advanced renal cell carcinoma (RCC). In addition, several clinical studies 
evaluating pazopanib in non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, 
soft tissue sarcoma (STS), cervical cancer, hepatocellular cancer (HCC), multiple myeloma 
(MM), and glioma are in progress or have been completed. 
1.5.3 
Clinical Efficacy of Pazopanib 
In a randomized, double-blind, placebo-controlled phase 3 study evaluating the efficacy and 
safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated subjects with 
advanced RCC, the median progression-free-survival (PFS) was significantly prolonged with 
pazopanib compared with placebo in the overall study population (9.2 vs. 4.2 months). The 
H
N
N
N
N
N
N
S
NH2
O
Pazopanib, GW786034


 
 
 
 
 
 
15 
             RTOG 0912, Version Date: March 6, 2020 
objective response rate (RR) was 30% with pazopanib and only 3% with placebo (Sternberg, in 
press). In subjects with ovarian cancer, 31% of subjects experienced a CA-125 response to 
pazopanib, with a median time to response of 29 days and median duration of response of 113 
days (Investigator’s Brochure, 2010).  Median PFS was 84 days and the overall RR was 18%.  
In advanced or metastatic STS, the rate of PFS at 12 weeks was 43.9% for leiomyosarcoma, 
48.6% for synovial sarcoma, 26.3% for adipocytic sarcoma, and 39% for other types of 
sarcoma (Sleijfer, 2008). In a phase 2 trial of subjects with early-stage NSCLC, 86% of subjects 
experienced a reduction in tumor volume after short-term, preoperative use of pazopanib (~2-6 
weeks) as assessed by high-resolution CT scanning (Altorki, 2008). Interim results from a 
phase 2 study of pazopanib in subjects with recurrent or metastatic breast invasive breast 
cancer showed that the clinical benefit rate was 26% (Taylor, 2009).  The median TTP was 3.7 
months, and 50% of subjects with measurable target lesions had some decrease in size.  PFS 
at 3 and 6 months was 55% and 28%, respectively.  Preliminary results from a randomized 
study in subjects with first-line advanced ErbB2-positive advanced or metastatic breast cancer 
showed that a higher response rate (36.2% vs. 22.2%) was observed in subjects on 
combination lapatinib 1000 mg once daily + pazopanib 400 mg once daily compared to 
monotherapy lapatinib 1500 mg once daily (Slamon, 2008).  In a randomized phase 2 study of 
pazopanib vs. lapatinib vs. the combination of pazopanib/lapatinib in advanced and recurrent 
cervical cancer, there was a 34% reduction in risk for progression in subjects receiving 
pazopanib relative to lapatinib. The median PFS was 17.1 weeks in the lapatinib group and 
18.1 weeks in the pazopanib group (Monk 2009). Interim analysis of data from 26 subjects 
showed that pazopanib has both a favorable toxicity profile and promising clinical activity in 
subjects with advanced and progressive differentiated thyroid cancers (Bible 2009). Five 
confirmed partial responses (PRs) [19%] were reported.  Pazopanib has not shown efficacy in 
phase 2 studies conducted in MM or glioma (Investigator’s Brochure, 2010) 
1.5.4 
Safety of Pazopanib 
The randomized, phase 3 study in mRCC subjects provided a key comparison of safety with 
pazopanib compared to placebo (Sternberg, in press).  The overall frequency of adverse events 
(AEs) reported during the study was higher in the pazopanib arm (92%) compared with placebo 
(74%). The most common AEs reported in >20% of subjects in the pazopanib arm were 
diarrhea (52%), hypertension (40%), hair color change (depigmentation; 38%), nausea (26%), 
anorexia (22%), and vomiting (21%).  Most of the events were grade 1 or 2.  A higher number 
of grade 3 AEs were reported in the pazopanib arm (33%) compared with the placebo arm 
(14%). The most frequent grade 3 AEs in the pazopanib arm were increased alanine 
aminotransferase (ALT), increased aspartate aminotransferase (AST), hypertension, and 
diarrhea.  The frequency of grade 4 and grade 5 AEs was similar between the pazopanib and 
placebo arms:  grade 4 in 7% and 6%, respectively; grade 5 in 4% and 3%, respectively. 
 
A comprehensive review of all completed and ongoing pazopanib clinical trials with a cut-off 
date of September 2009, lists 15 most commonly occurring serious AEs (SAEs) [Investigator’s 
Brochure, 2010].  Vomiting and diarrhea are the most commonly reported SAEs across all the 
pazopanib studies. As a consequence of this, dehydration also is seen with pazopanib 
treatment.  For most reports, the AEs resolved after supportive treatment such as antiemetics, 
antidiarrheal agents, and IV fluids.  GI perforation is commonly associated with VEGF pathway 
inhibitors.  This may manifest as abdominal pain which is not uncommon in cancer subjects for 
many reasons.  Of the 42 subjects in pazopanib trials with SAEs of abdominal pain, only three 
had a documented underlying intestinal perforation. In July 2006, the DCTD, NCI, issued an 
Action Letter to investigators using pazopanib describing the occurrence of bowel perforations 
in subjects on pazopanib clinical trials. 
 
Dyspnea also is frequently seen in pazopanib-treated subjects and may reflect the underlying 
disease under treatment. Anemia is commonly seen in cancer subjects in association with 
chemotherapy, hemorrhage, or infection. The SAEs of pyrexia were attributed to multiple 
causes:  concurrent infections, the underlying malignancy, hepatic events, other concomitant 
medications, and unknown causes.  Hepatic events are thought to be on-target tyrosine kinase 
inhibitor (TKI) class effects, as hepatic enzyme elevations have been seen with other agents of 
this class. Careful clinical evaluation is, therefore, warranted in subjects with hepatic 
abnormalities. Pneumonia can be a complication of chemotherapy or can result from 
debilitation and advanced disease. Review of the 33 SAEs showed the presence of an 


 
 
 
 
 
 
16 
             RTOG 0912, Version Date: March 6, 2020 
underlying cause other than pazopanib in 19 of the 30 subjects.  Fatigue and asthenia are 
commonly reported and have multiple causes. 
 
Hypertension observed with pazopanib is a known class effect. There have been 30 SAEs of 
hypertension and 3 SAEs of hypertensive crisis in pazopanib clinical trials.  There were 28 
subjects who were effectively treated with antihypertensive medication initiation or dose 
adjustment, while 4 had no such treatment. Although there were 29 SAEs of pleural effusion, 
the body of data does not suggest that any of these cases were due to pazopanib.  There have 
been 24 SAEs of pulmonary embolism (PE) reported in pazopanib trials.  This is of particular 
relevance since other members of this class have been associated with PE and other venous 
thromboembolic events. 
 
In addition, there have been reports of cardiac and cerebral ischemic events, GI perforation or 
hemorrhage, pulmonary hemorrhage, cerebrovascular hemorrhage, QT prolongation, and 
Torsades de Pointes in pazopanib clinical trials. 
1.5.5 
Clinical Pharmacokinetics of Pazopanib (2/27/12) 
The oral bioavailability of pazopanib reflects absorption that is limited by solubility above doses 
of 800 mg once daily (Investigator’s Brochure, 2010; Hurwitz, 2009).  Increases in doses above 
800 mg to 2000 mg, in the fasted state will not result in increased systemic exposure.  
Geometric mean pazopanib t½ values ranged from 18.1-52.3 hours.  The mean t½ was 30.9 
hours in the 800 mg once daily group (Hurwitz 2009).  Oral absorption is significantly enhanced 
when dosed with food; therefore, it is recommended to administer pazopanib on an empty 
stomach, at least 1-2 hours after a meal.   
 
A study evaluating the pharmacokinetics (PK) of pazopanib when crushed or delivered as an 
oral suspension demonstrated that administration of pazopanib as a suspension lead to 
increased systemic exposure to pazopanib compared to administration of the whole tablet. 
Administration of the oral suspension compared to whole-tablet pazopanib increased AUC  
(0-72) by 33% (Heath, 2011). A pediatric study of pazopanib oral suspension (ADVL0815, 
Children’s Oncology Group Study) has recently been completed and the PK data is currently 
being analyzed. 
 
Preliminary information on the PK of pazopanib administered in combination with lapatinib has 
been reported (Dejonge, 2006).  Thirty-three subjects received doses of lapatinib ranging from 
750-1500 mg once daily along with pazopanib at doses of 200-500 mg daily.  Preliminary mean 
plasma concentrations 24 hours after administration (C24) on day 22 were ~19 mcg/mL and 23 
mcg/mL after pazopanib doses of 250 mg and 500 mg, respectively.  These values are similar 
to the mean C24 values observed after administration of 800 mg pazopanib alone (23.1 
mcg/mL).  Plasma lapatinib concentrations at 750-1500 mg daily were similar to those observed 
after monotherapy.  Concurrent administration of pazopanib and lapatinib was generally well 
tolerated; coadministration of lapatinib may alter the PK of pazopanib (Dejonge, 2006). 
 
Preliminary PK information on the combination of pazopanib and paclitaxel administered to 
subjects with advanced cancer has been reported (Suttle, 2007). Twelve subjects received 
paclitaxel (15-80 mg/m2 on days 1, 8, and 15 every 28 days) and pazopanib at 400 or 800 
mg/day starting on day 2 of the first cycle.  Coadministration of pazopanib increased paclitaxel 
mean Cmax and AUC0-8 approximately 20-35% (Suttle, 2007). 
 
Age, body weight, gender, and race had no significant influence on pazopanib PK. 
1.5.6 
Effects of Pazopanib in Differentiated Thyroid Cancer Patients 
A three-outcome, one-stage Phase II clinical trial of pazopanib (800 mg orally daily until 
progression or intolerance) in patients with rapidly progressive radioiodine-refractory 
differentiated thyroid cancers is in progress. The median number of 4 week cycles administered 
thus far is 11 (range: 1-19+, total: 343+), with 14 of 37 patients still receiving protocol therapy.  
Fourteen of the 37 evaluable patients required dose reductions due to: elevated AST/ALT 
levels (4 patients), hypertension (2 patients), neurologic difficulties (1 patient), mucositis (1 
patient), radiation recall tracheitis (1 patient), diarrhea with intermittent phlebitis (1 patient), 
nausea and colonic inflammation (1 patient), fatigue with weight loss (1 patient), cough (1 
patient), and abdominal pain (1 patient).  In addition, 2 patients discontinued treatment due to 


 
 
 
 
 
 
17 
             RTOG 0912, Version Date: March 6, 2020 
adverse hemorrhagic events (one grade 3 GI hemorrhage and one grade 4 intracranial 
hemorrhage in the absence of brain metastases; both events were self limited with complete 
patient recovery upon discontinuation of study drug). Two patients (5.4%) died while on study: 
a 62 year old male presenting emergently with tachycardia, hypotension, and dehydration died 
during his first cycle of treatment due to an acute massive myocardial infarction; a 63 year old 
male hospitalized with acute cholecystitis after 2 cycles of treatment requiring surgery that was 
later complicated by a bowel volvulus with perforation at the site of a remote surgical 
anastomosis. 
 
Ten of the 20 patients (50%) who were not taking hypertensive medications prior to the start of 
study treatment required antihypertensive medication. Modest levels of fatigue, altered taste 
perception, and skin/hair hypopigmentation also were commonly encountered. 
 
There were no complete responses, but 18 confirmed RECIST partial responses (PR) [48.6%; 
90% CI: 34.3-63.2%]. The duration of response (time from when PR first documented to 
disease progression) ranged from 3.5+ months to 15+ months, with responses continuing over 
a year in 4 patients. In terms of cell type, there were 8 PRs among the 11 patients with follicular 
(72.7%), 5 PRs among the 11 patients with Hürthle cell (45.4%), and 5 PRs among the 15 
patients with papillary (33.3%) histologies. 
   
Twenty-five of 37 patients (67.6%; 9 with follicular, 6 with Hürthle cell, and 10 with papillary) 
remained on study treatment for at least 6 months.  The percentage decrease in tumor size 
from pre-treatment levels ranged from 30 to 59% in 19 of 37 patients (Figure 1 below) while the 
percentage decrease in thyroidglobulin from pre-treatment levels was at least 30% in 29 of the 
33 patient who were anti-thyroidglobulin antibody negative.  Examination of the effects of 
pazopanib on the rates of RECIST tumor measurement progression among responders (shown 
for 9 representative DTC patients in figure 1a) suggests that pazopanib therapy may be 
modifying disease natural history in a sizable fraction of patients. 
 
 
 
 
 
 
 
 
 
 
 
Figure 1:  Maximum Percentage Change in Tumor Size, DTC Patients 
-70 
-60 
-50
-40
-30 
-20 
-10 
0
10
20
30
Papillary 
Hürthle cell* 
Follicular 


 
 
 
 
 
 
18 
             RTOG 0912, Version Date: March 6, 2020 
 
Figure 1a: RECIST Changes In 9 Sample Patients 
 
1.5.7  
Effects of Pazopanib in Anaplastic Thyroid Cancer Patients  
A cohort of ATC patients are being treated with pazopanib in parallel with the trial of pazopanib 
in DTC discussed above. Although this trial has not yet reached interim analysis, there has 
been evidence of antitumor effect in several patients, with tumor shrinkage and cavitation of 
pulmonary nodules observed in several patients as illustrated in Figure 2 below.  However, to 
date, antitumor effects have not been durable in ATC patients attaining a response to 
pazopanib in the ongoing trial. 


 
 
 
 
 
 
19 
             RTOG 0912, Version Date: March 6, 2020 
Figure 2: Films Of 2 ATC Patients On Pazopanib 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5.8  
In Vitro effects of Pazopanib Combined with Paclitaxel in Anaplastic Thyroid Cancer Cell Lines  
There are no data available at present related to the combined effects of paclitaxel and 
pazopanib in ATC in patients.  Pilot studies in ATC cell lines, however, indicate that pazopanib 
has single agent effects at clinically achievable concentrations (Figure 3 below). Moreover, 
pazopanib can enhance the in vitro anti-tumor effects of paclitaxel in ATC cell lines, as shown 
in KTC2 ATC cells in panels B and C below (Figure 3). 
 
Figure 3: Pazopanib And Paclitaxel In ATC Cell Lines 
 
1.6  
Rationale to Use Paclitaxel, Pazopanib, and Radiation Therapy To Treat Anaplastic Thyroid Cancer 
Given the dismal prognosis of ATC patients (<10% 1-year survival), the fact that these tumors are highly 
vascular, the potential utility of VEGF inhibitors as radiosensitizers, and the preliminary evidence of 
activity in thyroid cancers of small molecule VEGF inhibitors including sorafenib, sunitinib, and pazopanib, 
it is logical to add a VEGF inhibitor to the current standard approach to ATC. In particular, bevacizumab, 


 
 
 
 
 
 
20 
             RTOG 0912, Version Date: March 6, 2020 
a monoclonal antibody that potently inhibits VEGF, when added to a platin/paclitaxel combination in a 
phase III study in lung cancer has produced an improvement in survival (Sandler 2006). In HNSCC, NRG 
Oncology has shown that the combination of cisplatin/paclitaxel/radiation therapy also can be given 
together safely with good efficacy (Garden 2004). Data has shown that doses of paclitaxel can be given 
as high as 50 mg/m2 weekly with radiation therapy (Hainsworth 2002). 
 
Paclitaxel and pazopanib have been evaluated in a phase I study (Tan 2008). This study showed that 
without radiation therapy, paclitaxel 80 mg/m2 weekly with pazopanib 800 mg daily could be given safely. 
Only 1 dose limiting toxicity was seen at this dose (grade 3 groin abscess). However, pazopanib did 
increase the mean paclitaxel AUC by 45% and Cmax by 40%. Due to this increase in mean exposure, it 
was felt by representatives at GSK and CTEP that it would be more reasonable to decrease the 
pazopanib dose during radiation therapy by 50% (i.e., 400 mg daily) and that the paclitaxel should be 
reduced by 25% after radiation therapy (Personal Communication with CTEP, 2009). 
 
Due to logistical reasons as well as patient ease considerations, it was decided by the investigators that 
standard fractionation using 2 Gy per fraction to a total dose of 66 Gy will be the radiotherapy regimen. 
This is biologically equivalent in terms of cell kill to the hyperfractionated regimen (Wang 2006). 
 
1.7  
Current Experience of the Use of Paclitaxel, Pazopanib, and Radiation Therapy to Treat Anaplastic 
Thyroid Cancer (6/5/14) 
Three run-in components for RTOG 0912 have been completed.  
• 
After the first run-in, there was concern about patients’ difficulty in swallowing pazopanib pills. It 
was decided to do a second run-in with a pazopanib slurry, and due to the lack of data in adults, 
pharmacokinetic data was collected during the 2nd run-in.  
• 
After the 2nd run-in, it was noted there was an increase in elevated liver enzymes requiring 
pazopanib to be held during the first few weeks of radiation therapy correlating to elevated serum 
levels of pazopanib on day 15 of treatment (prior to the start of radiation therapy). Therefore, a 
3rd run-in component was completed with a lower dose of pazopanib during the pre-radiation 
therapy period. 
• 
After the 3rd run-in, it was felt that toxicities were consistent with what is seen with concurrent 
chemotherapy and radiation therapy for the treatment of anaplastic thyroid cancer as defined in 
the protocol. Patients at this dose level received pazopanib slurry at 400 mg daily with paclitaxel 
80 mg/m2 weekly for 2-3 weeks followed by radiation therapy with paclitaxel at 50 mg/m2 weekly 
and pazopanib slurry at 300 mg daily. 
 
 
2.0 OBJECTIVES (6/5/14) 
2.1  
Primary Objective for Run-In Components  
To evaluate the safety of IMRT, paclitaxel, and pazopanib suspension 
 
 
2.2 
Primary Objective for Phase II Component 
To evaluate and compare overall survival at 1 year from study registration 
 
2.3 
Secondary Objectives for Phase II Component 
2.3.1 
To evaluate local-regional control at 6 and 12 months; 
2.3.2 
To evaluate the rate of grade 4 (CTCAE, v. 4.0) hemorrhage, grade 4 febrile neutropenia, or 
any Grade 5 adverse event assessed to be definitely, probably, or possibly related to the 
induction or concurrent treatment components of the protocol regimen; 
2.3.3 
To evaluate the rates of other adverse events (CTCAE, v. 4.0) assessed to be definitely, 
probably, or possibly related to the induction or concurrent treatment components of the 
protocol regimen; 
2.3.4 
To evaluate the rate of treatment discontinuation due to toxicity during the induction or 
concurrent treatment components of the protocol regimen; 
2.3.5 
To evaluate response (as per RECIST) of the primary site following the treatment component in 
subjects with measurable disease prior to chemoradiation.  
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
3.0 PATIENT SELECTION (6/5/14) 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED.  For questions 
concerning eligibility, please contact the study data manager. 
 
3.1 
Conditions for Patient Eligibility (3/8/16) 
3.1.1 
Pathologically (histologically or cytologically) proven diagnosis of anaplastic thyroid cancer (a 
diagnosis that is noted to be “consistent with anaplastic thyroid cancer” with the presence of a 
thyroid mass is acceptable); 
 
 
Note: Tissue collection for central review is mandatory (see Section 10.2), but central review is 
not required for eligibility. Due to the aggressiveness of this disease, treatment will be started 
prior to central review.   
3.1.2 
If there was a total or partial thyroidectomy completed within 3 months of enrollment, the 
surgical specimen must show the area of anaplastic thyroid cancer to be at least 1 cm in 
greatest dimension. 
3.1.3 
The following minimum diagnostic workup is required: 
• 
History/physical examination within 2 weeks prior to registration; 
• 
Imaging of neck and brain (CT scan or MRI) and chest/abdominal imaging (chest x-ray or 
chest CT scan, or full body PET/CT are acceptable) within 4 weeks prior to registration;  
 
Note: The CT scan of the neck must be done with contrast or if an MRI is done, with gadolinium; 
therefore, the CT portion of a full body PET/CT has to be a high resolution CT to be acceptable 
for eligibility.  
 
Abdominal imaging must cover the liver and adrenal glands; therefore, separate imaging is not 
required if these areas are covered by a chest CT scan. 
• 
 Electrocardiogram within 10 days prior to registration; 
3.1.4 
Zubrod Performance Status 0-2; 
3.1.5 
Age ≥ 18 years of age; 
3.1.6 
CBC/differential within 10 days prior to registration on study, with adequate bone marrow and 
organ function defined as follows: 
• 
Absolute neutrophil count (ANC) ≥ 1500 cells/mm3;  
• 
Platelets ≥ 100,000 cells/mm3;  
• 
Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb 
≥ 9.0 g/dl is acceptable); 
3.1.7 
Adequate hepatic function within 10 days prior to registration, defined as follows: 
• 
Total bilirubin < 1.5 x institutional ULN (except for patients with Gilbert’s syndrome and 
elevations of indirect bilirubin); 
• 
AST or ALT < 2.5 x institutional ULN; Note: patients who have both bilirubin > ULN and 
AST/ALT > ULN are not eligible (unless they have Gilbert syndrome and elevations of 
indirect bilirubin). 
3.1.8 
Adequate renal function, defined as follows: 
• 
Spot urine protein to creatinine ratio (UPCR) < 1 or a 24-hour urine protein collection < 1 
gm within 10 days prior to registration; 
• 
Creatinine <1.5 mg/dl or within normal institutional limits within 10 days prior to 
registration; Note: if neither criteria is met, the creatinine clearance must be > 50 
ml/min/1.73m2 per either 1) the Cockcroft-Gault equation; 2) Jeliffe method; or 3) 12- or 
24-hour urine collection.  
3.1.9 
(10/28/10) Serum electrolytes including sodium, potassium, BUN, creatinine, glucose, 
magnesium, phosphate, and calcium within 10 days prior to registration; 
3.1.10 
Documentation of the patient’s history of QTc prolongation, family history of prolonged QTc, 
and relevant cardiac disease within 10 days prior to registration; 
3.1.11 
(7/15/13) Evaluation of the patient’s medications within 10 days prior to registration with attempt 
to change any medication that affects CYP3A4 (see Sections 7.4.1, 9.2, and Appendix VII). 
3.1.12 
(4/18/12) Blood pressure ≤ 140/90 within 10 days of registration (must be taken and recorded 
by a health care professional); Note: if the systolic blood pressure is > 140 and/or diastolic 
blood pressure is > 90 at the time of registration, the patient’s blood pressure must be 
controlled. Systolic blood pressure must be < 140 and diastolic blood pressure must be < 90 on 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
at least 2 separate measurements prior to the start of treatment (see Section 4.1.1), and the 
treating physician must believe that this is feasible in order to enroll the patient. 
3.1.13 
PT/INR/PTT within 1.2 x the upper limit of normal within 10 days prior to registration unless the 
patient is receiving Coumadin and has a stable INR that is in range for the desired level of 
anticoagulation; 
3.1.14 
Negative pregnancy test (serum or urine) within 10 days of registration in women of child-
bearing potential; 
3.1.15 
Women of childbearing potential and male participants who are sexually active must agree to 
practice adequate contraception during treatment and for 6 months post-treatment; 
3.1.16 
The patient must provide study specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility (3/8/16) 
3.2.1 
Known active invasive malignancy (except non-melanomatous skin cancer or anaplastic thyroid 
cancer; the presence of prostate cancer confined to the prostate with a PSA < 1 for more than 6 
months also is allowed); 
3.2.2 
Prior systemic chemotherapy for anaplastic thyroid cancer;  
• 
Patients who have had chemotherapy or radiotherapy within 4 weeks of registration (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not 
recovered from adverse events due to agents administered > 4 weeks previously; 
• 
Patients receiving other investigational agents. 
3.2.3 
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields; 
3.2.4 
Patients with any of the following cardiovascular conditions within the past 6 months: 
• 
Cerebrovascular accident (CVA) or transient ischemic attack (TIA);  
• 
Admission for unstable angina; 
• 
Myocardial Infarction; 
• 
Cardiac angioplasty or stenting;  
• 
Coronary artery bypass graft surgery;  
• 
Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been 
treated with therapeutic anticoagulation for less than 6 weeks 
• 
arterial thrombosis;  
• 
Symptomatic peripheral vascular disease; 
• 
Class III or IV heart failure as defined by the NYHA functional classification system (see 
Appendix III); Note: a patient who has a history of Class III heart failure and is 
asymptomatic on treatment may be considered eligible for the study. 
3.2.5 
Certain medications that are associated with a risk for QTc prolongation and/or Torsades de 
Pointes, although not prohibited, should be avoided or replaced with medications that do not 
carry these risks, if possible.  Comprehensive lists of agents that that are associated with a risk 
for QTc prolongation and/or Torsades de Pointes can be found in Appendix VI. 
3.2.6 
Patients who require heparin (other than low-molecular weight heparin);  
3.2.7 
Patients with any condition that may impair the ability to absorb oral medications/investigational 
product including: 
• 
prior surgical procedures affecting absorption including, but not limited to major resection 
of stomach or small bowel; 
• 
active peptic ulcer disease; 
• 
malabsorption syndrome.  
3.2.8 
Patients with any condition that may increase the risk of gastrointestinal bleeding or 
gastrointestinal perforation, including: 
• 
active peptic ulcer disease; 
• 
known intraluminal metastatic lesions; 
• 
inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease) or other 
gastrointestinal conditions which increase the risk of perforation; 
• 
history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 
28 days prior to beginning study treatment.    
3.2.9 
History of hemoptysis within 30 days of registration. Note: patients who have minimal bleeding 
from the mouth, which is clearly not related to a source in the lungs, i.e. surgery such as a non-
lung biopsy, are eligible only after good hemostasis has been documented; 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
3.2.10 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or 
psychiatric illness/social situations that would limit compliance with study requirements; 
3.2.11 
Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception; this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic.  
3.2.12 
Prior allergic reaction to the study drug(s) involved in this protocol;  
3.2.13 
QTc prolongation defined as a QTc interval > 480 msecs or other significant EKG abnormalities 
are ineligible; Note: if unsure about EKG abnormality, the treating physician should discuss this 
with Drs. Sherman or Bible. 
3.2.14 
Known brain metastasis;  
3.2.15 
HIV-positive patients on combination antiretroviral therapy because of the potential for 
pharmacokinetic interactions with 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.  
3.2.16 
(7/15/13) Certain medications that act through the CYP450 system are specifically prohibited in 
patients receiving pazopanib and others should be avoided or administered with extreme 
caution.  
• 
Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinivir, retonavir, saquinavir, telithromycin, 
voriconazole may increase pazopanib concentrations and are prohibited; although, in 
exceptional circumstances, they may be administered in conjunction with lowering the 
dose of pazopanib by 50% of what would otherwise be administered. Grapefruit juice is 
also an inhibitor of CYP450 and should not be taken with pazopanib (see Section 7.4.1). 
• 
Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib concentrations, 
are strictly prohibited (see Section 7.4.1). 
• 
Medications that have narrow therapeutic windows and are substrates of CYP3A4, 
CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution  
(see Section 7.4.1). 
• 
A list of medications that are specifically prohibited or those that should be used with 
caution during this trial of pazopanib can be found in Section 9.0.  Comprehensive lists of 
agents that could affect pazopanib through the cytochrome P450 system can be found in 
Appendix VII. 
 
 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT 
NOTE: This section lists baseline evaluations needed before the initiation of protocol treatment that do 
not affect eligibility. 
 
4.1 
Required Evaluations/Management (2/10/15) 
4.1.1 
Systolic blood pressure must be  ≤ 140 and diastolic blood pressure must be ≤ 90 on at least 2 
separate measurements within 2 weeks prior to treatment, if > 140/90 at baseline (see Section 
3.1.12); 
4.1.2 
All wounds, whether surgical or other, must be completely healed prior to the initiation of 
treatment. 
 
4.2 
Highly Recommended Evaluations/Management 
The following pre-treatment evaluations/interventions are not required but are highly 
recommended: 
4.2.1 
PET/CT scan within 2 weeks prior to registration; 
4.2.2 
Dental evaluation and, if applicable, prophylaxis within 12 weeks prior to treatment (see 
Appendix IV); 
4.2.3 
Nutritional evaluation for a prophylactic gastrostomy (PEG) tube placement anytime prior to 
treatment; 
4.2.4 
Serum Thyroid Stimulating Hormone (TSH) suppression (i.e. lowering TSH below the lower 
limits of normal) through the use of thyroid hormone replacement (e.g. levothyroxine) should be 
considered at the start of and throughout the treatment course. However, the decision to 
suppress TSH is up to the treating physician after weighing the risks and benefits for an 
individual patient. If the treating physician is unsure or uncomfortable with this, it is strongly 
recommended that an endocrinologist be consulted. 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
 
 
5.0 REGISTRATION PROCEDURES (24-FEB-2020) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all individuals 
contributing to NCI-sponsored trials to register and to renew their registration annually. To register, all individuals 
must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator (IVR), Non-Physician 
Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, Rave, or acting 
as a primary site contact) must complete their annual registration using CTEP’s web-based Registration and 
Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications (e.g., Roster 
Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited access to 
NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, license, and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and Cancer 
Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs must list all clinical practice 
sites and Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow 
the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
 
In addition, all investigators act as the Site-Protocol PI or as, consenting/treating/drug shipment must be rostered 
at the enrolling site with a participating organization (i.e., Alliance). Additional information is located on the CTEP 
website at https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
Note: This trial is not utilizing the services of the ITC for dosimetry digital treatment data submission. 
See below for information on installing TRIAD for submission of digital RT data prior to enrolling 
patients. 
 
IMRT is required for this study. 
5.1 
Pre-Registration Requirements for IMRT Treatment Approach (6/5/14) 
5.1.1 
In order to utilize IMRT on this study, the institution must have met specific technology 
requirements and have provided baseline physics information. Instructions for completing these 
requirements or determining if they already have been met are available on the Imaging and 
Radiation Oncology Core (IROC) Houston (former Radiological Physics Center [RPC]) web 
site. Visit  http://irochouston.mdanderson.org and select “Credentialing” and “Credentialing 
Status Inquiry”. 
 
 
An IMRT phantom study with the IROC Houston must be successfully completed (if the 
institution has not previously met this IMRT credentialing requirement). Instructions for 
requesting and irradiating the phantom are available on the IROC Houston web site at  
http://irochouston.mdanderson.org; select “Credentialing” and “NRG Oncology”. Upon review 
and successful completion of the phantom irradiation, the IROC Houston will notify both the 
registering institution and NRG Oncology that the institution has completed this requirement. 
Subsequently, NRG Oncology will update the RSS web site. 
5.1.2 
The institution or investigator must update a current or complete a new Facility Questionnaire 
(available on the IROC Houston web site at http://irochouston.mdanderson.org ) 
and 
then 
complete a credentialing status inquiry form also found on the IROC Houston web site, to 
determine if the site has met all of the requirements. This will be completed in place of updating 
the previous Facility Questionnaire. When the requirements are met, (prior to enrolling 
patients), the site and NRG Oncology will be notified.  NRG Oncology then will update the RSS 
database.  
 
5.2 
Digital RT Data Submission to NRG Using TRIAD (24-FEB-2020) 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) image 
exchange application. TRIAD provides sites participating in clinical trials a secure method to 
transmit images. TRIAD anonymizes and validates the images as they are transferred. 
TRIAD Access Requirements: 
Site staff that will be submitting images via TRIAD will need to register with CTEP and have a 
valid and active CTEP-IAM account.  
• 
Must be registered as an Associate, Associate Plus, Non-Physician Investigator, or 
Investigator registration type. Refer to the CTEP Registration Procedures section for 
instructions on how to request a CTEP-IAM account and complete registration in Registration 
and Credential Repository (RCR). 
To submit images, site staff must hold the TRIAD Site User role on an NCTN or ETCTN roster. 
Individuals requiring a TRIAD Site User role should contact the person holding a primary role at 
the site for their affiliated NCTN or ETCTN roster.  
All individuals on the Imaging and Radiation Oncology Core provider roster have access to TRIAD, and 
may submit images for credentialing purposes, or for enrollments to which the provider is linked in OPEN. 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to install the TRIAD 
application on their workstation. TRIAD installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password and RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-Support@acr.org or 1-
703-390-9858. 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
5.3         Regulatory Pre-Registration Requirements (06-MAR-2020) 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
5.3.1 
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials Network 
(NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases after March 1, 
2019, all U.S.-based sites must be members of the NCI Central Institutional Review Board (NCI CIRB). In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at the site after March 
1, 2019. Local IRB review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should continue to submit 
Research Ethics Board (REB) approval to the CTSU Regulatory Office following country-specific 
regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local Context (SSW) 
to the CIRB using IRB Manager to indicate their intent to open the study locally. The NCI CIRB’s approval 
of the SSW is automatically communicated to the CTSU Regulatory Office, but sites are required to 
contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for 
applying NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network 
or protocol level. Questions about establishing site preferences can be addressed to the CTSU Regulatory 
Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office using the 
Regulatory Submission Portal located in the Regulatory section of the CTSU website. Acceptable 
documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB approval) 
must meet the following criteria to complete processing of the IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and on at 
least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR profile; 
and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the CTSU members’ 
website. Permission to view and download this protocol and its supporting documents is restricted based 
on person and site roster assignment. To participate, the institution and its associated investigators and 
staff must be associated with the LPO or a PO on the protocol.  
• 
Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM username 
and password; 
• 
Click on Protocols in the upper left of your screen 
o 
Enter the protocol number in the search field at the top of the protocol tree, or 


 
 
 
 
 
 
27 
             RTOG 0912, Version Date: March 6, 2020 
o 
Click on the By Lead Organization folder to expand, then select RTOG and protocol 
number RTOG-0912; 
• 
Click on Documents, select Site Registration, and download and complete the forms provided. 
(Note: For sites under the CIRB initiative, IRB data will load automatically to the CTSU as 
described above.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log on to the CTSU members’ website → Regulatory 
→ Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status 
You can verify your site’s registration status on the members’ side of the CTSU website.  
• 
Log on to the CTSU members’ website; 
• 
Click on Regulatory  at the top of your screen; 
• 
Click on Site Registration;  
• 
Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined above. It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
5.3.2 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
In addition to the requirements above, Canadian institutions must also complete and submit 
additional regulatory documents to the CTSU Regulatory Office (as noted in section 5.3.1): 
• 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site Information Form,  
• 
Qualified Investigator Undertaking Form, and  
• 
Research Ethics Board Attestation Form.  
 
5.4 
Registration (24-FEB-2020) 
5.4.1 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
 
Requirements for OPEN access:   
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a minimum 
of an AP registration type; 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, 
the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their Form FDA 
1572 in RCR.  
 
Prior to accessing OPEN, site staff should verify the following: 


 
 
 
 
 
 
28 
             RTOG 0912, Version Date: March 6, 2020 
 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
 
6.0 RADIATION THERAPY (3/25/14) 
Note: This trial is not utilizing the services of the ITC for dosimetry digital treatment data submission. 
See Section 5.2 for information on installing TRIAD for submission of digital RT data prior to enrolling 
patients. 
 
IMRT is required for this study. See the pre-registration requirements for IMRT in Section 5.1. 
 
IMRT must begin within 3 weeks from the start of Drug Therapy and at least 5 days (120 hours) after 
the last dose of pre-IMRT paclitaxel (see Section 7.0).  
 
6.1 
Dose Specifications (6/5/14) 
Prescription dose shall be according to the following (also see Section 6.4):  
6.1.1 
PTV66 (CTV66 + margin) will receive 66 Gy in 33 fractions at 2 Gy per fraction. PTV59.4 (CTV59.4 
+ margin) will receive 59.4 Gy in 33 fractions at 1.8 Gy per fraction. All targets will be delivered 
simultaneously. Treatment will be delivered once daily, 5 fractions per week, over 6.5 weeks 
6.1.2 
The reported doses for PTV66 shall include the prescription dose as well as the maximum point 
dose (maximum dose encompassing 0.03 cc volume) for that PTV, % PTV receiving ≥ 93%, ≥ 
110% and ≥  115% of the prescription dose of that PTV, and the mean dose for that PTV (see 
plan scoring table in Section 6.6.2).  
 
All plans shall be normalized such that 95% of the volume of PTV66 is covered by the 66 Gy 
isodose surface while more than 95% of the volume of PTV59.4 being covered by the 59.4 Gy 
isodose surface (see plan scoring table in Section 6.6.2)   
 
6.2 
Technical Factors (3/25/14) 
6.2.1 
External Beam Equipment and Beam Delivery Methods 
 
Megavoltage equipment capable of delivering static intensity modulation with a multileaf 
collimator or dynamic intensity modulation (using a multileaf collimator or tomotherapy) is 
required. Volume arc delivery techniques can be used, but re-credentialing might be necessary 
(see Section 5.1.1). Institutions should contact the IROC Houston if they intend to use volume 
arc delivery.    
 
6.3 
Treatment Planning, Imaging and Localization Requirements   
6.3.1  
The immobilization device should at least include the head and neck.  It is strongly encouraged 
that the participating centers also include the shoulders in the immobilization.  This is to further 
ensure accurate patient set-up on a daily basis.   
6.3.2  
Treatment planning CT scans will be required to define gross target volume(s), and clinical 
target volume(s). The treatment planning CT scan should be acquired with the patient in the 
same position and using the same immobilization device as for treatment. 
 
 
 
All tissues, including entire lung volumes (both lungs), to be irradiated must be included in the 
CT scan.  CT scan thickness should be ≤ 0.3 cm slices through the region that contains the 
primary target volumes.  The regions above and below the target volume may be scanned with 
0.5 cm slice thickness.   


 
 
 
 
 
 
29 
             RTOG 0912, Version Date: March 6, 2020 
6.3.3 
The GTV and CTV (see Section 6.4), and normal tissues must be outlined on all CT slices in 
which the structures exist.   
 
6.4 
Treatment Planning/Target Volumes (7/15/13) 
The definition of volumes will be in accordance with the 1993 ICRU Report #50, but the dose reporting 
and prescription are specified in Sections 6.1 and 6.6.2.   
6.4.1 
The Gross Tumor Volume (GTV) is defined as all known gross disease determined from CT, 
clinical information, and endoscopic findings. Grossly positive lymph nodes are defined as any 
lymph nodes > 1 cm or nodes with a necrotic center.  It is strongly encouraged that the 
radiation oncologist outline the radiologic extent of the primary tumor and neck nodes along 
with a radiologist. Whenever possible, it is recommended that the diagnostic images be fused 
to the planning CT scan image dataset to more accurately define the GTV. To further subdivide 
the GTV, gross disease at the primary site is designated as GTV-P and clinically involved gross 
lymph nodes are designated GTV-N.  In situations where the patient underwent surgery prior to 
IMRT, the GTV is defined as the preoperative gross disease plus the post-operative surgical 
bed. 
6.4.2 
The Clinical Target Volume (CTV): See the bulleted list below for delineation details. 
For patients without complete surgical resection: In terms of the GTV (GTV-P and GTV-N), a 
margin of ≥ 5 mm should be given circumferentially around the GTV (GTV-P and GTV-N) and 
this volume will be called the CTV66 (CTV66-P and CTV66-N).* This margin can be reduced to as 
low as 1 mm for tumors in close proximity to critical structures, e.g., tumors next to the spinal 
cord. For regions deemed to be at high risk for microscopic disease, all potential routes of 
spread for primary and nodal GTVs should be delineated by the treating radiation oncologist.  
This is known as CTV for subclinical disease or CTV59.4*  
• 
For patients who have undergone a complete surgical resection: CTV66 should include the 
preoperative gross disease at the primary disease site or any grossly involved lymph 
nodes as well as the post-operative bed. A CTV59.4 also can be delineated if the region is 
at risk for microscopic spread and the region has not had surgery. 
• 
To further define the subclinical region at risk for microscopic spread at the primary 
disease site, CTV59.4-P includes CTV66-P +5 mm margin and ensuring that the following is 
generously covered: tracheal-esophageal groove, levels II-VI, upper mediastinum to the 
level of the carina. At the discretion of the treating physician, level I and the 
retropharyngeal nodes can be covered when indicated.  
 
 
Note: The outer most boundary of CTV59.4-P should be at least 10 mm from the GTV-P. 
Typically, it is larger as coverage of the regions defined above is necessary.  In regions near 
the spinal cord, the margin can be as low as 1 mm.   
• 
(4/19/11) Regarding the lymph nodal subclinical regions, CTV59.4-N includes, as stated 
above, levels II-VI bilaterally and the upper mediastinum down to the level of the carina. At 
the discretion of the treating physician, level I and the retropharyngeal nodes can be 
covered when indicated. 
 
Note: The outer most boundary of the CTV59.4-N should be at least 10 mm away from the GTV-
N.  In regions near the spinal cord, the margin can be as small as 1 mm. 
 
 
 
Note: The consensus guideline, available on the NRG Oncology/RTOG web site,  
http://www.rtog.org/CoreLab/ContouringAtlases/HN.aspx for head and neck cancer is for NODE 
NEGATIVE patients only. One can use this guideline to treat the appropriate nodal levels only 
for NODE NEGATIVE patients for whom surgery was not done.  
6.4.3 
A separate planning Target Volume (PTV) will provide a margin around the CTV’s to 
compensate for the variabilities of treatment set up and internal organ motion. A minimum of 5 
mm around the CTV’s is required in all directions to define each respective PTV (PTV66, 
PTV59.4). Careful consideration should be made when defining the superior and inferior margins 
in three dimensions.  Note that at any given point, the margin from the GTV at the primary 
site to the PTV59.4 should be at least 15 mm.  This also applies to post-operative cases. 
The only exception is when the tumor is close to the spinal cord where CTV margin may 
be reduced to 1 mm with the intent of protecting the spinal cord. 
6.4.4 
Planning 
 
The treatment plan used for each patient will be based on an analysis of the volumetric dose, 
including dose-volume histogram (DVH) analyses of the PTVs and critical normal structures. An 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
“inverse” planning using computerized optimization should be used. The treatment aim will be 
the delivery of radiation to the PTVs and the exclusion of non-involved tissue. 
 
6.5 
Critical Structures (6/5/14) 
6.5.1 
Note: Structures marked “required” in the table below must be contoured and submitted for 
review. Resubmission of data may be required if labeling of structures does not conform 
to the standard DICOM name as listed. 
 
The following table outlines the naming of the various normal and critical structures for 
submission to TRIAD: 
 
New Standard Name 
Description 
GTV 
Required 
CTV_6600  
Primary Tumor Bed plus involved nodes  
Required 
CTV_5940  
At risk regions  
Required 
PTV_6600  
CTV-PTV 5 mm margin  
Required 
PTV_5940  
CTV-PTV 5 mm margin  
Required 
SpinalCord 
Spinal Cord  
Required 
SpinalCord_05 
Planning risk Volume of 5 mm margin 
Required 
Parotid_L 
Left Parotid  
Required 
Parotid_R 
Right Parotid  
Required 
OralCavity 
Oral Cavity 
Required  
BrachialPlexus 
Brachial Plexus  
Required 
Mandible 
Mandible  
Required 
Submandibula_L 
Left Submandibular gland 
Contouring Optional  
Submandibula_R 
Right Submandibular gland 
Contouring Optional  
Esophagus_Up 
Cervical Esophagus  
Required 
LarynxGSL 
Glottic/Supraglottic Larynx  
Required 
External 
External border of patient used to define Unspecified 
Tissue  
Required 
Lungs 
Total lung 
Required 
NonPTV 
Unspecified tissues outside PTV 
Contouring Optional  
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
6.5.2 
Critical Normal Structures  
 
Surrounding critical normal structures, including spinal cord, parotid glands, skin (in the region 
of the target volumes), oral cavity, mandible, brachial plexus, esophagus and glottic larynx 
must be outlined.  
 
 
Physicians should assist the planner in identifying the critical normal structures. A planning risk 
volume (PRV) is applied only to the true spinal cord. The spinal cord. PRV will be defined as a 
three-dimensional margin of 5 mm. The normal tissues will be contoured and considered as 
solid organs.  The tissue within the skin surface and outside all other critical normal structures 
and PTVs is designated as unspecified tissue. 
 
 
DVH’s must be generated for all critical normal structures, any corresponding PRVs, and the 
unspecified tissues.  Dose constraints for critical normal structures are listed in Sections 6.6.3 
and 6.6.4. 
 
 
 
 
The treating physician is encouraged to call Dr. Lee, the Co-Principal Investigator, at 
212-639-3341 should questions arise. 
6.5.3 
The method used for tissue heterogeneity calculations shall be reported. The dose prescription 
is to be based on a dose distribution corrected for heterogeneities. 
6.5.4 
Planning Priorities 
 
Critical normal structure constraints followed by the prescription goals are the most important 
planning priorities. The priorities in addressing the protocol aims and constraints will be in the 
following order:  
1) Spinal Cord Dose Constraints (Section 6.6); 
2) Dose coverage to tumor volumes (Section 6.6.2); 
3) Normal structure dose constraints for plan scoring (Section 6.6.3); 
4) Other normal structures not used for plan score (Section 6.6.4).  
 
6.6 
Compliance Criteria (9/30/15) 
6.6.1 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Holidays and weekends are not considered treatment breaks. 
Treatment breaks, if necessary, should ideally not exceed five treatment days at a time and ten 
treatment days total. Treatment breaks should be allowed only for resolution of severe acute 
toxicity and/or for intercurrent illness and not for social or logistical reasons. Any treatment 
break(s) exceeding two treatment days for reasons other than toxicity/illness will be considered 
a protocol deviation.   
6.6.2 
Treatment plans will be scored as Per Protocol, Variation Acceptable, or Deviation 
Unacceptable.  Institutions are encouraged to generate treatment that fall within the dose limits 
defining the per protocol category (see tables below). For those target to critical structures 
geometries that are more challenging, some variation from the per protocol dose limits is 
acceptable.  The variation acceptable dose limits are given in the table below.  Plans that fall 
outside of the variation acceptable dose limits are scored as deviation unacceptable. 
 
 
Per Protocol 
Variation Acceptable 
Variation 
Unacceptable 
                                                                        PTV_6600 
 
Total RT dose to 95% 
of the PTV_6600 
 66 Gy 
66 Gy - 62.7 Gy 
< 62.7 Gy 
Percentage of 
PTV_6600 receiving 
61.4 Gy (93% of 66 
Gy) 
≥ 99% 
≥ 97% 
≤ 97% 
Percentage of  
PTV_6600 receiving 
72.6 Gy (110% of 
66Gy) 
≤ 20% 
≤ 40% 
≥ 40%  
Percentage of 
≤ 5% 
<20% 
≥ 20% 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
PTV_6600 receiving 
75.9 Gy (115% of 66 
Gy) 
Mean dose of 
PTV_6600 
≤ 70.4 Gy 
70.4 -72.6 Gy 
≥ 72.6 Gy 
                                                                               
                                                                                     PTV_5940 
 
Total RT dose to  95% 
of PTV_5940 
59.4 Gy 
59.4 -56.4 Gy 
< 56.4 Gy 
Percentage PTV_5940 
receiving 55.2 Gy 
(93% of 59.4 Gy) 
≥ 99% Gy 
≥ 97% 
≤ 97% 
 
6.6.3 
Acceptable Dose Limits On Critical Structures for Plan Scoring  
 
                                                                   
                                                                              Critical Normal Tissue 
Maximum dose  to 0.03 
cc of SpinalCord 
≤ 45 Gy 
 45 - 48 Gy 
≥ 48 Gy 
Maximum dose to 0.03 
cc of SpinalCord_05 
≤ 50 Gy 
 50-54 Gy 
≥ 54 Gy 
Mean dose to one of 
Parotid glands 
≤ 26 Gy 
 
 
50% of one of the 
Parotid glands 
 
 ≤ 30 Gy 
≥ 30 Gy 
20 cc of both parotids 
 
 ≤ 20 Gy 
≥ 20 Gy 
Percentage of Lungs 
receiving 20 Gy 
≤ 20% 
≤ 25% 
≥ 25% 
  
   
  
  
 
6.6.4 
Suggested Dose Limits Not for Plan Scoring (Should Not Compromise Tumor Volume 
Coverage)  
 
Oral cavity (excluding PTV’s) 
Mean dose  ≤ 35 Gy 
Submandibular glands 
Mean Dose  ≤ 39 Gy 
 LarynxGSL 
Mean dose  ≤ 60 Gy 
Maximum dose to  1cc of un-
specified Tissue  
≤ 69.3 Gy 
Maximum dose to 0.03cc of 
BrachialPlexus  
Maximum dose to 0.03cc of 
BrachialPlexus when Tumor 
Volume is overlapped with 
BrachialPlexus 
≤ 60 Gy 
 
 
≤ 66 Gy 
 
 
6.7 
R.T. Quality Assurance Reviews (6/5/14) 
The Co-Principal Investigator, Nancy Lee, MD, will remotely perform RT Quality Assurance Reviews. 
These reviews will be ongoing and will be facilitated by IROC Philadelphia RT . 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
6.8 
Radiation Therapy Adverse Event Reporting (7/15/13) 
See Section 7.9 for adverse event reporting. 
 
7.0 DRUG THERAPY (10/21/16) 
 
 The drug therapy prior to IMRT must begin within 1 week of receiving pazopanib/placebo; however, it 
is recommended that treatment begin as soon as possible after sites receive the pazopanib/placebo. 
 
For Emergency Unblinding/Code Breaks, see Section 7.4.1 (2nd paragraph from the bottom of the 
section). 
 
7.1 
Treatment (7/15/13) 
Note: 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; see Section  
7.6.1, under “Management of QTc Prolongation”. 
 
(3/8/12) Patient Education: Institutions must provide patient education regarding the pazopanib/placebo 
suspension. Patients should be educated regarding swirling the suspension for 30 seconds prior to 
withdrawing the dose from the bottle, drawing up the prescribed dose, and storage of the suspension. 
Patients should demonstrate that they can draw up the appropriate daily dose and should be reminded to 
take the suspension on an empty stomach either 1 hour before or 2 hours after meals. Instructions to the 
patient for disposal of leftover pazopanib suspension and cleanup of pazopanib suspension spills have 
been included on the medication diary form (DP). 
7.1.1 
Run-In Components (Completed 6/5/14) 
 
Prior to Radiation Treatment: Patients will receive weekly paclitaxel and daily (7 days/week) 
pazopanib for 2-3 weeks. 
 
 
During Radiation Treatment: Patients will receive weekly paclitaxel and daily (7 days/week) 
pazopanib for 6-7 weeks with radiation treatment (or until radiation treatment is completed). 
 
 
 
Accrual will be suspended after 11 patients have been accrued to the run-in component; the 
study will remain closed until these 11 patients complete radiation therapy and a safety analysis 
is performed. See Section 13.2.1 for details. 
7.1.2 
Phase II Component (6/5/14) 
Prior to Radiation Treatment: Patients will receive weekly paclitaxel and either daily (7 
days/week) pazopanib or placebo for 2-3 weeks.  
 
 
During Radiation Treatment: Patients will receive weekly paclitaxel and either daily (7 
days/week) pazopanib or placebo for 6-7 weeks with radiation treatment (or until the end of 
radiation therapy). 
 
 
7.2 
Prior to Radiation Therapy: Treatment Details (2/10/15) 
7.2.1 
Patients will receive paclitaxel 80 mg/m2, administered intravenously weekly for 2 weeks. 
Radiation therapy should not begin until at least 5 days (or about 120 hours) after the last dose 
of paclitaxel during the pre-chemotherapy phase. For logistics reasons, a third dose of 
paclitaxel may be given at the investigator’s discretion. 
 
The body surface area (BSA) should be calculated using actual body weight. Note: It is not 
necessary to recalculate the BSA for each treatment if the patient’s weight has not changed by 
more than 10%.  
 
In addition, patients will take pazopanib/placebo 400 mg suspension orally daily for 2 weeks (or 
until the day before the start of radiation therapy), starting either on the same day as the first 
dose of paclitaxel or the day after the first dose of paclitaxel. However, as noted above in 
Section 7.0, pazopanib/placebo may be started up to a week later than the first dose of 
paclitaxel due to unforeseen circumstances such as a delay receiving the pazopanib/placebo. 
Please contact the Co-Principal Investigators, Drs. Sherman and Lee, or the Medical Oncology 
Co-Chair, Dr. Bible, with any questions. 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
Due to holidays or patients’ personal reasons, paclitaxel can be given within a 48 hour window 
each week without protocol violation, although it is highly recommended that this be avoided if 
possible. 
 
Patients will be asked to document daily pazopanib/placebo on a medication diary during pre-
radiation treatment, concurrent treatment, and post-concurrent treatment, which will be 
collected by the institution as source documentation. Institutions will submit the (DP) form to 
NRG Oncology at the end of treatment (see Sections 11.3, 11.4, 11.6, and 12.1). 
 
To calculate BSA, please use the Dubois formula (the use of other formulas will not be a 
deviation if the results are within 10% of the results obtained by the Dubois formula): 
 
 
 
 
BSA (m2) = 0.007184 x weight (kg)0.425 x height (cm)0.725 
 
BSA does not need to be recalculated on a weekly basis unless the patient’s weight has 
changed > 10% from the last time it was calculated. 
 
Note: If there is an unforeseen delay to start the radiation therapy after 2 weeks, a third week of 
treatment may be given after contacting and getting the consent of either Co-Principal 
Investigator, Drs. Sherman, Bible, or  Lee.  
 
 
Prior to starting pazopanib/placebo, an evaluation of the medications currently taken by the 
patient must be done; see Section 7.4.1. If a patient must continue to take a medication that 
strongly inhibits CYP3A4, Drs. Sherman or Bible must be contacted to discuss the 
reason(s) the patient must be on the drug. If Drs. Sherman or Bible approve the patient’s 
medication, the dose of pazopanib must be decreased by 50% of what otherwise would have 
been administered while the patient is on the drug.  
 
 
Pazopanib/placebo may be taken orally or through a feeding tube.  
Patients receive pazopanib/placebo on an outpatient basis. If taken orally, patients are 
instructed to swallow the suspension once a day (preferably in the morning) 7 days/week on an 
empty stomach, either 1 hour before or 2 hours after proximal food intake with about 1 cup (240 
mL) of water.  
 
If administered via a feeding tube, the suspension should be given with subsequent 
administration of sufficient water via the feeding tube to assure that the suspension is flushed 
through the tube. These instructions should be followed throughout the study at any point the 
suspension cannot be taken orally and needs to be taken through a feeding tube. 
 
It is preferable that pazopanib/placebo be taken prior to the start of radiation therapy and 
paclitaxel throughout the treatment course. 
 
 
Paclitaxel may be given intravenously according to institutional guidelines although it is 
recommended that it be given intravenously over 1 hour while diluted in 500 ml of 0.9% sodium 
chloride or 5% dextrose solution. The recommended premedications include the following 
(other regimens are permitted per institutional guidelines): 
1. Dexamethasone 10 mg intravenously approximately 30 minutes prior to the paclitaxel. 
2. Diphenhydramine 25 mg intravenously approximately 30 minutes prior to the paclitaxel. 
3. Ranitidine 50 mg or cimetidine 300 mg intravenously approximately 30 minutes prior to 
the paclitaxel 
7.2.2 
Pazopanib/placebo should be taken as described in section 7.2.1 until the day before radiation 
therapy is scheduled to begin. Radiation therapy should not begin until at least 5 days (or about 
120 hours) after the last dose of paclitaxel as noted in section 7.2.1. 
 
 
7.3 
During Radiation Therapy: Treatment Details (7/15/13) 
7.3.1 
Patients will receive paclitaxel 50 mg/m2, administered intravenously weekly, starting within 72 
hours of the start of radiation therapy, although the strong preference is that it starts on the first 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
day of radiation therapy. The body surface area (BSA) should be calculated using actual body 
weight (see Section 7.2.1).  
 
In addition, patients will take pazopanib/placebo 300 mg suspension orally daily, starting on the 
same day as the first fraction of radiation therapy is scheduled.  
 
 
 
Due to holiday or personal reasons, paclitaxel can be given within a 48 hour window each week 
without protocol violation, although it is highly recommended that this be avoided if possible. 
7.3.2 
Technique of administration — See Section 7.2.1  
7.3.3 
Paclitaxel will be given for approximately 6-7 weeks (or until the end of radiation therapy). The 
pazopanib/placebo will be given as outlined in Section 7.3.1 until radiation therapy is 
completed. Patients will be asked to document daily pazopanib/placebo on the medication diary 
(DP), which will be collected by the institution and submitted to NRG Oncology (see Section 
12.1).  
7.3.4 
If within the timeframe that drug (i.e. paclitaxel and pazopanib/placebo) should begin 
concurrently with radiation therapy the parameters for drug delivery (as stated in Section 7.6, 
“Dose Modifications”) are not met, radiation therapy should not be delayed. Radiation treatment 
should begin either with the drug dose being modified or delayed, as specified in Section 7.6. 
 
7.4 
Study Agents (9/13/16) 
7.4.1 
Pazopanib HCl (GW786034B) [NSC 737754]  
Chemical Name:  5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2 
methylbenzenesulfonamide monohydrochloride 
 
Other Names:  Pazopanib HCl, GW786034B (the suffix B denotes the monohydrochloride salt), 
Votrient. 
 
Classification:  VEGFR tyrosine kinase inhibitor 
 
Molecular Formula: C21H23N7O2S-HCl 
M.W.:   474.0 (monohydrochloride salt) 
 
437.5 (free base) 
 
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).  
 
Mechanism of Action:   Pazopanib is a highly potent inhibitor of vascular endothelial growth 
factor (VEGF) receptor tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3), platelet derived 
growth factor receptor (PDGFR alpha and beta) and C-Kit. Vascular endothelial growth factor 
receptor inhibition may block VEGF driven angiogenesis and, as a consequence, constrain 
tumor growth.  
 
How Supplied:  The Powder for Oral Suspension is supplied in 200 mL amber type III glass 
multi-dose bottles containing 5 g or 0 g of pazopanib. When reconstituted with 90 mL of purified 
or Sterile Water the suspension will contain 50 mg/mL or 0 mg/mL as free base/placebo. 
Powder for Oral Suspension excipients include Mannitol Pearlitol 100SD,Sucralose, Guar Gum 
5000, Hypromellose, Citric Acid Monohydrate, Sodium Phosphate, Dibasic, Anhydrous, 
Colloidal Silicon Dioxide, Methylparaben and Lemon Flavor. The placebo suspension contains 
the same excipients as the pazopanib suspension with the addition of microcrystalline cellulose 
and Opadry White YS-1-7003 to aid in visual blinding. Note: The suspension must be 
prepared by the institution’s pharmacy prior to dispensing it to the patient. 
 
Storage:  The Powder for Oral Suspension must be stored at Room Temperature. The 
reconstituted suspension must be refrigerated (2–8oC) and should be used within 35 days. 
 
Stability:  Stability studies are ongoing.   
 
Potential Drug Interactions:  In vitro data indicate that pazopanib is primarily metabolized by 
CYP3A4 isoenzyme.  Potent CYP3A4 inducers and inhibitors are prohibited on pazopanib 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
trials.  Pazopanib also is a substrate for p-glycoprotein and breast cancer resistance protein 
(BCRP) transporters and concomitant administration of inhibitors such as lapatinib will result in 
increased plasma pazopanib concentrations.  
 
Clinical studies indicate that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6.  
Use caution when combining pazopanib with CYP3A4, CYP2C8, and CYP2D6 substrates 
known to have a narrow therapeutic window.   
 
In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and 
OATP1B1. Pazopanib may increase concentrations of drugs primarily eliminated through these 
systems.  
 
Avoid co-administration of pazopanib with medicines that increase gastric pH.  If the 
concomitant use of a proton pump inhibitor (PPI) is medically necessary, pazopanib/placebo 
should be taken without food once daily in the evening with the PPI. If the concomitant 
administration of an H2-receptor antagonist is medically necessary, pazopanib/placebo should 
be taken without food at least 2 hours before or at least 10 hours after a dose of an H2-receptor 
antagonist. Administer pazopanib/placebo at least 1 hour before or 2 hours after administration 
of short-acting antacids.  
 
Avoid co-administration of pazopanib/placebo with simvastatin. Concomitant use of pazopanib 
and simvastatin increases the risk of ALT elevation. Data are not sufficient to assess the risk of 
concomitant administration of other statins and pazopanib.  
 
Precautions: Pazopanib/placebo should be used with caution in patients with a history of QT 
interval prolongation, in patients taking antiarrhythmics or other medications that may prolong 
QT interval, and those with relevant pre-existing cardiac disease. Monitor ECGs and serum 
electrolytes (e.g., calcium, magnesium, potassium) at baseline and periodically and maintain 
within the normal range.   
 
For patients who develop hepatic impairment, refer to the protocol document for appropriate 
dose modification or dose delay. 
 
 
Adverse Events (3/11/15) 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Pazopanib (GW786034, NSC 737754) 
The Comprehensive Adverse Events 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 (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 2383 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. 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
Version 2.61, January 21, 2015 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 2383] 
 
 
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) 
 
 
Hemolytic uremic syndrome2   
 
 
Thrombotic thrombocytopenic 
purpura2 
  
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
 
Sinus bradycardia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
  
 
 
Gastrointestinal fistula3 
 Gastrointestinal fistula3 (Gr 2) 
 
 
Gastrointestinal hemorrhage4   
 
 
Gastrointestinal perforation5 
 Gastrointestinal perforation5 (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INVESTIGATIONS 
  
 
Activated partial 
thromboplastin time 
prolonged 
 
  
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased (Gr 2) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase increased 
(Gr 3) 
Blood bilirubin increased 
 
 
 Blood bilirubin increased (Gr 3) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
 
Electrocardiogram QT 
corrected interval prolonged 
  
Lymphocyte count 
decreased 
 
 
 Lymphocyte count decreased (Gr 3) 
Neutrophil count decreased  
 
 Neutrophil count decreased (Gr 3) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 2) 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 2383] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 2) 
 
Hypercalcemia 
 
  
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
Hypermagnesemia 
 
  
 
Hypernatremia 
 
  
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 2) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr 2) 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
Hyponatremia 
 
 
 Hyponatremia (Gr 2) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
Tumor pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 3) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Urinary fistula 
 Urinary fistula (Gr 2) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
 
Female genital tract fistula 
 Female genital tract fistula (Gr 2) 
 
 
Uterine fistula 
 Uterine fistula (Gr 2) 
 
 
Vaginal fistula 
 Vaginal fistula (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
Respiratory hemorrhage6  
 Respiratory hemorrhage6 (Gr 2) 
 
 
Respiratory, thoracic and 
mediastinal disorders – Other 
(interstitial lung disease)7 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
  


 
 
 
 
 
 
39 
             RTOG 0912, Version Date: March 6, 2020 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 4.0 Term) 
[n= 2383] 
 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
Skin and subcutaneous 
tissue disorders - Other (hair 
color change/hair 
depigmentation) 
 
 
 Skin and subcutaneous tissue 
disorders - Other (hair color 
change/hair depigmentation) (Gr 2) 
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event8 
  
 
 
Vascular disorders - Other 
(arterial thromboembolic 
event)8 
  
 
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. 
 
2Thrombotic microangiopathy (TMA) which includes both Hemolytic uremic syndrome (HUS) and Thrombotic 
thrombocytopenic purpura (TTP) has been reported in clinical trials of GW786034. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical fistula, Esophageal 
fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, 
Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC.  
 
4Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and 
Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC.  
 
5Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC.  
 
6Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, Mediastinal 
hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS SOC.  
 
7Interstitial lung disease may include, Adult respiratory distress syndrome, Pneumonitis, Pulmonary fibrosis, 
Respiratory, thoracic and mediastinal disorders - Other (Acute respiratory distress syndrome), Respiratory, 
thoracic and mediastinal disorders - Other (Aveolitis), Respiratory, thoracic and mediastinal disorders - Other 
(Bronchiolitis obliterans), Respiratory, thoracic and mediastinal disorders - Other (Interstitial fibrosis), Respiratory, 
thoracic and mediastinal disorders - Other (Interstitial pneumonia), Respiratory, thoracic and mediastinal 
disorders - Other (Interstitial pneumonitis), Respiratory, thoracic and mediastinal disorders - Other (Organizing 
pneumonia), Respiratory, thoracic and mediastinal disorders - Other (Pulmonary infiltrates), Respiratory, thoracic 
and mediastinal disorders - Other (Toxic pneumonitis). 
 
8These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications.  
 
9Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
 


 
 
 
 
 
 
40 
             RTOG 0912, Version Date: March 6, 2020 
Adverse events also reported on Pazopanib (GW786034) trials but with the relationship to Pazopanib 
(GW786034) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac disorders - Other (sinus arrest); 
Cardiac disorders - Other (supraventricular extrasystoles); Cardiac disorders - Other (Takotsubo [Broken Heart 
Syndrome]); Cardiac disorders - Other (Torsades de Pointes); Chest pain - cardiac; Pericardial effusion; 
Supraventricular tachycardia 
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (asthenopia); Eye disorders – Other 
(eye/retinal hemorrhage); Eye disorders - Other (foreign body sensation in eyes); Eye pain; Floaters; Glaucoma; 
Photophobia; Retinal tear 
GASTROINTESTINAL DISORDERS - Abdominal distension; Dry mouth; Duodenal obstruction; Dysphagia; 
Esophagitis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (hyperactive bowel); 
Gastrointestinal disorders - Other (oropharyngeal pain); Gastrointestinal disorders - Other (pneumatosis 
intestinalis); Gastrointestinal pain; Oral pain; Pancreatitis; Periodontal disease; Proctitis; Small intestinal 
obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Malaise; Non-
cardiac chest pain; Pain 
INFECTIONS AND INFESTATIONS - Infection9 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Cardiac troponin T increased; Cholesterol high; Ejection fraction decreased; GGT increased; 
INR increased; Investigations - Other (blood lactate dehydrogenase increased); Investigations - Other (blood TSH 
increased); Lipase increased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Hypertriglyceridemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; Generalized 
muscle weakness; Head soft tissue necrosis; Muscle weakness lower limb; Muscle weakness upper limb; 
Musculoskeletal and connective tissue disorder - Other (muscle spasms); Neck pain 
NERVOUS SYSTEM DISORDERS - Extrapyramidal disorder; Intracranial hemorrhage; Ischemia 
cerebrovascular; Memory impairment; Paresthesia; Peripheral sensory neuropathy; Stroke; Syncope; Transient 
ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Hematuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Reproductive system and 
breast disorders - Other (vaginal necrosis); Vaginal discharge; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Laryngeal edema; Pharyngolaryngeal pain; 
Pleural effusion; Pleuritic pain; Pneumothorax; Postnasal drip; Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus; Purpura; Skin 
hyperpigmentation; Skin ulceration 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Vasculitis 
 
Note: Pazopanib (GW786034) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
Clinical Supplies (6/5/14) 
Pazopanib (NSC 737754/IND 75648) and matching placebo will be provided free of charge 
by GlaxoSmithKline and distributed by the Pharmaceutical Management Branch (PMB), 
Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis 
(DCTD), National Cancer Institute (NCI). Drug provided free of charge as part of a research 
protocol must be used only for the intended study. It is the responsibility of the Investigator 
to ensure the provided/investigational product is only dispensed to eligible study patients. 
 
Pazopanib powder for oral suspension and matching placebo for pazopanib will be supplied 
in a 200 ml amber type III glass bottle.  
 
Each blinded, patient-specific bottle will be labeled with the following: 
• the protocol number (i.e., “RTOG-0912”); 
• the bottle number (i.e., “Bottle 1 of 2” and “Bottle 2 of 2”); 


 
 
 
 
 
 
41 
             RTOG 0912, Version Date: March 6, 2020 
• the patient ID number (e.g.,"0912-YYY", where “0912-YYY” represents the protocol 
number and sequence number which represents the unique patient ID number 
assigned by NRG Oncology at the time of patient registration) 
• the patient initials (i.e., First initial, Middle initial, Last initial [e.g., “FML”]); 
• the agent identification (i.e. “Pazopanib  or Placebo suspension”); 
• a blank line for the pharmacist to enter the patient’s name; 
• administration instructions (i.e., “Take __ mL once a  day for [cycle length] days.”); 
• storage instructions (i.e., “Store at controlled room temperature [20ºC-25 ºC]).”; 
• emergency contact instructions; 
• a Julian date. 
 
The Julian date indicates the day the bottle was labeled and shipped and is composed of the 
last 2 digits of the calendar year (e.g., 2009 = 09, 2010 = 10) and a day count (e.g. January 
1 = 001, December 31 = 365).  For example, a bottle labeled and shipped on January 1, 
2009 would have a Julian date of ‘09001’, and a bottle labeled and shipped on December 
31, 2009 would have a Julian date of ‘09365’. The Julian date will be used by PMB for 
recalls.  When a lot expires, PMB will determine the last date the expired lot was shipped 
and will recall all bottles (i.e. both Pazopanib and Placebo) shipped on or before that date 
thus eliminating any chance of breaking the blind. 
 
 
Drug Ordering (9/13/16) 
BLINDED (pazopanib or placebo) THERAPY   
 
Note: This section reflects ordering instructions for the open label 2nd run-in component and 
the blinded (randomized phase II) component of the study. 
 
No blinded starter supplies will be available for this study. Blinded, patient-specific 
clinical supplies will be sent to the registering investigator at the time of randomization.  This 
randomization will be performed by NRG Oncology.  The patient ID number assigned by 
NRG Oncology must be recorded by the registering institution for proper study medication 
dispersion. Once a patient has been registered, NRG Oncology will electronically transmit a 
clinical drug request for that patient to the PMB.  This request will be entered and 
transmitted by NRG Oncology the day the patient is registered, will be processed by the 
PMB the next business day, and shipped the following business day.   
 
Note: Open label run-in supplies will be provided on a patient-specific basis, and no starter 
supplies will be available. Shipments within the United States will be sent by US Priority Mail 
(generally 2 to 3 day delivery).  Thus, if a patient is registered on Monday, NRG Oncology 
would enter a clinical drug request for that patient on Monday, and PMB would process that 
request on Tuesday and ship the drug on Wednesday.  Sites could expect to receive their 
order approximately Friday or Monday.  Shipments to United States sites can be expedited 
(i.e. receipt on Thursday in example above) by the provision of an express courier account 
name and number to NRG Oncology at the time the patient is registered/randomized. 
 
The initial shipment will be 5 x 5000 mg bottles of pazopanib/placebo suspension 50 mg/mL, 
a sufficient supply to complete the two to three week Pre-IMRT portion (400 mg/day) and 6 
to 7 weeks of concurrent therapy (300 mg/day). This supply should be sufficient to complete 
all of the protocol assigned treatment with pazopanib/placebo. If a bottle gets wasted or 
destroyed, sites may reorder bottles by using On-line Agent Ordering Processing (OAOP). 
Please include a note stating that the request is for replacement bottles. The assigned 
patient ID number (e.g., "0912-YYY") and the patient initials (e.g. "FML") should be entered 
in the "Patient or Special Code" field. The agent name for the pazopanib must be written on 
the order form as “Pazopanib or Placebo”. All drug orders should be shipped directly to the 
physician responsible for treating the patient. 
  
 
 
 
 
Drug Transfers (6/5/14) 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
Bottles MAY NOT be transferred from one patient to another patient or from one protocol 
to another protocol.  All other transfers (e.g. a patient moves from one participating clinical 
site to another participating clinical site, the principal investigator at a given clinical site 
changes) must be approved in advance by the PMB.  To obtain an approval for transfer, 
investigators should complete and submit to the PMB (fax number 240-276-7893) a 
Transfer 
Investigational 
Agent 
Form 
available 
on 
the 
CTEP 
home 
page 
(http://ctep.cancer.gov).  The patient ID number (e.g., "0912-YYY”) and the patient initials 
(e.g., "FML”) should be entered in the "Received on NCI Protocol No." and the 
"Transferred to NCI Protocol No." fields in addition to the protocol number (i.e., "RTOG-
0912"). 
 
 
Drug Returns (2/10/15) 
Only undispensed clinical supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g. sealed bottles remaining when a patient permanently 
discontinues protocol treatment, expired bottles recalled by the PMB), investigators should 
return the study drug to the PMB using the NCI Return Drug List available on the CTEP 
home page (http://ctep.cancer.gov). The patient ID number (e.g., "0912-YYY”) and the 
patient initials (e.g., "FML") should be entered in the "Lot Number" field.   
 
Emergency Unblinding/Code Breaks 
The decision to break the code must be based on a life-threatening event or extraordinary 
clinical circumstance for which knowledge of drug assignment will affect clinical judgment.   
 
During business hours (8:30 AM to 4 PM ET), call NRG Oncology at 215-574-3150 and 
ask to speak to the Study Statistician. For after hours, weekends, and holidays, call 215-
459-3576. NRG Oncology/Study Statistician will require the protocol number (i.e., “RTOG-
0912”), the patient ID number (e.g., “0912-YYY”), and the patient initials (e.g. “FML”) to 
unblind the patient. Note: If a patient is emergently unblinded, he/she is considered to 
be off-therapy and must discontinue protocol treatment. 
 
 
Drug Accountability (6/5/14) 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, disposition, and return of all drugs received from the PMB 
using the NCI Investigational Agent Accountability Record available on the CTEP home 
page (http://ctep.cancer.gov).  A separate NCI Investigational Agent Accountability Record 
must be maintained for each patient ID number (e.g., "0912-YYY”) on this protocol.  
 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575  Monday through Friday between 
8:30 am and 4:30 pm Eastern Time.  You may also contact PMB via e-mail at 
PMBAfterHours@mail.nih.gov.  
 
 
 
The Investigator Brochure (IB), if available, for this drug will be supplied by the PMB/NCI. 
All requests for IBs should be e-mailed to ibcoordinator@mail.nih.gov or the IB 
Coordinator may be contacted at 240-276-6575. 
 
The Julian Date – Order number (e.g., 2014352-0003) from the patient-specific label must 
be used as the Lot number on the NCI DARF. 
7.4.2 
Paclitaxel (7/15/13) 
 
 
Refer to the package insert for complete prescribing and toxicity information. 
 
Description 
Paclitaxel (Taxol®) is a poorly soluble plant product from the western yew, Taxus brevifolia.  
 
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
Preparation 
Paclitaxel is a sterile solution concentrate, 6 mg/ml in 5 ml vials (30 mg/vial); 100 mg/16.7ml 
vial; or 300 mg/50 ml vial, in polyoxyethylated castor oil (Cremophor EL) 50% and 
dehydrated alcohol, USP, 50%.  Improved solubility requires a mixed solvent system with 
further dilutions of either 0.9% sodium chloride or 5% dextrose in water. 
The contents of 
the vial must be diluted just prior to clinical use. Paclitaxel, at the appropriate dose, will be 
diluted in 1000 ml of D5W, USP, in 5% polyolefin containers due to leaching of 
diethylhexphthalate (DEHP) plasticizer from polyvinyl chloride (PVC) bags and intravenous 
tubing by the Cremophor vehicle in which paclitaxel is solubilized.  Each bag/bottle should 
be prepared immediately before administration.  Note: Formation of a small number of fibers 
in solution (acceptable limits established by the USP Particular Matter Test for LVP’s) have 
been observed after preparation of paclitaxel. Therefore, in-line filtration is necessary for 
administration of paclitaxel solutions. In-line filtration should be accomplished by 
incorporating a hydrophilic, microporous filter of pore size not greater than 0.22 microns 
(e.g.: Millex-GV Millipore Products) into the i.v. fluid pathway distal to the infusion pump. 
Although particulate formation does not indicate loss of drug potency, solutions exhibiting 
excessive particulate matter formation should not be used. 
 
 
Administration 
 
Paclitaxel, at the appropriate dose and dilution, will be given as a 1-hour infusion. See 
Section 7.1.  The paclitaxel is mixed in 500 or 1000 cc of D5W in non-PVC containers and 
infused via polyolefin-lined nitroglycerin tubing or low absorption AVI‰ with 0.22 m in-line 
filter. 
 
 
Adverse Events  
• 
Hematologic: neutropenia, leukopenia, thrombocytopenia, anemia 
• 
Gastrointestinal: nausea/vomiting, diarrhea, mucositis 
• 
Hepatic: elevated liver function tests 
• 
Cardiac: heart block, bradycardia 
• 
Neurologic: peripheral neuropathy, arthralgia/myalgia 
• 
Dermatologic: alopecia, onycholysis 
• 
Reproductive: Infertility; may be teratogen 
• 
Miscellaneous: moderate–severe hypersensitivity reactions, flushing, rash, dyspnea, 
fatigue 
 
 
Stability and Storage 
  
All solutions of paclitaxel exhibit a slight haziness directly proportional to the concentration of 
drug and the time elapsed after preparation, although when prepared as described above, 
solutions of paclitaxel (0.3-1.2 mg/ml) are physically and chemically stable for 27 hours. 
Paclitaxel vials should be stored between 2°-25°C (36°-77°F).   
 
 
Supply 
Paclitaxel is commercially available in the United States.    
 
7.5 
Clinical Trials Agreement 
The agents supplied by CTEP, DCTD, NCI used in this protocol is provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company (hereinafter 
referred to as a Collaborator 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/ipo.html) contained within the terms of award, apply to the 
use of the Agent in this study: 
 
1. 
The Agent may not be used for any purpose outside the scope of this protocol, nor can 
the Agents be transferred or licensed to any party not participating in the clinical study.  
The Collaborator’s data for the Agent are confidential and proprietary to the Collaborator 
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 or patient’s family member participating on the study, the individual should sign 


 
 
 
 
 
 
44 
             RTOG 0912, Version Date: March 6, 2020 
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 
another investigational Agents, each the subject of different collaborative agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”. 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with 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. 
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, 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 the Collaborator 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 by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to the Collaborator for advisory review and 
comment prior to submission for publication.  The Collaborator will have 30 days from the 
date of receipt for review.  The 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 the Collaborator’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to the Collaborator 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 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov 
 
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. 
 
7.6 
Dose Modifications (9/30/15) 
7.6.1 
Pazopanib/Placebo 
Appropriate dose modifications for 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 treating physician should contact Drs. Sherman or Bible to review the 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
subject’s condition prior to resuming the patient’s treatment, except for delays due to 
hypertension (see “Hypertension” below).  As a patient progresses from one treatment to 
another (i.e., pre-radiation therapy, radiation therapy), the patient should remain at the SAME 
DOSE LEVEL. Dose level reductions follow: 
               
            Pre-Radiation Therapy  
 
Dose level 
Pazopanib/Placebo suspension 
DL 1 
400 mg (8 mL) daily 
DL-1 
 300 mg (6mL) daily 
DL-2 
 200 mg (4 mL) daily 
DL-3 
100 mg (2 mL) daily 
 
During Radiation Therapy 
 
Dose level 
Pazopanib/Placebo suspension 
DL 1 
300 mg (6 mL) daily 
DL-1 
150 mg (3 mL)daily 
DL-2 
100 mg (2 mL) daily  
DL-3 
50 mg (1 mL)daily  
 
 
Hypertension (4/19/11) 
Increases in blood pressure 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 pazopanib 
treatment has been seen in animal studies as well as clinical trials.   
• 
While patients are receiving treatment with pazopanib/placebo, the early initiation of 
antihypertensive treatment for grade 1 or 2 hypertension to minimize more severe or 
persistent hypertension is not considered a grade 3 adverse event. 
• 
Decisions to hold or decrease the pazopanib/placebo dose during treatment must be 
based on BP readings taken in the clinic by a medical professional. 
• 
In case of new-onset or worsening (grade ≥ 2) hypertension, refer to the chart on the 
following page. 
• 
Ultimately, antihypertensive treatment must be individualized based on the presence 
of comorbidity such as diabetes, cardiovascular, or renal disease, additionally taking 
into account the safety and efficacy of any prior antihypertensive therapy received.  In 
addition, oral and/or intravenous sodium intake should be carefully monitored in 
these patients.  Blood pressure should be performed at least once weekly until stable 
blood pressure control is achieved.  Early consultation with a cardiologist is strongly 
encouraged in case of uncontrolled hypertension. 
Dose Modifications for Pazopanib/Placebo Due to Hypertension (7/15/13) 
Grade 
(CTCAE,  v. 4.0) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Pazopanib/Placebo 
Dose Modification 
Persistent Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-90  
 
 
Standard       
 
No Change 
Persistent Grade 2- 
Moderate 
Systolic 140-159  
Diastolic 90-99  
   
Protocol-specific 
guidance supersedes 
any other management 
Step 1)  Initiate BP treatment and  
if needed, after 24-48 hr Rx,  
increase dose in stepwise  
fashion every 24-48 hours  until 
BP is controlled or at max dose 
of Rx. BP treatment is 
unnecessary if BP  drops to 
grade < 1 within 1 hour without 
BP should be 
monitored as 
recommended by 
the treating 
physician  
No change except 
as described in Step 
4. 


 
 
 
 
 
 
46 
             RTOG 0912, Version Date: March 6, 2020 
guidelines, including 
CTCAE, v. 4.0.  
any intervention. It also does not 
need to be initiated if other 
causes are strongly suspected 
(severe anxiety), although this 
would require permission from a 
co-chair (Keith Bible, Eric 
Sherman, or Nancy Lee). 
 
Step 2) If BP still not controlled, 
add another anti-hypertensive 
Rx, a LA DHP CCB,  ACE1, ARB, 
or ABB; increase dose of this 
drug as described in Step 1.   
 
Step 3) If BP still not controlled, 
add 3rd drug from the list of 
antihypertensives in Step 2; 
increase dose of this drug as 
described in Step 1. 
 
Step 4) If BP still not controlled, 
consider either 1 dose reduction 
of pazopanib/placebo or stopping 
pazopanib/placebo.  
 
NOTE: Stopping or reducing the 
dose of pazopanib/placebo is 
expected to cause a decrease in 
BP The treating physician should 
monitor the patient for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
Persistent Grade 3 
Severe  
Systolic >160 
Diastolic >100  
 
Protocol-specific 
guidance supersedes 
any other management 
guidelines, including 
CTCAE, v. 4.0. 
HOLD pazopanib/placebo until 
systolic BP <159 and diastolic BP 
<99.  
 
BP management is identical to 
that for Grade 2 (see Steps 1-4 
above) with 2 major 
exceptions:  
1)  If systolic BP >180 or 
diastolic BP >110 and the 
patient is symptomatic: 
optimal management with 
intensive IV support in ICU; 
STOP pazopanib/placebo and 
notify hospital staff that 
stopping pazopanib/placebo 
may result in a decrease in BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and the 
patient is asymptomatic, 
2 new antihypertensives must 
be given together in Step 1 
(and dose escalated 
appropriately as in Step 1). 
 
NOTE: Stopping or reducing the 
dose of pazopanib/placebo is 
expected to cause a decrease in 
BP. The treating physician should 
monitor the patient for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be 
monitored as 
recommended by 
the treating 
physician unless 
the patient is 
symptomatic 
with  
systolic BP >180 
or diastolic BP 
>110 in which 
case, monitoring 
should be 
intensive. 
 
 
HOLD 
pazopanib/placebo 
until systolic BP 
<159 and diastolic 
BP <99. 
 
In most 
circumstances, if BP 
cannot be controlled 
after an optimal trial 
of antihypertensive 
medications, 
consider either 1 
dose reduction of 
pazopanib/placebo 
or stopping 
pazopanib/placebo. 
HOWEVER, 
If the patient 
requires 
hospitalization for 
management of  
symptomatic 
systolic BP >180 
or diastolic BP 
>110,  permanently 
discontinue 
pazopanib/placebo 
or if BP is 
controlled, re-start 
pazopanib/placebo 
at 1 lower dose 
level after 
consultation with 
Drs. Sherman or 
Bible. 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management with 
intensive IV support in ICU; 
STOP pazopanib/placebo and 
notify hospital staff that 
stopping pazopanib/placebo 
may result in a decrease in BP 
Intensive 
Permanently 
discontinue 
pazopanib/placebo 
or if BP is 
controlled, re-start 
pazopanib/placebo 
at 1 lower dose 
level after 
consultation with 
Drs. Sherman or 
Bible. 
Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), Angiotensin 
Converting Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB), alpha beta blocker (ABB) 
• 
*See Appendix V 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 
pazopanib/placebo. 
• 
 24-48 hours should elapse between modifications of antihypertensive therapy. 
 
 
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
Oral Antihypertensive Medications 
 
Agents in bold characters in the table below are suggested as optimal choices to use with 
pazopanib in order to avoid or minimize potential drug interactions through CYP450: 
 
Agent 
Class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
Felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate and 
inhibitor 
Selective 
 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 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 and  
Blocker 
labetalol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 
substrate and 
inhibitor 
 
 
Proteinuria (2/27/12) 
A 24-hour urine collection for quantitative protein determination must be obtained for a urine 
protein: creatinine ratio (UPCR) >1.  If the UPCR had previously been greater than 1 in the 
past and the 24-hour urine for protein was found to be under 1 gram, a 24-hour urine 
collection for protein does not need to be repeated unless the UPCR is 20% higher. 
Pazopanib/placebo should be held while awaiting the results of the 24 hour urine collection 
for protein. Instructions for dose modifications due to proteinuria are summarized below. 
 
Dose Modifications for Pazopanib/Placebo Due to Proteinuria  
 
Proteinuria 
Action to be Taken 
UPC >1and <3 
Obtain 24-hr urine protein and if <3 g, continue at current dose and 
monitor as clinically indicated 
UPC ≥3 or 24-h 
urine protein ≥3 g 
1. Interrupt pazopanib/placebo suspension. 
2.  Weekly UPC or 24-hr urine protein monitoring until UPC is <3 or 24-
hr urine protein is <3 grams.  Then restart pazopanib dose-reduced 
by 1 level. 
3. If UPC >3 or 24-h urine protein 3g recurs, repeat steps 1 and 2. 
4. If UPC ≥3 or 24-hr urine protein ≥3 recurs and the pazopanib dose 
can no longer be reduced, discontinue pazopanib and follow patient 
as specified in protocol. 
Nephrotic 
syndrome  
Permanently discontinue pazopanib and remove subject from study 
 
 
 
Management of Metabolic Adverse Events (2/27/12) 
 
Adverse Event/ 
CTCAE, v. 4.0 Category 
Grade 
Treatment Modification 
Follow Up 
Hypokalemia 
or 
hyper- 
kalemia 
Grade ≥ 2 
Hold pazopanib/placebo. 
Perform an EKG. 
Correct as soon as 
possible as treating 
physician determines. 
Resume treatment when 
resolved to grade 1 or 
less; 
Monitor as clinically 
indicated. 
Hypocalcemia/hypercalcemia;  
Hypophosphatemia/hyper- 
phosphatemia;  
Hypomagnesium/hypermag- 
nesimia 
Grade ≥ 3 
Hold pazopanib/placebo. 
Perform an EKG. 
Correct as soon as 
possible as treating 
physician determines. 
Resume treatment when 
resolved to grade 2 or 
less; 
Correct remaining 
abnormal lab values 
to normal, if 
possible. Monitor as 
clinically indicated. 
 
Management of QTc Prolongation  
A repeat EKG must be performed on day 1 of concurrent and post-concurrent treatment (see Appendix I). 
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, protocol treatment should be discontinued and the patient should be followed 
as specified in the protocol. 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 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
repeat EKG again shows a ≥ 60 msec increase in the QTc interval from baseline, consideration should be 
given to discontinuing pazopanib/placebo or increasing monitoring, after discussion with Drs. Sherman or 
Bible. 
 
Management of QTc prolongation of 500 msec and management of QTc prolongation of 60 msec or more 
from baseline: 
 
If EKG reveals an increase in the QTc to >500 
msec or an increase in the QTc by at least 60 
msec from baseline 
Repeat EKG before re-administration of 
pazopanib. 
If repeat EKG shows QTc interval is >500 msec 
Stop protocol treatment and follow patient 
as specified in protocol. 
If on repeat ECG, QTc remains at least 60 msec 
longer than baseline but is less than 500 msec  
Consider stopping protocol treatment and 
following patient as specified in protocol.. 
 
 
Management of Other Adverse Events for Pazopanib/Placebo (2/10/15) 
 
Adverse Event/ 
CTCAE, v. 4.0 
Category 
Grade 
Treatment Modifications 
Follow Up 
Gastrointestinal 
Perforation, GI 
Grade > 1 
Discontinue treatment and 
go to event monitoring 
Monitor and treat as 
clinically indicated. 
Diverticulitis/typhilitis 
Grade > 1 
Hold pazopanib/placebo 
therapy until resolved, then 
resume pazopanib/placebo 
at the discretion of treating 
physician after complete 
resolution; no dose 
reduction. 
Hold 
pazopanib/placebo 
until resolved, treat 
aggressively, then 
resume 
pazopanib/placebo; 
no dose reduction. 
Hemorrhage/bleeding 
Grade 1 
No interruption in treatment 
unless hemoptysis.  If 
hemoptysis, contact PI to 
determine if it is 
appropriate to continue 
pazopanib/placebo.   
Maintain current dose. 
Monitor as clinically 
indicated. 
Hemorrhage/bleeding 
Grade 2 
For non-pulmonary 
bleeding, hold 
pazopanib/placebo unless 
resolved to ≤grade 1; 
reduce dose to next lower 
dose level, and continue 
treatment.  
 
For pulmonary bleeding, 
permanently discontinue 
pazopanib/placebo and 
follow patient as specified 
in protocol. 
 
 
If grade 2 or greater 
hemorrhage/ bleeding 
recurs following dose 
reduction, stop 
pazopanib/placebo and 
follow patient as specified 
in protocol. 
 
Monitor as clinically 
indicated. 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
Management of Other Adverse Events for Pazopanib/Placebo (Cont’d) 
Adverse Event/ 
CTCAE, v. 4.0 
Category 
Grade 
Treatment Modifications 
Follow Up 
Hemorrhage/bleeding 
Grade 3-4 
Discontinue treatment. 
Monitor as clinically 
indicated. 
Vascular/Thrombosis 
Grade 1 
No interruption in 
treatment; maintain current 
dose. 
Monitor as clinically 
indicated. 
Vascular/Thrombosis 
Grade 2, 3  
• Hold pazopanib until 
patient is on stable 
dose of low 
molecular weight 
heparin (LMWH). 
Treatment  may resume 
during the period of full-
dose anticoagulation if all 
of the following criteria are 
met: 
• The patient must have 
been treated with an 
anticoagulant at the 
desired level for at least 
one week. 
• The patient must not 
have had a grade 3 or 4 
or significant grade 2 
hemorrhagic event 
while on anticoagulant. 
 
Patient should be 
monitored as clinically 
indicated during 
anticoagulation 
treatment and after 
resuming study 
treatment.  When 
treating with warfarin, 
international 
normalized ratio (INR) 
should be monitored 
within three to five 
days after any change 
in pazopanib/placebo 
dosing (e.g. re-
initiating, 
escalating/de-
escalating, or 
discontinuing 
pazopanib/placebo), 
and then at least 
weekly until the INR is 
stable.  The dose of 
warfarin (or its 
derivatives) may need 
to be adjusted to 
maintain the desired 
level of 
anticoagulation. 
Vascular/Thrombosis 
Grade 4 or 
pulmonary embolus 
Discontinue treatment, and 
follow patient as specified 
in protocol. 
Monitor as clinically 
indicated. 
Arterial Thrombosis/ 
ischemia 
All grades  
Discontinue pazopanib and 
follow patient as specified 
in protocol. 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
Management of Other Adverse Events for Pazopanib/Placebo (Cont’d) 
Adverse Event/ 
CTCAE, v. 4.0 
Category 
Grade 
Treatment Modifications 
Follow Up 
Anemia1 
Grades 1 or 2 
No interruption in 
treatment; maintain current 
dose. 
Monitor as clinically 
indicated. 
Anemia1 
Grade 3 or 4 
Interrupt treatment until 
toxicity is ≤grade 2; reduce 
one dose level.  
 
If no recovery to ≤grade 2 
or recurrent grade 3 or 4, 
discontinue 
pazopanib/placebo and 
follow patient as specified 
in protocol. However, if the 
patient is benefiting from 
therapy, contact Drs. 
Sherman or Bible to 
discuss course of action. 
Monitor as clinically 
indicated. 
1 The dose delays and modifications for anemia apply only to anemia which is due to hemorrhage or 
bleeding.  No specific dose delays or dose reductions are required for anemia due to other causes, but 
the investigator should dose delay and dose-decrease, if he/she feels it is necessary, in a manner 
consistent with good medical practice. 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
Management of Elevations in AST, ALT and/or Bilirubin 
Adverse Event/ 
CTCAE, v. 4.0 
Category 
Grade 
Treatment Modifications 
Follow Up 
Elevations in AST, ALT, 
and/or bilirubinc 
ALT ≤ 3.0 x ULN 
 
Continue at current dose.  
Discontinue simvastatin if 
patient has been receiving 
simvastatin and has ALT 
>ULN. 
Monitor as clinically 
indicated. 
Elevations in AST, ALT, 
and/or bilirubinc 
ALT > 3.0 x ULN to ≤ 
8.0 x ULN without 
bilirubin elevation 
(defined as total 
bilirubin < 2.0 x ULN 
or direct bilirubin ≤ 
35%)a and without 
hypersensitivity 
symptoms (e.g., 
fever, rash) 
 
1) Continue pazopanib at 
current dose levels.  
Discontinue simvastatin 
if patient has been 
receiving simvastatin. 
 
2) Monitor patient closely 
for clinical signs and 
symptoms; perform full 
panel LFTsb at least 
weekly until ALT/AST is 
reduced to Grade 1. 
Monitor as clinically 
indicated. 
Elevations in AST, ALT, 
and/or bilirubinc 
ALT > 8.0 x ULN 
without bilirubin 
elevation (defined as 
total bilirubin < 2.0 x 
ULN or direct 
bilirubin ≤ 35%)a and 
without 
hypersensitivity 
symptoms (e.g., 
fever, rash) 
 
1st occurrence  
1) Interrupt pazopanib until 
toxicity resolves to 
≤Grade 1 or baseline.  
Discontinue simvastatin 
if patient has been 
receiving simvastatin. 
Repeat full panel LFTs 
and clinical liver 
assessment within 24-
72 hours, then full panel 
LFTs at least weekly 
until ALT/AST is 
reduced to Grade 1.  
Follow patient clinically 
as appropriate. 
 
Monitor as clinically 
indicated 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
Management of Elevations in AST, ALT and/or Bilirubin (Cont’d) 
Adverse Event/ 
CTCAE, v. 4.0 
Category 
Grade 
Treatment Modifications 
Follow Up 
Elevations in AST, ALT, 
and/or bilirubinc 
ALT > 8.0 x ULN 
without bilirubin 
elevation (defined as 
total bilirubin < 2.0 x 
ULN or direct 
bilirubin ≤ 35%)a and 
without 
hypersensitivity 
symptoms (e.g., 
fever, rash) 
 
1st occurrence (cont’d) 
2) 
If the potential benefit 
for reinitiating 
pazopanib treatment 
is considered to 
outweigh the risk for 
hepatotoxicity, then 
consult Dr. Sherman 
or Dr. Bible before 
reintroducing 
pazopanib at a 
reduced dose (usually 
a decrease of 1 dose 
level.) Re-challenge 
may be considered if 
ALL following criteria 
are met: 
- ALT/AST reduced 
to Grade 1 
- Total bilirubin < 1.5 
x ULN or direct 
bilirubin ≤ 35% 
- No hypersensitivity 
signs or symptoms 
- Patient is benefiting 
from therapy.  
If approval for re-treatment 
is granted, the patient must 
be re-consented (ensuring 
documentation that patient 
is aware of all associated 
hepatotoxicity risks). 
 Measure full panel LFTs at 
least weekly for 8 weeks at 
the reduced dose.  
 
Recurrence  
Discontinue pazopanib 
permanently and monitor 
patient closely for clinical 
signs and symptoms; 
perform full panel LFTs at 
least weekly until ALT/AST 
is reduced to Grade 1. 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
Management of Elevations in AST, ALT and/or Bilirubin (Cont’d) 
Adverse Event/ 
CTCAE, v. 4.0 
Category 
Grade 
Treatment Modifications 
Follow Up 
Elevations in AST, ALT, 
and/or bilirubinc 
ALT >3.0 x ULN with 
concomitant 
elevation in bilirubin 
(defined as total 
bilirubin ≥ 2.0 x ULN; 
with direct bilirubin 
>35%)a or with 
hypersensitivity 
symptoms (e.g., 
fever, rash). 
 
 
1) Permanently disconti-
nue pazopanib (and 
simvastatin, if patient is 
receiving simvastatin) 
and report the event to 
Dr. Sherman within 24 
hours.  Have patients 
return to the clinic within 
24 hours, if possible, for 
repeat full panel LFTs 
and liver event follow up 
assessments. 
2) Consult a 
gastroenterologist / 
hepatologist to identify 
potential co-factors. 
3) Monitor patient closely 
for clinical signs and 
symptoms.  Perform full 
panel LFTs at least 
weekly until LFTs are 
reduced to Grade 1.  
Monitor as clinically 
indicated. 
Elevations in AST, ALT, 
and/or bilirubinc 
For isolated total 
bilirubin elevation 
without concurrent 
ALT increases 
(defined as ALT < 3 
X ULN). 
 
Continue at current dose.  
Discontinue simvastatin if 
patient has been receiving 
simvastatin and has ALT > 
ULN. 
Monitor as clinically 
indicated. 
a. Serum bilirubin fractionation should be performed if testing is available.  If testing is unavailable 
and a patient meets the criterion of total bilirubin > 1.5 x ULN, then the event should be promptly 
reported as an SAE. 
b. Full panel LFTs include: AST, ALT, alkaline phosphatase, GGT, and total bilirubin.  Coagulation 
tests should be performed as clinically indicated. 
c. If a patient receiving concomitant simvastatin develops ALT elevations, follow guidelines for 
pazopanib dose modification and discontinue simvastatin. 
 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function 
test; SAE, serious adverse event; ULN, upper limit of normal 
 
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
(2/27/12) Management of Other Clinical Specific Non-Hematologic Toxicities Not Otherwise 
Addressed, That Are Possibly, Probably, or Definitely Related to Pazopanib/Placebo 
If not addressed in protocol, but treating physician feels continuation of treatment a current 
dose level will be unsafe, the treating physician must discuss with a co-chair of the study first 
before making any dose adjustments or treatment delays. 
 
Observation 
Action 
AE resolves promptly with supportive care 
Maintain dose level 
Grade 3-4 AE (possibly, probably, or definitely related) to 
pazopanib/placebo. 
Reduce one dose level* 
AE does not resolve to grade 2 or below after treating subject 
at the lowest reduced dose level. 
In general, remove subject from 
study treatment** 
*Alternatively and if medically appropriate, investigators may choose to hold dose for up to 14 
days or withdraw patient from study treatment. If it is felt the toxicity is more likely related to 
another factor (e.g. radiation therapy or disease), the investigator may consult with a study 
chair (Drs. Sherman, Bible, or Lee) about continuing at the current dose level without delaying 
treatment. 
 
**After consultation with a study chair (Drs. Sherman, Bible, or Lee), the investigator may 
consider treating the patient at the lowest dose level, if the investigator feels the patient is 
benefitting from the agent. 
 
 
Management of Hematologic Adverse Events (2/27/12) 
(3/8/12) With the exception of Neutropenic fever, changes in dose levels will only occur if the 
abnormal blood counts are within 24 hours of when paclitaxel is scheduled. This pertains to 
changes in dose levels for paclitaxel and pazopanib. 
 
Adverse 
Event/ 
CTCAE, v. 
4.0 Category 
Grade/Counts 
Paclitaxel  
Modification 
Pazopanib/Placebo Modification 
Neutropenia* 
3 (500-999/m3) 
Hold therapy. Maintain 
dose level if recovered to 
grade 2 ( ≥ 1000/m3) in 1 
week. If not, decrease by 
one dose level and restart 
when absolute neutrophil 
count is  ≥ 1000/m3. 
Hold therapy. Maintain dose level if 
recovered to grade 2 (≥ 1000/m3) 
in 1 week. If not, decrease by one 
dose level and restart when 
absolute neutrophil count is 
 ≥ 1000/m3. 
 
  
 
Neutropenic 
Fever 
 
Hold therapy and 
decrease by one dose 
level. Restart when 
absolute neutrophil count 
is > 1000/m3. 
Hold therapy. Reduce by one dose 
level. Restart when recovered (≥ 
1000/m3).  
Thrombo-
cytopenia* 
3 or 4  
(< 50,000 m3) 
Hold therapy. Maintain 
dose level if recovered in 
1 week (> 50,000/m3). If 
not, decrease by one 
dose level and restart 
when platelet count is > 
50,000/m3. 
Hold therapy. Maintain dose level if 
recovered in 2 weeks 
(≥ 50,000/m3). If not recovered in 2 
weeks, decrease by one dose level 
and restart when platelet count is > 
50,000/m3. 
*Recurrent grade 3 or 4 neutropenia and/or thrombocytopenia will result in permanent 
discontinuation of pazopanib, unless Drs. Sherman or Bible approves continuing treatment. 
 
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
 
7.6.2 
Paclitaxel (9/13/16) 
Appropriate dose modifications for paclitaxel-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 (NRG Oncology) to review the 
subject’s condition prior to resuming the patient’s treatment except for delays due to 
hypertension (see Section 7.6, “Dose Modifications”).  As a patient progresses from one 
treatment group to another (i.e., pre-radiation therapy (7.1), radiation therapy (7.2), the patient 
should remain at the SAME DOSE LEVEL unless otherwise noted. Dose level reductions 
follow: 
 
Pre-Radiation Therapy 
Dose level 
Paclitaxel 
DL 1 
80 mg/ m2 intravenously weekly 
DL -1 
60 mg/ m2 intravenously weekly 
DL -2 
45 mg/ m2 intravenously weekly 
 
  
 
 
 
During Radiation Therapy 
Dose level 
Paclitaxel 
DL 1 
50 mg/ m2 intravenously weekly 
DL -1 
38 mg/ m2 intravenously weekly 
DL -2 
30 mg/ m2 intravenously weekly 
 
 
  
Management of Non-Hematologic Adverse Events That Are Possibly, Probably, or Definitely 
Related To Paclitaxel (9/13/16) 
 
 
 
Adverse Event/ 
CTCAE, v. 4.0 Category 
Grade 
Treatment Modifications 
Neuropathy 
Grade 3 
Hold therapy until grade <=2. Then reduce by 
one dose level. 
Grade 4 
Discontinue paclitaxel. 
Allergic Reaction 
Grade 3-4 
Discontinue paclitaxel. If it occurs before the 
start of radiation therapy, patient should be 
taken off protocol treatment (refer to Section 
11.8 for follow up and data collection). 
Elevations in AST, ALT, and/or 
bilirubin 
AST/ALT 2 to 
<10 X ULN and 
total bilirubin 
elevations < 1.5 
X ULN  
Decrease paclitaxel 1 dose level until 
AST/ALT < 2 x ULN, at which time, may 
return to original dose. If liver metastasis is 
present, do not decrease unless > 3 x ULN. 
 
AST/ALT >2 X 
ULN and < 10 X 
ULN and 
concurrent 
bilirubin 
elevations >1.5 
X ULN  
If elevation in bilirubin is predominantly direct 
(> 35%), decrease dose level by 2.  Once 
bilirubin is < 1.5 x ULN, paclitaxel can be 
increased 1 dose level. Once AST/ALT < 2 x 
ULN and bilirubin < 1.5 x ULN, paclitaxel can 
be returned to normal dose. Contact study 
chairs (Drs. Sherman or Bible) if any 
questions. 
 
If AST/ALT > 10 
X ULN 
Hold paclitaxel until  AST/ALT < 10 X ULN 
and bilirubin < 1.5 X ULN, and then restart at 
a reduction of 1 dose level. Once AST/ALT < 
2 x ULN, paclitaxel can be increased to 
original dose level. 
 
Bilirubin > 5x 
ULN 
Discontinue Paclitaxel 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
Dysphagia during radiation 
therapy 
Grade 3-4 
• 
If 
disease 
related 
(not 
related 
to 
treatment), no change.  
• 
If related to radiation therapy or paclitaxel 
before the fifth dose of paclitaxel, 
permanently decrease paclitaxel by 1 
dose level during radiation therapy 
• If related to radiation therapy or paclitaxel 
before the third dose of paclitaxel, 
permanently decrease paclitaxel to dose 
level 2 during radiation therapy, but 
increase paclitaxel by 1 dose level once 
post radiation therapy starts. 
Other non-hematologic 
toxicities 
Grade 3-4 
Hold paclitaxel until  ≤ grade 2. Maintain dose 
level. Treating physician may decrease by 
one dose level with approval from study co-
chair (Keith Bible, Nancy Lee, or Eric 
Sherman). If the treating physician feels that 
the 
continuation 
of 
treatment 
benefit 
outweighs the risk, the physician may 
discuss with a study co-chair and continue 
treatment with approval (grade 3 toxicity 
only). 
 
  
Management Of Hematologic Adverse Events (7/15/13) 
See Section 7.6, “Dose Modifications”. 
 
7.7 
Modality Review (2/27/12) 
The Co-Principal Investigator, Eric Sherman, MD, and the Medical Oncology Co-Chair, Keith Bible, MD, 
PhD will perform a Chemotherapy Assurance Review of all patients who receive or are to receive 
chemotherapy in this trial.  The goal of the review is to evaluate protocol compliance.  The review process 
is contingent on timely submission of chemotherapy treatment data as specified in Section 12.1. The 
scoring mechanism is: Per Protocol/Acceptable Variation, Unacceptable Deviation, and Not 
Evaluable.  A report is sent to each institution once per year to notify the institution about compliance for 
each case reviewed in that year. 
   
The Principal Investigator, Eric Sherman, MD, and the Medical Oncology Co-Chair, Keith Bible, MD, PhD 
will perform a Quality Assurance Review after complete data for the first 20 cases enrolled has been 
received at NRG Oncology. Drs. Sherman and Bible will perform the next review after complete data for 
the next 20 cases enrolled has been received at NRG Oncology. The final cases will be reviewed within 3 
months after this study has reached the target accrual or as soon as complete data for all cases enrolled 
has been received at NRG Oncology, whichever occurs first. 
 
7.8 
Adverse Events (3/25/14) 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for 
adverse event (AE) reporting. The CTCAE version 4.0 is located on the CTEP website at                                                
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be reported 
via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via the CTEP web 
site (https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613). 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 1-800-
227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is restored, an AE report 
submitted by phone must be entered electronically into CTEP-AERS 
7.8.1 
Adverse Events (AEs) (3/25/14) 
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Therefore, an AE can be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, 
possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6). 
[CTEP, NCI Guidelines: Adverse Event Reporting Requirements. February 29, 2012;] 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]  
7.8.2 
Serious Adverse Events (SAEs) (3/25/14) 
 
Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table in 
Section 7.9 will be reported via CTEP-AERS.  SAEs that require 24 hour CTEP-AERS 
notification are defined in the expedited reporting table in Section 7.9.  Contact the CTEP-
AERS Help Desk if assistance is required. 
 
 
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment 
and 30 days after that results in any of the following outcomes: 
▪ 
Death; 
▪ 
A life-threatening adverse drug experience; 
▪ 
Inpatient hospitalization or prolongation of existing hospitalization; 
▪ 
A persistent or significant disability/incapacity; 
▪ 
A congenital anomaly/birth defect. 
▪ 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner.  
7.8.3 
Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (3/25/14) 
 
AML or MDS that is diagnosed during or subsequent to treatment in patients on NCI/CTEP-
sponsored clinical trials must be reported via the CTEP-AERS system within 30 days of 
AML/MDS diagnosis.  
 
Secondary Malignancy:  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under 
an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the 
event: 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified. 
  
7.9 
CTEP-AERS Adverse Event Reporting Requirements (6/5/14) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table below will 
be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed via the CTEP web 
site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613.  
 


 
 
 
 
 
 
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Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG Oncology 
requirements for expedited adverse event reporting. 
 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation 
therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 1-800-
227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is restored, an AE report 
submitted by phone must be entered electronically into CTEP-AERS. 
 
• 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is electronically 
submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 24-hour notification 
must be followed by an CTEP-AERS 5 Calendar Day Report. Serious adverse events that require 24 
hour CTEP-AERS notification are defined in the expedited reporting table below. 
• 
Supporting source document is not mandatory.  However, if the CTEP-AERS report indicates in the 
Additional Information section that source documentation will be provided, then it is expected.  If 
supporting source documentation accompanies an CTEP-AERS report, include the protocol number, 
patient ID number, and CTEP-AERS ticket number on each page, and fax supporting documentation 
to both the NCI at 301-230-0159 and the NRG Oncology dedicated SAE FAX, 215-717-0990. 
• 
A serious adverse event that meets expedited reporting criteria outlined in the following table but is 
assessed by the CTEP-AERS System as “expedited reporting NOT required” must still be reported to 
fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT Required” assessment; 
the CTEP-AERS System allows submission of all reports regardless of the results of the assessment.  
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the table 
below. Important: All AEs reported via CTEP-AERS also must be reported on the AE section of the 
appropriate case report form (see Section 12.1).  
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent (panitumumab) and the commercially available agents in this study1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 


 
 
 
 
 
 
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Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
NOTE: Deaths clearly due to progressive disease should NOT be reported via CTEP-AERS but rather should 
be reported via routine reporting methods (e.g., CDUS and/or CTMS). 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for Phase 2 and 
3 Trials Utilizing an Agent under a CTEP-IND:  None 
 
8.0 SURGERY 
Any salvage surgery (i.e. surgery to remove any part of the tumor) after the patient is registered for the study 
would require the patient to be removed from protocol treatment. (The patient would be followed as specified 
in the protocol.) 
 
The exception would be if it is felt that the surgery would not affect any of the objectives/outcomes for the 
study—a very special circumstance. If the treating physician believes this circumstance exists, the physician 
must obtain approval from one of the Co-Principal Investigators (Drs. Sherman or  Lee) in order for the patient 
to continue to receive protocol treatment. 
 
 
9.0 OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during the study period at the discretion of 
the attending physician(s) within the parameters of the protocol and documented on each site’s source 
documents as concomitant medication. 
 
9.2 
Non-permitted Supportive Therapy (9/30/15) 
9.2.1 
The patient’s medications will be evaluated within 4 weeks prior to treatment (see Section 
3.2.16) with attempt to change any medication that affects CYP3A4 (see Appendix VI).  
 
Certain medications that act through the CYP450 system are specifically prohibited in patients 
receiving pazopanib. Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
voriconazole may increase pazopanib concentrations and are prohibited although, if absolutely 
necessary, they may be administered in conjunction with lowering the dose of pazopanib to 400 
mg daily.  Grapefruit juice is also an inhibitor of CYP450 and should not be taken with 


 
 
 
 
 
 
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pazopanib. CYP3A4 inducers such as rifampin may decrease pazopanib concentrations and 
therefore are strictly prohibited.  Caution should be used when strong inhibitors and/or inducers  
of  CYP2D6 are co-administered with pazopanib. Concomitant use of pazopanib with agent 
with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6 or CYP2C8 should 
be avoided. In addition, the use of St. John’s Wart is not permitted. 
 
Pazopanib, 800 mg once daily, has no effect on CYP2C9, CYP1A2 or CYP2C19 in vivo 
although it does in vitro. Therefore, therapeutic doses of warfarin, a substrate of CYP2C9, and  
omeprazole, a substrate of CYP2C19 are permitted. Caffeine, a substrate of CYP1A2, is also 
permitted. A list of medications that are specifically prohibited or that should be used with 
caution during this trial of pazopanib can be found in Section 7.4.1. Comprehensive lists of 
agents that could affect pazopanib through the cytochrome P450 system can be found in 
Appendix VII. 
9.2.2 
Certain medications that are associated with a risk for QTc prolongation and/or Torsades de 
Pointes are not prohibited but should be avoided or replaced with medications that do not carry 
these risks, if possible. Comprehensive lists of agents that that are associated with a risk for 
QTc prolongation and/or Torsades de Pointes can be found in Appendix VI. 
 
 
10.0 
TISSUE/SPECIMEN SUBMISSION 
NOTE: Patients must be offered the opportunity to participate in the correlative components of the 
study, such as tissue/specimen submission. If the patient consents to participate in the 
tissue/specimen banking in the study, the site is required to submit the patient’s specimens as specified in 
Section 10.0 of the protocol. Note: Sites are not permitted to delete the tissue component from the 
protocol or from the sample consent. 
 
10.1 
Tissue/Specimen Submission (6/5/14) 
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and 
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved through 
careful block storage and processing. NRG Oncology encourages participants in protocol studies to 
consent to the banking of their tissue and blood. NRG Oncology Biospecimen Bank provides specimens 
to investigators for translational research studies. Translational research studies integrate the newest 
research findings into current protocols to investigate important biologic questions.  The NRG Oncology 
Biospecimen Bank also collects tissue for central review of pathology. 
 
In this study, tissue must be submitted prior to treatment to the NRG Oncology Biospecimen Bank for the 
purpose of central review of pathology (mandatory), but central review is not required for eligibility. Due to 
the aggressiveness of this disease, treatment will be started prior to central review.  Collection of tissue 
and blood pre-treatment for banking is recommended, but not required. 
 
10.2 
Tissue Collection for Central Review – Mandatory (9/13/16) 
The following material must be provided to the NRG Oncology Biospecimen Bank for Central Review: 
10.2.1 
One H & E stained slide per positive biopsy site (required); the slide can be a duplicate cut 
stained H&E of the diagnostic slide or block; it does not have to be the diagnostic slide itself. In 
addition, a digital slide is acceptable in lieu of the H&E.  
10.2.2 
A paraffin-embedded tissue block of the tumor (preferred), or 10 unstained tumor slides (5 
micron thickness per slide), or a 2 mm diameter core of tumor tissue, punched from the tissue 
block containing the tumor with a skin punch and submitted in a plastic tube labeled with the 
surgical pathology number. NOTE: A kit with the punch, tube, and instructions can be obtained 
free of charge from the NRG Oncology Biospecimen Bank; see Appendix VIII. Block or core 
must be clearly labeled with the pathology identification number and block number that 
corresponds to the Pathology Report. 
• The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.2.3 
A Pathology Report documenting that the submitted block, core, or slides contain tumor; the 
report must include the NRG Oncology protocol number and patient’s case number. The 
patient’s name and/or other identifying information should be removed from the report. The 
surgical pathology numbers and information must NOT be removed from the report. 


 
 
 
 
 
 
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• The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.2.4 
A Specimen Transmittal (ST) Form stating that the tissue is being submitted for Central Review.  
The Form must include the NRG Oncology protocol number and the patient’s case number. 
10.2.5 
Central Review will be performed for every case by the Pathology Co-Chair, Ronald A. 
Ghossein, MD, Memorial Sloan-Kettering Cancer Center. Central review will be performed after 
the study is closed 
 
10.3 
Specimen Collection for Banking – Recommended (2/10/15) 
 
For patients who have consented to participate in the tissue/blood component of the study (See the 
sample consent form) 
 
See Appendices IX-XI for detailed collection instructions, including information pertaining to 
collection kits. Note: Kits include a shipping label for frozen biospecimen shipments. 
 
Tissue should be collected pre-treatment. The following must be provided in order for the case to be 
evaluable for the NRG Oncology Biospecimen Bank:  
10.3.1 
One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide or 
block; it does not have to be the diagnostic slide itself.) 
10.3.2 
A paraffin-embedded tissue block of the tumor (preferred), or 10 unstained tumor slides (5 
micron thickness per slide), or a 2 mm diameter core of tumor tissue, punched from the tissue 
block containing the tumor with a skin punch and submitted in a plastic tube labeled with the 
surgical pathology number. NOTE: A kit with the punch, tube, and instructions can be obtained 
free of charge from the NRG Oncology Biospecimen Bank; see Appendix X. Block or core must 
be clearly labeled with the pathology identification number and block number that corresponds 
to the Pathology Report. 
• The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
 
If an institution is uncomfortable with obtaining the punches and wants to retain the tissue 
block, the site can send the entire block to the NRG Oncology Biospecimen Bank, and the 
Bank will obtain the core punches from the block and return the remaining block to the site.  
Please indicate this request (to obtain the sections, perform the core punch procedure, and 
return the block) on the submission form and include a return airbill for the block being 
returned.  
10.3.3 
A Pathology Report documenting that the submitted block, or unstained slides, or core contains 
tumor. The report must include the NRG Oncology protocol number and patient’s case number. 
The patient’s name and/or other identifying information should be removed from the report. The 
surgical pathology numbers and information must NOT be removed from the report. 
10.3.4 
A Specimen Transmittal (ST) Form clearly stating that tissue is being submitted for the NRG 
Oncology  Biospecimen Bank documenting the date of collection of the biospecimen; the NRG 
Oncology protocol number, the patient’s case number, and method of storage, for example, 
stored at -20° C, must be included. 
10.3.5 
Serum, Plasma, and Whole Blood (4/19/11) 
 
Serum, plasma, and whole blood should be collected pre-treatment. The following must be 
provided in order for the case to be evaluable for the NRG Oncology Biospecimen Bank: A 
Specimen Transmittal Form documenting the date of collection of the serum, plasma, and 
whole blood; the NRG Oncology protocol number, the patient’s case number, the method and 
time of storage (for example, stored at -80° C for 3 days). 
 
 
If the institution does not have any access to centrifuges for serum/plasma separation, it is 
allowed to submit only whole blood samples which do not require any separation steps (See 
Appendix IX for processing and shipping instructions.) 
 
Storage Conditions 
 
Store frozen specimens at –80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available:  


 
 
 
 
 
 
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• Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
• Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
• Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; 
Canada: Monday-Tuesday). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time 
stored. 
 
 
 
10.3.6 
Specimen Collection Summary (9/13/16) 
Note: See Appendices IX-X for collection kits and instructions. 
 
Specimens for Banking 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E stained 
slides of the primary tumor 
Pre-treatment 
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
A paraffin-embedded tissue 
block of the primary tumor taken 
before initiation of treatment, or 
10 unstained tumor slides (5 
micron thickness per slide), or a 
2 mm diameter core of tissue, 
punched from the tissue block 
with a punch tool  
Pre-treatment 
Paraffin-embedded 
tissue block, or 
unstained tumor slides, 
or punch biopsy (must 
match the H&E slide 
being submitted) 
 
Block or punch shipped 
ambient 
 
SERUM: 5-10 mL of whole 
blood in 1 red-top tube and 
centrifuge  
Pre-treatment 
Frozen serum samples 
containing a minimum of 
0.5 mL per aliquot in 1 
mL cryovials (five) 
Serum sent frozen on dry 
ice via overnight carrier 
PLASMA: 5-10 mL of 
anticoagulated whole blood in 
EDTA tube #1 (purple/lavender 
top) and centrifuge  
Pre-treatment 
Frozen plasma samples 
containing a minimum of 
0.5 mL per aliquot in 1 
mL cryovials (five) 
Plasma sent frozen on dry 
ice via overnight carrier 
DNA: 5-10 mL of anticoagulated 
whole blood in  EDTA tube #2 
(purple/lavender top) and mix 
Pre-treatment 
Frozen whole blood 
samples containing  1 
mL per aliquot in 1 mL 
cryovials (three to five) 
Whole blood sent frozen 
on dry ice via overnight 
carrier 
 
10.3.7 
Submit materials for Central Review and Banking as follows: (9/13/16) 
 
Courier Address (FedEx, UPS, etc.) For Trackable FFPE and ALL Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
Questions: 415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu 
 
10.4 
Reimbursement (2/10/15) 
 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per 
the requirements/methods specified by the new National Clinical Trials Network (NCTN) Program. 
This information will be made available with the other registration materials in the Oncology 
Patient Enrollment Network (OPEN) portal system.  
 


 
 
 
 
 
 
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10.5 
Confidentiality/Storage (4/19/11) 
 
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further details.) 
10.5.1 
Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the 
patient’s case number only. The NRG Oncology Biospecimen Bank database only includes the 
following information: the number of specimens received, the date the specimens were 
received, documentation of material sent to a qualified investigator, type of material sent, and 
the date the specimens were sent to the investigator. No clinical information is kept in the 
database. 
10.5.2 
Specimens for tissue banking will be stored for an indefinite period of time. Specimens for 
central review will be retained until the study is terminated. If at any time the patient withdraws 
consent to store and use specimens, the material will be returned to the institution that 
submitted it. 
 
11.0 
PATIENT ASSESSMENTS 
 
11.1 
Study Parameters (2/27/12) 
See Appendix I for a summary of assessments and timeframes. Note: Clarifications of or exceptions to 
the study parameters are indicated in Appendix I with an asterisk (*) and are discussed in Sections 11.2-
11.7 below. 
 
 
Laboratory Tests: All laboratory tests (i.e. CBC, serum electrolytes) may be done 1 day prior to 
scheduled treatment day (e.g. if scheduled in the calendar on a Tuesday, it may be done the day before, 
on a Monday). Liver function tests may be done up to 2 business days prior to scheduled treatment day. 
 
Urine Tests for Protein/Creatinine: Urine tests may be done up to 2 business days prior to scheduled 
treatment day. If a 24-hour urine collection for protein has been completed within 5 business days prior, a 
urine for protein/creatinine ratio is not necessary. 
 
(3/8/12) Patient Education: Institutions must provide patient education regarding the pazopanib/placebo 
suspension. Patients should be educated regarding swirling the suspension for 30 seconds prior to 
withdrawing the dose from the bottle, drawing up the prescribed dose, and storage of the suspension. 
Patients should demonstrate that they can draw up the appropriate daily dose and should be reminded to 
take the suspension on an empty stomach either 1 hour before or 2 hours after meals. Instructions to the 
patient for disposal of leftover pazopanib suspension and cleanup of pazopanib suspension spills have 
been included on the medication diary form (DP). 
 
11.2 
Pre-Treatment Evaluations (9/30/15) 
11.2.1 
Note: In the event that the patient’s condition is deteriorating, lab tests done prior to registration 
and any other relevant tests should be repeated within 48 hours prior to treatment. 
11.2.2 
In the review of the patient’s medications: Medications must be checked to see if they are listed 
in Appendices VII and VIII. If the medications are listed in Appendix VI, appropriate changes to 
the patient’s medications must be made. 
11.2.3 
Systolic blood pressure must be  ≤ 140 and diastolic blood pressure must be  ≤ 90 on at least 2 
separate measurements within 2 weeks prior to treatment, if > 140/90 at baseline.  
11.2.4 
The recommended (but not required) dental evaluation and, if applicable, prophylaxis, should 
be performed within 12 weeks prior to treatment. 
11.2.5 
Imaging of the neck: The CT scan must be done with contrast or if an MRI is done, with 
gadolinium. 
11.2.6 
Chest/abdominal imaging: Abdominal imaging must cover the liver and adrenal glands; 
therefore, separate imaging is not required if these areas are covered by a chest CT scan. 
11.2.7 
All wounds, whether surgical or other, must be completely healed prior to the initiation of 
treatment (see Section 4.1.2). 
11.2.8 
Serum electrolytes should include sodium, potassium, chloride, carbon dioxide, BUN, 
creatinine, magnesium. Liver function tests include at least serum glutamic oxaloacetic 
transaminase/aspartate 
transaminase 
(SGOT/AST), 
serum 
glutamic 
pyruvic 
transaminase/alanine transaminase (SGPT/ALT), total bilirubin, and albumin. Note: Bilirubin 


 
 
 
 
 
 
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with fractionation should be done if the total bilirubin is greater than ULN. These definitions 
pertain throughout the study and in follow up. 
 
11.3 
Evaluations During Pre-Radiation Treatment (3/11/15) 
11.3.1 
On day 1, the CYP3A4-affecting agents (see Appendix VII) that the patient is taking should be 
recorded. 
11.3.2 
Day 8 of treatment may be given within 2 days of day 8, if necessary. 
11.3.3 
Typically, Day 15 (+/- 2 days) of paclitaxel will not take place, and patients will start the 
concurrent treatment (radiation therapy) on this date. However, there may be an unforeseen 
delay to starting the radiation therapy after 2 weeks. If this occurs, a 3rd week of treatment (i.e. 
paclitaxel 80 mg/m2 on day 15 and pazopanib (or placebo) 400 mg oral suspension daily 
(unless reduced for safety reasons) until radiation therapy begins may be given after contacting 
and getting approval from Drs. Sherman, Lee, or Bible (see Section 7.2.1) if radiation therapy is 
ready to begin by day 17.  
11.3.4 
Institutions will collect the patient’s medication diary for pazopanib/placebo during patient visits. 
Institutions will keep the medication diary as source documentation and will submit the DP form 
at end of treatment (see Section 12.1). 
11.3.5 
Serum liver tests must be monitored at Day 1 and at week 3 of treatment if radiation therapy 
has not begun. Note: Bilirubin with fractionation should be done if the total bilirubin is greater 
than ULN. 
 
11.4 
Evaluations During Concurrent Treatment (3/11/15) 
11.4.1 
Imaging should be done within 2-4 weeks after radiation therapy is completed. If RECIST 
measurable disease was present prior to the start of treatment, response should be recorded. 
11.4.2 
Urine protein/urine creatinine only needs to be done on week 1 and then every 3 weeks until 
end of radiation therapy. 
11.4.3 
On day 1, an EKG should be performed (see Section 7.6.1). 
11.4.4 
On day 1 (+/- 3 days), the CYP3A4-affecting agents (see Appendix VII) that the patient is taking 
should be recorded. This should be repeated every 2 weeks until the end of radiation therapy. 
11.4.5 
Institutions will collect the patient’s medication diary for pazopanib/placebo during patient visits. 
Institutions will keep the medication diary as source documentation and will submit the DP form 
at end of treatment (see Section 12.1). 
11.4.6 
Serum liver tests must be monitored in all odd weeks (e.g. 1, 3, 5, 7) of concurrent treatment 
and at 2 weeks after completion of treatment (+/- 2 days). Note: Bilirubin with fractionation 
should be done if the total bilirubin is greater than ULN. 
 
11.5 
Imaging After Completion of Radiation Therapy (3/8/16) 
After radiation therapy is completed, imaging studies for staging purposes should be completed. This 
must include (1) imaging of the neck (CT scan or MRI);  (2) imaging of the chest and abdomen by CT 
scan and (3) imaging of the brain (CT scan or MRI). All CT scans and MRIs should include contrast 
unless clinically contraindicated. Imaging should take place between 2-4 weeks following the completion 
of radiation therapy. Imaging of the neck, chest, and adrenal glands should continue every 3 months from 
the end of RT for 2 years (see Section 11.6).  
 
11.6 
Long-Term Follow up (9/30/15) 
If/when a subject begins a new type of treatment for anaplastic thyroid cancer, long-term follow up may 
cease, with the exception of noting whether the subject is alive or dead. To document this, it is not 
necessary that the patient return for office visits. Follow up may be done through other means (e.g., 
through telephone calls or registered mail). Note: The Follow-up Form (F1) must be submitted as 
specified in Section 12.1. If a subject dies, the date of death must be recorded and submitted to NRG 
Oncology.  
 
If a subject comes off treatment due to disease progression or recurrence, or if this happens during long-
term follow up, further radiology studies as per protocol are no longer required. 
 
Radiology studies should include imaging of the neck (MRI or CT scan) and chest (CT scan). A PET/CT 
can be substituted for the CT scans. The first set of follow-up scans and the follow-up visit should be 3 
months after the end of radiation treatment, NOT after the prior scans. If the above imaging does not 
include the adrenal glands, an abdominal CT scan also must be done during follow-up imaging. Patients 


 
 
 
 
 
 
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may be evaluated +/- 2 weeks of the scheduled follow-up visit during the first 2 years and +/- 1 month 
during years 3-5. If imaging is required for clinical reasons prior to the per-protocol-scheduled evaluation, 
all future evaluations may be delayed up to 2 months. Imaging is not required after 2 years but is highly 
recommended. The patient’s evaluation schedule should be modified only after discussion with one of the 
study co-chairs (Drs. Bible, Lee, or Sherman).  
 
11.7 
Measurement of Response (2/27/12) 
11.7.1 
Measurement of Response Prior to Study Entry 
 
The revised RECIST guideline, v. 1.1 [European Journal of Cancer. 45: 228-247, 2009] will be 
used as applicable to the protocol. See  
http://ctep.info.nih.gov/protocolDevelopment/docs/recist_guideline.pdf for further details. 
Additional definitions beyond the RECIST guidelines specific to this protocol are incorporated to 
define local control as described below. 
 
 
 
 
11.7.2 
Response Criteria: Evaluation of Target Lesions 
  
 
 
Complete Response (CR): 
Disappearance of all target lesions; Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered 
progressions). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study 
11.7.3   Assessment of Failure Patterns 
• 
Local or Regional Relapse 
Relapse is defined as reappearance of tumor after complete response.  If possible, relapse 
should be confirmed by biopsy. 
• 
Local or Regional Progression 
Progression is defined as an estimated increase in the size of the tumor (product of the 
perpendicular diameters of the two largest dimensions) of greater than 25%, taking as 
reference the smallest value of all previous measurements or appearance of new areas of 
malignant disease. This should be compared to radiology reassessment done after the 
completion of radiation therapy. 
• 
Distant Metastasis Progression 
Progression (of distant metastasis [lung, bone, brain, liver, etc…]) is defined as an estimated 
increase in the size of the tumor (product of the perpendicular diameters of the two largest 
dimensions) of greater than 25%, taking as reference the smallest value of all previous 
measurements or appearance of new areas of malignant disease. This should be compared 
to radiology reassessment done after the completion of radiation therapy. 
 
11.8 
Criteria for Discontinuation of Protocol Treatment (9/13/16) 
• 
Progression of disease; 
• 
A delay in protocol treatment, as specified in Sections 6.0 and/or 7.0; 
• 
Intercurrent illness that prevents further administration of treatment; 
• 
Unacceptable adverse event(s), as defined in Section 6.0 and/or 7.0; 
• 
Patient noncompliance as determined by the judgment of the investigator that would make further 
treatment potentially unsafe or make outcomes of the trial difficult to interpret; 


 
 
 
 
 
 
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• 
Patient decides to withdraw from the study; 
• 
General or specific changes in the patient’s condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. Patients who have received no protocol treatment should be followed for overall survival only. 
 
12.0 
DATA COLLECTION (24-FEB-2020) 
Data should be submitted to: 
NRG Oncology* 
 50 South 16th Street, Suite 2800 
 Philadelphia, PA 19102 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be 
used (first-last). Last names with apostrophes will be identified by the first letter of the last name. 
 
 
 
12.1 
Summary of Data Submission  (9/13/16) 
 
 
 
Item 
Due 
Demographic Form (A5) 
Initial Evaluation Form (I1) 
Pathology Report (P1) 
Slides/Blocks (P2)  
Within 2 weeks of study entry 
 
 
Treatment Form (TF) 
At the completion of pre-IMRT component and at 
the completion of concurrent therapy component 
 
 
Medication diary (DP) 
At end of treatment 
 
 
Initial Follow-up Form (F0) 
3 months from the start of treatment, after re-
staging imaging  
 
 
Follow-up Form (F1) 
After the F0, q 3 months for years 1 and 2; q 6 
months for year 3, then annually; also at death. 
 
 
 
12.2 
Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 5.0 for account 
access and installation instructions ) (3/25/14) 
 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
Digital Data Submission – Treatment Plan submitted to 
NRG Oncology via TRIAD exported from treatment 
planning machine by Physicist 
Within 1 week of start of RT  
Digital data submission includes the following: 
 
• 
DICOM CT Data 
 
• 
DICOM Structure 
 
• 
DICOM RT Plan 
 
• 
DICOM Dose 
 
All required structures MUST be labeled per the 
specifications in Section 6.5. 
 
All digital RT data MUST be in DICOM format. 
 
Upon submission of digital data via TRIAD, complete a 
Digital Data Submission Information Form (DDSI) –
located at 
 


 
 
 
 
 
 
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http://www.rtog.org/CoreLab/RTQASubmissionInformatio
n.aspx 
 
 
 
Final Dosimetry Information 
Within 1 Week of RT End 
Radiotherapy Form (T1) Via Web 
 
Daily Treatment Record (T5) [Copy To HQ only] 
 
 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Endpoints (7/15/13) 
13.1.1  
Primary Endpoint for Run-In Components (2/27/12) 
Grade 4 (CTCAE, v. 4.0) hemorrhage, grade 4 febrile neutropenia, discontinuation of treatment 
due to toxicity (< 75% of planned radiation therapy delivered), or any Grade 5 adverse event 
assessed to be definitely, probably, or possibly related to the induction or concurrent treatment 
components of the protocol regimen (that is not definitely related to disease progression). 
 
13.1.2 
Primary Endpoint for Phase II Component 
Overall survival (OS) at 1 year from study registration 
13.1.3 
Secondary Endpoints for Phase II Component (6/5/14) 
• 
Local-regional control at 6 and 12 months; 
• 
Grade 4 (CTCAE, v. 4.0) hemorrhage, grade 4 febrile neutropenia, discontinuation of 
treatment due to toxicity (< 75% of planned radiation therapy delivered), or any Grade 5 
adverse event assessed to be definitely, probably, or possibly related to the induction or 
concurrent treatment components of the protocol regimen; 
• 
Other adverse events (CTCAE, 4.0) assessed to be definitely, probably, or possibly 
related to the induction or concurrent treatment components of the protocol regimen; 
• 
Response as per RECIST of the primary site in patients with measurable disease following 
chemoradiation. 
 
13.2 
Background and Sample Size Determination (2/27/12)  
13.2.1 
Run-in Components  
Since there is limited experience with pazopanib added to concurrent chemoradiation for 
treatment of patients with thyroid cancer, a two-stage design based on binomial distribution will 
be utilized to monitor safety endpoints. The first stage will be a run-in component enrolling 11 
patients to assure that the induction and the concurrent components of the protocol regimen 
are safe. A safety analysis will be performed after the 11 patients complete radiation therapy. 
There is particular concern of a possibly unacceptable increase in the incidence of patients with 
grade 4 bleeding, grade 4 febrile neutropenia, discontinuation of treatment due to toxicity (< 
75% of planned radiation therapy delivered), and any grade 5 adverse event (that is not 
definitely related to disease progression). Discontinuation of treatment due to toxicity is defined 
as discontinuation of treatment by a treating physician due to a grade 3 or 4 toxicity/toxicities 
that are possibly, probably, or definitely related to treatment and causes < 75% of planned 
radiation therapy to be delivered. This incidence is assumed to be no greater than 20%; an 
increase of 25% or more is considered unacceptable. Eleven patients will be initially entered on 
the run-in component to guard against the possibilities that disease may progress during 
treatment or a patient withdraws consent. Patient accrual then will be suspended until the 
analysis of the run-in component is completed. With 9 evaluable patients, if 4 or fewer patients 
experience the adverse events of concern, then the induction and the concurrent components 
will be judged to be safe. If 5 or more patients with such events are observed, then the 
induction and the concurrent components will be judged as too toxic. The run-in component 
may be repeated following dose modification. The data that will be collected for analysis will 
include all the adverse events reported through 4 weeks after the completion of concurrent 
chemoradiation, as well as dose delays, dose modifications, and delays in initiating radiation 
therapy. The probability of the induction and the concurrent components being judged to be too 
toxic when the true toxicity rate is 45% or higher is at least 84%. If the true toxicity rate is 20% 
or lower, the probability that the therapy will be safe is 95%. The second stage of the analysis 
will be done when 30 patients have been randomized on the phase II component, given the trial 
is not stopped at the first analysis. With 15 more patients and total of 24, if 8 or fewer patients 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
experience the adverse events of concern, then the induction and concurrent components will 
be judged to be safe. Otherwise, the trial will be stopped due to the toxic nature of the therapy. 
The data that will be collected for analysis will include all the adverse events reported through 4 
weeks after the completion of concurrent chemoradiation, as well as dose delays, dose 
modifications, and delays in initiating radiation therapy. For this second analysis, accrual to the 
study will be not suspended. Analysis results of the run-in components will be reviewed by the 
NRG Oncology Data Safety Monitoring Board (DSMB) and shared with CTEP. Analysis results 
of the phase II component will be reviewed by the NRG Oncology Data Monitoring Committee 
(DMC). 
13.2.2 
Phase II Screening Component (10/28/10) 
After the run-in component is completed, the study will be a randomized phase II screening trial 
as proposed by Rubinstein, et al. (2005).  It is designed as a one-sided test to detect a ≥ 37.5% 
reduction of the hazard rate associated with overall survival (OS) favoring the addition of 
pazopanib. The type I (alpha) is set at 0.15 while the statistical power is set at 0.80.  There is a 
paucity of outcome data available for this study population. Currently, the best available data 
comes from a population-based study that reported a 1-year survival rate of 19% with standard 
of care treatment (Goutsouliak 2005). It should be noted that this rate is consistent with the 
long-term experience at Memorial Sloan-Kettering (personal communication, Sherman). OS will 
be assumed to follow an exponential distribution for planning purposes. East® software for 
group sequential design was used in calculating the sample size with one planned interim 
analysis for early efficacy and futility testing (East 2005). The O’Brien-Fleming boundary for 
efficacy and futility were utilized. The interim analysis will occur when there are 35 deaths seen 
from both arms. If the p<=0.0418, this result will be interpreted as an indication of pazopanib in 
improving overall survival in these patients.  If p>=0.5324, we will declare futility. If either 
boundary is crossed, further patient accrual will be discontinued, and the result will be reported. 
If no boundary is crossed, the final analysis will occur when there are 71 deaths. The 
significance level 0.1379 for the final analysis was derived in order to preserve a 0.15 
significance level for the entire study. If the resulting p-value is < 0.1379, the result will be 
interpreted as an indication of pazopanib tending to improve overall survival in these patients. 
In order to have 71 deaths (total from both arms combined), 79 analyzable patients are 
targeted for phase II portion of this trial. Assuming that up to 10% of patients may be ineligible 
or lost to follow up, the sample size required for the phase II screening portion of the trial 
will be 88 patients. The analysis will be restricted to eligible patients with follow-up data and 
may possibly exceed 79 patients. 
 
13.3 
Patient Accrual (2/27/12) 
Patient accrual is projected to be 2 per month after the first 2 months in which institutions are obtaining 
IRB approval. At this rate, it will take approximately 8 months to complete accrual for each run-in 
component. Analysis will begin 4 weeks after the last subject has completed radiation therapy.  The total 
duration of each component will be 14 months, including 4 months to finish the proposed treatment and 2 
months for data collection and data analysis. The data will be provided to CTEP for review prior to starting 
the phase II component of the study. For the randomized phase II component, it will take approximately 
44 months to complete accrual for a total of 88 patients, with 12 months follow up and six month for data 
collection and analysis. 
 
13.4 
Randomization (2/27/12) 
For the randomized phase II component, the treatment allocation scheme described by Zelen (1974) will 
be used as it balances patient factors other than treating institution. The randomization ratio between the 
2 arms will be 1:1.  Additionally, patients will be stratified according to presence of metastatic disease (M0 
vs. M1 vs. Mx). 
 
13.5 
Analysis Plan (06-MAR-2020) 
13.5.1 
Statistical Methods 
 
Overall survival rates will be estimated using the Kaplan-Meier method (1958) and rates of 
local-regional control (LRC) by the cumulative incidence method (Kalbfleisch 1980) to account 
for the competing risk of death without local-regional failure. The distributions of the overall 
survival times will be compared between treatment arms with a one sided log rank test (Mantel, 
1966). If the resulting p-value for OS is < 0.1379 with all patients, the result will be interpreted 
as an indication of pazopanib in improving overall survival of these patients Failure for LRC is 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
defined as local regional progression in the thyroid bed or regional lymph nodes. For overall 
survival, death from any cause will be considered a failure. All failure times will be measured 
from the date of study registration to the date of failure or last follow up.  
 
For the endpoints in Sections 13.1.1 and 13.1.3, only adverse events (AEs) assessed to be 
definitely, probably, or possibly related (if relationship is missing, it will be assumed to be 
definitely, probably, or possibly) to protocol treatment will be considered. The rates of adverse 
events, discontinuation of treatment, and response will be estimated using a binomial 
distribution along with their associated 95% confidence intervals and will be compared using 
Fisher’s exact test. 
13.5.2 
Interim Analysis to Monitor Study Progress (2/27/12) 
 
Interim reports will be prepared twice each year until the final analysis has been accepted for 
presentation or publication. In general, these reports will contain information about the accrual 
rate with projected completion date for the accrual phase, exclusion rates and reasons, 
pretreatment characteristics of patients accrued, compliance rate of treatment delivered with 
respect to the protocol prescription, and the frequency and severity of AEs. This study will be 
monitored by the Clinical Data Update System (CDUS), version 3.0. Cumulative CDUS data will 
be submitted quarterly by electronic means. Analysis results of the run-in components will be 
reviewed by the NRG Oncology Data Safety Monitoring Board (DSMB). Analysis results of the 
phase II component will be reviewed by the DMC twice a year in conjunction with the NRG 
Oncology semi-annual meetings with respect to patient accrual and morbidity. The DMC also 
will review this study on an “as needed” basis between meetings. 
13.5.3 
Special Interim Analysis to Monitor Adverse Events  
Since there is limited experience with the experimental regimen, a two stage interim analysis of 
AEs will be performed to assure that there are no unexpected problems. This analysis will occur 
after 9 analyzable patients are entered into the run-in component and 15 patients are entered 
into the experimental arm. If 4 or fewer and 8 or fewer patients experience the AEs of concern 
at the first and second interim analysis, then the induction and the concurrent components will 
be judged to be safe. After reviewing the results from each analysis, the study chairs and study 
statistician will make a recommendation to the NRG Oncology Head and Neck Steering 
Committee, the NRG Oncology DSMB, and the corporate sponsor for their consideration. 
These committees and individuals jointly will decide the future course of action for the study. 
13.5.4 
Significance Testing for Early Termination and Reporting (8/24/11) 
One interim treatment comparison will be performed when 50% (35 deaths) of the 71 required 
number of failures are observed. Only the primary endpoint will be tested in the interim 
analysis. The efficacy will be tested using O’Brien-Fleming boundaries of 0.0418 for the interim 
tests and 0.1379 for the final analysis to preserve an overall alpha level of 0.15 for the study. 
The futility will be tested using the lower boundary at P>0.5324. The results will be reported to 
the NRG Oncology DMC with the treatment blinded. The responsible statistician may 
recommend early reporting of the results and/or stopping accrual (if applicable) of the trial if the 
treatment effect with respect to OS is highly significant or if it is not likely to be; that is, if the p-
value is less or greater than the nominal value specified in a sequential design for either 
efficacy or futility. If the resulting p-value for efficacy is <0.1379, this result will be interpreted as 
an indication of pazopanib in improving overall survival in these patients.   
13.5.5 
Analysis for Reporting the Initial Treatment Results 
The analysis to report the initial results of treatment was originally planned when 71 events 
(total from both arms) have been reported for the primary endpoint, OS, unless the criteria for 
early stopping are met. However, not enough OS events have been observed with the 
projected follow-up time, and the required number of OS events (71) for this final analysis will 
not be obtained given that the number of eligible patients at risk of death is lower than the 
required number of OS events due to a higher than projected ineligibility rate and consent 
withdrawals. Given that, the final analysis will now be time driven and will be done after all 
eligible patients had been potentially followed for 3 years. This change was done in a blinded 
fashion regarding the clinical outcomes. A sensitivity analysis based on all randomized patients 
at risk of anaplastic thyroid cancer death (after excluding one patient with renal cell carcinoma 
histology) will also be done. 
 
The time from opening this trial to patient entry to this analysis is projected to be approximately 
5.5 years if the projected accrual rate is realized. Only eligible patients with both on-study and 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
follow-up information will be included. Eligible patients that do not start protocol treatment will 
be included in this intent-to-treat analysis. The usual components of this analysis are: 
• 
Tabulation of all cases entered, and any excluded from analysis with reasons for 
exclusion; 
• 
Patient accrual rate; 
• 
Institutional accrual; 
• 
Distribution of important baseline prognostic variables; 
• 
Frequency and severity of adverse events; 
• 
Observed results with respect to the endpoints described in Sections 13.1.1 and 13.1.2.  
 
The difference in OS between the control arm and the experimental arm will be tested using the 
one sided log-rank statistic at the significance level of 0.1379 given that the one interim 
analysis is carried out and shows no statistical significance. If the resulting p-value for efficacy 
is <0.1379, this result will be interpreted as an indication of pazopanib in improving overall 
survival in these patients. 
 
13.6 
Gender and Minorities (7/15/13) 
Both men and women of all races and ethnic groups are eligible for this study. In conformance with the 
National Institutes of Health Revitalization Act of 1993 with regard to inclusion of women and minorities in 
clinical research, we have considered the possible interactions (treatment by race and treatment by 
gender). The study was designed under the assumption of the same results between the gender and 
among the races. Based on Gilliland (1997), we project that 32% of patients enrolled on this study will be 
male, 87% white, and 3% Hispanic. The following table provides the projected number of patients in each 
race, ethnicity, and gender group. 
 
 
 
Projected Distribution of Gender and Minorities  
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
2 
1 
3 
Not Hispanic or Latino 
79 
39 
118 
Ethnic Category: Total of all subjects 
81 
40 
121 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
11 
6 
17 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
70 
34 
104 
Racial Category: Total of all subjects 
81 
40 
121 
  


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
REFERENCES (2/27/12) 
 
Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-
molecule mitogen-activated protein kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced 
cancers. J Clin Oncol. 26:2139-46, 2008. 
 
Ain KB, Tofiq S, Taylor KD. Antineoplastic activity of taxol against human anaplastic thyroid carcinoma cell lines in 
vitro and in vivo. J Clin Endocrinol Metab. 81:3650-3, 1996. 
 
Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with paclitaxel: Phase 2 trial using 
ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. 
Thyroid. 10:587-94, 2000. 
 
Altorki N, Guarino M, Lee P, et al.  Preoperative treatment with pazopanib (GW786034) a multikinase 
angiogenesis inhibitor in early stage non-small cell lung cancer (NSCLC): A proof-of-concept phase II study.  J 
Clin Oncol.  26 (suppl):A7557, 2008. 
 
Bauer AJ, Terrell R, Doniparthi NK, et al. Vascular endothelial growth factor monoclonal antibody inhibits growth 
of anaplastic thyroid cancer xenografts in nude mice. Thyroid. 12:953-61, 2002. 
 
Bible KC, Smallridge RC, Maples WJ, et al. Phase II trial of pazopanib in progressive, metastatic, iodine-
insensitive differentiated thyroid cancers. J Clin Oncol (Meeting Abstracts). 27:3521-, 2009. 
 
Cheung M, Boloor A, Hinkle KW. Discovery of indazolylpyrimidines as potent inhibitors of VEGFR2 tyrosine 
kinase.  Proc AACR-NCI-EORTC Intl Conf Mol Targets Cancer Therap.  Abstr. C42, 2003. 
 
Dejonge M, Savage S, Verweij J, et al.   A phase I, open-label study of the safety and pharmacokinetics (PK) of 
pazopanib (P) and lapatinib (L) administered concurrently.  J Clin Oncol.  24 (suppl):A3088, 2006. 
 
Garden AS, Harris J, Vokes EE, et al. Preliminary results of Radiation Therapy Oncology Group 97-03: A 
randomized phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of 
the head and neck. J Clin Oncol. 22:2856-64, 2004. 
 
Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid cancer. Cancer. 79(3): 564-573, 1997. 
 
Gorski DH, Mauceri HJ, Salloum RM, et al. Potentiation of the antitumor effect of ionizing radiation by brief 
concomitant exposures to angiostatin. Cancer Res. 58:5686-9, 1998. 
 
Goutsouliak V, Hay JH. Anaplastic thyroid cancer in British Columbia 1985-1999: A population-based study. Clin 
Oncol (R Coll Radiol). 17:75-8, 2005. 
 
Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin 
Oncol. 26:4714-9, 2008. 
 
GW786034 Investigator’s Brochure, Version 7 (February 2010).  GlaxoSmith Kline, Collegeville, PA. 
 
Haigh PI, Ituarte PHG, Wu HS, et al. Completely resected anaplastic thyroid carcinoma combined with adjuvant 
chemotherapy and irradiation is associated with prolonged survival. Cancer. 91:2335-2342, 2001. 
 
Hainsworth JD, Meluch AA, McClurkan S, et al. Induction paclitaxel, carboplatin, and infusional 5-FU followed by 
concurrent radiation therapy and weekly paclitaxel/carboplatin in the treatment of locally advanced head and neck 
cancer: A phase II trial of the Minnie Pearl Cancer Research Network. Cancer J. 8: 311-21, 2002. 
 
Heath EI, Forman K, Malburg L, et al. A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing 
administered as crushed tablet or oral suspension in patients with advanced solid tumors. Invest New Drugs. 
2011 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
References (Continued) 
 
Hess C, Vuong V, Hegyi I, et al. Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] 
combined with ionizing radiation on endothelial cells and tumour growth. Br J Cancer. 85:2010-6, 2001. 
 
Hurwitz HI, Dowlati A, Saini S, et al.  Phase I trial of pazopanib in subjects with advanced cancer.  Clin Cancer 
Res.  15:4220-4227, 2009. 
 
Kalbfleisch JD, Prentice RL. The statistical analysis of failure data. New York, NY: John Wiley and Sons;1980. 
 
Kaplan, E. and P. Meier, Nonparameteric estimation from incomplete observations. J Amer Stat Assoc. 53: 457-
481, 1958. 
 
Kumar,R, Harrington LE, Hopper TM, et al.  Correlation of anti-tumor and anti-angiogenic activity of VEGFR 
inhibitors with inhibition of VEGFR2 phosphorylation in mice.  J Clin Oncol.  23 (suppl): A9537, 2005. 
 
Lee N, Xia P, Fischbein N.  Intensity-modulated radiation therapy for head-and-neck cancer: The UCSF 
experience focusing on target volume delineation. Int J Radiat Oncol Biol Phys. 57(1):49-60, 2003. 
 
Mantel, N., Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem 
Reports. 50: 163-170, 1966. PMID: 5910392 
 
Monk B, Mas L, Zarba JJ, et al. A randomized phase II study: Pazopanib (P) versus lapatinib (L) versus 
combination of pazopanib/lapatinib (L+P) in advanced and recurrent cervical cancer (CC).  J Clin Oncol. 27 
(suppl):A5520, 2009. 
 
Nieder C, Wiedenmann N, Andratschke NH, et al. Radiation therapy plus angiogenesis inhibition with 
bevacizumab: rationale and initial experience. Rev Recent Clin Trials. 2:163-8, 2007. 
 
Nutting C, Convery D, Cosgrove V, et al. Improvements in target coverage and reduced spinal cord irradiation 
using intensity-modulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland. Rad and Onc. 60: 
173-180, 2001. 
 
Posner M, Quivey JM, Akazawa PF. Dose optimization for the treatment of anaplastic thyroid carcinoma: a 
comparison of treatment planning techniques. Int J Radiat Oncol Biol Phys. 48(2):475-83, 2000. 
 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung 
cancer. N Engl J Med. 355:2542-50, 2006. 
 
Slamon D, Gomez HL, Amit O, et al.   Pazopanib + Lapatinib is more active than Laptinib alone: Updated results 
from a randomized study in subjects with first-line ErbB2-positive advanced or metastatic breast cancer [ESMO 
abstract 139P].  Ann Oncol.  19 (supp 8):viii 64-65, 2008. 
 
Sleijfer S, Ray-Coquard, I, Papai Z, et al. on behalf of the EORTC Soft Tissue Bone Sarcoma Group.  Phase II 
study of pazopanib in subjects with relapsed or refractory soft tissue sarcoma. Ann Oncol. 19 (suppl 8): A868O, 
2008.  
 
Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: 
Results of a randomized phase III trial. J Clin Oncol.  In press. 
 
Suttle B, Jones S, Dowlati A, et al.   Phase I study of the safety and pharmacokinetics (PK) of paclitaxel or 
paclitaxel with carboplatin administered in combination with pazopanib (GW786034).  J Clin Oncol.  25 
(suppl):A14118, 2007. 
 
Tan AR, Jones SF, Dowlati A, et al. Phase I study of the safety, tolerability, and pharmacokinetics (PK) of weekly 
paclitaxel administered in combination with pazopanib (GW786034). J Clin Oncol (Meeting Abstracts). 26:3552, 
2008. 


 
 
 
 
 
 
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References (Continued) 
 
Taylor SK, Chia S, Dent S, et al.   A phase II study of Pazopanib (GW786034) in subjects with recurrent or 
metastatic invasive breast carcinoma: Results after completion of stage I: A trial of the Princess Margaret Hospital 
Phase II Consortium.  J Clin Oncol.  27 (suppl):A1133, 2009. 
 
Wang Y, Tsang R, Asa S, et al. Clinical outcome of anaplastic thyroid carcinoma treated with radiotherapy of 
once- and twice-daily fractionation regimens. Cancer. 107:1786-92, 2006. 
 
Zelen, M., The randomization and stratification of patients to clinical trials (MI #7506064). J Chronic Dis. 27: 365-
375, 1974. PMID: 4612056 
 
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (9/30/15) 
*See Sections 11.2 through 11.7 for details and exceptions 
 
 
Assessments 
Within 10 Days  
Prior to Registration  
Unless Otherwise Noted 
Prior to Treatment 
Tissue for central review 
 
X 
History/physical 
2 weeks 
 
BP 
X* 
 
EKG 
X 
 
CT or MRI of Neck*  
4 weeks  
 
Imaging of Chest, Abdomen, 
Liver and Adrenal glands* 
4 weeks 
 
Performance status 
X 
 
PT/INR/PTT 
X 
 
CBC w/ diff & ANC 
X 
 
Liver function tests* 
X 
 
Serum electrolytes* 
X 
 
Urine protein & urine creatinine 
X 
 
Serum pregnancy test (if 
applicable) 
X 
 
Documentation of QTC history  
X 
 
Wound healing 
 
X 
Review/recording of medications 
X* 
 
PET/CT  
Dental evaluation 
Nutritional evaluation 
TSH suppression 
Recommended, not required 
 
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 2020 
APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT (6/5/14) 
*See Sections 11.2 through 11.7 for details and exceptions 
 
 
Assessments 
During Pre-IMRT Treatment 
During Concurrent Treatment 
 
Day 1 
Day 8  
(+/- 2 days) 
*Day 15-see 
Section 
11.3 
 
Weekly during 
Treatment 
2 weeks after 
completion of 
Treatment 
 (+/- 2 days) 
History/physical 
X 
X 
X 
X 
X 
BP 
X 
X 
X 
X 
X 
EKG 
 
 
 
Day 1* 
 
CT or MRI of 
Neck* and Brain 
 
 
 
 
X* 
Imaging of Chest, 
Abdomen, Liver 
and Adrenal 
glands* 
 
 
 
 
X* 
Performance 
status 
 
 
 
X 
X 
CBC w/ diff & ANC 
X 
X 
X 
X 
X 
Serum 
electrolytes* 
X 
X 
X 
X 
X 
Serum liver tests* 
X 
 
X 
In all odd 
weeks  
X 
Urine protein & 
urine creatinine 
 
 
X 
X* 
X 
Serum 
thyroglobulin, 
thyroglobulin 
antibodies, & 
thyroid stim. 
hormone 
X 
 
 
 
 
Review/recording 
of medications 
X* 
 
 
*Day 1 (+/- 3) 
 
Medication diary 
 
X 
 
 
X 
Adverse event 
eval 
X 
X 
X 
X 
X 
 


 
 
 
 
 
 
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APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP (3/8/16) 
*See Sections 11.2 through 11.7 for details and exceptions 
 
 
Assessments 
Long-Term Follow up 
q 3 mos. for years 1-2; q 6 months for 
year 3, then annually  
History/physical 
X 
BP 
X 
CT or MRI of Neck*  
X* 
Imaging of Chest, Abdomen, Liver and Adrenal 
glands* 
X* 
Performance status 
X 
CBC w/ diff & ANC 
X 
Serum electrolytes* 
X 
Serum thyroglobulin, thyroglobulin antibodies, & 
thyroid stim. hormone 
X 
Adverse event eval 
X 


 
 
 
 
 
 
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APPENDIX II: ZUBROD PERFORMANCE SCALE AND CLASSIFICATION OF CARDIAC DISEASE 
 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature.  For example, light housework, office 
work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed  
 
5 
Death  
 
 
 
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 III: AJCC STAGING SYSTEM (7/15/13) 
 
Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 
 
HEAD & NECK  
 
ANAPLASTIC THYROID CANCER 
 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
 
T1 
 
T2 
 
T3 
 
T4a 
Intrathyroidal anaplastic carcinoma—surgically resectable 
T4b 
Extrathyroidal anaplastic carcinoma—surgically unresectable 
 
 
REGIONAL LYMPH NODES (N)  
 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Regional lymph node metastasis 
 
N1a 
Metastasis to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph 
nodes) 
 
N1b 
Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph 
nodes 
 
 
DISTANT METASTASIS (M) 
 
 
M0 
No distant metastasis 
M1 
Distant metastasis 
MX 
Distant metastasis cannot be assessed 
 
 
 
STAGE GROUPING 
 
 
Stage IVA 
T4a,  Any N,  M0 
Stage IVB 
T4b,  Any N,  M0 
Stage IVC 
Any T, Any N, M1 
 
 


 
 
 
 
 
 
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APPENDIX IV: MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED PATIENTS 
 
Dental Care for Irradiated Patients 
Goals for a dental care program include: 1) To reduce incidence of bone necrosis; 2) To reduce incidence 
of irradiation caries; 3) To allow proper fitting of dentures following treatment. 
 
Pre-irradiation Care and Procedures 
The patients may be grouped into four groups in accordance with the problems they present prior to 
irradiation. 
 
Group 1 
Includes edentulous patients.  They may require surgical removal of any symptomatic cysts, infected 
retained root tips, or alveolar hyperplasia.  These patients require hygiene instruction and precautionary 
instruction about trauma with premature use of a prosthesis. 
 
Group 2 
Includes those with poor dental hygiene, including those patients whose teeth are beyond repair by 
ordinary dental procedure, those with generalized oral sepsis, those with generalized periodontal disease, 
and those with chronic periapical abscesses or granulomas. 
 
Procedures performed on this group include removal of all remaining teeth prior to irradiation with primary 
closure and surgical preparation of the alveolar ridges to laterally support a prosthesis.  There should be 
antibiotic coverage during the healing stage and adequate time prior to the start of radiation therapy.  
These patients need complete hygiene instruction and precautionary instruction about premature use of a 
prosthesis. 
 
Group 3 
Includes those in whom dental condition is fair, including those patients whose teeth are restored, 
ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious lesions are not in 
proximity to the pulp, and no more than 20 restorable carious lesions are present.  X-ray examinations 
show at least 1/2 of the bone still present around root surfaces.  These patients require removal of any 
teeth that are non-salvageable in accordance with the above and restorations of the remaining teeth as 
required.  The patients are instructed for dental prophylaxis and the patients utilize custom-made fluoride 
carriers. 
 
Group 4 
Includes those in whom dental hygiene is good.  This includes patients who do not have severe 
malocclusion in whom few carious lesions are present.  Carious lesions are not in close proximity to the 
pulp and are correctable by conventional methods.  These patients require periodontal evaluation and 
dental prophylaxis training, restorations as needed, no extractions prior to radiation therapy, and fitting for 
custom carriers. 
 
Extraction of Teeth 
If extraction of teeth is necessary prior to radiation therapy, the bone must be contoured so that closure at 
the extraction site is possible.  All loose spicules and sharp projections must be removed.  The 
approximation of the gingival tissue must be such that the closure is neither too loose nor too tight.  At 
least 10 days are required for adequate healing prior to initiation of therapy. 
 
Causative Factors 
The major causative factors appear to be the reduction of the amount of saliva and secondarily, reduced 
pH in the mouth.  This occurs following high dose radiation to the major salivary glands using parallel 
opposed fields.  The decay process usually occurs in the first year following radiation therapy.  It tends to 
occur more quickly in teeth which have a large amount of root cementum exposed to those teeth with 
large amounts of plaque formation present.  Doses of radiation in excess of 20 Gy to salivary tissue place 
the teeth at risk. 
 


 
 
 
 
 
 
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APPENDIX IV (Continued) 
 
Preventive Program 
The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible to the 
decay process.  This is accomplished by a combination of increasing fluoride concentration on the tooth 
surface and by the effect of fluoride on the plaque and flora that are present in the oral cavity.  Adequate 
results are obtained by:  1) cleansing the teeth thoroughly, followed by a good home care dental 
prophylaxis program, 2) construction of  
fluoride carriers, custom-made mouth guards, which provide local application of fluoride solution to the 
gingiva and tooth surfaces.  Fluoride carriers are made individually with the use of casts.  Material used 
for making a mouth guard is "Sta-Guard" plastic used in conjunction with vacutrole unit produced by 
Jelrus Technical Products, Corp., both of which are available through local dental supply.  This material is 
molded to the cast impression and allowed to harden.  A fluoride solution prepared at the M.D. Anderson 
Hospital is now available from the Emerson Laboratories, Inc., Dallas, Texas 75221.  It has been used to 
coat the plastic carrier for use in the mouth.  The patients are instructed to cleanse their teeth prior to 
placement of the carrier.  It is then worn in place for 5 minutes each day.  The patients are instructed to 
rinse their mouths thoroughly following the use of the carrier.  This will be continued for an indefinite 
period of time.  Close follow-up is necessary. 
 
Results 
In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 304 patients 
shows that the incidence of necrosis of the jaw was reduced to approximately 21% compared to 37% 
prior to initiation of the study.  Groups 3 and 4 patients randomized with and without fluoride treatment 
showed reduction in radiation carries from 67% to 34% among Group 3 patients, and from 65% to 22% 
among Group 4 patients. 
 
Failure to Control Decay 
Management of failure to control radiation decay includes silver fillings with continued use of fluoride 
treatments.  If the decay process is sufficiently advanced that a filling will no longer stay in place, these 
teeth are merely smoothed so that there will be no sharp, irritating edges.  The mere existence of such a 
decayed tooth is not necessarily reason for extraction, for it must be remembered that extraction could 
lead to complications such as bone necrosis. 
 
Pulp exposure resulting from the decay process can usually be handled by use of antibiotics and/or root-
canal therapy. 
 
Hypersensitivity of Teeth 
Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished amounts of 
saliva.  This has been shown to be reduced in incidence with the fluoride treatments.  Should this problem 
become manifest, increasing the fluoride treatment to 10 to 15 minutes 3 times a day is recommended. 
 
Infections 
Infections occurring in patients under or after radiation therapy are best managed conservatively with 
good oral hygiene, irrigation and flushing procedures, and systemic antibiotics. 
 
Bone Necrosis 
The patients receiving radiation therapy to a high dose to the head and neck region have increased 
susceptibility to bone necrosis for several reasons including:  impairment of normal metabolism, increased 
susceptibility to infection and severely limited repair process.  Bone necrosis occurs most often after 
dental or oral surgery in patients who have been previously radiated.  Conservative management should 
be tried first, though in more aggressive lesions a more radical approach may ultimately be necessary. 
 


 
 
 
 
 
 
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APPENDIX V: ORAL ANTIHYPERTENSIVE MEDICATIONS 
Agents in bold are suggested as optimal choices to avoid or minimize potential drug-interactions with pazopanib 
through CYP450. 
Agent  
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate and 
inhibitor 
Selective 
 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 
labetalol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 substrate and 
inhibitor 
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 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 pazopanib.  Based on prior clinical experience with pazopanib, the use of calcium channel blockers 
(dihydropyridine category) and ACE inhibitors as first-line and second-line therapy is recommended. 


 
 
 
 
 
 
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APPENDIX VI: 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® 


 
 
 
 
 
 
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APPENDIX VI (Continued) 
Ibutilide /Corvert® 
Lapatinib /Tykerb® 
Paroxetine /Paxil® 
Levomethadyl 
/Orlaam® 
Lapatinib /Tyverb® 
Protriptyline /Vivactil® 
Mesoridazine 
/Serentil® 
Levofloxacin /Levaquin® 
Sertraline /Zoloft® 
 
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® 
  


 
 
 
 
 
 
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APPENDIX VI (Continued) 
 
  
Sunitinib /Sutent® 
  
  
Tacrolimus /Prograf® 
  
  
Tamoxifen /Nolvadex® 
  
  
Telithromycin /Ketek® 
  
  
Tizanidine /Zanaflex® 
  
  
Vardenafil /Levitra® 
  
  
Venlafaxine /Effexor® 
  
  
Voriconazole /VFend® 
  
  
Ziprasidone /Geodon® 
  
 


 
 
 
 
 
 
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APPENDIX VII: DRUGS KNOWN TO BE METABOLIZED BY SELECTED 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 
Lotrimin  
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.  
    
Carbamazepine 
    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 co-administration of ‘inducers’ 
would potentially lower plasma   (Study Agent) concentrations. 
 
 


 
 
 
 
 
 
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APPENDIX VII (Continued) 
 
DRUGS THAT MAY HAVE POTENTIAL INTERACTIONS WITH 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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APPENDIX VII (Continued) 
 
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 
Cimetidine 
Tagamet 
Anticonvulsants: e.g.   
    Carbamazepine 
    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 
 
 
 
 
Carbamazepine 
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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APPENDIX VII (Continued) 
 
DRUGS THAT MAY HAVE POTENTIAL INTERACTIONS WITH CYP3A4 
 
Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
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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APPENDIX VII (Continued) 
 
DRUGS THAT MAY HAVE POTENTIAL INTERACTIONS WITH  CYP3A4 (Continued) 
 
Inhibitors 
Acetaminophen 
Acetazolamide 
Amiodarone 
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 
Carbamazepine 
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 VIII: NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS (9/13/16) 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen 
Bank. The plug kit contains a shipping tube and a punch tool.    
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at 
room temperature. Place the punch tool on the paraffin block over 
the selected tumor area. (Ask a pathologist to select area with 
tumor.) Push the punch into the paraffin block. Twist the punch tool 
once around to separate the plug from the block. Then pull the 
punch tool out of the block. The punch should be filled with tissue 
sample. 
 
 
Step 2 
Label the punch tool with the proper specimen ID and block number.  
DON’T remove specimen from the punch. 
 
 
Use a separate punch tool for every specimen. Call or e-mail us if 
you have any questions or need additional specimen plug kits. 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to 
address below. Please do not mix specimens in the same tube.    
 
 
 
   
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank and we will sample a plug from the block 
and return the remaining block to your facility.  Please indicate on the submission form the request to 
perform the plug procedure and return of the block. 
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For 
Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact 
the NRG Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.edu or call 415-476-7864/Fax 415-
476-5271. 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
Campus Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For All Frozen Specimens or Trackable shipments 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 


 
 
 
 
 
 
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APPENDIX IX: NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (9/13/16) 
 
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as 
specified by the protocol): 
 
Kit contents: NOTE: SITES MUST PROVIDE THEIR OWN BLOOD DRAW TUBES. 
• 
Fifteen (15) 1 ml cryovials 
• 
Biohazard bags (3) and Absorbent shipping material (3) 
• 
One Styrofoam container (inner) and Cardboard shipping (outer) box per case 
• 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
• 
Specimen Transmittal Form (ST) and Kit Instructions 
 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
(A) Serum (if requested): Red Top Tube (One 10 ml or two 5 ml Red Top tubes) 
❑ 
Label as many five (5) 1mL cryovials for the serum collected. Label them with the NRG 
Oncology study and case number, collection date, time, and time point, and clearly mark 
cryovials “serum”. 
Process: 
1. Allow one red top tube to clot for 30 minutes at room temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites 
are unable to process samples at 4C then spinning at room temperature is acceptable if 
done within 2 hours of draw but must be noted on the ST Form. 
3. Aliquot a minimum of 0.5 ml serum into five (5) cryovials as are necessary for the serum 
collected labeled with NRG Oncology study and case numbers, collection date/time, protocol 
time-point collected (e.g. pretreatment, post-treatment), and clearly mark specimen as 
“serum”. 
4. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90 C, and 
store frozen until ready to ship. See below for storage conditions. 
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form. 
 
(B) Plasma (If requested): Purple Top EDTA tube #1 (One 10 ml or two 5 ml Red Top tubes) 
❑ 
Label five (5) 1ml cryovials for the plasma collected. Label them with the NRG Oncology 
study and case number, collection date, time, and time point, and clearly mark cryovials 
“plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 
RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted 
on the ST Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one 
hour, keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot a minimum of 0.5 ml plasma into five (5)  cryovials for the plasma 
collected (5 to 10)  labeled with NRG Oncology study and case numbers, collection date/time, 
time point collected and clearly mark specimen as “plasma”.  Avoid pipetting up the buffy coat 
layer. 
5. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90C. 
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 
 
 
 
 
 
 
 
 
(continued on next page) 


 
 
 
 
 
 
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APPENDIX IX (9/13/16) 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS (Continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 (One 5 ml or one 10ml EDTA 
tube) 
❑ 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected..Label them with 
the NRG Oncology study and case number, collection date/time, and time point, and clearly mark 
cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can 
also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the 
blood collected (3 to 5) labeled with NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze tubes upright immediately at -70 to -80 
Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
ST Form. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
❑ 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
▪ 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only; Canada: Monday-
Tuesday only). 
OR: 
▪ 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
▪ 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday only). 
❑ 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
 
 
 
 
 
 
 
 
(continued on next page) 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 
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APPENDIX IX (9/13/16) 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
Shipping/Mailing: 
❑ 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
❑ 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the 
Styrofoam box. 
❑ 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard 
bag.  Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg 
minimum).  Add padding to avoid the dry ice from breaking the tubes.  
❑ 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 
❑ 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
❑ 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-
mail NRGBB@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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             RTOG 0912, Version Date: March 6, 
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APPENDIX X: PREPARATION OF 50 MG/ML OF PAZOPANIB ORAL SUSPENSION (6/5/14) 
 
 
Pazopanib Powder for Oral Suspension is presented with a label claim of 5 grams per bottle in a 200 
mL amber type III glass bottle. This powder is to be reconstituted into a 50 mg/mL suspension using 
90 mL of purified or sterilized water. This suspension must be refrigerated and should be used within 
35 days. 
 
The label claims of 5 grams/bottle (50 mg/mL) refers to 5 grams (50mg/mL) of pazopanib 
hydrochloride-free base. 
 
Reconstitution Instructions for Pazopanib Powder for Oral Suspension with Purified or 
Sterilized Water. 
 
1. Tap the sides of the Powder in Bottle to loosen the powder. Add 90 mL of the room-temperature 
Purified or Sterilized Water to the bottle. Replace the cap tightly and shake vigorously with 
inversion for at least 2 minutes to ensure complete powder reconstitution.  
 
2. Allow the bottle to sit for at least 3 minutes to allow any foam to dissipate. The suspension is now 
ready for use as an elegant white suspension with Lemon flavor. This suspension is designed for 
multiple uses and may be used for up to 35 days when refrigerated (2 – 8oC).  
 
Dosing Instructions for 50 mg/mL Pazopanib Multi-Use Oral Suspension 
 
3. Immediately prior to the removal of the required dose for administration, swirl gently for at least 30 
seconds to ensure homogeneity of the suspension. 
 
4. Insert a Baxa “Press-In-Bottle Adapter (PIBA®) into the neck of the bottle. Please ensure that the 
lip of the Adapter fits snugly with the top of the bottle.   
 
5. Remove the require dose using a suitable graduated syringe: 
a. Ensure that the syringe plunger is fully pushed into the barrel. 
b. Insert the syringe tip into the Adaptor, then invert the bottle and dispense at least 5 mL of 
suspension into the syringe and then pump the entire suspension back into the bottle to 
purge the syringe of any air bubbles. Repeat this step until the syringe is free from air 
bubbles. 
c. Withdraw the required dosing volume. Then re-invent the bottle and remove the syringe from 
the Adapter and administer the dose to the patient as soon as possible.  For example, 8 mL 
aliquot of suspension contains 400 mg pazopanib. 
6. Store the suspension refrigerated (2 – 8oC). Do not freeze. The suspension may be used for up to 
35 days after reconstitution.