Clinical trial NCT02015065
Conditions: GIST
Keywords: GIST Small Molecule Mesenchymal Tumor Receptor Tyrosine Kinase Survival
Sponsor: National Cancer Institute (NCI)
Start date: 2013-12-14; Completion date: 2019-12-10
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

-Some people with wild-type gastrointestinal stromal tumors (WT-GIST) have a deficiency in one of their proteins called succinate dehydrogenase (SDH). Vandetanib is a cancer drug that has been approved to treat thyroid cancer and has been used with some success in other tumors that have a similar loss of SDH. Researchers want to see if this drug can also decrease tumor growth in people with WT-GIST.

Objectives:

-To test whether the study drug will benefit people with WT-GIST.

Eligibility:

-Adults and children 3 years old and older with WT-GIST.

Design:

* Researchers will test participants tumor tissue to confirm it is the wild type of GIST.
* Participants will be screened with a medical history, physical exam, and blood tests. They will also have electrical recording of the heart (Eastern Cooperative Oncology Group (ECOG)) and scans of the tumor.
* Participants will take the study drug in 28-day cycles. Their doctor will decide how many cycles they can complete.

  * They will take the study drug once every day and record it in a diary.
  * On Day 14, they will also visit their doctor to look for side effects.
* Before cycles 2, 3 and 4, participants will have a physical exam, urine tests, blood pressure check, and blood tests. These tests will then be done periodically for as long as they are in the study.
* Before cycle 4, scans will be done to check the size of the cancer. Most of these will be repeated every 3-6 cycles.
* When they stop taking the study drug, participants will return to the clinic for a physical exam and blood tests.

Detailed description:
Background:

* Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, resistant to cytotoxic chemotherapy and radiation therapy. KIT and platelet derived growth factor receptor alpha (PDGFRA) mutations have been identified as tumor initiating events in 85% of adult patients with GIST, but 85% of GISTs in pediatric patients lack KIT and PDGFRA mutations (wild-type) and imatinib is not as effective in eliciting objective responses.
* Recent work in the Pediatric and Wild-Type (wt) GIST Clinic at the National Cancer Institute (NCI) led to the identification of succinate dehydrogenase (SDH) germline mutations in 12% patients with wt-GIST (6/34). SDH protein expression evaluated using immunohistochemistry (IHC) was markedly decreased or absent in 18/18 patients with pediatric wt-GIST. Thus the majority of wt-GIST are SDH-deficient. Vandetanib (ZACTIMA; ZD6474; AstraZeneca) is an oral small molecule antineoplastic drug that inhibits vascular endothelial growth factor receptor 2 (VEGFR2), estimated glomerular filtration rate (EGFR), and rearranged during transfection (RET)-dependent signaling. Preliminary preclinical data demonstrate marked growth inhibition of SDH-mutant/deficient renal cell carcinoma cell lines when treated with vandetanib.

Objective(s):

-Primary: To assess the clinical activity (radiographic response Response Evaluation Criteria in Solid Tumors (RECIST v1.1) of vandetanib in children and adults with wt-GIST using RECIST (v1.1).

Eligibility:

-Adults and children with measurable localized or metastatic wt-GIST confirmed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory will be eligible for trial participation. Patients must have measurable disease by RECISTv1.1 and adequate organ function.

Design:

* This phase II trial will determine whether daily oral vandetanib is active in patients with wt-GIST. Vandetanib activity will be assessed primarily by radiographic response of measurable disease using RECISTv1.1.
* Vandetanib will be administered orally once daily continuously in the absence of toxicity or disease progression, using a 28-day cycle.
* Patients will be carefully monitored for toxicity and response. A small, optimal two-stage phase II design with a target response rate of 25% will be used. Nine evaluable patients will be enrolled initially. If 1 or more of the first 9 have a response, then accrual would continue until a total of 24 patients have enrolled. If there are 3 or more responses in 24 (12.5% or more) patients, then this would be sufficiently interesting activity to warrant further study.

Arms: arm 1: Children with measurable localized or metastatic wt-GIST arm 2: Adults with measurable localized or metastatic wt-GIST
Interventions: intervention 1: Vandetanib
Intervention descriptions: intervention 1: Vandetanib administered orally once per day continuously using a 28 day cycle until disease progression or unacceptable toxicity

Protocol documents:
ICF_002.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
13-C-0208 
PRINCIPAL INVESTIGATOR: 
Brigitte Widemann, M.D. 
STUDY TITLE:  
Phase II Trial of Vandetanib (ZD6474, Caprelsa®) in Children and Adults with Wild-
Type Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors 
 
Continuing Review Approved by the IRB on 12/03/18 
Amendment Approved by the IRB on 12/06/17 (F) 
 
Date posted to web:  12/13/18 
Parent QoL 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (2) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
You have a have a son or daughter who is 8 years of age or older who has Gastrointestinal 
stromal tumors (GIST), one of the most common forms of tumors in the mesenchymal tissue 
(loose connective tissue) in the GI system (mouth, esophagus, stomach and intestines).   He/She 
is taking part in a research study with a new cancer drug called vandetanib.  The overall purpose 
of this study is to see if vandetanib can shrink tumors in people with GIST.  In addition to 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  13-C-0208 
CONTINUATION: page 2 of 5 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
studying the physical effects of vandetanib, we are also trying to understand the effects of GIST 
and vandetanib on your child’s symptoms.  We are giving a number of questionnaires to your 
son or daughter to assess some known symptoms of GIST and some of the known side effects of 
vandetanib.  The information obtained from parent questionnaires is an important and standard 
part of a comprehensive neuropsychological assessment of a child.   
Therefore we ask for your participation in the study to complete 7 questionnaires assessing your 
child’s everyday social-emotional functioning and symptoms.  It will take about 10 minutes to 
complete these questionnaires.  We will ask you to fill out these questionnaires once before your 
child starts vandetanib, once at the first restaging visit (about month 3) and then again after 
stopping vandetanib.   
Your participation is voluntary, and you can decide to participate now, but withdraw your 
consent at any time. 
The information obtained from these questionnaires will be put into a secure computer database 
and used to answer questions being asked in this study.  We also would like to ask for your 
additional permission to possibly use this information that we already are collecting and storing 
for this study to answer other questions that may arise in the future or after the current study 
ends.  Anything we learn and share with others will not include any names or other information 
that could identify you.   
 
If you decide not to have this information stored for possible future GIST research you can still 
participate in the current study.   
 
Please indicate below if you agree or disagree to storage and possible use of information 
obtained from the parent questionnaires on this study for future GIST research: 
 
Agree:  
Disagree: 
 
 
Initials:____ 
 
Risks or Discomforts of Participation 
There are no risks to completing the questionnaires other than the time it will take to do so.  The 
questionnaires are saved in a locked file, and your results are saved in a secure, password-
protected database to which only investigators on this study have access.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  13-C-0208 
CONTINUATION: page 3 of 5 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
These questionnaires are for research purposes and there is no direct benefit to you.  However, 
your participation in this study and the knowledge gained from these questionnaires may benefit 
those who are diagnosed with GIST taking vandetanib in the future.  In addition, these results 
can be used to better understand side effects your child may be having because of the vandetanib 
and to develop recommendations to help your child with any problems in these areas. 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
You may choose not to complete the questionnaires described above.  If you decide not to 
participate in this part of the study, your son or daughter will still be able to participate in the 
vandetanib protocol. 
Research Subject’s Rights 
Joining this research study is voluntary.  You may ask the study doctor, psychologist, or other 
members of the GIST research team any questions about the questionnaires involved in this 
study.  If you decide at any time that you do not want to participate in this portion of the study 
any more, then tell us and we will stop it. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or other authorized people including 
representatives of the NCI or AstraZeneca, the pharmaceutical company that makes vandetanib. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0208 
CONTINUATION: page 4 of 5 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Brigitte Widemann, M.D., Building 10, Room 1-5750, Telephone: 240-
760-6203. You may also call the Clinical Center Patient Representative at 301-496-2626. If you 
have any questions about the use of your data for future research studies, you may also contact 
the Office of the Clinical Director, Telephone:  240-760-6070. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0208 
CONTINUATION: page 5 of 5 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby consent to take part in this 
study. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby give permission for my 
child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/ 
Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the 
study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM DECEMBER 03, 2018 THROUGH DECEMBER 17, 2019. 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name 
 

Prot_SAP_000.pdf: 
Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Abbreviated Title: PhII Vandetanib in GIST 
CC Protocol #: 13-C-0208 F 
Version Date: 11/07/2017 
NCT Number: NCT02015065 
 
Title: Phase II Trial of Vandetanib (ZD6474, Caprelsa®) in Children and Adults with Wild-
Type Gastrointestinal Stromal Tumors 
 
NCI Principal Investigator:    
Brigitte Widemann, M.D., POB, NCIA-E 
10 Center Drive, MSC 1104 
Bldg. 10 CRC, Rm. 1-3750 
Bethesda, MD 20814-1104  
Phone: 240-760-6203  
E-mail: widemanb@mail.nih.gov  
 
NIH Associate Investigators:    
Alice Chen, M.D., DCT, NCIA-E  
John Glod, M.D., Ph.D., POB, CCR, NCI A-E 
Melissa Amaya, R.N., OCD, CCR, NCI A,B,C,E 
Trish Whitcomb, R.N., OCD, CCR, NCI A,B,C,E 
Andrea Baldwin, MS, CRNP, POB, CCR, NCI A-E 
Joanne Derdak, CRNP, POB, CCR, NCI A-E 
Seth Steinberg, Ph.D., BDMS, CCR, NCIF 
Markku Miettinen, M.D., LP, CCR, NCI E 
Eva Dombi,  POB, CCR, NCIE-F 
Lori Wiener, Ph.D., POB, CCR, NCI A,B,E 
Paul Meltzer, MD, Ph.D., CGB, CCR, NCI E 
J Keith Killian, MD, Ph.D., CGB, CCR, NCIE 
Peter Choyke, M.D., MIP, CCR, NCI A,B,E 
Marston Linehan, M.D., UOB, CCR, NCIE 
Ramaprasad Srinivasan, M.D., Ph.D., UOB, CCR, NCIE 
Choh L. Yeung, B.S., POB, CCR, NCIE 
Paul Jarosinski, PharmD., CC, NIH A,B 
 
Non-NIH Associate Investigators:  Claudia Derse-Anthony, R.N., Contractor, Leidos 
Biomedical Research, Inc.A,B,C,E 
 
Referral Contact/Study Coordinator:  Claudia Derse-Anthony 
phone: 240-760-6102 
e-mail: claudia.derse-anthony@nih.gov 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
For each person listed above, roles are identified with the appropriate letter: 
A. Obtain information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
Investigational Agents:     
Drug Name: 
Vandetanib (Caprelsa®) 
IND Number: 
77570 
Sponsor: 
Center for Cancer Research (CCR) 
Manufacturer: 
AstraZeneca 
COMMERCIAL AGENTS: NONE


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
PRÉCIS 
Background: 
• Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the 
gastrointestinal tract, resistant to cytotoxic chemotherapy and radiation therapy. KIT and 
PDGFRA mutations have been identified as tumor initiating events in 85% of adult 
patients with GIST, but 85% of GISTs in pediatric patients lack KIT and PDGFRA 
mutations (wild-type) and imatinib is not as effective in eliciting objective responses.  
• Recent work in the Pediatric and Wild-Type (wt) GIST Clinic at the NCI led to the 
identification of succinate dehydrogenase (SDH) germline mutations in 12% patients with 
wt-GIST (6/34). SDH protein expression evaluated using immunohistochemistry (IHC) 
was markedly decreased or absent in 18/18 patients with pediatric wt-GIST. Thus, the 
majority of wt-GIST are SDH-deficient. Vandetanib (CAPRELSA®; ZD6474; 
AstraZeneca) is an oral small molecule antineoplastic drug that inhibits VEGFR2, EGFR, 
and RET-dependent signaling. Preliminary preclinical data demonstrate marked growth 
inhibition of SDH-mutant/deficient renal cell carcinoma cell lines when treated with 
vandetanib.  
Objective(s):  
• Primary: To assess the clinical activity (radiographic response RECIST v1.1) of vandetanib 
in children and adults with wt-GIST using RECIST (v1.1). 
Eligibility:  
• Adults and children with measurable localized or metastatic wt-GIST confirmed in a 
CLIA laboratory will be eligible for trial participation.  Patients must have measurable 
disease by RECISTv1.1 and adequate organ function. 
Design:  
• This phase II trial will determine whether daily oral vandetanib is active in patients with 
wt- GIST. Vandetanib activity will be assessed primarily by radiographic response of 
measurable disease using RECISTv1.1.  
• Vandetanib will be administered orally once daily continuously in the absence of toxicity 
or disease progression, using a 28-day cycle.  
• Patients will be carefully monitored for toxicity and response. A small, optimal two-stage 
phase II design with a target response rate of 25% will be used. Nine evaluable patients 
will be enrolled initially. If 1 or more of the first 9 have a response, then accrual would 
continue until a total of 24 patients have enrolled.  If there are 3 or more responses in 24 
(12.5% or more) patients, then this would be sufficiently interesting activity to warrant 
further study. 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 4 
1. 
INTRODUCTION .................................................................................................................. 7 
1.1 
STUDY OBJECTIVES ........................................................................................................... 7 
1.2 
BACKGROUND AND RATIONALE: ....................................................................................... 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 15 
2.1 
ELIGIBILITY CRITERIA ..................................................................................................... 15 
2.2 
SCREENING EVALUATION ................................................................................................ 19 
2.3 
REGISTRATION PROCEDURES .......................................................................................... 20 
2.4 
TREATMENT ASSIGNMENT AND RANDOMIZATION/STRATIFICATION PROCEDURES ......... 21 
2.5 
BASELINE EVALUATION .................................................................................................. 21 
3 
STUDY IMPLEMENTATION ............................................................................................ 22 
3.1 
STUDY DESIGN ................................................................................................................ 22 
3.2 
DRUG ADMINISTRATION ................................................................................................. 26 
3.3 
DOSE MODIFICATIONS .................................................................................................... 27 
3.4 
QUESTIONNAIRES ............................................................................................................ 29 
3.5 
STUDY CALENDAR .......................................................................................................... 29 
3.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA........... 31 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 33 
4.1 
PROHIBITED MEDICATION ................................................................................................ 33 
4.2 
HTN MANAGEMENT ALGORITHM ................................................................................... 34 
4.3 
MANAGEMENT OF QTC PROLONGATION ......................................................................... 34 
4.4 
MANAGEMENT OF SKIN TOXICITY................................................................................... 34 
4.5 
MANAGEMENT OF GASTROINTESTINAL TOXICITY ........................................................... 34 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 35 
5.1 
CORRELATIVE STUDIES FOR RESEARCH .......................................................................... 35 
5.2 
BLOOD DRAWING LIMITS FOR RESEARCH PURPOSES ...................................................... 36 
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION ............................................................ 36 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 37 
6.1 
DATA COLLECTION ......................................................................................................... 37 
6.2 
DATA SHARING PLANS .................................................................................................... 38 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
6.3 
RESPONSE CRITERIA........................................................................................................ 38 
6.4 
TOXICITY CRITERIA ........................................................................................................ 43 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
43 
7.1 
DEFINITIONS .................................................................................................................... 43 
7.2 
NCI-IRB AND CLINICAL DIRECTOR (CD) REPORTING .................................................... 45 
7.3 
IND SPONSOR REPORTING CRITERIA .............................................................................. 46 
7.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS ................. 47 
7.5 
DATA AND SAFETY MONITORING PLAN .......................................................................... 48 
8 
STATISTICAL SECTION ................................................................................................... 49 
8.1 
PRIMARY ENDPOINT ........................................................................................................ 49 
8.2 
ANALYSIS OF SECONDARY ENDPOINTS ........................................................................... 49 
8.3 
ACCRUAL TARGET AND STUDY DURATION ..................................................................... 50 
9 
COLLABORATIVE AGREEMENTS ................................................................................. 50 
9.1 
AGREEMENT TYPE........................................................................................................... 50 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 50 
10.1 RATIONALE FOR SUBJECT SELECTION ............................................................................. 50 
10.2 PARTICIPATION OF CHILDREN ......................................................................................... 51 
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT .............................................. 51 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS .................................................... 51 
10.5 RISKS/BENEFITS ANALYSIS ............................................................................................. 52 
10.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION ................................................ 52 
11 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION .............. 53 
11.1 VANDETANIB (IND #77570) ........................................................................................... 53 
12 APPENDIX 1: PERFORMANCE STATUS SCALES/SCORES ........................................ 58 
13 APPENDIX 2: NORMAL BLOOD PRESSURE RANGE FOR CHILDREN .................... 59 
14 APPENDIX 3: BLOOD PRESSURE MONITORING ALGORITHM IN CHILDREN ..... 61 
15 APPENDIX 4: BLOOD PRESSURE COLLECTION AND MANAGEMENT IN ADULT 
PATIENTS .................................................................................................................................... 64 
16 APPENDIX 5: ADULT ANTIHYPERTENSIVE MEDICATION LIST ............................ 66 
17 APPENDIX 6: NEW YORK HEART ASSOCIATION (NYHA) CARDIAC 
CLASSIFICATION ...................................................................................................................... 67 
18 APPENDIX 7: MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL OR 
INDUCE TORSADES DE POINTES .......................................................................................... 68 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
19 APPENDIX 8: PATIENT DIARY FOR VANDETANIB (PART 1) .................................. 72 
20 APPENDIX 9: REQUIRED STUDY EVALUATIONS ...................................................... 76 
21 APPENDIX 10:  PATIENT LOG FOR REACTIONS/SYMPTOMS ................................. 78 
22 APPENDIX 11: PROTOCOL FOR MRI STUDY OF KNEE ............................................. 80 
23 APPENDIX 12: PEDIATRIC PROMIS INSTRUMENTS (6) AND PARALLEL PARENT 
PROXY PROMIS INSTRUMENTS (6) AND ADULT PATIENT PROMIS INSTRUMENTS 
(6) 81 
24 APPENDIX 13: PARALLEL PARENT PROXY PROMIS INSTRUMENTS (6).............. 87 
25 APPENDIX 14: ADULT PATIENT PROMIS INSTRUMENTS (6) .................................. 93 
26 APPENDIX 15: THE DISTRESS AND SYMPTOM CHECKLIST: THE DISTRESS 
THERMOMETER ...................................................................................................................... 100 
27 REFERENCES ................................................................................................................... 102 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 PRIMARY OBJECTIVE: 
1.1.1.1 To assess the clinical activity (radiographic response RECIST v1.1) of vandetanib 
in children and adults with wild-type gastrointestinal stromal tumor (wt-GIST) 
using RECIST (v1.1). 
1.1.2 SECONDARY OBJECTIVE(S): 
1.1.2.1 To assess the safety and toxicity of vandetanib in children and adults with wt- GIST 
at established doses. 
1.1.2.2 To determine overall-, and progression free survival in children and adults with wt- 
GIST.  
1.1.2.3 To evaluate the utility of FDG-PET in disease characterization and response 
evaluation of patients ≥ 15 years of age with wt- GIST. 
1.1.2.4 To assess SDH expression using immunohistochemistry (IHC) in archival tumor 
tissue and to analyze the relationship of SDH expression and response. 
1.1.2.5 To assess archival tumor tissue for SDH, RET, EGFR, VEGFR and somatostatin 
receptor expression. 
1.1.2.6 To assess SDHB expression when new surgery/biopsy is clinically indicated. 
1.1.2.7 To establish pediatric wt-GIST cell lines to assess the effects of vandetanib on 
signaling pathways in sensitive and resistant cells lines in vitro, when new 
surgery/biopsy is clinically indicated. 
1.1.2.8 To describe health-related quality of life (as measured by PROMIS Patient 
Outcome Measures) and patient-reported symptoms (as measured by the Distress 
and Symptom Checklist) in patients ≥ 8 years of age at the start of therapy, at first 
staging (3 months) and at off treatment evaluation.   
1.2 
BACKGROUND AND RATIONALE: 
1.2.1 GASTROINTESTINAL STROMAL TUMOR (GIST) 
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the 
gastrointestinal tract. KIT and PDGFRA mutations are present in 85% of these tumors. However, 
GISTs that affect most pediatric patients are wild-type for KIT and PDGFRA, and, not 
surprisingly, imatinib and sunitinib are not as effective as they are in “classic” GIST.  The exact 
number of pediatric GIST in the US is not known. St. Jude Children’s Research Hospital 
reported that GIST accounted for 2.5% of all pediatric non-rhabdomyosarcoma soft tissue sarcoma 
(STS). Memorial Sloan Kettering Cancer Center estimated that 1 to 2% of all GIST seen at the 
institution is diagnosed in pediatric patients. According to the most recent population estimates of 
the SEER population database, the expected incidence of pediatric GIST in the United States in 
patients 18 years or younger would be approximately 0.08 per million  (1)  
The cell of origin is thought to be the interstitial cells of Cajal (ICC)(2), which function as 
“pacemakers” of bowel peristalsis. The initial therapeutic approach is usually surgical resection. 
GISTs are resistant to cytotoxic chemotherapy and radiation therapy and can present both local 


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recurrence and distant metastases, including lung and bone(3). KIT (CD117) and PDGFRA 
mutations have been identified as tumor initiating events in 85 % of adult patients with GIST. 
Inhibition of these kinases with imatinib mesylate has become the mainstay of GIST therapy and 
prolongs survival in this patient population.  Patients with classic GIST may also respond to 
nilotinib, sunitinib or sorafenib (3).  
In contrast to GISTs in adult patients, 85 % of GISTs occurring in pediatric patients lack KIT and 
PDGFRA mutations (wild-type) and not surprisingly imatinib and sunitinib are not as effective in 
eliciting objective responses in this group of patients as they are in classic KIT-mutant GIST (4). 
Therefore, there is no specific targeted therapy available for patients with wt-GIST. Wild-type 
GISTs are slow growing tumors that can have an indolent course. However, metastatic disease can 
cause significant morbidity. There is currently no standard medical approach for patients with wt-
GIST. Although some patients respond to imatinib or sunitinib, those responses are often short-
lived and subtler than the ones observed in patients with “classic” GIST harboring KIT or 
PDGFRA mutations (5).  Other notable differences between WT and standard adult GIST are the 
preponderance of gastric location in WT GIST, the marked predilection for females, and frequent 
multifocal presentation in WT GIST.  Given the multifocal and recurrent nature of the disease, 
experts advocate against radical surgical approaches with the aim of achieving local control from 
the oncological perspective, favoring the use of surgery when indicated to control tumor-related 
symptoms such as gastrointestinal bleeding(1, 5). 
1.2.1.1 Succinate Dehydrogenase (SDH) Germline Mutations 
Since germline inactivation of SDHB, C and D have been described in Carney-Stratakis syndrome, 
a condition in which affected individuals are predisposed to paragangliomas and WT-GIST, we 
recently evaluated pediatric and adult patients seen in the Pediatric and Wild-Type GIST Clinic at 
the NCI. We have found succinate dehydrogenase (SDH) germline mutations in 12 % patients with 
wt-GIST (6/34).  More recent data suggests that the rate of germline mutation in WT GIST patients 
may be significantly higher.  SDH (as SDH-ubiquinone complex II) is a component of the Krebs 
cycle and the respiratory chain. It is composed of four different subunits (A, B, C and D). SDH 
protein expression evaluated using immunohistochemistry (IHC) was markedly decreased or 
absent in 18/18 patients with wt-GIST (0-5% tumor cells reactive by standard IHC scores (4). 
Transmission of Carney-Stratakis Syndrome is autosomal dominant with incomplete penetrance.  
Demonstration of loss of the non-mutated copy of the SDH gene is consistent with a tumor 
suppressor gene model (6, 7).  
The lack of cell lines or animal models to evaluate preclinical activity is a major obstacle in the 
development of therapies aimed towards wt-GIST. However, SDH deficient renal cell carcinomas 
have also been described and cell lines are available for study and have led to important 
observations that may have relevance to SDH deficient GISTs.   
The best surrogate model currently available is a SDH deficient cell line from a patient with renal 
cell carcinoma (RCC).  Due to the loss of SDH, this cell line has accumulation of succinate and 
subsequent increase in hypoxia inducible factor 1 alpha (HIF1a)(8, 9). 
Mutations in another Kreb’s cycle member, fumarate hydratase (FH) lead to hereditary 
leiomyomatosis renal cell carcinoma (HLRCC)(10-12).  Work utilizing a cell line derived from a 
patient with FH deficiency has shown increased concentration of fumarate, inhibition of HIF prolyl 
hydroxylase and subsequent stabilization and accumulation of HIF1a (13, 14).  The latter promotes 
the transcription of genes that are relevant for growth and survival of cancer cells.  Additional 


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pathways that are implicated in HIF1a activation include EGFR and VEGFR2, amongst others.  
Agents that target these receptors, such as erlotinib and bevacizumab and more recently 
vandetanib, show promising results in vitro.  This has resulted in a phase II trial at the NCI 
evaluating erlotinib and bevacizumab in subjects with HLRCC(15).  Moreover, an aggressive 
phenotype of renal cell carcinoma associated with SDH germline mutations has recently been 
described (16).  
In general, SDHB is ubiquitously expressed in all cells, whether normal or neoplastic, and this 
typically manifests as granular cytoplasmic staining.  A small group of SDH-deficient tumor is 
now recognized to exist, and these include approximately 30% of extra-adrenal paragangliomas, 
7.5% gastric GISTs, and rare renal carcinomas (< 1%).  
These SDH-deficient tumors, among them SDH-deficient GISTs are detected by 
immunohistochemical loss of SDHB in the tumor cells.  These tumor cells do not show granular 
cytoplasmic staining, although they may show weak diffuse cytoplasmic staining.  The loss is 
assessed comparing tumor cells with non-neoplastic elements, such as endothelial cells, smooth 
muscle, epithelia, and lymphoid cells, which may appear as streaks and nests of high expression 
around the neoplastic elements.  SDH-deficient GISTs demonstrate a strong contrast between 
immunostaining of non-neoplastic elements and tumor cells. 
Parallel examination of SDHA could be helpful for assessment of the SDHB-
status.  Approximately 30% of SDH-deficient GISTs lack SDHA-immunoreactivity, similar to 
lack of SDHB.  However, in the rest of cases observation of strong retained SDHA-
immunoreactivity helps in comparison with SDHB-loss. 
The SDHB-loss is generally all or none phenomenon, and percentage of loss is not used as a 
definitional measure.  In very rare cases, the SDHB-status may remain ambiguous by 
immunohistochemistry.  It is theoretically possible that some genetic alternations allow partial 
retention of expression.  
SDHB-loss is accompanied with mutations in the SDH-complex (A, B, C or D subunits) in 
approximately 50% of cases, so that SDHB-loss is by no means synonymous with SDH-
mutations.  The other half of SDHB-negative tumors may have other deficiencies, especially 
epigenetic silencing.  Based on available information, it is best to consider loss of SDHB-
expression the umbrella feature that identifies SDH-deficient GISTs. 
The results of the SDH staining are reported as negative (loss), positive, or indeterminate (the 
latter to be reserved for rare cases that cannot be interpreted in a straightforward manner). 
SDH deficiency causes accumulation of succinate.  Succinate links TCA cycle dysfunction to 
oncogenesis by inhibiting HIF-prolyl hydroxylase, as widely shown in different tumor models by 
several investigators (9).  
As noted above, most wt-GIST are SDH deficient, and many of them harbor mutations in the 
various genes encoding for SDH subunits  (4). Although the rarity of the tumors and the lack of 
preclinical models does not allow us to directly show this in SDH-deficient GIST, evidence of HIF 
activation in GISTs has been published (17).  
Examples of SDH staining as they pertain to SDH-deficient GISTs are highlighted in Figure 1 
and Figure 2 below: 
 


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Figure 1 
 
 
Figure 2 
 
Unfortunately, no wt-GIST cell lines are available for preclinical studies. However, a SDH-
deficient  renal cell carcinoma has been generated. 
UOK269 cell line was established at the Urologic Oncology Branch (CCR, NCI) and is derived 
from the tumor of a 36 year old woman with a metastatic kidney cancer due to a germline mutation 
in the gene encoding for SDH-B. The effect of vandetanib on the viability of SDHB-deficient 
tumor cells was assessed. With an IC50 of about 50nM in two different clones of UOK269 (labeled 
as “UOK269EV”) and no significant cytotoxicity on two molecularly restored cell lines 


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(UOK269WT1 and UOK269WT2; i.e. cell lines in which SDH-B function had been restored), 
vandetanib might have a therapeutic value in targeting SDHB-deficient tumors. 
 
Figure 3. Vandetanib is cytotoxic to SDHB-deficient tumor cells in vitro. Viability of SDHB-
deficient cells (UOK269EV1, UOK269EV2) and of molecularly restored cells (UOK269WT1, 
UOK269WT2) was assessed after 24hrs treatment with vandetanib. 
 
A phase II trial of vandetanib in patients with clear cell renal cell carcinoma (RCC) at the NCI 
was recently terminated due to low accrual rate. (18). Clinical evaluation of vandetanib in 
patients with VHL-related RCC is ongoing.  Combined VEGF/EGFR blockade has significant 
activity in metastatic papillary renal cell carcinoma (RCC) associated with hereditary 
leiomiomatosis renal cell carcinoma syndrome (HLRCC). HLRCC is a familial condition 
resulting from germline alterations in fumarate hydratase (FH) and is characterized by an 
aggressive form of RCC.  FH-/- kidney cancer cell lines rely on aerobic glycolysis for energy 
production.  
Eighteen patients with metastatic RCC received systemic therapy from 1998-2008; 7/18 patients 
received combined VEGF/EGFR blockade (bevacizumab 10 mg/Kg IV every 2 weeks plus either 
erlotinib [N=6] or gefitinib [N=1] PO daily). The remaining patients received a variety of agents. 
Patients receiving VEGF/EGFR blockade had an overall response rate of 71% (5/7), including 
one patient with a complete response (14%) and 4 patients with a partial response (57%). 
Responses were durable, with one patient remaining disease free 74 months after treatment 
initiation.  Combined VEGF/EGFR blockade resulted in significantly improved overall survival 
compared to other regimens (median 51 months vs. 14 months; P=0.0012). A phase II trial 
combining bevacizumab plus erlotinib (NCT 01130519) is currently ongoing. (Srinivasan et al, 
Can J of Urol, 2012, 19:5 6510-6511) 
Preliminary preclinical data demonstrate marked growth inhibition of SDH-mutant/deficient RCC 
cell lines when treated with vandetanib. This effect may be due to VHL-independent HIFs 
stabilization since accumulation of fumarate and succinate inhibit prolyl hydroxylases therefore 
causing increased expression of HIF downstream targets such us EGFR and VEGF(9). Thus, there 
might be a role for vandetanib in the treatment of GIST. Interestingly, SDH polymorphisms have 
been described in patients with MTC (19), a disease for which vandetanib has demonstrated 
activity. 


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1.2.2 VANDETANIB 
Vandetanib (CAPRELSA®; ZD6474; AstraZeneca, Macclesfield, UK) is a small molecule 
receptor tyrosine kinase (RTK) inhibitor, given as a once-daily oral drug that inhibits VEGFR2- 
and EGFR- dependent signaling.  It is also potent inhibitor of RET, which is frequently activated 
by mutation or rearrangement in medullary thyroid carcinoma (MTC)(20).  Vandetanib has activity 
in MTC in adults at doses ranging from 100 to 300 mg once daily on a continuous dosing schedule 
and in children receiving 100 mg/m2/dose (equivalent to 180 mg fixed dose based on a BSA of 1.8 
m2), or 150 mg/m2/dose (equivalent to 270 mg fixed dose).  At this time the active dose in children 
with GIST is unknown; we therefore will use the highest tolerable dose evaluated in children: 150 
mg/m2/dose for children 13 years and older, and 100 mg/m2/dose with option for dose escalation 
to 150 mg/m2/dose for children less than 13 years old.  In children and adults with MTC vandetanib 
has been well tolerated with prolonged administration with diarrhea, rash, and TSH elevation being 
the most frequent toxicities.  Tumor shrinkage is occurring slowly over multiple treatment 
cycles(20, 21).   
Vandetanib is currently undergoing evaluation in a phase II trial for patients with clear cell renal 
cell carcinoma at the NCI based on concomitant VEGFR and EGFR inhibition(18).  Preliminary 
data from this trial demonstrate marked growth inhibition of SDH-mutant/deficient RCC when 
treated with vandetanib.  Thus, there might be a role for vandetanib in the treatment of wt-GIST 
and SDH mutations.   
1.2.2.1 Prior Clinical Experience in Pediatric Patients 
A phase I/II trial (NCI# 07-C-0189) of vandetanib for children and adolescents with hereditary 
MTC is ongoing with the primary objectives to define a safe dose, the drug’s toxicity profile, 
pharmacokinetics, and the activity of vandetanib in children (ages 5 to 18 years of age) with 
hereditary medullary thyroid cancer (MTC).  The starting dose level was 100 mg/m2/ dose once 
daily on a continuous dosing schedule with the option for a dose increase to 150 mg/m2.  A single 
stage design targeting a response rate of 30% using RECIST is used for the phase II component; a 
response rate of ≥5/21 is consistent with up to 40% response rate.  Since initiation of the trial, 16 
patients were enrolled, 10 in the adolescent cohort (age 13-18 years) and 6 in childhood cohort 
(age 5-12 years). Vandetanib has been well tolerated without evidence of cumulative toxicity.  One 
of 6 patients 5-12 years old enrolled at 100 mg/m2/dose developed dose-limiting diarrhea. Of 8 
adolescents 13-18 years old, who were eligible to receive vandetanib at 150 mg/m2/dose, one 
developed dose-limiting diarrhea, one had a dose reduction for non dose-limiting diarrhea, and one 
patient had a dose reduction for non-dose-limiting hypertension in presence of baseline 
bradycardia. Common non-dose-limiting toxicities included prolonged QTc interval, 
hypertension, diarrhea, rash and TSH elevation necessitating an increase in levothryroxine dosage 
in athyrotic patients who were previously on a stable dose. Patients received a median (range) of 
27 (2-52) cycles. For subjects with M918T RET germline mutations (n=15) the confirmed 
objective partial response rate was 47% (95%CI, 34%, 60%). Durable responses were achieved in 
children and adolescents at 150 mg/m2/d (n=2, duration 40-52 cycles), 100 mg/m2/d (n=4, duration 
20-44 cycles) and 67 mg/m2/d (n=1, 48 cycles). While both dose levels were tolerated in the 
patients studied, the activity of vandetanib at the 100 mg/m2 dose level combined with the better 
tolerability of vandetanib was recommended for pediatric patients with MTC (22).  
Thus, the previous experience in patients with SDH-mutant/deficient clear cell renal carcinoma 
and the recent observation that the vast majority of patients with wt-GIST lack SDH expression 


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supports the role of vandetanib in the treatment of wt-GIST.  In addition, our ongoing study of 
vandetanib in MTC has demonstrated the safety of vandetanib in children and adolescents at doses 
proposed in this clinical trial.  
1.2.3 HEALTH-RELATED QUALITY OF LIFE AND PATIENT-REPORTED SYMPTOMS 
The psychosocial stresses associated with living and coping with cancer have been well described 
for adults, as well as in children and their family members.  Most of these studies have been 
conducted in heterogeneous cohorts that are not disease specific. Gastrointestinal stromal tumors 
(GISTs) are rare in children and adults, and limited data are available on how the disease impacts 
the quality of life of those living with this disease.  What is known about the common physical 
symptoms associated with these tumors raises concern pertaining to psychosocial outcomes. These 
include anemia and symptoms related to bleeding, mild epigastric discomfort, and for some, 
chronic to acute abdominal pain (23, 24). The importance of abdominal pain and discomfort in the 
HRQOL of children, adolescents or adults with GIST has not been examined.  
Numerous articles have shown that children with chronic abdominal pain were more likely to have 
increased health service use, restrictions in daily living, and suffer from functional impairments in 
adulthood (25-27). The association of abdominal pain with mental health outcomes has been 
studied in adolescents, with patients living with irritable bowel disease (28), and with those living 
with juvenile rheumatoid arthritis (JRA). Adolescents with frequent abdominal pain have been 
found to be at increased risk for depressive symptoms, social isolation, and for more somatic 
complaints compared with healthy children, including headache, stomachache, backache, and 
morning fatigue, possibly as a response to stress (27, 29). Frequent abdominal pain in children and 
adolescents has also been associated with social and peer withdrawal, school absenteeism, and a 
poor quality of life for patients and their parents (30).  
Psychiatric morbidities are also common in adults who suffer from frequent abdominal pain. Adult 
patients with chronic pain have higher rates of suicidal ideation(31). Suicidal ideation has been 
shown to increase with symptom severity and perceived pain interference in adults with irritable 
bowel syndrome (32). 
While it is understood that frequent abdominal pain places individuals at increased risk for 
depressive symptoms, social isolation, and missing work/school, the role that pain plays in the 
quality of life of individuals living with GIST is not known. In order to learn about the psychosocial 
concerns of both children and adults living with GIST, 60 adults and 18 pediatric patients who 
participated in the NIH GIST clinic completed a self-administered psychosocial screening tool. 
Frequently reported chronic pain and significant anxiety was found in the pediatric and adult 
cohorts, regardless of time since diagnosis.  Furthermore, those who endorsed pain were 
significantly more likely to be prescribed psychotropic medication (33).    
Particularly in a Phase I/II trial, it is important for toxicities and their outcomes to be specified and 
measured so that appropriate interventions can be designed to prevent or diminish their effects. 
Known toxicities associated with Vandetanib include insomnia (11%) and depression (4.7%) and 
anxiety (4.4%) (As described in Investigator’s Brochure, Vandetanib, 17 October 2012).  
Therefore, using patient reported outcome measures (PROMIS) and a symptom checklist, we will 
extend the knowledge gained from our initial psychosocial screening study and assess 
psychosocial symptoms associated with GIST and Vandetanib treatment, including physical 
function, anxiety, depressive symptoms, fatigue, pain interference, and global health.  


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As parents tend to underrate their child’s health related quality of life, they may be poor judges of 
which consequences of illness matter most to their children and may be influenced by their own 
response to their child’s illness (34).  Therefore, for the pediatric patients over the age of 8, we 
will include patient and parent-proxy reports of patients’ quality of life and symptom experience 
during each clinic visit.  
1.2.3.1 Study Measures 
Distress and Symptom Checklist (Appendix 15): The Distress Thermometer (35) is a brief 
screening tool endorsed by the National Comprehensive Cancer Network (NCCN) to assess for 
distress in adult cancer patients. The Distress Thermometer (DT) is a visual-analog scale similar 
to those used to assess pain. The DT obtains an overall distress score based on the visual analog 
scale, and includes a “problem list”, or checklist, where patients can identify specific physical and 
emotional symptoms and practical and family concerns that can cause their distress.  The DT has 
been widely validated in adult (>18 years old) cancer patients, and has been recognized as a good 
alternative to many of the longer measures commonly used to screen for distress in cancer patients 
(36-38). 
Whereas the Distress Thermometer was originally written for adult cancer patients, early 
evaluation of the scale shows validity for children and adolescents with cancer (39). In an ongoing 
study at the NIH with 163 pediatric patients ages 7-21 undergoing treatment for cancer, NF1, HIV 
or a primary immune deficiency and their caregivers, an adapted DT has shown convergent validity 
when compared with standardized measures and with specific items on the symptom checklist. It 
has also shown reasonable concordance with parent and provider ratings (40). For this study, we 
will use the DT as a distress and symptom rating tool. It is quick to administer and a low burden 
to patients and their caregivers (40). In order to assess how the severity of symptoms may change 
over the course of treatment, the participant will rank each endorsed symptom (from the problem 
checklist) on a scale of 1-5, with “1” indicating a little problem and “5” indicating maximum 
amount of difficulty. Two versions of the tool will be available for this protocol, one for parents 
of children (caregiver) to complete about their child, and a second for patients ages 8 and older to 
complete on their own.  Whereas most patient reported outcome measures utilize a 7–day recall 
period (including the PROMIS measures), the adapted DT utilizes a 30 day recall period which 
allows problems or symptoms that might have been present in the past month, but not necessarily 
the past week to be documented. The distress and symptom rating scales will take approximately 
5 minutes to complete. 
Patient-Reported Outcomes Measurement Information System (PROMIS) is a health related 
quality of life measurement tool that was developed by NIH to standardize patient-reported 
outcomes for national use by research clinicians. Two versions of PROMIS are available to 
researchers: computer-adaptive tests (CATs) and short forms. The short forms are brief, static 
instruments that have demonstrated similar reliability to the longer, dynamic CATs, which provide 
precise measures for studying populations with widely varied responses and longitudinal self-
report data (41). Each short form includes 4 to 8 items, measures reported health outcomes in the 
past 7 days on a Likert type scale, and takes approximately 5 minutes to complete.  PROMIS 
instruments, measuring a broad range of health domains, have been validated for adults (>18) with 
a variety of health conditions (42).  
Early evaluation of PROMIS pediatric instruments indicates validity for children ages 8 to 17 (43). 
Six pediatric PROMIS instruments and six parallel Parent Proxy PROMIS instruments (See 


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Appendix 13) are available to assess five quality of life health domains (physical function, pain 
interference, fatigue, emotional health, and social health) and are intended for use with both 
healthy and chronically ill pediatric populations. This protocol will utilize pediatric PROMIS short 
forms and the Parent Proxy short forms to assess symptoms that can be associated with GIST. 
These include physical function, anxiety, depressive symptoms, fatigue, pain interference, and 
peer relationships.  
Assessments of Health Related Quality of Life will be administered at the start of therapy, at first 
staging (3 months) and at off treatment evaluation. The PROMIS Patient Outcome Measures (6) 
and patient-reported symptom severity (Distress and Symptom Checklist) will provide us with 
essential information regarding how symptoms may change over the course of treatment, and will 
also provide a more in-depth assessment of the known toxicities associated with Vandetanib 
(insomnia, anxiety and depression) in this patient population.   
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
Subjects must meet the following criteria to be eligible to participate: 
2.1.1 INCLUSION CRITERIA 
2.1.1.1 Age: ≥ 3 years of age and BSA ≥ 0.5 m2 
2.1.1.2 Diagnosis 
2.1.1.2.1 Histologically or cytologically confirmed GIST by the Laboratory of 
Pathology, NCI.  
2.1.1.2.2 Absence of Kit and PDGFRA mutation confirmed in a CLIA certified 
laboratory.  
2.1.1.3 Participants must have measurable disease as defined in RECIST (v1.1) as the 
presence of at least one lesion, not previously irradiated, that can be accurately 
measured at baseline ≥ 10 mm in the longest diameter (except lymph nodes which 
must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) and which is suitable for accurate repeated measurements.    
2.1.1.4 Prior therapy:   
There are no standard chemotherapy regimens known to be effective for wt-GIST.  
Therefore, previously untreated participants are eligible if their tumor(s) are 
measurable.  
2.1.1.4.1 Participants must be at least 4 weeks from prior surgical procedures and 
surgical incisions must be healed. 
2.1.1.4.2 Participants must have had their last fraction of external beam radiation therapy 
at least 4 weeks prior to enrollment. 
2.1.1.4.3 Participants must have had their last dose of cytotoxic chemotherapy at least 28 
days prior to enrollment, their last dose of biological therapy, such as biological 
response modifiers (e.g., cytokines), immunomodulatory agents, vaccines, 
differentiating agents, used to treat their cancer at least 7 days prior to 
enrollment, their last dose of a monoclonal antibody at least 30 days prior to 


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enrollment, and their last dose of any investigational agent at least 30 days prior 
to enrollment. 
2.1.1.4.4 Participants must have received their last dose of short acting colony stimulating 
factor, such as filgrastim or sargramostim at least 72 hours prior to enrollment 
and their last dose of long-acting colony stimulating factors, such as PEG-
filgrastim at least 7 days prior to enrollment. 
2.1.1.4.5 Participants must have recovered from the acute toxic effects of prior therapy to 
a grade 1 (CTCAE v.4.0) level prior to enrollment (does not apply to alopecia). 
2.1.1.5 Performance Status:  Lansky (for participants 10 years of age or younger) or 
Karnofsky (for participants older than 10 years) performance score greater than 50 
(Appendix 1) 
2.1.1.6 Patients must have normal organ and marrow function as defined below: 
2.1.1.6.1 Hematological Function:  The peripheral absolute neutrophil count must be at 
least 1,500/µL and the platelet count must be at least 100,000/µL within 72 hours 
prior to enrollment. 
2.1.1.6.2 Coagulation:  PT and PTT must not be more than 1.5 x ULN within 72 hours 
prior to enrollment.  PT and PTT should drawn by venipuncture, rather than 
from a central venous catheter when feasible. 
2.1.1.6.3 Hepatic Function: Bilirubin must not be more than 1.5 x ULN (does not apply 
to patients with Gilbert’s Disease) and the AST and ALT must not be more than 
2.5 x ULN within 72 hours prior to enrollment, or greater than 5.0 X ULN if in 
the Investigator’s judgment it is related to liver metastases.  AST and ALT may 
be up to 5 x ULN within 72 hours prior to enrollment in participants with hepatic 
metastases. 
2.1.1.6.4 Renal Function: Participants must have an age-adjusted normal serum creatinine 
(see Table) or a creatinine clearance of at least 50 ml/min/1.73 m2. 
 
Maximum Serum 
Creatinine (mg/dL) 
Age (years) 
Male 
Female 
3 to 5 
.42 
.42 
5 to <10 
1 
1 
10 to <13 
1.2 
1.2 
13 to <16 
1.5 
1.4 
16 and older 
1.7 
1.4 
2.1.1.7  Hypertension:  
Participants should have normal blood pressure according to age. Participants 18 years of 
age and younger should have a blood pressure ≤ 95th percentile for age, height and 
gender, and should not be receiving medication for treatment of hypertension.  
Preexisting hypertension in adults should be controlled (either with pharmacological or 
non-pharmacological methods) at the time of enrollment (See Appendix 2). 


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2.1.1.8 Birth Control:  
Participants of child-bearing or child-fathering potential must be willing to use a medically 
effective form of birth control, which includes abstinence, while taking vandetanib and for 
3months after the last dose. [Female patients must be 1 year post-menopausal, surgically 
sterile, or using an acceptable method of contraception (an acceptable method of 
contraception is defined as a barrier method in conjunction with a spermicide) for the 
duration of the study (from the time they sign the informed consent form [ICF]) and for 3 
months after the last dose of vandetanib to prevent pregnancy. In addition, oral 
contraceptives, approved contraceptive implant, long-term injectable contraception, 
intrauterine device, or tubal ligation are allowed. Oral contraception alone is not 
acceptable; additional barrier methods in conjunction with spermicide must be used. 
Male patients must be surgically sterile or using an acceptable method of contraception 
(defined as barrier methods in conjunction with spermicides) for the duration of the study 
(from the time they sign the ICF) and for 3 months after the last dose of vandetanib to 
prevent pregnancy in a partner.] 
Negative pregnancy test for women of childbearing potential. 
2.1.1.9 Informed Consent:  
Participants who are ≥ 18 years of age or Legally Authorized Representative (LAR) of 
participants who are younger than 18 years must sign an informed consent for the POB 
Screening Protocol (01-C-0157: Eligibility Screening and Tissue Procurement for the 
National Cancer Institute (NCI), Pediatric Oncology Branch (POB) Clinical Research 
Protocols) prior to participating in studies required to determine eligibility for this trial.  
After confirmation of eligibility, participants who are ≥ 18 years of age or LAR of minor 
participants must sign an informed consent document for this trial, indicating that they are 
aware of the investigational nature of the proposed treatment, the risks and benefits of 
participating and the alternatives to participating, prior to the conduct of any study 
procedures. 
 
2.1.2 EXCLUSION CRITERIA 
Presence of any of the following will prevent a subject from participation: 
2.1.2.1 Pregnant or breastfeeding females because vandetanib may be harmful to the 
developing fetus or nursing infant and has been found to be embryotoxic, fetotoxic 
and teratogenic in rats. 
2.1.2.2 Subjects who are receiving any other investigational agents or who have received an 
investigational agent within 28 days prior to enrollment (does not apply to 
participation in survival follow up), or who have previous exposure to vandetanib. 
2.1.2.3 Abnormal Electrolyte Levels: Participants with a serum potassium less than 3.5 
mmol/L or a serum ionized calcium or magnesium below the lower limits of normal 
(or above CTCAE Grade 1 upper limit).  Correction of these electrolyte abnormalities 
with supplements is allowed.  (Serum calcium above the CTCAE Grade 1 upper limit. 
In cases where the serum calcium is below the normal range, the calcium adjusted for 


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albumin is to be obtained and substituted for the measured serum value. Exclusion is 
to then be based on the calcium adjusted for albumin values falling below the normal 
limit: Corrected Calcium = Ca + 0.8 x (4-serum albumin).) 
2.1.2.4 Presence of hypertension: Diastolic blood pressure above the 95% for age in children 
(Appendix 2) and > 160 mmHg systolic or >100 mmHg diastolic in adults on at least 
2 of 3 measurements with an appropriate-size cuff who are unable to achieve blood 
pressure control with optimal anti-hypertensive therapy. Patients who are treated with 
antihypertensive medications with good response are eligible.  
2.1.2.5 History of Cardiac Disorder:  
2.1.2.5.1 Participants with a history of arrhythmia (multifocal premature ventricular 
contractions, bigeminy, trigeminy, ventricular tachycardia, uncontrolled atrial 
fibrillation, left bundle branch block) that is symptomatic or requires treatment 
(except for controlled atrial fibrillation).   
2.1.2.5.2 History of any significant cardiac event (e.g. myocardial infarction), superior 
vena cava syndrome, New York Heart Association (NYHA) classification of 
heart disease ≥ 2 within 12 weeks before starting treatment (See Appendix 3), 
or presence of cardiac disease that in the opinion of the Investigator increases 
the risk of ventricular arrhythmia. 
2.1.2.5.3 Participants with a history of congenitally prolonged QTc, a first-degree relative 
with unexplained sudden death under 40 years of age, or a measured QTcB 
(Bazett’s correction) longer than 480 msec on ECG.  ECGs should be performed 
after correction of electrolyte abnormalities. Participants with a prolonged QTcB 
should have a repeat ECG twice, at least 24 hours apart, and the average of the 
3 QTcBs should not exceed 480 msec.  History of QT prolongation associated 
with other medications that required discontinuation of that medication. 
2.1.2.5.4 Participants receiving a medication that has a known risk of QTc prolongation 
or is associated with Torsades de Pointes (Appendix 7) or any prohibited 
medications, concomitantly or within 14 days (28 days for levomethadyl) of 
enrollment. 
2.1.2.6 Other clinically severe or uncontrolled systemic illness or any concurrent condition 
that in the view of the principal investigator could compromise the participant’s ability 
to tolerate vandetanib or could compromise study procedures or endpoints, including 
interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which 
required steroid treatment or any evidence of clinically active interstitial lung disease. 
2.1.2.7 Unstable brain metastases or spinal cord compression that requires treatment, unless 
the treatment ended at least 4 weeks before starting treatment and the condition has 
been stable without steroid treatment for at least 10 days. 
2.1.2.8 Major surgery (includes surgery that carries significant risk of blood loss, extended 
periods of general anesthesia, or requires at least an overnight hospital admission) 
within 28 days before starting treatment. 
2.1.2.9 Involvement in the planning and/or conduct of the study. 
2.1.2.10 Previous enrollment in the present study. 


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2.1.2.11 Previous or current malignancies of other histologies within the last 5 years, with the 
exception of in situ carcinoma of the cervix and adequately treated basal cell or 
squamous cell carcinoma of the skin. 
2.1.3 RECRUITMENT STRATEGIES 
The NCI, POB has established a collaborative wt-GIST Clinic with the goals to increase the 
understanding of the molecular biology and natural history of wt-GIST and to develop effective 
therapies for these tumors.  The following recruitment strategies will also be employed to elicit 
potential candidates for this trial: 
1. Listed on www.clinical trials.gov;  
2. Listed in PDQ;  
3. In addition, patients from POB clinic who are eligible for participation will be offered 
participation in this study 
Prior to distribution of any recruitment materials, such materials will be submitted to the NCI 
IRB for review. 
2.2 
SCREENING EVALUATION 
The following evaluations should be performed within 7 days of enrollment unless otherwise 
specified.   
2.2.1 CLINICAL EVALUATION 
2.2.1.1 History and Physical Examination:  
A complete history and physical examination, (including vital signs with blood pressure, 
pulse, respiratory rate and temperature), and a description of signs and symptoms is 
required.  
• Baseline blood pressure (BP) is defined as the blood pressure obtained at the 
examination used for study enrollment.  This baseline BP should be obtained as 
follows:   
1) Obtain 3 serial blood pressures from the same extremity with the patient in the 
same position that are separated by at least 5 minutes.  Avoid using the lower 
extremity if possible.  
2) Average the systolic blood pressure from the 2nd and 3rd measurements.   
3) Average the diastolic blood pressure from the 2nd and 3rd measurements.   
4) The baseline BP is the average of the systolic over the average of the diastolic 
measurements. 
2.2.1.2 Height, Weight and Body Surface Area: 
For patients < 18 years old, the BSA should be calculated from the average of 3 repeated 
measurements of weight and height on the same day by the standard formula in use at the 
NCI: 
BSA=Weight (kg)0.425*Height (cm)0.725 
 
 
 
 
 
 
 
 
 
139.315 


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2.2.1.3 Performance status determination 
2.2.2 LABORATORY STUDIES 
The following laboratory studies will be performed within 7 days of enrollment. 
2.2.2.1 β-HCG pregnancy test on all women of child-bearing potential 
2.2.2.2 Hematology: complete blood count, differential, platelet count, PT, PTT. 
2.2.2.3 Chemistries: BUN, creatinine, electrolytes (sodium, potassium, chloride, CO2), 
calcium, magnesium, phosphorus, uric acid, total protein, and albumin LDH, and 
glucose. 
2.2.2.4 Hepatic Panel: Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, (Direct 
Bilirubin, if total bilirubin is elevated) 
2.2.3 ELECTROCARDIOGRAM (ECG) 
ECG with Calculation of QTc using Bazett’s correction (QTc = QT/RR0.5).  
Electrocardiograms will be evaluated by suitably qualified personnel for the presence of 
QTcB prolongation or other abnormalities, in particular, any changes in the T-wave 
morphology that would suggest a higher likelihood for the development of any arrhythmia.   
2.2.4 SCANS AND X-RAYS 
Scans must be performed within 4 weeks of enrollment. 
2.2.4.1 CT scan of chest, abdomen and pelvis;  
2.2.4.2 MRI of abdomen and pelvis. 
2.3 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  Prior to registration, contact the research nurse, Claudia 
Derse-Anthony (240-760-6102) or claudia.derse-anthony@nih.gov.  A registration Eligibility 
Checklist from the web site (http:// http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) 
must be completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov.  After confirmation of eligibility at Central Registration 
Office, CRO staff will call pharmacy to advise them of the acceptance of the patient on the 
protocol prior to the release of any investigational agents.  Verification of Registration will be 
forwarded electronically via e-mail to the research team. A recorder is available during non-
working hours. 


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2.4 
TREATMENT ASSIGNMENT AND RANDOMIZATION/STRATIFICATION PROCEDURES 
Cohorts 
Number 
Name 
Description 
1 
Adults and children (patients 
older than 3 years) with wild 
type GIST 
Adults and children with measurable localized or metastatic wt-
GIST.   
2 
Parents of children with wild 
type GIST enrolled on this 
clinical trial 
Consenting parents of children with wild type GIST who are 
enrolled on this clinical trial 
Arms 
Number 
Name 
Description 
1 
Experimental therapy 
Patients younger than 18 years of age at the time of enrollment 
receive vandetanib at a dose of 100 mg/m2/dose for cycles 1, 2 and 
3; and 150 mg/m2/dose for Cycles ≥4 
2 
Experimental therapy 
Patients 18 years and older at the time of enrollment receive 
vandetanib at a fixed dose of 200 mg once daily (QD) for cycles 1, 
2, and 3; and 300 mg/dose for Cycles ≥4. 
3 
Companion parental 
questionaire 
Consenting parents will be asked to complete the parent version of 
the QOL questionnaires. 
Randomization and Arm Assignments 
• There is no Randomization in this study.  
• Patients in cohort 1 will be directly assigned to arm 1 or 2, depending on their age at the 
time of enrollment.  
• Patients in cohort 2 will be directly assigned to arm 3. 
2.5 
BASELINE EVALUATION 
2.5.1 LABORATORY EVALUATIONS 
Pre-treatment laboratory tests should be repeated if necessary within 7 days prior to starting 
therapy. 
2.5.1.1 Hematology: complete blood count, differential, platelet count, PT, PTT. 
2.5.1.2 Chemistries: BUN, creatinine, electrolytes (sodium, potassium, chloride, CO2), 
calcium, magnesium, phosphorus, uric acid, total protein, and albumin, LDH, and 
glucose. 
2.5.1.3 Hepatic Panel: Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, (Direct 
Bilirubin, if total bilirubin is elevated) 
2.5.1.4 Thyroid Function Tests:  TSH, Free T4 
2.5.1.5 Urinalysis  


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2.5.2 SCANS 
2.5.2.1 MRI of abdomen and pelvis. In the exceptional event of extraabdominal disease, 
MRI will be obtained of the relevant anatomic sites at discretion of the PI.  
2.5.2.2 CT (CT of chest, abdomen and pelvis) with contrast since MRI might overlook small 
lesions.  
2.5.2.3 FDG-PET (torso)  
2.5.2.4 Lower extremity scanogram (x-ray to evaluate bone, leg length and growth plates) in 
all participants less than 18 years old.   
Patients with fused growth plates will not undergo additional evaluations.  
Patients with open growth plate(s) will also undergo a unilateral knee MRI to 
determine the growth plate volume at baseline to evaluate for bony toxicity 
according to Appendix 11.  Scanogram (when clinically indicated) and growth 
plate knee MRIs are performed in patients with open growth plates to monitor 
for potential bony toxicity of VEGFR inhibitors.   
2.5.3 HEALTH-RELATED QUALITY OF LIFE AND PATIENT-REPORTED SYMPTOMS  
English or Spanish speaking parents and/or caregivers of enrolled minor subjects and 
research subjects 8 years of age and older will be undergo psychosocial evaluation.  The 
following evaluations will be administered prior to starting the study agent. 
2.5.3.1 Distress and Symptom Checklist:  The Distress Thermometer will be administered to 
patients (8 years of age and older) and parents (on behalf of their child), and will be 
completed prior to initiating Vandetanib therapy (Appendix 15). 
2.5.3.2 PROMIS Patient Outcome Measures:  The PROMIS short forms will be administered 
to patients (8 years of age and older) and parents of minor participants who will be 
completing the form as an evaluation of their child’s functioning, and will be 
completed prior to initiating Vandetanib therapy (Appendix 12). 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
3.1.1 STUDY OVERVIEW 
This phase II trial is designed to determine whether daily oral vandetanib is active (clinical activity 
as per RECIST v1.1) in patients with wt- GIST.  Vandetanib activity will be primarily assessed by 
response of measurable disease using RECIST (v1.1), but change in tumor-related symptoms from 
baseline will also be monitored to assess drug effect.  
Adults and children (patients older than 3 years) with measurable wt-GIST will be eligible for trial 
participation.  Patients must have measurable disease by RECIST and adequate organ function. 
Vandetanib will be administered orally once a day on a continuous dosing schedule.  One treatment 
cycle equals 28 days.   
• Patients 18 years and older at the time of enrollment on this study will start vandetanib at 
a fixed dose of 200 mg once daily (QD) for cycles 1, 2, and 3.  


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• Patients younger than 18 years of age at the time of enrollment will start vandetanib at a 
dose of 100 mg/m2/dose for cycles 1, 2 and 3. (see table below).   
 
 
 
 
 
 
 
 
 
 
 
 
 
A one time intra patient dose escalation to 150 mg/m2/dose for patients < 18 years, and to 300 
mg/dose for patients ≥ 18 years will be allowed after completion of 3 cycles, provided provided 
the intra patient dose escalation criteria below are fulfilled: 
Vandetanib is well tolerated at the starting dose defined as: 
• All vandetanib related toxicities during cycle 1-3 are less than grade 2, except grade 2 
toxicities that are: 
o isolated laboratory abnormalities and not present at repeat blood draw, or 
o short lived and resolve within approximately 72 hours with or without supportive 
therapy. 
There is no limit on the number of cycles that a patient may receive. The dosing nomogram 
provided in section 3.2 will be used to determine the vandatenib dose for pediatric patients. 
Patients will be carefully monitored for toxicity during treatment with vandetanib including 
history, physical exam, blood pressure monitoring, and laboratory evaluations and assessment of 
concomitant medications. Section 3.1.2 details treatment limiting toxicities. Restaging studies 
(RECIST) with appropriate imaging studies and evaluation of disease-related symptoms will be 
performed after every 3 cycles x 4 (prior to cycles 1 (baseline), 4, 7, 10, and 13) and then after 
every 6 cycles.  In addition the health related quality of life (PROMIS) and patient-reported 
symptoms (Distress and Symptom Checklist) will be administered to consenting patients 8 years 
of age and older at the first restaging visit (3 months) and at the time the patient is taken off-
treatment (Appendices 10 and 11).  Consenting parents will be asked to complete the parent 
version of these assessments. Vandetanib will be discontinued if there is evidence of tumor 
progression clinically or by RECIST or there is intolerable toxicity that is not alleviated by dose 
reduction.  
Table 1: Vandetanib Dose Escalation Schedule 
Age at Enrollment  
Daily Dose of Vandetanib  
Patients < 18 years of 
age 
Cycles 1-3: 100 mg/m2/dose 
If vandetanib is well tolerated :  
Cycles ≥4: 150 mg/m2/dose 
Patients ≥ 18 years of 
age 
Cycles 1-3: 200 mg/dose 
 
If vandetanib is well tolerated :  
Cycles ≥4: 300 mg/dose 


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Secondary endpoints on this trial include progression-free survival and evaluation of safety and 
toxicity of vandetanib. In addition to evaluation of response by RECIST, FDG-PET at baseline 
and on treatment with vandetanib will be used to evaluate response. The PET scan at baseline and 
restaging (prior to cycle 4) will be considered standard of care. Additional PET scans will be 
performed as clinically indicated. The option of one additional PET scan day 3 to day 6 after 
starting treatment with vandetanib will be offered to consenting patients aged 15 years or older 
who do not require sedation to undergo PET scans. The purpose of this research PET scan will be 
to evaluate the utility of FDG-PET to predict response early in the treatment of wt- GIST. 
3.1.2 TREATMENT LIMITING TOXICITY 
Although not a phase 1 study, toxicity will be evaluated and treatment limited by the toxicities 
defined below.  This study will utilize the CTEP Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 for toxicity and Adverse Event grading and reporting.  An adverse 
event must be judged to be possibly, probably, or definitely related to vandetanib to be a treatment 
limiting toxicity. Vandetanib will be held for treatment-limiting toxicities and re-started after 
resolution of toxicity at reduced dose as described in section 3.3. 
Treatment-limiting toxicity is defined as: 
• Hematologic Toxicity (H-T):  
o Neutrophil count below 1,000/µL (grade 3) on 2 consecutive measurements drawn at 
least 72 hours apart OR a single neutrophil count below 500/µL (grade 4). 
o Platelet count below 50,000/µL (grade 3) on 2 consecutive measurements drawn at 
least 72 hours apart OR a single platelet count below 25,000/µL (grade 4).  A platelet 
transfusion administered when platelet count is below 50,000/µL is treatment -limiting 
thrombocytopenia, unless the transfusion is being administered for peri-operative 
coverage. 
o Grade 3 or 4 decrease in hemoglobin that can be corrected to at least 8.0 g/dl (grade 2) 
by transfusion of red blood cells is not a treatment-limiting toxicity.  However, grade 
3 or 4 hemolysis is a treatment -limiting toxicity if it is judged to be vandetanib-related. 
o Grade 3 or 4 leucopenia or lymphopenia will not be considered treatment -limiting 
toxicities. 
• Non-Hematologic Toxicity (NH-T): NH-T is any grade 3 or higher non-hematologic 
toxicity, with the exception of:  
o Grade 3 nausea or vomiting that is controlled by symptomatic treatment with anti-
emetics (see Appendix 7 to avoid agents that can prolong the QTc) within 48 hours. 
o Any grade of diarrhea that is tumor-related (present at baseline and associated with 
elevated calcitonin levels) or grade 3 diarrhea that is related to vandetanib and is 
controlled by symptomatic treatment within 48 hours.  
o Grade 3 serum transaminase elevation (ALT/AST) that returns to grade 2 or less within 
14 days.  The drug may be held until the transaminase elevation subsides, but if the 
grade 3 transaminase elevation recurs when the drug is re-instituted, this will be 
considered treatment-limiting toxicity. 


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o Grade 3 electrolyte abnormalities that are asymptomatic and correctable to grade 2 or 
less within 48 hours. 
• Hypertension (HTN):   
o Pediatric Participants: 
For pediatric patients, the ULN for blood pressure is defined as a diastolic BP at the 
95th percentile from age and gender-appropriate normal values (see Appendix 2).  
Pediatric patients with a diastolic blood pressure >95% for age and gender should have 
blood pressure measurement repeated x2 with an appropriate size cuff, and 
hypertension (HTN) is defined as at least 2 (of 3) measurements exceeding the ULN 
(See Appendix 2 and Appendix 3).  Treatment-limiting hypertension is defined as: 
o A diastolic BP on at least 2 of 3 measurements that is more than 25 mm Hg 
above the ULN for age and gender. 
o A diastolic BP on at least 2 of 3 measurements that is above the ULN but not 
more than 25 mm Hg above the ULN and that does not return to within the 
normal range after 14 days on single agent antihypertensive therapy. 
o Grade ≥4 (CTCAE v.4) hypertension. 
o Adult Participants: 
Appendix 4 will be used for the grading of vandetanib-associated hypertension in 
adults, for immediate and intermediate-term management, and for the determination of 
vandetanib modification.  Hypertension in adult patients is defined as a systolic blood 
pressure > 150 mmHg or a diastolic pressure > 90 mm HG despite optimal medical 
management, for patients ≥18 years of age, and may include hypertension-related 
symptoms as reported by patient (e.g., headache), or other relevant changes associated 
with development of hypertension (e.g., ECG abnormalities) (See Appendix 4 and 
Appendix 5). 
Treatment-limiting hypertension is defined as: 
o A diastolic BP on at least 2 of 3 measurements that is more than 90 mm Hg or 
systolic BP that is more than 150 mm Hg, that does not return to within the 
normal range after 14 days despite maximum medical therapy. 
o Grade ≥4 (CTCAE v.4) hypertension. 
• QTc Prolongation:   
Any clinically significant abnormal findings or QTcB prolongations will be recorded as 
AEs. 
Participants with QTc prolongation should have serum electrolytes (including potassium, 
calcium and magnesium) measured.  If serum electrolytes are outside the normal range, the 
abnormality should be corrected before determining whether a patient has treatment -
limiting QTc prolongation.   
In addition to scheduled ECG, additional ECGs should also be performed in the event of 
QTcB prolongation, both during and post the prolongation period. 


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• 
During the QTcB prolongation period: For a single QTcB value of >500 ms, 
vandetanib must be withheld.  Electrocardiograms will be followed at least once per 
week (done at the same day each week) along with electrolytes, until QTcB falls ≤480 
ms.  Vandetanib treatment may be resumed at a permanently lower dose after the 
QTcB returns to ≤480 ms.  
Treatment-limiting QTc prolongation is defined as a single QTc value ≥500 msec. Post the 
QTcB prolongation period: If vandetanib (at the reduced dose) is restarted after the QTcB 
prolongation has resolved, ECGs and electrolytes (including potassium, calcium and 
magnesium) must be obtained at 3, 8, and 12 weeks following the start of the lower dose.  
Serum potassium levels should be maintained at 4 mEq/L or higher, and serum magnesium 
and serum calcium should be kept within normal range to reduce the risk of QT prolongation.  
ECG and electrolyte monitoring can then resume every 3 weeks at the normal visit schedule 
for the patient. 
If a patient is on 100 mg vandetanib dose and has QTcB >500 ms, vandetanib 100 mg may 
be given every other day. 
3.1.3 CRITERIA FOR STARTING SUBSEQUENT TREATMENT CYCLES 
Patients who complete a treatment cycle (28 days) may receive another cycle if: 
3.1.3.1 Disease Status: The patient does not have radiographic or clinical evidence of 
progressive disease (see section 6.3) for cycles prior to which the patient is re-staged, 
or in the opinion of the investigator the patient is benefiting from the therapy with 
vandetanib as evidenced by stable or decreased tumor-related symptoms such as pain, 
nausea or vomiting, or stable for cycles that are not proceeded by restaging. 
3.1.3.2 Toxicity: Patients who experienced treatment-limiting toxicity in the previous cycle 
should have the dose modified (see Section 3.3).  
3.1.3.3 Criteria for discontinuation of protocol treatment or off-study criteria (see Section 3.6) 
have not been met. 
There is no limit on the number of cycles that a patient may receive. 
Criteria for intra patient dose escalation after completion of cycles 1, 2, and 3 of vandetanib 
are provided in Section 3.1.1. 
3.2 
DRUG ADMINISTRATION 
Vandetanib (50 mg and 100 mg tablets) is administered orally, once daily continuously. A cycle 
of vandetanib is defined as 28 consecutive days starting with the first day of treatment (day 1).  
Patients 18 years or older at the time of enrollment on this study will receive a fixed initial dose of 
200 mg orally daily, which can be increased to 300 mg orally daily after 3 cycles, if tolerated 
(Section 3.1.1).  The dose of vandetanib in children and adolescents is determined from the 
patient’s body surface area using the dosing nomogram below.  The BSA should be recalculated 
at the time of restaging evaluations, and the dose should be adjusted if necessary based on the 
nomogram.  Treatment will be administered in an outpatient setting. 


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Dose 
Level 
(mg/m2) 
 
 
 
 
 
 
100 
BSA (m2) 
0.50-0.74 
0.75-1.24 
1.25-1.74 
≥ 1.75 
 
Dose(mg) 
50 
100 
150 
200 
 
150 
BSA (m2) 
0.50-0.83 
0.84-1.16 
1.17-1.49 
1.5-1.83 ≥1.84 
Dose mg) 
100 
150 
200 
250 
300 
 
Vandetanib is supplied as 50 and 100 mg tablets.  Vandetanib should be stored at room 
temperature in the original pack until use. 
Patients will receive their assigned dose of vandetanib once daily at the same time of the day (An 
every other day dosing schedule can be used to achieve lower dose levels in patients requiring a 
dose reduction, see Section 3.3).  Vandetanib absorption is not affected by a meal, so it need not 
be administered in the fasted state.   
The tablet should be swallowed whole or dissolved in water (see Section 11.1.5).  If a patient 
misses a scheduled dose of vandetanib and less than 12 hours have passed since the scheduled 
dosing time, the dose should be taken immediately.  If more than 12 hours have passed since the 
scheduled dosing time, the patient should not take the missed dose but should wait and take the 
next regularly scheduled dose. 
If the patient vomits within 30 minutes of taking vandetanib, then another dose can be 
administered.  The dose may only be repeated once.  If more than 30 minutes has passed from the 
time of oral dosing then no additional doses should be given. 
Patients or their guardians will keep a diary (Appendix 8) to document the intake of each dose, 
concomitant medications, and any toxicity.  The diary should be evaluated at each clinic visit.  
Self-Administered Study Drugs: Policy, procedures and forms are available on the CCR Intranet 
for internal monitoring for study drug compliance and accountability at the CCR Intranet site: 
http://home.ccr.cancer.gov/intra/clin_ops/policies/. 
3.3 
DOSE MODIFICATIONS 
3.3.1 GENERAL GUIDANCE 
Vandetanib should be held for any treatment-limiting toxicity (see Section 3.1.2).  For treatment 
limiting toxicities that include a duration in the definition, such as a neutrophil count below 
1,000/µL (grade 3) on 2 consecutive measurements drawn at least 72 hours, the drug will be held 
after the toxicity reaches the grade defined in treatment limiting (e.g., after the second ANC 
<1,000/µL). 
If vandetanib-related treatment-limiting toxicity resolves to grade ≤1 or baseline in ≤6 consecutive 
weeks of drug free period, vandetanib may be restarted at a reduced dose. 


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If the vandetanib-related treatment-limiting toxicity does not resolve to grade ≤1 or baseline in ≤ 
6 consecutive weeks of a drug free period the patient should discontinue protocol therapy and be 
monitored until the toxicity resolves. 
The cycle duration remains 28 consecutive days in patients who have dose interruptions.   
If a patient happens to miss 6 weeks of dosing for non-toxic events, if monitoring is initiated as 
described in Section 3.5.1, the patient may initiate re-dosing. 
Refer to Section 4 Concomitant Medications/Measures for management of specific toxicities. 
Refer to Section 3.1.1 for intra patient dose escalations. 
3.3.2 DOSE MODIFICATION RULES 
The NCI Principal Investigator should be consulted for all dose reductions.  Dose modifications 
will be conducted according to the following guide: 
• Patients who experience a treatment-limiting toxicity (Section 3.1.2) that is possibly, 
probably, or definitely related to vandetanib should have a dose reduction of their 
vandetanib dose after recovery from toxicity (to a CTCAE Grade 1 or baseline) (Section 
3.2 Drug Administration) following the table below for the remainder of the current course 
and for the subsequent cycles of treatment.   
Vandetanib starting dose 
(mg/dose) once daily 
Dose reduction (mg/dose) 
Dose reduction (%) 
50 
50 mg 5 times/week (e.g. 
Monday, Tuesday, Thursday, 
Friday, Sunday) 
29% 
100 
100 mg 5 times/week (e.g. 
Monday, Tuesday, Thursday, 
Friday, Sunday) 
29% 
150 
100 daily 
33% 
200 
200 mg 5 times/week (e.g. 
Monday, Tuesday, Thursday, 
Friday, Sunday) 
29% 
250 
200 mg 6 times/week 
(Monday, Tuesday, Wednesday, 
Thursday, Friday, Saturday) 
40% 
300 
200 daily 
33% 
 
• Patients who experience treatment-limiting toxicity after a dose reduction can have one 
additional dose reduction. All dose reductions should be approximately 30% of the 
administered dose. The protocol PI or lead AI should confirm the dose reduction.   


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• Patients who have a dose reduction for a non-life-threatening treatment-limiting toxicity 
(diarrhea, nausea, vomiting, constipation, anorexia, weight loss, fatigue or skin rash) and 
who tolerate ≥2 cycles at the reduced dose can have their dose re-escalated to the prior dose 
level.  The toxicity type that was previously treatment-limiting toxicity at the higher dose 
level must not have exceeded grade 1 at the reduced dose level in order to re-escalate the 
dose.   
3.3.3 DOSE MODIFICATION TO PROMOTE WOUND HEALING 
• Subjects who require elective surgery, vandetanib should be held for 2 weeks prior to the 
procedure and for 2 weeks after surgery.  The treatment should resume only after the 
surgeon has determined that the wound is healed.  Subjects should have restaging studies 
performed prior to restarting the treatment. 
• Subjects who require emergency surgery or who experience a significant injury, the 
vandetanib should be held for at least 2 weeks and only resumed when the wounds are 
judged to be healed.  If the vandetanib is held for 4 or more weeks, then restaging studies 
should be performed prior to restarting the treatment. 
3.4 
QUESTIONNAIRES 
As described in Section 1.2.3, the pediatric PROMIS instruments and the Distress Rating Tool 
will be administered to all consenting patients who speak English or Spanish with parallel Parent 
Proxy instruments administered to parents of patients ages 8-17.  These instruments will be 
administered at baseline, at the first re-staging visit (3 months) and at the time a patient is taken 
off treatment (See Appendix 12, Appendix 13, and Appendix 14).  Since the measures have not 
been validated in other languages, participation in this portion of the study will be limited to 
subjects who speak either English or Spanish.   
3.5 
STUDY CALENDAR 
See Appendix 9. 
Subjects will be monitored according to study requirements, including history and physical 
examinations, blood pressure monitoring, performance status, urinalysis and routine laboratory 
tests (blood counts and chemistries), as per Appendix 9.   
3.5.1 MONITORING DURING DRUG THERAPY 
3.5.1.1 Blood Pressure 
Blood pressure should be monitored and recorded prior to the first dose of vandetanib, and 
with physical exams during cycle 1.  In addition, blood pressure should be monitored and 
recorded cycle 1, day 14, prior to each cycle on cycles 2, 3, 4, then every 3 cycles (prior to 
cycle 7, 10, 13, etc).  See Appendix 2 for management of elevated diastolic BP. 
3.5.1.2 Physical Examination:  
A physical examination should be performed at Day 14 during cycle 1. Then prior to cycle 
2, 3 and 4; then every 3 cycles prior to cycle 7, 10, 13, etc.  


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3.5.1.3 Height, Weight, and BSA:  
Recorded prior to the first treatment and then on each restaging cycle (cycle 4, 7, 10, 13, 
and then every 6 cycles, i.e. prior to cycle 19, 25, 31, etc.).  
3.5.1.4 Performance Status:  
Record prior to the first treatment cycle and then on each restaging cycle (cycle 4, 7, 10, 
13, and then every 6 cycles, i.e. prior to cycle 19, 25, 31, etc.) (Appendix 1). 
3.5.1.5 Laboratory 
3.5.1.5.1 Hematology:  
Complete blood count, differential and platelet count on Day 14 (more frequent 
monitoring may be performed if the ANC <1,000/µL or platelet count <50,000/µL) for 
cycle 1, and then prior to cycle 2, cycle 3 and cycle 4; then every 3 cycles prior to cycle 
7, 10, 13, etc. 
3.5.1.5.2 Chemistries:  
On Day 14: BUN, creatinine, electrolytes (including (sodium, potassium, chloride, 
CO2),), LDH, AST, ALT, alkaline phosphatase, bilirubin (total and direct if total is 
elevated), calcium, magnesium, phosphorus, glucose, and uric acid during cycle 1, and 
then prior to cycle 2, 3, and 4.  Then every 3 cycles prior to cycle 7, 10, 13, etc.   
3.5.1.5.3 Thyroid Stimulating Hormone:  
Prior to cycle 2, 3 and 4; then every 3 cycles i.e. cycle 7, 10, 13, etc. If TSH is 
abnormal, T4 will be evaluated. 
3.5.1.5.4 Urinalysis:  
Prior to cycle 2, 3 and 4; then every 3 cycles i.e. cycle 7, 10, 13, etc. 
3.5.1.5.5 Serum/Urine Pregnancy Test:   
Prior to the first cycle in females with child bearing potential, and then prior to cycles 
4, 7, 10, 13, then every 6 cycles (19, 25, 31, etc). 
3.5.1.6 ECG with Calculation of QTc 
Prior to cycle 1, 2, 3 and 4; then every 3 cycles i.e. cycle 7, 10, 13, etc. See Section 4 for 
management of QTc prolongation.   
Use Bazett’s correction (QTcB = QT/RR0.5). 
3.5.1.7 A unilateral knee MRI: 
Will be performed in all patients with open growth plates on lower extremity scanogram 
(See Appendix 11).  Repeat knee MRIs will be performed every 3 cycles x 4 (prior to 
cycle 4, 7, 10, 13) and then every 6 cycles (prior to cycle 19, 25, 31, etc) until growth 
plates are fused. 
3.5.1.8 Patient Diary 
Patients will document daily reactions/symptoms and concomitant meds on the patient 
diary until cycle 13 (See Appendix 10).  The patient diary will be reviewed at each clinic 


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visit.  After cycle 13, patients will be asked to document their reactions/symptoms and 
concomitant medications on the log (See Appendix 10). 
3.5.2 RESPONSE EVALUATION 
Restaging studies (RECISTv1.1) with appropriate imaging studies and evaluation of disease-
related symptoms will be performed at NIH after every 3 cycles x 4 (prior to cycle 4, 7, 10, 13) 
and then every 6 cycles (prior to cycle 19, 25, 31, etc).  
• MRI of the abdomen/pelvis will be performed for restaging purposes. In the exceptional 
case of extraabdominal disease, the anatomical sites to be evaluated by MRI will be at 
discretion of the PI.   
• FDG-PET will be performed prior to cycle 4, and then as clinically indicated.  Patients ≥ 
15 years of age will be given the option to consent for an early research FDG-PET (on day 
3 to day 6) after initiation of therapy during cycle 1.  
• CT of the chest will be performed for restaging purposes and if clinically indicated. 
3.5.3 POST TREATMENT FOLLOW UP 
3.5.3.1 Off-Treatment Evaluation 
Patients who have been taken off treatment for any of the criteria in Section 3.6.1, will be 
monitored until resolution of toxicity, as clinically indicated, and efforts will be made to return to 
NIH at least once for Off-Treatment evaluation (at least 60 days after the last dose of vandetanib) 
for: 
• Physical Examination with vital signs 
• Laboratory Evaluation: CBC and differential, chemistry and liver function tests 
• Toxicity assessment  
Patients unable to return to NIH will be contacted by a member of the research team approximately 
60 days after the last dose of investigational drug for an evaluation of toxicity.  
Patients or the local medical provider will be contacted at least annually to obtain current status on 
patients who have completed the off treatment evaluation, until one of the off study criteria 
(Section 3.6.2) are met. 
3.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 60 days following the last dose of study therapy. 
3.6.1 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY 
Subjects will be removed from study therapy and followed until off-study criteria are met for any 
one of the following: 
• Unacceptable toxicity (treatment limiting toxicity after two dose reductions, or treatment-
limiting toxicity does not resolve to grade ≤1 or baseline in ≤ 6 weeks of a drug free period).  
Patients who are removed from therapy for unacceptable toxicity will continue to undergo 
disease evaluations as per Appendix 9 until they develop progressive disease.  


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• Concurrent use of agents that prolong the QTc:  Vandetanib use must be discontinued if 
one of the QTc prolonging agents in Group 1 of Appendix 7 is started. 
• Progressive disease; clinical or radiographic evidence of progressive disease will 
discontinue vandetanib (see Section 6.3).  If possible, tumor progression should be 
documented radiographically. 
• Participant requests to be withdrawn from active therapy 
• Positive pregnancy test 
• Investigator discretion, which may include 
o The development of a concurrent serious medical condition that might preclude or 
contraindicate the further administration of vandetanib. 
o It is deemed in the best interest of the patient, and the reasons for discontinuation of 
vandetanib should be noted in the patient's medical record.  
o Serious protocol violation, such as non-compliance, as determined by the Principal 
Investigator. 
• Death 
3.6.2 OFF-STUDY CRITERIA 
Subjects will be removed from study for any of the following criteria: 
• Patient or guardian withdrawal of consent.  Reasons must be noted on the patient's medical 
record. 
• Lost to follow up after three documented attempts to contact patient/family/local 
referring physician. 
• Death 
Note: Minors are to be retained on the study at least until they reach the age of majority if 
possible and can be consented for the future use of their specimens and data.  if you are enrolling 
minors, you need to leave them on study until they reach age 18 and can be consented for the 
future use of their specimens and data. If this consent is not obtained, samples and data may not 
be used in this study or future research unless the reason for removal is loss to follow up (for 
which a waiver has been requested in section 10.6.1) or death (as these samples would no longer 
fall under human subjects’ protections). 
Overall survival is an endpoint on this trial.  Patients will remain on this trial to be monitored for 
this endpoint. 
3.6.3 OFF PROTOCOL THERAPY AND OFF-STUDY PROCEDURE 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http:// http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov. 


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4 
CONCOMITANT MEDICATIONS/MEASURES 
At screening, all prior anti-cancer therapy and administration of all other concomitant medication 
in use on the day of enrollment (signature of the ICF) will be recorded.  All concomitant 
medications that the patient has been taking since the time of the last visit, medications the patient 
started between visits and all new medications will be recorded at each visit until the completion 
of the final analysis.  If a patient discontinues vandetanib before the final analysis, all medications 
including any medications started within the 60 days after the last dose of vandetanib, will be 
recorded at the appropriate discontinuation visit and the 60-day follow-up visit. 
4.1 
PROHIBITED MEDICATION 
Patients are not eligible to enter the study if they have taken any of the medication specified in 
the exclusion criteria 
4.1.1 TREATMENT FOR CANCER 
Prior to starting treatment (according to Section 2.1) and while the patient remains on study 
treatment, patients must not be given any concurrent cancer therapy, including cytotoxic agents, 
radiotherapy, biological response modifiers (including cytokines), hormonal therapy (used 
specifically for cancer treatment), or any other investigational agents. 
4.1.2 CYP3A4 INDUCER 
The administration of vandetanib with strong CYP3A4 inducers (those that induce ≥ 80% decrease 
in AUC) should be avoided (per Caprelsa package insert), including avasimibe, carbamazepine, 
phenytoin, rifampin, St. John’s wort. A potent CYP3A4 inhibitor has been shown to have little 
effects on the exposure to vandetanib and therefore, these agents can be co-administered with 
vandetanib when indicated. 
4.1.3 MEDICATIONS KNOWN TO PROLONG QT INTERVAL AND/OR INDUCE TORSADES DE POINTES 
Concomitant use of medications generally accepted as having a risk of causing Torsades de Pointes 
(see Appendix 7) are not allowed within the 2 weeks prior to starting treatment or during study 
(at least 4 weeks prior for levomethadyl).  These drugs should also be avoided for at least 4 weeks 
following discontinuation of study treatment. 
4.1.4 RESTRICTED MEDICATIONS 
All medications prohibited in this study as indicated in Appendix 7 must have been withdrawn at 
least 2 weeks prior to registration, and should be avoided for at least 4 weeks following 
discontinuation of study treatment. 
Co-administration of drugs that in some reports might be associated with Torsades de Pointes but 
at this time lack substantial evidence of Torsades de Pointes (see Appendix 7) should be avoided 
within the 2 weeks prior to registration, and during the study.  However, these drugs will be 
allowed, at the discretion of the Investigator, if considered absolutely necessary.  In such cases, 
the patient must be closely monitored including regular checks of QTcB and electrolytes.  The 
electrolytes should be maintained within the normal range using supplements if necessary. 
Warfarin is allowed in therapeutic and low-doses and these patients should be monitored regularly 
for changes in their International Normalized Ratio, at the discretion of the Investigator. 


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Appropriate clinical and/or laboratory monitoring is recommended for patients receiving 
concomitant metformin and vandetanib, and such patients may require a lower dose of metformin.  
Appropriate clinical and/or laboratory monitoring is recommended for patients receiving 
concomitant digoxin and vandetanib, and such patients may require a lower dose of digoxin. 
4.1.5 COMPLEMENTARY AND ALTERNATIVE THERAPIES 
All complementary or alternative therapies including herbal preparations, vitamins, and 
supplements should be discussed with the PI or an Associate Investigator.  All agents will be 
recorded on the electronic case report forms. 
4.2 
HTN MANAGEMENT ALGORITHM 
See Appendix 2 and Appendix 4 for monitoring and management of hypertension in children 
and adults. 
4.3 
MANAGEMENT OF QTC PROLONGATION 
See Section 3.1.2, Treatment Limiting Toxicity. 
4.4 
MANAGEMENT OF SKIN TOXICITY 
• Vandetanib must be held when any CTCAE grade 3 or 4 vandetanib-related skin toxicity 
occurs.  For grade 3 or 4 allergic skin reactions, vandetanib should be discontinued.  For 
non-allergic reactions, treatment may be resumed at a lower dose (Section 3.3) if the 
toxicity recovers to grade ≤1 or baseline within 14 days of discontinuing the drug. If the 
skin toxicity does not resolve to grade ≤1 or baseline in ≤14 days, vandetanib should be 
discontinued.  Rashes should be graded as soon as possible according to the CTCAE 
cutaneous toxicity criteria. 
• Agents that can be used to manage skin rashes include mild to moderate strength steroid 
creams, topical or systemic antibiotics, topical or systemic antihistamines, and occasionally 
retinoid creams.  If a patient develops a skin rash, the following actions are recommended 
for the management of this toxicity: 
• For a grade ≥2 vandetanib-related rash, immediate symptomatic treatment with topical 
creams or systemic anti-histamines should be provided. 
• For grade ≥3 vandetanib-related rash (non-allergic), vandetanib should be held until 
recovery to grade ≤1. After recovery, vandetanib may be restarted at a reduced dose 
(Section 3.3) after discussion with the protocol PI. If the rash does not resolve to grade ≤1 
in ≤14 days OR the rash is an allergic rash, vandetanib will be discontinued. 
• It is strongly recommended that all patients use sun-protective measures while receiving 
vandetanib and for 3-4 weeks after discontinuing vandetanib to reduce the risk of 
developing skin rash or minimize the severity of skin rash. 
4.5 
MANAGEMENT OF GASTROINTESTINAL TOXICITY 
Electrolytes should be closely monitored in the event of persistent vomiting or diarrhea. 
Vandetanib should be held in patients who develop electrolyte abnormalities from vomiting or 
diarrhea until the electrolyte abnormalities are corrected because of the risk of QTc prolongation 
and subsequent arrhythmias. 


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4.5.1 NAUSEA OR VOMITING 
Nausea, vomiting, or both may be controlled with antiemetic therapy. The use of somatostatin or 
a somatostatin analogue is allowed to control diarrhea.  There is a risk that the use of 5HT-3 
antagonists may prolong QTc interval; therefore, these agents are prohibited.  The dose of 
vandetanib may be repeated once if emesis occurs within 30 minutes of taking the dose.  
4.5.2 VANDETANIB-RELATED DIARRHEA 
Diarrhea that occurs after initiation of vandetanib is likely to be treatment-related and should be 
treated symptomatically to avoid dose modification or interruption.  Diarrhea due to vandetanib 
has been successfully managed in adults with anti-diarrheal agents such as loperamide. No dose 
modifications will be made for Grade 1 or 2 diarrhea, however, electrolyte supplementation with 
regular laboratory monitoring should be used when appropriate, to maintain electrolytes within 
normal limits and prevent an increased risk of QTc prolongation.  Any electrolyte imbalance must 
be promptly corrected since hypokalaemia and hypomagnesaemia are potential risk factors for 
drug-induced arrhythmia. 
If grade 3 diarrhea that cannot be controlled by symptomatic treatments within 48 h or grade 4 
diarrhea develops, or diarrhea worsens by one grade level (grade 3 to grade 4) while on vandetanib 
and is not alleviated by symptomatic treatment within 48 h, vandetanib should be held until 
diarrhea resolves to grade ≤1 or baseline.  Once the diarrhea resolves, vandetanib may restarted at 
a reduced dose (Section 3.3). Dose reduction should only occur if the investigator believes the 
diarrhea is related to vandetanib. 
 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
5.1.1 EVALUATION OF ARCHIVAL TUMOR TISSUE 
Archival tumor tissue will be evaluated for SDH expression in consenting patients if tissue is 
available.  Additional Immunohistochemistry (IHC) studies will be performed at the Laboratory 
of Pathology, CCR, NCI as they become available.  
5.1.2 TUMOR TISSUE (OPTIONAL) 
Patients who require surgery will be invited to participate in (prior to participation, patient must 
have consented to this optional analysis as contained in the informed consent document): 
5.1.3 ANALYSIS OF TUMOR TISSUE 
Patients who agree to allow tumor tissue for research study will have tissue evaluated for SDH 
expression; immunohistochemistry (IHC) performed at the Laboratory of Pathology, CCR, NCI.  
5.1.4 CELL LINE ESTABLISHMENT:  
Given the rare nature of tissue available from this patient population, attempts will be made to 
establish wt-GIST cell lines when surgery or biopsy during the trial are clinically indicated.  Gene 
expression arrays and eventually protein lysate arrays will be created with the aim to identify 
potential molecular targets for new therapy development.  Cell lines will also be used to perform 
in vitro testing of new agents.  Informed consent will be required for this purpose, and subjects 
will be given the option to decline having cell lines established from their samples. 


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Fresh tumor samples from consenting patients who require clinically indicated surgery or biopsy 
will be placed immediately into tissue culture medium and transported directly to the Molecular 
Oncology Section of the Pediatric Oncology Branch. 
Samples should be submitted to:  
Choh Yeung 
10 Center Drive 
Bldg 10 CRC, 1W3816 
Bethesda, MD 20892 
Phone: (301) 496-1259 
 
5.1.5 [18F]-FDG-PET/CT SCAN (OPTIONAL) 
Patients who are 15 years of age and older will be asked to participate in one additional [18F]-FDG 
PET/CT scan (optional) on day 3 to day 6 after starting treatment with vandetanib. The purpose of 
this research [18F]-FDG PET/CT scan will be to evaluate the utility of [18F]-FDG -PET/CT to 
predict response early in the treatment of wt- GIST. 
Patients will be required to have nothing by mouth at least 4 hours prior to the [18F]-FDG PET/CT 
scan.  They must arrive in the PET Department with IV access already in place.  [18F]-FDG will 
be administered over one minute IV in a dimly lit, quiet prep room.  The patient must then remain 
still in a quiet room with lights dimmed and refrain from talking.  Thirty minutes after the initial 
injection, the patient will be asked to empty their bladder.  Forty- to forty-five minutes post-
injection, scanning will begin.  Patients will be asked to void again at 90 minutes after [18F]-FDG 
injection and then at least every 3-4 hours for the remainder of the day.   
Patients will receive radiation from one optional [18F]-FDG PET/CT for research purposes on this 
protocol.  The [18F]-FDG PET/CT scan will entail the injection of 10mCi dose for all ages and 
body sizes.  In adults, the total additional radiation dose for research purposes will be 1.14 rem, 
and in children 15 years of age and older, the total additional radiation dose for research purposes 
will be 1.4 rem.  
5.2 
BLOOD DRAWING LIMITS FOR RESEARCH PURPOSES  
The amount of blood that may be drawn from adult patients and volunteers (i.e., those persons 18 
years of age or older) for research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is 
smaller, over any eight week period. The amount of blood to be drawn from volunteers and the 
frequency of collection shall be specified in the clinical research protocol, and exceptions to the 
10.5 mL/kg or 550 mL limitations shall be approved by the IRB.  
For pediatric patients, no more than 5 mL/kg may be drawn for research purposes in a single day, 
and no more than 9.5 mL/kg may be drawn over any eight-week period.  
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  Samples 
will not be sent outside NIH without IRB notification and an executed MTA. 
Blood and tissue collected during the course of this study will follow NIH guidelines for the 
research use of human samples and OHRP Issues to Consider in the Research Use of Stored Data 


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or Tissues.  All samples (blood or tissue) are documented in LabMatrix and tracked by distinct 
identification labels that include a unique subject identifier and date of specimen collection with 
computer backup according to established standards for the Central Repository for NCI-Frederick. 
All cryopreserved samples are tracked for freezer location and storage criteria. All samples are 
stored in monitored freezers/refrigerators either in the Central Repository for NCI-Frederick or in 
the investigator’s laboratory at specified temperatures with alarm systems in place.  The system 
will contain data that includes, but is not limited to the unique sample identifiers, storage locations 
and conditions, biologic study results, clinical information, and corresponding records of all 
derivatives generated from samples/tissues collected on this protocol.  The system will employ 
mechanisms for restricting users to viewing only the level of data appropriate for each individual 
user, will provide the capability to audit any data modification, and will be maintained and backed 
up according to established standards.  
At the termination of this protocol, if additional studies are to be performed on any human subject 
samples retaining patient identifiers or codes obtained during the conduct of this trial, a Request 
to Conduct Research for Stored Human Samples Specimens, or Data Collected in a Terminated 
NCI-IRB Protocol will be submitted. Otherwise, specimens will be disposed of in accordance with 
the environmental protection laws, regulations and guidelines of the Federal Government and the 
State of Maryland. Any new uses of human subject samples collected during the course of this trial 
must be reviewed and approved by the NCI IRB. Any loss or unintentional destruction of the 
samples will be reported to the IRB. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 


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• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
Clinical data will be shared with AstraZeneca. 
Questionnaire (PROMIS and Distress Thermometer) data will be entered into an SPSS (version 
12.0.1), SPSS, Chicago, IL) database by a research assistant.  Personal identifiers will not be used 
when collecting and storing data.  Questionnaire data will be linked with clinical data through the 
use of the unique subject identification number.  Files will be stored in password-protected folders 
and accessible only to the personnel in the POB NCI Psychosocial Support and Research Program. 
6.2 
DATA SHARING PLANS 
6.2.1 GENOMIC DATA SHARING PLAN 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, participants must have measurable disease as defined in RECIST 
(v1.1) as the presence of at least one lesion that can be accurately measured in at least one dimension 
with longest diameter of at least 20 mm using conventional techniques or at least 10 mm with spiral 
CT scan.  Patients should be re-evaluated for response every 3 cycles x 4 (prior to cycle 4, 7, 10, 
13) and then every 6 cycles.  In addition to a baseline scan, confirmatory scans should also be 
obtained at least 4 weeks following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (44) Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
6.3.1 DEFINITIONS 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with Vandetanib. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 


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6.3.2 DISEASE PARAMETERS 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).  The same criteria will be applied to 
measurements from MRI. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. The same criteria will be applied to measurements from MRI. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion, which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.3 METHODS FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 


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


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clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published (45-47).  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria, which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer(48). 
Cytology, Histology:  These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). In this study, we will explore the utility of 
FDG-PET in the management of patients with wt-GIST.  New lesions on the basis of FDG-PET 
imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.3.4 RESPONSE CRITERIA 
6.3.4.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 


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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. 
6.3.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
6.3.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 


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Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
6.3.5 DURATION OF RESPONSE 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
6.3.6 PROGRESSION-FREE SURVIVAL 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first. 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 ADVERSE EVENT 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event is 
considered related to the treatment or clinically significant.  


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• 
 
7.1.2 SUSPECTED ADVERSE REACTION 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 UNEXPECTED ADVERSE REACTION 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure, package insert, or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure or package insert as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation. 
7.1.4 SERIOUS  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 SERIOUS ADVERSE EVENT 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 DISABILITY 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 LIFE-THREATENING ADVERSE DRUG EXPERIENCE 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that had it occurred in a more severe form, might have caused death. 


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7.1.8 PROTOCOL DEVIATION (NIH DEFINITION) 
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9 NON-COMPLIANCE (NIH DEFINITION) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, 
IRB requirements, or regulatory requirements for the protection of human research subjects. 
7.1.10 UNANTICIPATED PROBLEM 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
All treatment-limiting toxicities (see Section 3.1.2) that are possibly, probably, or definitely related 
to vandetanib and all serious adverse drug experiences (see Section 7.1), including oncology 
related events that meet the criteria for a serious adverse drug experience, whether related to 
vandetanib or not, will be reported to Dr. Brigitte Widemann by telephone within 24 hours of being 
made aware of the event:  
Brigitte Widemann, M.D. 
Pharmacology & Experimental Therapeutics Section 
Pediatric Oncology Branch 
National Cancer Institute 
10-CRC, 1-5750, MSC 1101 
10 Center Drive 
Bethesda MD 20892 
Phone: 240-760-6203 
Pager: (301) 496-1211 
FAX: (301) 480-8871 
E-mail:  widemanb@mail.nih.gov 
7.2 
NCI-IRB AND CLINICAL DIRECTOR (CD) REPORTING 
7.2.1 NCI-IRB AND NCI CD EXPEDITED REPORTING OF UNANTICIPATED PROBLEMS AND 
DEATHS 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 


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• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NCI-IRB REQUIREMENTS FOR PI REPORTING AT CONTINUING REVIEW 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NCI-IRB REPORTING OF IND SAFETY REPORTS 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.3 
IND SPONSOR REPORTING CRITERIA  
During the first 30 days after the subject receives investigational agent/intervention, the 
investigator must immediately report to the sponsor, using the mandatory MedWatch form 3500a 
or equivalent, any serious adverse event, whether or not considered drug related, including those 
listed in the protocol or investigator brochure and must include an assessment of whether there is 
a reasonable possibility that the drug caused the event. For serious adverse events that occur 
more than 30 days after the last administration of investigational agent/intervention, only report 
those that have an attribution of at least possibly related to the agent/intervention. 
Required timing for reporting per the above guideline: 
• Deaths (except death due to progressive disease) must be reported via email within 24 
hours.  A complete report must be submitted within one business day.  
• Other serious adverse events as well as deaths due to progressive disease must be 
reported within one business day 
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov  
and to the CCR PI and study coordinator. 
7.3.1 REPORTING PREGNANCY 
7.3.1.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of 


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exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be 
documented in box B5 of the MedWatch form “Describe Event or Problem”. 
Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study 
risk intrauterine exposure of the fetus to agents which may be teratogenic, the CCR is requesting 
that pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, puerperium 
and perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
If any pregnancy occurs in the course of the study, then the investigator should inform the 
Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes 
aware of it. 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available. 
7.3.1.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months after the last dose of Vandetanib. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 3 months after the last 
dose should, if possible, be followed up and documented. 
7.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below. 
The study PI IND holder will notify AstraZeneca (SAE Fax line, 1-866-984-7229) in a written 
IND Safety Report (MedWatch, Form 3500A) of any adverse experience associated with the use 
of vandetanib that is both serious and unexpected at the time the MedWatch is reported to the 
FDA. 
The study PI IND holder will also notify AstraZeneca by telephone or by FAX (302-886-1528) 
of any unexpected fatal or life-threatening experience associated with the use of vandetanib as 
soon as possible but in no event later than 7 calendar days of initial receipt of the information (at 
the time the MedWatch is submitted to the FDA).   
A Fax cover page should accompany any MedWatch form that is sent to AstraZeneca indicating 
the following: 
• Vandetanib Investigator Sponsored Study (ISS) 


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• The investigator IND number assigned by the FDA 
• The investigator’s name and address 
• The trial name/title and AstraZeneca reference number 
The Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
Any event or hospitalization that is unequivocally due to progression of disease, as determined by 
the PI, will not be reported as an SAE, however should be communicated to AstraZeneca. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the 
investigational product.  All SAEs will be documented.   
7.5 
DATA AND SAFETY MONITORING PLAN 
Vandetanib has been approved by the US Food and Drug Administration (FDA) for treatment of 
advanced MTC and currently has a well-established toxicity profile.  Therefore, only unexpected 
≥ grade 2 adverse events at least possibly related to study drug or any ≥ grade 3 or adverse events 
observed in patients enrolled on the trial will be recorded by the Principal and Associate 
Investigators, and attribution of these events to vandetanib will be determined at the end of each 
treatment cycle in each subject.  
7.5.1 PRINCIPAL INVESTIGATOR/RESEARCH TEAM 
The clinical research team will meet on a regular basis when patients are being actively treated on 
the trial to discuss each patient.  Decisions about dose modification or discontinuation will be 
determined.  
All data will be collected in a timely manner and reviewed by the principal investigator or a 
designated associate investigator.  Adverse events will be reported as required above.  Any safety 
concerns, new information that might affect either the ethical and or scientific conduct of the trial, 
or protocol deviations and violations will be immediately reported to the IRB using iRIS and if 
applicable to the FDA and drug manufacturer.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy.  The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.5.2 SPONSOR MONITORING PLAN 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study data 
with source documentation focusing on: 
• 
Informed consent process 
• 
Eligibility confirmation 
• 
Drug administration and accountability 
• 
Adverse events monitoring 


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• 
Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
8 
STATISTICAL SECTION   
8.1 
PRIMARY ENDPOINT 
The study will be conducted as a small, optimal two-stage phase II trial(49), in order to rule out an 
unacceptably low 5% overall response rate (ORR; p0=0.05), in favor of a slightly higher response 
rate of 25% (p1=0.25).  With alpha=0.10 (probability of accepting a poor treatment=0.10) and beta 
= 0.10 (probability of rejecting a good treatment=0.10), the study will initially enroll 9 evaluable 
patients and if 0 of the 9 have a response, then no further patients will be accrued. If 1 or more the 
first 9 (11.1% or more) have a response, then accrual would continue until a total of 24 patients 
have enrolled. Only complete responses (CR) and partial responses (PR) will be counted towards 
the overall response rate.   As it may take several weeks to months to determine if a patient has 
experienced a response, a temporary pause in the accrual to the trial may be necessary to ensure 
that enrollment to the second stage is warranted. If there are 1 to 2 responses in 24 patients, this 
would be an uninterestingly low response rate, while if there were 3 or more responses in 24 
(12.5% or more) patients, then this would be sufficiently interesting to warrant further study in 
later trials. Under the null hypothesis (5% response rate), the probability of early termination is 
63%.  
8.2 
ANALYSIS OF SECONDARY ENDPOINTS 
Safety and Tolerability 
Patients will be carefully monitored for adverse events; which will be recorded in a daily patient 
diary and documented by the care providers.  These will be graded according to CTCAE version 
4.0. Information regarding type of adverse event, grade, attribution, temporal occurrence and 
frequency will be summarized using descriptive methods.  
Progression-Free Survival (PFS) and Overall Survival 
The progression free survival and overall survival for all patients enrolled on the trial will also be 
determined using Kaplan-Meier curves and reported along with their associated 95% two-sided 
confidence intervals at selected time points.  
 
Analysis of Exploratory Pharmacodynamic Endpoints  
A variety of biologic parameters will also be evaluated and the results reported as exploratory 
and hypothesis generating, without adjustment for multiple comparisons. 
Analysis of patients’ health-related quality of life (as measured by patient and parent report 
PROMIS measures) and patient-reported symptoms (as measured by the Distress and Symptom 
Checklist)  


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Patient’s PROMIS scores (patient and parent report for minors) will be converted to t-scores and 
recorded at each time point.  Assuming accrual of 24 patients, T-scores at baseline, first staging 
and study endpoint will be compared using repeated measures ANOVA to detect significant 
changes over time.  While the sample size will not permit controlling for gender, age group, or 
disease status, scores will be descriptively reported stratified by these variables.  Additionally, 
PROMIS scores that fall more than 1 standard deviation below the mean will be considered to 
reflect low QOL.  Patient reported symptoms on the Distress and Symptom Checklist will be 
evaluated using frequency distributions and will be descriptively followed over the course of 
treatment on this protocol.  These data will be reported as exploratory and hypothesis generating, 
without adjustment for multiple comparisons. 
8.3 
ACCRUAL TARGET AND STUDY DURATION 
A total of 24 evaluable patients may need to be enrolled to meet the primary objective of this study, 
if 1 or more of the first 9 patients has a response.  The actual accrual ceiling will be set at 27 to 
allow for the possibility of a small number of inevaluable patients (withdrawal prior to meeting 
progression or toxicity) being enrolled. It is anticipated that 1-2 patients per month may enroll on 
this trial for the first 6 months, and then approximately 6-8 patients per year thereafter. Thus, 2 to 
3 years is anticipated as the accrual period for this study. 
Please Note:  Nine patients and their parents were enrolled on the study before it was closed to 
accrual. The parents were not included in the initial accrual ceiling of 27; but they need to be 
accounted for. Because the study is no longer recruiting, it is not necessary to increase the accrual 
ceiling; the parents will be included in the 27. 
9 
COLLABORATIVE AGREEMENTS 
9.1 
AGREEMENT TYPE 
AstraZeneca has agreed to provide the drug (vandetanib) to patients participating in this clinical 
trial. The trial will be performed under a Clinical Trial Agreement (NCI CTA #00940-13) with 
AstraZeneca.  
10 HUMAN SUBJECTS PROTECTIONS  
10.1 RATIONALE FOR SUBJECT SELECTION 
Patients of both genders, from all racial and ethnic groups are eligible for this trial if they meet the 
eligibility criteria outlined in Section 2.1.  There is no clinical information that suggests differences 
in vandetanib metabolism or response among racial or ethnic groups or between the genders, 
indicating that results of the trial will be applicable to all groups.  This phase II trial of vandetanib 
will be conducted in children greater than two years of age and adults measurable wt-GIST which 
is considered a low prevalence disease.  Efforts will be made to extend the accrual to a 
representative group from this population, but with a rare disease and with a planned accrual of 24 
patients, a balance must be struck between completing the trial in a timely fashion on the one hand 
and the need to explore gender, racial, and ethnic aspects of clinical research on the other.  If 
differences in outcome that correlate to gender, racial, or ethnic identity are noted, accrual may be 
expanded or additional studies may be performed to investigate those differences more fully.   


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10.2 PARTICIPATION OF CHILDREN 
This trial is designed to determine the response rate of wt-GIST to vandetanib in children and 
adults.  There is currently no experience with vandetanib in wt-GIST, so the tolerability of 
vandetanib and the toxicity are also being studied.  The safety of vandetanib dosing in children has 
been established in NCI protocol 07-C-0189.  Children and adolescents will be enrolled onto this 
research trial, which will be conducted by pediatric oncologists who have extensive experience in 
performing investigational drug trials in children.  Patients enrolled at the POB, NCI will be cared 
for in the POB outpatient clinic or day hospital. When patients require hospital admission, they 
will be cared for on the 1NW Pediatric Unit by the POB staff or on the adult inpatient unit by the 
MOB staff. 
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.5), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MAS Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
10.4.1 RISKS OF VANDETANIB 
The primary risk to patients participating in this research study is from toxicity of vandetanib.  In 
adults, vandetanib has been relatively well tolerated.  The most common adverse events have been 
rash, diarrhea and asymptomatic QTc prolongation, which are reversible and generally can be 
alleviated by dose reduction.  In the ongoing NCI protocol 07-C-0189 the most common toxicities 
in children have been diarrhea, rash, and TSH elevation.  The response rate in subjects with wt-
GIST is unknown, but vandetanib has show clinical activity in MTC.  A complete summary of 
Vandetanib risks is contained in Section 11.1.6. 
10.4.2 RISK OF FDG-PET (OPTIONAL) 
The additional risks of one optional FDG-PET are expected to be minimal and are related to the 
risks of the F-18 FDG tracer agent injection, which include rare cases of transient hypotension, 
hyper- or hypoglycemia and transient increases in alkaline phosphatase.  Pregnant or breast-
feeding women will not be allowed to participate in this study and should not be exposed to 
FDG18 contrast agent injection as the effects on a fetus or growing child are not known.  This 
optional scan will be limited to consenting participants who do not require sedation to lie still for 
the duration of the scan. 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
10.5 RISKS/BENEFITS ANALYSIS 
Current data demonstrates that GIST is resistant to cytotoxic chemotherapy and radiation therapy 
and while imatinib mesylate has become the mainstay of GIST therapy in adults with GIST who 
have KIT and PDGFRA mutations, 85 % of GISTs occurring in pediatric patients lack KIT and 
PDGFRA mutations, wild-type (wt) GIST, and therefore known therapies are not as effective.  The 
emerging biology of wt-GIST has demonstrated decreased or absent SDH protein expression in 
this patient population, and Vandetanib may have activity in this subpopulation of patients with 
GIST.  Therefore, this phase II protocol involves greater than minimal risk to children, but presents 
the prospect for direct benefit to individual child-subjects (Category 2). 
The biopsies being performed to obtain tumor samples will only be performed if there is clinical 
indication for the biopsy or surgical procedure.  Patients will be asked to provide consent for use 
of tissue for research purposes when a clinically indicated biopsy or surgical procedure is 
scheduled as it will potentially provide valuable data regarding the gene expression in wt-GIST 
and changes in response to vandetanib.  In addition, establishment of pediatric wt-GIST cell lines 
will be invaluable in allowing future research into the diagnosis, pathophysiology and treatment 
avenues of this uncommon disease entity. 
10.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The treatment consent for this study will explain the investigational nature and research objectives 
of this trial, the procedures and treatment involved and the attendant risks and discomforts and 
benefits, and potential alternative therapies.  These issues will also be carefully explained to the 
patient's parents or guardian (or the patient if he/she is 18 years old), and a signature will be 
obtained on the informed consent document prior to entry onto the study. Where deemed 
appropriate by the clinician and the child's parents or guardian, the child will also be included in 
all discussions about the trial and verbal assent will be obtained for participation in the treatment 
portion of the trial.  The parent or guardian will sign the designated line on the informed consent 
attesting to the fact that the child has given verbal assent.  Senior investigators from the CCR will 
lead this discussion.   
The investigators are requesting a waiver from the IRB to allow only one parent to sign the 
treatment informed consent form to enter a child on the protocol.  Because many patients must 
travel to the NIH from long distances at substantial expense, requiring both parents to be present 
for the consent process could be a financial hardship for many families.  The parent who signs the 
consent for a minor must be a legally recognized parent or guardian.  When guardianship status of 
the child is uncertain, documentation of custody status must be obtained. 
In situations where there is joint custody of a child, both parents must sign consent. If only one 
parent can be present at NIH, the other parent’s consent can be obtained by telephone via the 
procedure described in section 10.6.2.   
10.6.1 CONSENT  FOR MINORS WHEN THEY REACH THE AGE OF MAJORITY 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require consenting of the now 
adult with the standard protocol consent document to ensure legally effective informed consent 
has been obtained. We request waiver of informed consent for those individuals who have been 
lost to follow up during their participation in the research study. 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to 
subjects. 
(2) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects. 
a. Retention of these samples or data does not affect the welfare of subjects.  
(3) The research could not practicably be carried out without the waiver or alteration. 
a. Considering the length of time between a minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again.  A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research.  
(4) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We only plan to request a waiver of consent for those subjects who have been 
lost to follow-up or who, prior to the approval of Amendment F, have been 
taken off study prior to reaching the age of majority. 
10.6.2 TELEPHONE RE-CONSENT 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained  via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record. 
11 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION   
11.1 VANDETANIB (IND #77570) 
11.1.1 DESCRIPTION 
Other Names:  ZD6474, vandetanib, CAPRELSA® 
Chemical Structure:  N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(l-methylpiperidin-4-
yl)methoxy]quinazolin-4-amine 
Molecular Formula:  C22H24BrFN4O2 
Molecular Weight:  475.36 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
11.1.2 SOURCE:  
Vandetanib will be supplied by the manufacturer AstraZeneca and will be administered under an 
investigator held IND (BB-IND 77570). 
AstraZeneca Pharmaceuticals Investigational Products will pack, label, and supply the 
investigational product (IP) for this study.  Tablets will be packed into white high-density 
polythene (HDPE) bottles with child resistant, tamper evident closures.  Study drug must be kept 
out of the reach of children.  Each bottle will contain 100 tablets.  Patients will be supplied with 
sufficient amounts of tablets at each dispensing visit plus overage. 
Investigational product 
Dosage form and strength 
Manufacturer 
Vandetanib (unblinded) 
Tablet; 50 mg 
AstraZeneca Pharmaceuticals 
Vandetanib (unblinded) 
Tablet; 100 mg 
AstraZeneca Pharmaceuticals 
11.1.3 FORMULATION AND PREPARATION:  
The 50 and 100 mg tablets contain vandetanib, calcium hydrogen phosphate, microcrystalline 
cellulose, crospovidone, povidone, and magnesium stearate with a film coating containing 
methylhydroxypropylcellulose, polyethylene glycol 300 and titanium dioxide. 
11.1.4 STABILITY AND STORAGE:  
The tablets and bottles should be stored at room temperature in the original pack until use. 
Documentation indicating Vandetanib was destroyed will be sent to AstraZeneca. 
11.1.5 ADMINISTRATION PROCEDURES:  
Vandetanib is administered orally, once daily continuously.  A cycle of vandetanib is defined as 
28 consecutive days starting with the first day of treatment (day 1).  The dose of vandetanib for 
children less than 18 years old is determined from the patient’s body surface area using the dosing 
nomogram (Section 3.2). Treatment will be administered in an outpatient setting.   
Vandetanib tablets must be taken whole or dispersed in water, without crushing.  If tablets cannot 
be taken whole, the tablets can be dispersed in a glass containing 60 mL of non-carbonated water 
and stirred for approximately 10 minutes until the tablets are dispersed (will not completely 
dissolve).  No other liquids should be used.  The mixture should be swallowed immediately.  To 
ensure the full dose is received, the patient should refill the glass with an additional half glass of 
water and mix with any remaining drug and drink it. 
There are no food restrictions for the administration of vandetanib tablets.  Vandetanib tablets 
should be taken in the morning at about the same time each day with a glass of water. 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
11.1.6 TOXICITIES 
Adverse events (>0.1%) by system organ class and preferred term in vandetanib 
emerging safety profile (As described in Investigator’s Brochure, Vandetanib, 
17 October 2012) 
Event by system organ class 
Percentage of patients from patients 
receiving vandetanib 300 mg 
monotherapy (N=1846) 
Cardiovascular 
N (%) 
ECG QT prolongation 
139(7.5) 
Myocardial infarction 
12 (0.7) 
Angina pectoris 
11 (0.6) 
Cardiac Failure 
7 (0.4) 
Ventricular tachycardia 
2 (0.1) 
Torsade de pointes 
1 (0.1) 
Nervous System 
 
Headache 
236 (12.8) 
Dysgeusia 
62 (3.4) 
Cerebrovascular accident 
6 (0.3) 
Gastrointestinal 
 
Diarrhea 
946 (51.2) 
Nausea 
489 (26.5) 
Vomiting 
264 (14.3) 
Constipation 
235 (12.7) 
Abdominal pain 
127 (6.9) 
Abdominal pain upper 
104 (5.6) 
Stomatitis 
94 (5.1) 
Dry mouth 
88 (4.8) 
Pancreatitis 
5 (0.3) 
Endocrine disorders 
 
Hypothyroidism 
25 (1.4) 
Blood and lymphatic system  
 
Thrombocytopenia 
16 (0.9) 
Ecchymosis 
2 (0.1) 
Investigations 
 
Weight loss 
149 (8.1) 
Elevated liver function tests 
36-45 (2.0 – 2.4) 
Hemoglobin increased 
6 (0.3) 
Metabolic and nutritional disorders 
 
Decreased appetite 
265 (14.4) 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Event by system organ class 
Percentage of patients from patients 
receiving vandetanib 300 mg 
monotherapy (N=1846) 
Anorexia 
185 (10.0) 
Hypokalemia 
90 (4.9) 
Hypocalcemia 
75 (4.1) 
Dehydration 
54 (2.9) 
Hypomagnesemia 
25 (1.4) 
Hypophosphatemia 
4 (0.2) 
Skin and subcutaneous tissues 
 
Rash 
672 (36.4) 
Dry skin 
194 (10.5) 
Pruritis 
167 (9.0) 
Acne 
159 (8.6) 
Photosensitivity reaction 
98 (5.3) 
Alopecia 
71 (3.8) 
Nail disorder 
25 (1.4) 
Palmar-plantar erythrodysaesthesia 
syndrome 
20 (1.1) 
Erythema multiforme 
8 (0.4) 
Stevens-Johnson syndrome 
6 (0.3) 
Renal and urinary disorders 
 
Proteinuria 
132 (7.2)  
Hematuria 
29 (1.6) 
Nephrolithiasis 
24 (1.3) 
Respiratory 
 
Epistaxis 
81 (4.4) 
Interstitial lung disease (including 
pneumonitis)§ 
6 (0.3) 
Eye disorders 
 
Vision blurred 
56 (3.0) 
Conjunctivitis 
36 (2.0) 
Dry eye 
34 (1.8) 
Corneal opacity 
16 (0.9) 
Visual impairment 
13 (0.7) 
Vascular 
 
Hypertension 
413 (22.4) 
Hypertensive crisis 
7 (0.4) 
Peripheral ischemia 
2 (0.1) 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Event by system organ class 
Percentage of patients from patients 
receiving vandetanib 300 mg 
monotherapy (N=1846) 
Psychiatric disorders 
 
Insomnia 
213 (11.5) 
Depression 
86 (4.7) 
Anxiety 
82 (4.4) 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
12 APPENDIX 1: PERFORMANCE STATUS SCALES/SCORES 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
Karnofsky 
Lansky 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically 
strenuous activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time 
spent in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of 
the day; no active play, able to 
participate in all quiet play and 
activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet 
play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
Patients >10 years old: use Karnofsky performance criteria 
Patients ≤ 10 years old: use Lansky performance criteria 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
  
13 APPENDIX 2: NORMAL BLOOD PRESSURE RANGE FOR CHILDREN 
Diastolic blood pressure levels for BOYS aged 1-18 years   
 
1 
2 
3 
4 
Age 
(years) 
ULN* DBP 
mmHg 
DBP ≤10 
mmHg 
above ULN 
10<DBP ≤25 
mmHg above 
ULN 
DBP>25 
mmHg 
above ULN 
1 
58 
59-68 
69-83 
84 
2 
62 
63-72 
73-87 
88 
3 
66 
67-76 
77-91 
92 
4 
69 
70-79 
80-94 
95 
5 
71 
72-81 
82-96 
97 
6 
73 
74-83 
84-98 
99 
7 
74 
75-84 
85-99 
100 
8 
75 
76-85 
86-100 
101 
9 
77 
78-87 
88-102 
103 
10 
78 
79-88 
89-103 
104 
11 
79 
80-89 
90-104 
105 
12 
80 
81-90 
91-105 
106 
13 
82 
83-92 
93-107 
108 
14 
83 
84-93 
94-108 
109 
15 
83 
84-93 
94108 
109 
16 
84 
85-94 
95-109 
110 
17 
84 
85-94 
95-109 
110 
18 
84 
85-94 
95-109 
110 
* ≤95th percentile for age and 50% height percentile 
Diastolic blood pressure levels for GIRLS aged 1-18 years  
 
1 
2 
3 
4 
Age 
(years) 
ULN* DBP 
mmHg  
DBP ≤10 
mmHg above 
ULN 
10<DBP ≤25 
mmHg above 
ULN 
DBP>25 
mmHg 
above ULN 
1 
57 
58-67 
68-82 
83 
2 
61 
62-71 
72-86 
87 
3 
65 
66-75 
76-90 
91 
4 
68 
69-78 
79-93 
94 
5 
71 
72-81 
82-96 
97 
6 
74 
75-84 
85-99 
100 
7 
76 
77-86 
87-101 
102 
8 
77 
78-87 
88-102 
103 
9 
79 
80-89 
90-104 
105 
10 
80 
81-90 
91-105 
106 
11 
80 
81-90 
91-105 
106 
12 
81 
82-91 
92-106 
107 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
13 
82 
83-92 
93-107 
108 
14 
82 
83-92 
93-107 
108 
15 
83 
84-93 
94-108 
109 
16 
85 
86-95 
96-110 
111 
17 
87 
88-97 
98-112 
113 
18 
87 
88-97 
98-112 
113 
* ≤95th percentile for age and 50% height percentile 
These Charts list DBP levels within the ULN (1), within 10 mmHg above the ULN (2), 
within 11-25 mmHg above the ULN (3), and >25 mmHg above the ULN (4).  
Instructions for using this BP Chart: 
1. Measure the patient’s blood pressure using an appropriate size cuff. 
2. Select appropriate chart for a female or male patient. 
3. Using the “age” row determine if the DBP is within the ULN (1) or elevated (2, 3, 4).  
4. See Section 3.1.2 for definition of dose limiting hypertension. 
5. See Appendix 2 for management of vandetanib related hypertension. 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
14 APPENDIX 3: BLOOD PRESSURE MONITORING ALGORITHM IN CHILDREN 
 
 
 
• Refer to Appendix 2 for age and gender normal blood pressure ranges in children and 
adolescents. 
Directions for Algorithm: 
• Arm 1 of algorithm: If diastolic blood pressure ≤95% for age and gender, continue 
vandetanib at the same dose or dose escalate (Section 3.1.2)  
• Arm 2 of algorithm:  If diastolic blood pressure ≤10 mm Hg above the ULN for age and 
gender, continue vandetanib at the same dose and recheck the DBP within 72 h. 
o If the DBP is ≤95% for age and gender on recheck, continue vandetanib at the same 
dose or dose escalate (Section 3.1.2). 
o If the DBP remains above the ULN for age and gender on recheck, then start 
antihypertensive therapy (Section 3.1.2) and follow Arm 3 of the algorithm 
from the point that anti-hypertensive therapy is started. 
• Arm 3 of algorithm: If diastolic blood pressure is 11 to 25 mm Hg above the 95% for 
age on ≥2 of 3 measurements, start single agent anti-hypertension therapy (see Section 
3.1.2), continue vandetanib at the same dose, and monitor blood pressure at least every 3 
days. 
o If the diastolic blood pressure drops to ≤95% for age within 14 days, continue 
vandetanib at the same dose and continue concurrent single agent anti-hypertensive 
therapy. 
Monitor DBP 
(Appendix 2)
DBP   >25 mm Hg
above ULN ¤ for age
or Grade 4 HTN*
10< DBP   ² 25 mm Hg
above ULN ¤ for age
Continue
Vandetanib at
same dose
Restart
Vandetanib at
reduced dose
(Section 3.3.1)
Discontinue
Vandetanib
(Section 3.8)
DBP ² ULN for
age within 14d
off anti-HTN
DBP >ULN for
age for >14d
Hold
Vandetanib
Continue
Vandetanib at
same dose or
dose escalate
(Section 3.1.2)
DBP   ² ULN¤
forÊage
DBP ² ULN for
age within 14d
DBP >25 mm Hg
above ULN for
age*
DBP ² 25 mm Hg
above ULN for
age for >14d*
Start anti-HTN therapy
(Section 4.1.2)
  Elevated diastolic blood pressure (DBP) measurements should be repeated x 2 to confirm the elevation
¤  ULN (Upper Limit of Normal) is a diastolic BP at the 95
th percentile from age and gender-appropriate normal values (Appendix 2)
* If DBP >25 mm Hg above ULN for age (verified) or grade 4 HTN at any time, hold 
Vandetanib.  Antihypertensive agents can be used to control hy pertension as
clinically indicated after Vandetanib is held.
Hold Vandetanib ;
continue anti-HTN
until DBP <10 mm
Hg above ULN for
age x 2
DBP   ² 10 mm Hg
above ULN ¤ for age
Continue Vandetanib
at same dose; recheck
BP within 72 h
DBP ² ULN
for age on
recheck
DBP   >ULN¤
on recheck
Grade 4 HTN*
1
2
3
4


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
o If the diastolic blood pressure remains elevated ≤25 mm Hg above the 95% for age 
for more than 14 days after the institution of single agent anti-hypertensive therapy, 
hold vandetanib, monitor blood pressure at least every 3 days, and follow Arm 4 of 
the algorithm from the point that vandetanib is held.  The antihypertensive therapy 
should be continued until the DBP <10 mm Hg above the ULN for age and gender.   
▪ If the diastolic blood pressure drops to ≤95% for age within 14 days and the 
antihypertensive therapy can be discontinued, restart vandetanib at a reduced dose 
(Section 3.3.1). 
▪ If the diastolic blood pressure remains >95% for age for more than 14 days, 
discontinue vandetanib (Section 3.6). 
o If the diastolic blood pressure increases to >25 mm Hg above the 95% for age despite 
anti-hypertensive therapy or the participant develops grade 4 hypertension (CTCAE 
v.4), hold vandetanib, but continue the anti-hypertensive agent until the diastolic 
blood pressure is <10 mm Hg above the 95% for age on 2 measurements at least 3 
days apart.  Monitor the blood pressure at least every 3 days and follow Arm 4 of the 
algorithm from the point that vandetanib is held. 
▪ If the diastolic blood pressure is ≤95% for age within 14 days off of anti-
hypertensive therapy, restart vandetanib at a reduced dose (Section 3.3.1). 
▪ If the diastolic blood pressure is >95% for age for more than 14 days, discontinue 
vandetanib (Section 3.6) 
• Arm 4 of algorithm: If diastolic blood pressure is >25 mm Hg above the 95% for age or 
the participant develops grade 4 hypertension (CTCAE v.3), hold vandetanib and monitor 
blood pressure at least every 3 days.  Anti-hypertensive therapy can be used until the 
diastolic blood pressure is <10 mm Hg above the 95% for age on 2 measurements at least 
3 days apart. 
o If the diastolic blood pressure drops to ≤95% for age within 14 days off of anti-
hypertensive therapy, restart vandetanib at a reduced dose (Section 3.3.1). 
o If the diastolic blood pressure is >95% for age for >14 days, discontinue vandetanib 
(Section 3.6) 
• The cycle duration remains 28 consecutive days in patients who have dose interruptions. 
Single Agent Anti-Hypertensive Therapy 
Based on the clinical situation, the recommended agents may be substituted with alternatives at 
the discretion of the investigator. 
• Participants with a persistently (>72 h) elevated DBP that is ≤10 mm Hg above the 95% 
for gender and age (ULN, Appendix 2) or with ≥2 of 3 DBP measurements on a single 
day that are 11-25 mm Hg above the ULN should be started on appropriate anti-
hypertensive therapy.  
• Blood pressure should be monitored 4 hours after the first dose (day 1), 24 hours after the 
first dose, and then every 48 hours until the DBP is ≤ULN x 2 measurements. 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
• If the DBP remains elevated at ≤25 mm Hg above the ULN after 14 days of optimal anti-
hypertensive therapy, then the vandetanib should be held (see Section 3.3). 
• If the DBP increases to >25 mm Hg above the ULN on ≥2 of 3 measurements at any time 
during treatment or the participant develops grade 4 hypertension at any time, then the 
vandetanib should be held. Antihypertensive therapy should be continued until the DBP 
is <10 mm Hg above the 95% for age and gender on 2 measurements at least 3 days apart 
(see Section 3.3). 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
15 APPENDIX 4: BLOOD PRESSURE COLLECTION AND MANAGEMENT IN 
ADULT PATIENTS 
General Guidelines 
Frequency of monitoring:  Blood pressure (BP) should be monitored on day 14 and then prior to 
cycle 2, 3, and 4 and then every 3 cycles, prior to cycle 7, 10, 13, etc.  Patients with significant 
elevation in blood pressure requiring medications will evaluate BP more frequently as clinically 
indicated.  If blood pressure elevation occurs requiring drug therapy, the frequency of monitoring 
blood pressure after cycle 2 will be determined by the study doctors and the patient instructed 
appropriately. 
Data recording: All required data should be recorded in the appropriate eCRF or on the patient’s 
diary, as appropriate.  The following data are required at baseline and at each subsequent 
assessment: 
• Assessment date and time 
• Pulse 
• Systolic and diastolic BP  
Risk factors for hypertension (assess and record data in eCRF) 
• Diabetes (type 1 or type 2) 
• Renal disease (specify on CRF) 
• Endocrine condition associated with HTN (specify on CRF) 
• Use of steroids or NSAIDs (specify all concomitant meds) 
• Underlying cardiovascular condition – specify (i.e., ischemic heart disease) 
Baseline data collection (at registration) 
All patients: 
• Current BP 
• Proteinuria, if present 
Patients with preexisting hypertension (i.e., those for whom “hypertension” is entered as a 
concomitant condition at registration, or those who are currently receiving therapy with 
antihypertensive medication) – also record: 
• Date of HTN diagnosis (original) 
• Type HTN (essential or secondary) 
• CTCAE v4.0 grade of HTN (at time of study entry) 
• Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following: 
- Antihypertensive agents taken at study entry 
- Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of 
efficacy) 
Follow up BP data collection (while on study) 
All patients (at each clinic visit): 
• Current BP 
• Proteinuria, if present 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Patients with treatment-emergent hypertension [defined as BP >150/90 for patients ≥18 years 
of age] – record at time of hypertension diagnosis and at all subsequent visits: 
• BP changes from baseline (or from previous assessment) (specify grade changes) 
• Hypertension-related symptoms as reported by patient (e.g., headache) 
• Other relevant changes associated with development of hypertension (e.g., ECG 
abnormalities) 
• Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently 
prescribed antihypertensive agents 
Patients with preexisting hypertension at study entry – record at each visit: 
• BP changes from previous clinic visit (specify grade changes) 
• Hypertension-related symptoms reported by patient (e.g., headache) 
• Other relevant changes associated with development of hypertension (e.g., ECG 
abnormalities) 
• Changes in antihypertensive medications since last assessment (e.g., dose change, 
add/discontinue drug) 
Management of Hypertension in Adults 
BP measurements - 
systolic/diastolic 
 
Interval 
 
Treatment/Dose Modification 
Patients not receiving maximal antihypertensive therapy: 
> 150 mmHg (systolic) 
OR 
> 100 mmHg (diastolic) 
 
2 BP readings at 
least 1 hour apart 
• Add new or additional antihypertensive meds or 
increase dose of existing meds 
 
• Maintain dose of vandetanib 
> 200 mmHg (systolic) 
OR 
> 110 mmHg (diastolic) 
2 BP readings 
during a 1-week 
period 
• Hold vandetanib 
 
• Monitor patient closely for hypotension (if on 
antihypertensive meds) until vandetanib is restarted. 
 
• Resume treatment when BP falls to <150/100 
Patients receiving maximal antihypertensive therapy*: 
> 160 mmHg (systolic) 
OR 
> 105 mmHg (diastolic) 
2 BP readings at 
least 1 hour apart 
• Hold vandetanib 
 
• Maintain antihypertensive meds and monitor patient 
closely for hypotension until vandetanib is restarted. 
 
• Resume treatment at one lower dose level when BP 
falls to <150/100 
* 
Maximal antihypertensive therapy is defined as four antihypertensive medications given for 2 weeks. 
Notes: 
• While patients are receiving treatment with vandetanib, 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 vandetanib dose during treatment must be based on BP 
readings taken in the clinic by a medical professional. 
*Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha 
blockers, beta blockers, diuretics, angiotensin II receptor antagonists. 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
16 APPENDIX 5: ADULT ANTIHYPERTENSIVE MEDICATION LIST 
 
Dihydropyridine calcium-channel blockers (DHP CCB) 
Agent 
Initial dose 
Intermediate dose Maximum dose 
Hepatic metabolism 
Nifedipine 
XL 
30 mg po qd 
60 mg po qd 
90 mg po qd 
CYP 3A4 substrate 
Amlopidine 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
CYP 3A4 substrate 
Felodipine 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
CYP 3A4 substrate + 
inhibitor 
Selective β blockers (BB) 
Agent 
Initial dose 
Intermediate dose Maximum dose 
Hepatic metabolism 
Metoprolol 
25 mg po bid 
50 mg po bid 
100 mg po bid 
CYP 2D6 substrate 
Atenolol 
25 mg po qd 
50 mg po qd 
100 mg po qd 
No 
Acebutolol 
100 mg po bid 
200-300 mg po 
bid 
400 mg po bid 
Yes (CYP450 
unknown) 
Bisoprolol 
2.5 mg po qd 
5-10 mg po bid 
20 mg po qd 
Yes (CYP450 
unknown) 
Angiotensin Converting Enzyme Inhibitors (ACEIs) 
Agent 
Initial dose 
Intermediate dose Maximum dose 
Hepatic metabolism 
Captopril 
12.5 mg po tid 
25 mg po tid 
50 mg po tid 
CYP 2D6 substrate 
Enalapril 
5 mg po qd 
10-20 mg po qd 
40 mg po qd 
CYP 3A4 substrate 
Ramipril 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
Yes (CYP450 
unknown) 
Lisinopril 
5 mg po qd 
10-20 mg po qd 
40 mg po qd 
No 
Fosinopril 
10 mg po qd 
20 mg po qd 
40 mg po qd 
Yes (CYP450 
unknown) 
Rarely used: 
 
 
 
 
Perindopril 
4 mg po qd 
none 
8 mg po qd 
Yes but not CYP450 
Quinapril 
10 mg po qd 
20 mg po qd 
40 mg po qd 
No 
Angiotensin II Receptor Blockers (ARBs) 
Agent 
Initial dose 
Intermediate dose Maximum dose 
Hepatic metabolism 
Losartan 
25 mg po qd 
50 mg po qd 
100 mg po qd 
CYP 3A4 substrate 
Candesartan 
4 mg po qd 
8-16 mg po qd 
32 mg po qd 
CYP 2C9 substrate 
Irbesartan 
75 mg po qd 
150 mg po qd 
300 mg po qd 
CYP 2C9 substrate 
Telmisartan 
40 mg po qd 
none 
80 mg po qd 
Yes but not CYP450 
Valsartan 
80 mg po qd 
none 
160 mg po qd 
Yes but not CYP450 
α and β blocker 
Agent 
Initial dose 
Intermediate dose Maximum dose 
Hepatic metabolism 
Labetolol 
100 mg po bid 
200 mg po bid 
400 mg po bid 
CYP 2D6 substrate + 
inhibitor 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
17 APPENDIX 6: NEW YORK HEART ASSOCIATION (NYHA) CARDIAC 
CLASSIFICATION 
 
The NYHA classification system relates symptoms to everyday activities and the patient’s quality of life. 
Class 
Symptoms 
Class I (Mild) 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical activity is undertaken, discomfort is increased. 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
18 APPENDIX 7: MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL OR 
INDUCE TORSADES DE POINTES 
It has been recognized for a number of years that certain prescription medications can prolong 
the QT/QTc interval and cause a form of acquired Long QT syndrome, known as drug induced 
LQTS.  The drugs that prolong the QT interval and/or have a risk of inducing Torsades de 
Pointes (TdP) are listed below.  We have divided these into two groups based on their known or 
perceived risk of causing TdP:  
Group 1: Drugs that are generally accepted by authorities to have a risk of 
causing Torsades de Pointes 
Concomitant use of these drugs is not allowed during the study or within 2 weeks of 
randomization (at least four weeks for levomethadyl).  These drugs should also be avoided for 
up to 4 weeks following discontinuation of study treatment: 
Table 1 
Group 1 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Amiodarone  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males,TdP risk regarded 
as low 
Arsenic trioxide  
Anti-cancer/Leukemia 
 
Astemizole  
Antihistamine/Allergic rhinitis 
No Longer available in U.S. 
Azithromycin 
Antibiotic/bacterial infection 
 
Bepridil  
Anti-anginal/heart pain 
Females>Males 
Chloroquine 
Anti-malarial/malaria infection 
 
Chlorpromazine  
Anti-psychotic/Anti-emetic/schizophrenia/ 
nausea 
 
Cisapride 
GI stimulant/heartburn 
No longer available in U.S. 
  
Citalopram 
Anti-depressant/depression 
 
Clarithromycin 
Antibiotic/bacterial infection 
 
Disopyramide  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Dofetilide  
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Domperidone 
Anti-nausea/nausea 
Not available in U.S. 
Droperidol  
Sedative;Anti-nausea/anesthesia adjunct, 
nausea 
 
Erythromycin  
Antibiotic;GI stimulant/bacterial infection; 
increase GI motility 
Females>Males 
Flecainide 
Anti-arrhythmic/abnormal heart rhythm 
 
Halofantrine  
Anti-malarial/malaria infection 
Females>Males 
Haloperidol  
Anti-psychotic/schizophrenia, agitation 
TdP risk with I.V. or excess dosage 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Table 1 
Group 1 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Ibutilide 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Levomethadyl 
Opiate agonist/pain control, narcotic 
dependence 
Not available in U.S. 
Mesoridazine 
Anti-psychotic/schizophrenia 
 
Methadone 
Opiate agonist/pain control, narcotic 
dependence 
Females>Males 
Moxifloxacin  
Antibiotic/bacterial infection 
 
Pentamidine  
Anti-infective/pneumocystis pneumonia 
Females>Males 
Pimozide 
Anti-psychotic/Tourette's tics 
Females>Males 
Probucol 
Antilipemic/Hypercholesterolemia 
No longer available in U.S. 
Procainamide  
Anti-arrhythmic/abnormal heart rhythm 
 
Quinidine 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Sotalol  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Sparfloxacin  
Antibiotic/bacterial infection 
No longer available in U.S. 
Terfenadine 
Antihistamine/Allergic rhinitis 
No longer available in U.S. 
Thioridazine 
Anti-psychotic/schizophrenia 
 
Vandetanib 
(*Does not apply 
to this study) 
Anti-cancer/Thyroid cancer 
 
a 
Source: www.QTdrugs.org. Last revised: 17 May 2012 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Group 2: 
Drugs that in some reports may be associated with Torsades de 
Pointes but at this time lack substantial evidence of causing Torsades de 
Pointes. 
Concomitant use of these drugs is not allowed within 2 weeks of randomization or during the 
study.  These drugs will be allowed during the study, at the discretion of the Investigator, if 
considered absolutely necessary.  In such cases, the patient must be closely monitored, including 
regular checks of QTc and electrolytes. 
Table 2 
Group 2 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Alfuzosin 
Alpha1-blocker/Benign prostatic 
hyperplasia 
 
Amantadine 
Dopaminergic/Anti-viral/Anti-infective/ 
Parkinson's Disease 
 
Artenimol + 
piperaquine 
Anti-malarial/ 
Not available in U.S. 
Atazanavir 
Protease inhibitor/HIV 
 
Chloral hydrate 
Sedative/sedation/ insomnia 
 
Clozapine 
Anti-psychotic/schizophrenia 
 
Dolasetron 
Anti-nausea/nausea, vomiting 
 
Dronedarone 
Anti-arrhythmic/Atrial Fibrillation 
 
Eribulin 
Anti-cancer/metastatic breast neoplasias 
 
Escitalopram 
Anti-depressant/Major depression/Anxiety 
disorders 
 
Famotidine 
H2-receptor antagonist/Peptic ulcer/ GERD 
 
Felbamate  
Anti-convulsant/seizure 
 
Fingolimod 
Immunosuppressant/Multiple Sclerosis 
 
Foscarnet  
Anti-viral/HIV infection 
 
Fosphenytoin 
Anti-convulsant/seizure 
 
Gatifloxacin 
Antibiotic/bacterial infection 
Oral/I.V. forms no longer available 
in U.S. and Canada, only 
ophthalmic 
Gemifloxacin 
Antibiotic/bacterial infection 
 
Granisetron 
Anti-nausea/nausea and vomiting 
 
Iloperidone 
Antipsychotic, atypical/Schizophrenia 
 
Indapamide 
Diuretic/stimulate urine & salt loss 
 
Isradipine 
Anti-hypertensive/high blood pressure 
 
Lapatinib 
Anti-cancer/breast cancer, metastatic 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Table 2 
Group 2 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Levofloxacin 
Antibiotic/bacterial infection 
 
Lithium 
Anti-mania/bipolar disorder 
 
Moexipril/HCTZ  
Anti-hypertensive/high blood pressure 
 
Nicardipine  
Anti-hypertensive/high blood pressure 
 
Nilotinib 
Anti-cancer/Leukemia 
 
Octreotide  
Endocrine/acromegaly, carcinoid diarrhea 
 
Ofloxacin 
Antibiotic/bacterial infection 
 
Ondansetron 
Anti-emetic/nausea and vomiting 
 
Oxytocin 
Oxytocic/Labor stimulation 
 
Paliperidone 
Antipsychotic, atypical/Schizophrenia 
 
Perflutren lipid 
microspheres 
Imaging contrast agent/Echocardiography 
 
Quetiapine  
Anti-psychotic/schizophrenia 
 
Ranolazine 
Anti-anginal/chronic angina 
 
Risperidone  
Anti-psychotic/schizophrenia 
 
Roxithromycin* 
Antibiotic/bacterial infection 
*Not available in U.S. 
Sertindole 
Antipsychotic, atypical/Anxiety, 
Schizophrenia 
Not available in U.S. 
Sunitinib 
Anti-cancer/RCC, GIST 
 
Tacrolimus  
Immunosuppressant/Immune suppression 
 
Tamoxifen  
Anti-cancer/breast cancer 
 
Telithromycin 
Antibiotic/bacterial infection 
 
Tizanidine  
Muscle relaxant/ 
 
Vardenafil 
phosphodiesterase inhibitor/vasodilator 
 
Venlafaxine  
Anti-depressant/depression 
 
Voriconazole 
Anti-fungal/anti-fungal 
 
Ziprasidone 
Anti-psychotic/schizophrenia 
 
a 
Source: www.QTdrugs.org. Last revised: 17 May 2012 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
19 APPENDIX 8: PATIENT DIARY FOR VANDETANIB (PART 1) 
mail to:Patient ID number:     Daily Dose (mg):   
 Cycle Number: ______  Cycle Start Date:_________Cycle Start Day: ______ 
WEEK # 
 
         Date  
 
 
 
 
 
 
 
                                                       Day     
 
 
 
 
 
 
 
                                                       Dose # 
 
 
 
 
 
 
 
Time vandetanib dose taken†  
 
 
 
 
 
 
 
Indicate reason for missed doses  
 
 
 
 
 
 
 
SIDE EFFECTS** 
 
 
Vomiting1 
 
 
 
 
 
 
 
Diarrhea2 
 
 
 
 
 
 
 
Nausea3 
 
 
 
 
 
 
 
Rash 
 
 
 
 
 
 
 
OTHER SIDE EFFECTS 
Should you need additional space, continue with table on back. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OTHER MEDICATIONS (Name) 
(Not your regular daily medications) 
 
Dose 
 
Frequency 
 
Start Date 
 
Stop Date 
 
Reason for Use of Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
† Vandetanib can be taken with a meal or in between meals. If you vomit within 30 minutes of taking of vandetanib, you may re-take the dose. If more than 30 minutes has passed 
from the time of taking vandetanib then do not retake the dose. 
1 For vomiting indicate number of episodes per day.  
2 For diarrhea, indicate the number of episodes per day and the consistency (F for formed, W for watery, L for loose or partially formed). 
3 Rate nausea mild if you are able to eat and drink a reasonable amount, moderate if you can eat and drink but the amount is substantially decreased, or severe if you  
    are unable to eat and drink. 
**Contact your study center team or local physician right away if you experience skin rash, rapid or irregular heartbeat, dizziness, light-headedness, 
chest discomfort, shortness of breath, loss of consciousness, or pregnancy (you or your partner)** 
Your skin may be more sensitive to the sun, avoid exposure and use sunblock > 45+ 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Completed form should be returned immediately at the end of each cycle to Ms. Claudia Derse-Anthony (FAX 301-480-8871, PHONE: 240-760-6102, e-
mail: claudia.derse-anthony@nih.gov) 
Patient/Parent Signature:  
 
  Date:  
         Reviewed By: 
RN/MD   Date: 
 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Appendix 8: Patient Log for Symptoms/Reactions and Concomitant medications (Part 2) 
 
 
 
 
 
 
 
 
 
Cycle(s): ______________ 
 
Patient ID#: ____________       Vandetanib dose (mg): _________    Frequency: ___________  
 
 
 
 
 
 
 
Symptom/Reaction              Start Date    End Date   Did you take something for it? List below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication                   Reason for Use                Dose          Start Date       
Stop Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
 
 
 
 
 
 
 
 
 
 
 
Please take your study medication about the same time every day. If you miss a dose and more than 6 hours has passed from your 
usual dosing time, DO NOT take the dose. Record any missed doses on your diary.  
 
**Contact your study center team or local physician right away if you experience skin rash, rapid or irregular heartbeat, dizziness, 
light-headedness, chest discomfort, shortness of breath, loss of consciousness, or pregnancy (you or your partner).** 
 
Your skin may be more sensitive to the sun, avoid exposure and use sunblock > 45 SPF.   
 
Patient/Parent signature: __________________    Date:______________________ 
 
Reviewed by:_____________________ RN/MD   Date:______________________ 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
20 APPENDIX 9: REQUIRED STUDY EVALUATIONS 
Clinical and laboratory tests to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory 
values used to assess eligibility must be no older than 7 days at the start of therapy. Laboratory tests need not be repeated if therapy starts with in 7 
days of obtaining labs for eligibility. For further details see section 2.2.  
STUDIES TO BE OBTAINED1 
Screening 
 
Baseline 
During Cycle 1 
Prior To Subsequent Cycles 
End of Therapy8  
PT/PTT 
X 
 
 
 
 
Lower leg scanogram2 
 
X 
History, physical exam, viral signs (HR, BP, Temp) 
 
X 
 
 
 
Day 14 
 
Prior to cycles 2, 3, 4, and then 
after every 3 cycles prior to 
cycle 7, 10, 13, etc) 
 
X 
CBC, differential, platelets 
Chemistries: [Acute Care Panel (sodium, potassium, 
chloride, CO2, creatinine, glucose, BUN), Mineral 
Panel (calcium, magnesium, phosphorus, albumin) 
Hepatic Panel (alk phos, ALT/AST, Total bilirubin, 
(if T Bili is elevated, draw Direct bilirubin) total 
protein,  uric acid, LDH. 
Urinalysis 
 
X 
 
- 
Prior to cycles 2, 3, 4, and then 
after every 3 cycles prior to 
cycle 7, 10, 13, etc) 
X 
Thyroid function (TSH; T4 if TSH abnormal) 
 
X 
EKG  
X 
 
Height, weight, BSA, Performance Status 
 
X 
 
 
 
Prior to cycle 4, 7, 10, 13, and 
then after every 6 cycles (prior 
to cycle 19, 25, 31, etc) 
 
X 
β-HCG pregnancy test: (if applicable)3 
Disease evaluation:  
CT chest/abdomen/pelvis, 
MRI abdomen/pelvis 
Unilateral knee MRI5 
FDG-PET scan6 
X 
 
Day 3 to 66 
Prior to cycle 4 
 
QOL: PROMIS and Distress Thermometer 
 
X 
 
Prior to cycle 4 
X 
Patient diary:  
reactions/symptoms and concomitant meds7 
- 
X 
Daily 
Daily until prior to cycle 13 
- 
Study calendar7 
- 
 
- 
From cycle 13 on 
X 
NIH Advance Directives Form9 
 
X 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
 
1With exception of the optional FDG-PET scan, study evaluations for cycles 1 though 4 may be 
performed within +/- 3 days of the scheduled date. 
 Study evaluations for cycles ≥5 may be obtained within +/- 7days of the scheduled date.  
2Lower extremity scanogram in all participants less than 18 years old.  Patients with fused growth plates 
will not undergo additional evaluations.  Patients with open growth plate(s) will also undergo follow up 
scanogram only if clinically indicated. 
3Required in females of childbearing potential. 
5A unilateral knee MRI in all patients with open growth plates on lower extremity scanogram (see 
Appendix 11). Repeat knee MRIs at time points indicated until growth plates are fused. 
6Optional FDG-PET for patients ≥ 15 years old on day 3 to day 6 after starting vandetanib on cycle 1 to 
evaluate for early response. 
7From cycle 13 on vandetanib intake will be monitored during patient interviews at the NIH, and patients 
will document adverse events and any concomitant medications on Reactions/Symptoms and 
Concomitant Medications Logs (see Appendix 10). 
8Patients who experience adverse events at the end of therapy will continue to be monitored until at least 
60 days after the last dose of vandetanib and until resolution of toxicity. 
9As indicated in section 10.3, all subjects ≥ age 18 will be offered the opportunity to complete an NIH 
advance directives form.  This should be done preferably at baseline but can be done at any time during 
the study as long as the capacity to do so is retained.  The completion of the form is strongly 
recommended, but is not required. 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
21 APPENDIX 10:  PATIENT LOG FOR REACTIONS/SYMPTOMS 
Protocol # ___-__-______*  
 
Patient ID#: _________________  
 
Vandetanib dose (mg): _________    Frequency: _________ 
          Cycle(s):_______ 
 
 
 
 
 
 
 
 
 
Symptom/Reaction                       
Start Date    End Date        Took Medication (Y/N) 
               
 
 
 
 
 
 
 
        Complete reverse side. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please take your study medication about the same time every day. If you miss a dose and more 
than 6 hours has passed from your usual dosing time, DO NOT take the dose. Record any missed 
doses on your diary.  
**Contact your study center team or local physician right away if you experience skin rash, rapid 
or irregular heartbeat, dizziness, light-headedness, chest discomfort, shortness of breath, loss of 
consciousness, or pregnancy (you or your partner).**  
 
Your skin may be more sensitive to the sun, avoid exposure and use sunblock > 45 SPF.   
 
Patient/Parent signature: __________________    Date:______________________ 
 
Reviewed by:_____________________ RN/MD   Date:______________________ 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
Patient Log for Concomitant Medication  
 
 
Patient  ID#: _________     Vandetanib dose (mg): ________         Frequency: _once daily__ 
 
 
 
 
 
 
Medication                   Reason for Use                Dose          Start Date       
Stop Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Patient/Parent signature: __________________    Date:______________________ 
 
Reviewed by:_____________________RN/MD   Date:_____________________  
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
22 APPENDIX 11: PROTOCOL FOR MRI STUDY OF KNEE 
PATIENT ID NUMBER: _________ 
Note: Unilateral knee MRI.  Right knee preferred over left unless prohibited by contractures, 
lesions, pain, or hypertrophy.  This is done to examine the femoral and tibial growth plates.  Only 
the series outlined below are required for the knee MRI for evaluation of femoral and tibial growth 
plates and must be performed within protocol specifications as indicated below.  Two sequential 
scans of the knee will be performed per patient.  The patient must step off the scanner and placed 
back on the scanner in between the two scans. 
 
T1 Weighted 
Sagittal 
Protocol 
Specifications 
Actual 
Specifications 
Reason For Change 
Echo Train Length 
72 
 
 
TR 
500-600 
 
 
TE 
min full 
 
 
Slice Thickness 
3 
 
 
Bandwidth 
20 kHz 
 
 
GAP 
1.5mm 
 
 
FOV 
18 
 
 
FREQ 
512 
 
 
Phase 
256 
 
 
NEX 
1 
 
 
PHFVO 
Full 
 
 
Saturation 
no FS 
 
 
OPTIONS 
Fast 
 
 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
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23 APPENDIX 12: PEDIATRIC PROMIS INSTRUMENTS (6) AND PARALLEL 
PARENT PROXY PROMIS INSTRUMENTS (6) AND ADULT PATIENT PROMIS 
INSTRUMENTS (6) 
Pediatric PROMIS Instruments (6)  
 


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24 APPENDIX 13: PARALLEL PARENT PROXY PROMIS INSTRUMENTS (6) 
 


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25 APPENDIX 14: ADULT PATIENT PROMIS INSTRUMENTS (6) 
 
 


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26 APPENDIX 15: THE DISTRESS AND SYMPTOM CHECKLIST: THE DISTRESS 
THERMOMETER  
 


Abbreviated Title:  PhII Vandetanib in GIST 
Version Date11/07/2017 
 
 
 
 
 


Abbreviated Title:  PhII Vandetanib in GIST 
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27 REFERENCES 
 
1. 
Pappo AS, Janeway K, Laquaglia M, Kim SY. Special considerations in pediatric 
gastrointestinal tumors. Journal of surgical oncology. 2011;104(8):928-32. Epub 2011/11/10. 
2. 
Wang X, Mori I, Tang W, Utsunomiya H, Nakamura M, Nakamura Y, et al. 
Gastrointestinal stromal tumors: are they of cajal cell origin? Exp Mol Pathol. 2002;72(2):172-7. 
Epub 2002/03/14. 
3. 
Antonescu CR. The GIST paradigm: lessons for other kinase-driven cancers. J Pathol. 
2011;223(2):251-61. Epub 2010/12/03. 
4. 
Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, et al. Defects in succinate 
dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. 
Proceedings of the National Academy of Sciences of the United States of America. 
2011;108(1):314-8. Epub 2010/12/22. 
5. 
Janeway KA, Pappo A. Treatment guidelines for gastrointestinal stromal tumors in 
children and young adults. J Pediatr Hematol Oncol. 2012;34 Suppl 2:S69-72. Epub 2012/05/02. 
6. 
Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and 
pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal 
sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern 
Med. 2009;266(1):43-52. Epub 2009/06/16. 
7. 
Matyakhina L, Bei TA, McWhinney SR, Pasini B, Cameron S, Gunawan B, et al. 
Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in 
genes associated with paragangliomas and gastrointestinal stromal tumors. J Clin Endocrinol 
Metab. 2007;92(8):2938-43. Epub 2007/05/31. 
8. 
King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking 
mitochondrial dysfunction and cancer. Oncogene. 2006;25(34):4675-82. Epub 2006/08/08. 
9. 
Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. 
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl 
hydroxylase. Cancer cell. 2005;7(1):77-85. Epub 2005/01/18. 
10. 
Linehan WM, Bratslavsky G, Pinto PA, Schmidt LS, Neckers L, Bottaro DP, et al. 
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2010/01/12. 
11. 
Linehan WM, Pinto PA, Srinivasan R, Merino M, Choyke P, Choyke L, et al. 
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12. 
Linehan WM, Pinto PA, Bratslavsky G, Pfaffenroth E, Merino M, Vocke CD, et al. 
Hereditary kidney cancer: unique opportunity for disease-based therapy. Cancer. 2009;115(10 
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13. 
Yang Y, Valera VA, Padilla-Nash HM, Sourbier C, Vocke CD, Vira MA, et al. UOK 262 
cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell 


Abbreviated Title:  PhII Vandetanib in GIST 
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Cancer Genet Cytogenet. 2010;196(1):45-55. Epub 2009/12/08. 
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Koivunen P, Hirsila M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J. Inhibition 
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2006/12/22. 
15. 
Eric A. Singer JCF, Geri Hawks, Cathy Vocke, Adam R. Metwalli, Peter A. Pinto, 
Gennady Bratslavsky, W. Marston Linehan, Ramaprasad Srinivasan. A phase II study of 
bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell 
cancer (HLRCC) or sporadic papillary renal cell cancer (RCC). JCO. 2012;30((suppl; abstr 
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Ricketts C SB, Vocke K, Metwalli A, Bratslavsky G, Middelton L, Yang Y, Wei W, 
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Linehan M. Succinate Dehydrogenase Kidney Cancer  (SDH-RCC): an aggressive example of 
the Warburg effect in cancer. Journal of Urology. 2012;in press. 
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characteristics. J Pediatr Gastroenterol Nutr. 2008;46(2):164-71. Epub 2008/01/29. 
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ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
13-C-0208 
PRINCIPAL INVESTIGATOR: 
Brigitte Widemann, M.D. 
STUDY TITLE:  
Phase II Trial of Vandetanib (ZD6474, Caprelsa®) in Children and Adults with Wild-
Type Gastrointestinal Stromal Tumors 
 
Continuing Review Approved by the IRB on 12/03/18 
Amendment Approved by the IRB 12/06/17 (F) 
 
Date posted to web:   12/13/18 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
If you are signing for a minor child, “you” refers to “your child” throughout the consent 
document. 
Why is this study being done?  
You have been diagnosed with Gastrointestinal Stromal Tumor (GIST), wild type, called WT-
GIST. We have found that some people with WT-GIST have a mutation (or change) in one of 
their genes.  Some cancer agents have successfully treated diseases with a similar gene mutation.  
Vandetanib is one cancer treatment that has been recently approved by the US Food and Drug 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 2 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Administration (FDA) for treatment of adults with medullary thyroid cancer, but has not been 
previously given to people with your type of cancer, and is therefore considered experimental.  
The purpose of this study is to test whether vandetanib will benefit people with Wild-type GIST. 
Vandetanib is a pill that is to be taken once a day.  The purposes of this research study: 
 to see if Vandetanib can shrink tumors in people with wt-GIST. 
 to test the safety and tolerability of vandetanib in children and adults, and to see if it 
prolongs survival. 
 to study if a scan (FDG-PET scan) is helpful in evaluating patients who are 15 years of 
age or older with wt-GIST, 
 to study tumor cells from patients with wt-GIST to better understand the biology of the 
disease, and  
 to describe the impact of taking vandetanib on your quality of life and symptoms if you 
are 8 years of age or older.   
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you are 3 years of age or older and have 
been diagnosed with wild-type GIST.  
How many people will take part in this study?  
A minimum of 9 and a maximum of 24 patients will be enrolled in this study. 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study 
First we will test your tumor tissue to make sure it is the wild-type GIST.  If it is wild-type GIST, 
you will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor.   
 A medical history 
 Physical exam 
 Vital signs (blood pressure, pulse, temperature, height and weight) 
 Standard blood tests 
 Electrocardiogram (ECG), which is an electrical recording of your heart 
 Pregnancy test (if you are a female who could have children) 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 3 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 Scans of the tumor (CT and MRI) or other tests needed to check the status of your tumor. 
For your safety and to get valid study results, your test results must be within the limits outlined 
for eligibility to participate in this study.  Your study doctor will tell you if you are eligible for 
this or another study. 
The effects of the drug used in this study on an unborn child (fetus) are unknown.  For this 
reason, if you are pregnant or nursing, you may not participate.  You/your partner must be 
willing to use an effective form of contraception (hormonal or barrier method of birth control, or 
commitment to sexual abstinence) prior to your entering this study and for 3 months after you 
finish vandetanib on this study.  If you or your partner becomes pregnant while you are 
participating in this study, you should notify your doctor immediately.  Women who are able to 
get pregnant must have a negative pregnancy test. 
Note: it is very important for you to give the researchers accurate and complete information 
about your medical history and condition. 
During the study 
Prior to starting vandetanib, you will have standard tests to allow us to watch for any changes 
while you are taking vandetanib.  The following standard tests will be done: 
 Routine blood tests including thyroid function, liver function, and chemistries. 
 Routine urine testing 
 Scans, including MRI, CT and FDG-PET 
 If you are younger than 18 years old, lower extremity x-ray to check bone growth. 
 If you are 8 years of age or older (and all parents or caregivers) complete questionnaires 
about quality of life. 
You will take vandetanib once every day continuously (a cycle of vandetanib is 28 days).   
Adults will receive 200 mg every day for the first 3 cycles, which has been shown to be safe in 
adult studies.  If you tolerate this dose, the dose may be increased to 300 mg every day.   
Children will receive a dose based upon weight and height starting at 100 mg/m2/dose for cycles 
1, 2 and 3.  If this dose is tolerated, the dose will be increased to 150 mg/m2/dose for subsequent 
cycles. 
Taking vandetanib is not affected by food so you do not need to take it when you eat, but it 
should be taken about the same time every day.   
The tablet should be swallowed whole or dissolved in water.  If you miss a dose of vandetanib 
and less than 12 hours have passed since the scheduled dose, you should take your dose 
immediately.  If more than 12 hours have passed, then do not take the missed dose but wait and 
take the next scheduled dose the next day. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 4 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
If you vomit within 30 minutes of taking vandetanib, then you can take another dose.  The dose 
may only be repeated once.  If more than 30 minutes has passed since you took the dose, then do 
NOT repeat the dose.  Take the next scheduled dose the next day. 
We will ask you to write down the dose of vandetanib and the time and date you took it every 
day in a medication diary.  Make sure you bring your medication diary with you to every clinic 
visit.   
If you have side effects with vandetanib, be sure to discuss them with your doctor or nurse.  You 
may be given medications to make you feel better, or the dose may need to be adjusted.  DO 
NOT take other medications without first discussing them with your doctor or research nurse. 
During the first 28-day cycle, you will be examined by a doctor at the NIH or at home at about 
day 14 of the cycle to look for side effects of vandetanib. 
After the first cycle you will need to have a physical exam, urine tests, blood pressure checked 
and routine blood tests before cycles 2, 3, and 4.  These tests will then be done periodically for as 
long as you are on the study.  Procedures or tests that need to be done by your own physician at 
home will incur costs that may or may not be covered by your health insurance. 
The effect of vandetanib on your cancer will also be closely monitored while you are on the 
study: 
 scans to assess the size of your cancer (may include CT scan and MRI) will be done 
before cycle 4 and then every 3-6 cycles, and 
 FDG-PET will be done before cycle 4, and then again only if the doctor thinks you need 
it. 
If you are female and able to have children, a urine or blood pregnancy test will be done prior to 
starting cycles 4, 7, 10, and 13 of vandetanib and then every 6 cycles while you are taking the 
study drug. 
If you are still growing (children and adolescents) we will do an MRI of your knee to see if your 
bones are still growing.  If so, you will need to have an MRI periodically during your 
participation in this study to see any side effects on your growing bones. 
You may continue to receive vandetanib indefinitely unless you decide to stop for any reason, 
you have unacceptable side effects that are not controlled by lowering the dose, your tumor 
grows, you are unable to keep scheduled medical appointments or take the study medication as 
instructed, the doctors taking care of you feel it is not in your best interest to continue, or a better 
therapy becomes available.   
If you become pregnant you will need to stop taking vandetanib. While you are being treated 
with vandetanib, doctors at the NIH will provide you with any new information that develops 
which may affect your health, welfare, or willingness to stay on the study.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 5 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Quality of Life (QOL) Questionnaires and other Optional Tests (if you are 8 years of age or 
older) 
We will offer you participation in some tests that include Quality of Life Questionnaires, tissue 
tests in case a biopsy or surgery is clinically necessary, and imaging studies (PET-CT). They are 
all described at the end of this informed consent. 
When you are finished taking the drugs (treatment) 
If you come off the treatment for any of the reasons listed above, we would like you to return to 
NIH for one visit about 60 days after your last dose of vandetanib for a physical exam and 
standard blood tests.  We will continue to check up on your condition periodically through phone 
calls to you, your family or your home doctor’s office. 
Study Chart 
Cycle 1 
Subsequent Cycles  
DAY 
WHAT YOU DO 
DAY 
WHAT YOU DO 
Before 
starting 
study 
Come into the clinic and do the 
following: 
 
Get routine blood tests 
 
Get an ECG 
 
Get a pregnancy test (if you are a 
female able to get pregnant) 
 
Get a physical exam by your doctor 
(including blood pressure, heart 
rate, weight, temperature) 
 
Get a disease evaluation (CT and 
MRI) that will be done by your 
doctor.  
If you are able to be in the study, you 
will have: 
 
FDG-PET scan  
 
Urine tests 
 
MRI of your lower leg if you are still 
growing 
 
QOL questionnaires (if you are 8 
years of age or older) 
 
Day 1 
Come into the clinic: 
 
Get a physical exam by your doctor, 
check blood pressure 
 
Get a Patient Diary that you will 
need to write in daily 
Days 
1-27 
 
Take vandetanib once a day 
 
Write the dose in your Patient 
Diary daily 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 6 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
Start taking vandetanib once a day 
for 28 days, continuously without 
interruption 
Day 
2 
thru 27  
 
Take your vandetanib once a day 
 
Write the dose in your Patient Diary 
daily 
 
[18F]-FDG-PET/CT scan between 
day 3-6 after starting vandetanib 
(optional if you are older than 15 
years of age) 
Also on 
Day 15 
 
Get a physical exam, check blood 
pressure 
 
Get routine blood tests 
Day 28 
Come into the clinic: 
 
Get a physical exam by your doctor  
 
Get blood pressure measurement 
 
Get an ECG 
 
Get routine blood tests 
 
Get urine test 
 
Get a pregnancy test (if you are a 
female able to get pregnant) 
 
If continuing treatment, get 
vandetanib for the next cycle and a 
new Patient Diary to write in daily 
Day 
28 
Come into the clinic: 
 
Get a physical exam with blood 
pressure by your doctor (before 
cycles 2, 3 and 4, then every 3 
cycles (7, 10, 13)  
 
Get an ECG (before cycles 2, 3, 
and 4, and then every 3 cycles, i.e. 
7, 10, 13) 
 
Get routine blood and urine tests 
(before each cycle for cycles 2, 3 
and 4, then every 3 cycles (before 
cycle 7, 10, 13). 
 
Get a pregnancy test (if you are a 
female able to get pregnant) 
(before cycles 4, 7, 10, 13, then 
every 6 cycles, i.e. 19, 25, 31) 
 
If continuing treatment, get 
vandetanib for the next cycle and 
a new Patient Diary to write in 
daily 
 
Evaluate tumors with CT and 
MRI every 3 cycles (before cycle 
4, 7, 10 and 13) then every 6 
cycles (19, 25, 31, etc) 
 
FDG-PET scan before cycle 4, 
then if your doctor sees a need. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 7 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
QOL questionnaires (if you are 8 
years of age or older) before cycle 
4, and then when you stop taking 
vandetanib 
 
Risks or Discomforts of Participation 
The study medication may cause some side effects. Depending on the severity of the side effect, 
the dose of vandetanib may need to be decreased, or stopped. 
The following side effects were observed in patients receiving 300mg vandetanib alone (with no 
other treatment).  Vandetanib may involve other risks, including possible life-threatening 
reactions that are not known at present.  You may experience some, none, or all the possible side 
effects of vandetanib.  The side effects most likely to occur are: 
Very common – experienced by more than 10% of patients taking vandetanib: 
 headache 
 diarrhea 
 fatigue 
 nausea and/or vomiting 
 constipation 
 loss of appetite 
 skin rash or dry skin 
 weight loss 
 trouble sleeping 
 high blood pressure, or  
 weakness. 
Patients taking vandetanib may develop a skin rash that may become severe but is 
manageable with proper treatment.  Vandetanib may also make your skin more 
sensitive to the sun.  It is recommended that you take preventative action to prevent the 
rash from occurring while receiving study medication and for 3 to 4 weeks after stopping 
treatment by using the following guidelines: 
 Avoiding direct sunlight 
 Covering sun exposed skin with clothing (long pants, long sleeve shirts and hats) 
 Using a SPF 45 or higher sunblock or sun protection cream 
 Notifying study doctor when the first sign of a rash occurs so he or she may take the 
appropriate steps in preventing the rash from becoming severe 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 8 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Common (Experienced by 1 – 10% of patients taking vandetanib) 
 Changes in heart function (called QTc prolongation), abnormal taste in mouth, abdominal 
pain, swelling in your mouth, dry mouth, decrease in thyroid hormone, weight loss, 
elevated blood levels of certain proteins produced by the liver, anorexia, low potassium 
in the blood, low calcium in the blood, dehydration, low magnesium in the blood, 
changes in your skin (sensitivity to the sun, itchy skin, redness), acne, hair loss, nail 
disorders, mild nose bleeding, protein or blood in the urine, kidney stone, changes in your 
eyes (vision problems, swollen, dry or irritated eyes), feeling depressed, and anxiety. 
 AstraZeneca, the company that makes Vandetanib, has observed changes in ECGs in 
some patients being treated with vandetanib. These changes in the ECG may be drug-
related and usually occur without symptoms. Similar changes in the ECGs of patients 
receiving other medications have led to heart rhythm changes, some of which have been 
life threatening.  It is estimated that between 0.1 to 1% of patients receiving vandetanib 
300 mg have developed heart rhythm changes linked to life-threatening arrhythmia called 
Torsades de Pointes.  Torsades de Pointes has been associated with sudden death.  If any 
such changes are noted on your ECGs, you may need to attend additional visits for 
further safety assessments.  
 The risk of developing changes in the ECG and serious heart rhythm changes will be 
greater if you have diarrhea, imbalance of minerals in your blood, vomiting, high fever, 
faintness or dizzy spells, or are unable to maintain a normal diet.  You should report any 
of these symptoms to your study doctor immediately.  You should review your 
medications and diet with your study doctor at each visit while you are continuing to 
receive study drug.  
 Changes in the heart rhythm may cause rapid or irregular heartbeat, dizziness, light-
headedness, chest discomfort, shortness of breath, or losing consciousness.  We will be 
checking your heart function with an electrocardiogram (ECG).  If significant changes 
occur, we may need to stop therapy.  These or other new symptoms or possible side 
effects should be reported immediately to your study doctor. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 9 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Uncommon (Experienced by fewer than 1% of patients taking vandetanib) 
 Certain heart conditions (heart failure – a weakening of the heart’s ability to pump blood, 
a fast heart beat that can be dangerous), chest pain, inflammation in the pancreas, 
decrease in platelets in the blood, small bluish/purple spots on the skin, increase in 
haemoglobin in the blood, and severe skin disorders.  
 Some patients have had seizures while taking vandetanib, which can be a result of 
swelling in the brain.  This can be seen on an MRI scan, and is expected to improve after 
vandetanib has been stopped.  If you develop seizures, dizziness, headache, changes in 
your vision, or confusion, you should let your study doctor know as soon as possible. 
These may be symptoms of reversible posterior leukoencephalopathy syndrome (RPLS) 
which is expected to be uncommon. 
 A very small number of patients with lung cancer receiving vandetanib have developed 
shortness of breath and cough because of an inflammation of scar tissue formation in the 
lungs, although this symptom could also be due to the underlying lung cancer. 
Women of Child-Bearing Potential and Men with Partners of Child-Bearing Potential 
There might be unknown risks to the unborn baby if you are or if you become pregnant during 
the study. Due to these risks, you must not take part in this study if you are pregnant, plan to 
become pregnant during the research study period, or are breast-feeding a baby. 
If you are a woman of child-bearing potential: 
 By signing this consent form, you confirm to the best of your knowledge that you are not 
pregnant now and you do not intend to become pregnant during this study 
 A pregnancy test will be done to confirm that you are not pregnant before you take part in 
this study 
 You must avoid becoming pregnant and use an acceptable method of birth control during 
your participation in this study. An acceptable method of birth control is defined as a 
barrier method in conjunction with a spermicide (i.e., condom with spermicide, 
diaphragm with spermicide), approved contraceptive implants, long-term injectable 
contraception, intrauterine devices, or tubal ligation. The oral contraceptive pill is 
acceptable, but it must be combined with a barrier method in conjunction with a 
spermicide. You should avoid becoming pregnant for 3 months following the last dose of 
vandetanib. 
If at any time during this study you think you might be pregnant, or later learn that you were 
pregnant during the study, you must contact the study doctor immediately for further instructions 
about your participation in this study and follow-up.  You will be asked about the results of the 
pregnancy/birth and may need to have follow-up visits. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 10 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
If you are a man with a partner of childbearing potential, then you must immediately 
contact the study doctor if any of the following occur: 
 
Your partner becomes pregnant during the study 
 
You learn that your partner became pregnant during the study 
 
You learn that your partner became pregnant within 3 months after your last dose of 
the study drug. 
You will be given further instructions for follow-up. 
Male patients must avoid unprotected sex with a pregnant partner (or woman of child-bearing 
potential not using birth control) or donating sperm during the study and for three months 
following the last dose, since the potential for problems with the fetus has not yet been 
thoroughly investigated.  Men should use a condom during the trial and for three months 
following the last dose. 
The study doctor may ask you about any partner pregnancy during your study visits, and again 
up to 3 months after the last dose of study drug. If you report a pregnancy of your partner, the 
study doctor will collect information about the results of the pregnancy/birth and schedule any 
follow-up visits that are needed. 
This health information will become part of the research study records. It will be shared with the 
drug manufacturer. With this information, the drug manufacturer may be able to determine if 
there are any effects of the study drug upon unborn children. 
Additional Risk (not associated with vandetanib, but may be associated with participation 
in the study): 
Drawing Blood 
Taking blood samples may cause some discomfort.  Risks associated with drawing blood from 
your arm include pain, bruising, light-headedness, and on rare occasions, infection. 
Risks of Scans 
You will have a CT scan and MRI to measure the size of your cancer(s) before starting the 
treatment and some or all of these scans will be used to periodically monitor the change in the 
size of your cancer(s) on vandetanib.  These scans are common standard imaging tests used in 
the diagnosis and monitoring of many diseases.  Although these tests have been in use for many 
years, their potential long term effects on the body are still being learned.   
The most common discomfort is the length of time you must lay still or flat while a scan is being 
performed.  Occasionally, a patient may become uncomfortable within the enclosed space of the 
scanners (claustrophobia), particularly during a MRI.  If this occurs, cool air can be blown over 
you by a fan if desired or your doctor can order a medicine to help you relax during this scan.  
Keeping the room well lit can also reduce this claustrophobic feeling.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 11 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
If a contrast agent (the special dye) is given with the scan there is a small risk of having a 
reaction to the contrast.  These reactions can include nausea, pain in the vein where the contrast 
was given, headache, a metallic or bitter taste in the mouth, and a warm or flushing feeling that 
lasts from 1-3 minutes.  Rarely, these symptoms may require treatment.  In very rare cases, 
people have had more severe allergic reactions that result in shortness of breath, wheezing, or 
lowering of the blood pressure.  If you have had a reaction in the past, be sure to tell your doctor 
or nurse about it.   
The radiation dose you receive, if your scans include the use of X-rays or radioactive chemicals, 
is considered essential for your medical care. 
In some cases, you may require medicines to make you sleep so you can be still during the 
procedure.  The risks from this sedation or anesthesia are dependent on the types of medication 
used.  These risks will be fully explained to you prior to the procedure and a separate informed 
consent will be obtained for anesthesia. 
We may need to insert an IV line for administration of the contrast or anesthesia.  This can cause 
pain at the site where the IV is placed and carries a small risk of bruising or infection. 
Patients with a cardiac pacemaker, neural pacemaker, some types of surgical clips, ear implants, 
foreign metal objects, permanent dental retainers, or any iron-containing material within the 
body should not undergo a MRI, because of the effect of the strong magnet on these objects. 
FDG-PET Scan 
FDG-PET Scan, which is a nuclear medicine test also called a Positron Emission Tomography 
(PET) scan.  This is an imaging technique that is used to detect and follow the presence of a 
variety of tumors.  Positron emission tomography (PET) uses a radioactive sugar molecule called 
fluorodeoxyglucose, or FDG for short.  This sugar is similar to glucose, an ordinary form of 
sugar that the body uses for fuel.  The FDG is labeled with a type of radioactive element, an 
isotope, called Fluorine-18 (F-18) that emits particles called positrons that can be detected by a 
special camera and viewed on a computer screen.  The FDG will be injected into the vein.  You 
will need to be fasting (you will not be able to eat or drink) for 4 to 6 hours before the FDG-PET 
scan.   
There is a slight risk of developing an allergic-type reaction to the radioactive drug, FDG which 
is given in a catheter put in your vein (intravenously) before the PET scanning is done.  There 
may be discomfort when the needle is put into your arm vein.  There is a slight risk of bruising, 
bleeding or infection at the site of injection.  There may be discomfort associated with lying still 
on the enclosed scanning table.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 12 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
Vandetanib may cause your cancer to stop growing or shrink in size for a period of time or it 
may lessen the symptoms, such as diarrhea, that are caused by the cancer.  Because there is little 
information about the drug's effect on cancer in children and adolescents, we do not know if you 
will benefit from taking part in this study, although the knowledge gained from this study may 
benefit others. 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Alternatives to Vandetanib include:  
 conventional drugs that were previously used in the treatment of your cancer,  
 other conventional anticancer drugs that are not routinely used to treat your type of 
cancer,  
 other experimental therapies, or  
 getting no anticancer treatment but receiving comfort care, also called palliative care.  
This type of care tries to reduce pain, tiredness, appetite problems, and other problems 
caused by cancer.  It does not treat the cancer directly, but instead tries to improve how 
you feel.  Comfort care tries to keep you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy  
Could the researchers take me out of the study even if I want to continue to participate? 
Your doctor may decide to stop your therapy for the following reasons: 
 if he/she believes that it is in your best interest 
 if you become pregnant 
 if your disease comes back during treatment 
 if you have side effects from the treatment that your doctor thinks are too severe 
 if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to collaborators. If you 
withdraw your consent and leave the trial, any samples of yours that have been obtained for the 
study and stored at the NCI can be destroyed upon request. However, any samples and data 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 13 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
generated from the samples that have already been distributed to other researchers or placed in 
the research databases cannot be recalled and destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
 The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
 National Cancer Institute Institutional Review Board 
 Qualified representatives from AstraZeneca, the pharmaceutical company who produces 
Vandetanib. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
What Happens if You Have an Injury Resulting from this Study? 
Please see the information in #2 on page 17.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 14 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
 will be used for auditing or program evaluation internally by the NIH; or  
 must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
 is necessary for your medical treatment and you have consented to this disclosure;  
 is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.    This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
 
Astra-Zeneca is providing the drug for this study to NIH without charge.  No NIH investigator 
involved in this study receives payments or other benefits from any company whose drug, 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 15 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
product or device is being tested.  However, there are some non-NIH collaborators on this study 
who may receive payments or benefits, limited by the rules of their workplace. 
Quality of Life Questionnaires (if you are 8 years of age or older) 
We would like to gather information about the effects of vandetanib on you and your daily life 
by having you complete a series of questionnaires (2 forms). It will take about 10 minutes to 
complete the questionnaires.  We will ask you to fill them out 3 times.  Participation will not 
benefit you.  It might help other people in the future.   
Optional Tissue Research  
Archival Tumor Tissue 
We would like to study tumor tissue from people with GIST to learn more about how to prevent 
or treat GIST.  If you have tumor tissue available from a prior biopsy or surgery, we would like 
your permission to use your previously collected tissue to study these research questions in our 
laboratory. Participation is optional and will not benefit you.  It might help other people in the 
future.  Even if you sign "yes" to allow us to study your tumor tissue, you can change your mind 
at any time.  Please read the sentence below and think about your choice. After reading, circle 
and initial the answer that is right for you.  The decision to participate in this part of the research 
is optional, and no matter what you decide to do, it will not affect your care. 
 
I agree to allow previously collected tumor tissue to be used for research tests in this study.  
 
Yes              No               Initials_________ 
 
Tissue Collected While on this Study 
If you need a biopsy or surgery while you are on this study, we would like to use a small piece of 
any tumor obtained during the surgery to study any genetic changes present in your cancer. 
Because your type of cancer is very rare, attempts will be made to grow cancer cells from your 
tumor cells in test tubes (establishing so-called “cell lines”).  Cancer cells taken directly from 
you have a limited time of survival and cannot be studied in the future.  Cells grown under 
specific laboratory conditions can be made into a cell line, which can survive indefinitely, 
allowing us to study the best ways to diagnose and treat future patients with wt-GIST.  These 
tests are only done for research purposes and will not affect your medical management on this 
study. Therefore, if you have surgery or a biopsy of your tumor we would like to study your 
tissue.  Participation is optional and will not benefit you.  It might help other people in the future.  
Even if you sign "yes" to allow us to study your tumor cells, you can change your mind at any 
time.  Please read each sentence below and think about your choice. After reading, circle and 
initial the answer that is right for you.  The decision to participate in this part of the research is 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 16 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
optional and will not benefit you, and no matter what you decide to do, it will not affect your 
care.  
 
I agree to allow part of my tumor tissue from a biopsy or medically indicated surgery be used for 
research tests in this study.  
 
Yes              No               Initials_________ 
Optional additional [18F]-FDG-PET/CT scan 
If you are 15 years of age or older, we invite you to participate in one additional [18F]-FDG 
PET/CT scan (only if you do not require sedation).  This scan is optional and is done solely for 
research purposes and is not required for your medical care.  This additional scan will be done 3-
6 days after you start taking Vandetanib to see if the [18F]-FDG PET/CT scan can help us see 
who will benefit from Vandetanib therapy. 
This research [18F]-FDG-PET/CT scan involves exposure to radiation from the one [18F]-
FDG PET/CT scan with an injection of 10 millicuries of F-18 FDG tracer, which is given 
before the [18F]-FDG PET/CT scan.  Please note that this radiation exposure is not 
necessary for your medical care and is for research purposes only.  The amount of radiation 
you will receive in this study is 1.4 rem in children 15 years oldwhich is above the NIH 
Radiation Safety Committee guidelines of 0.5 rem per year in children, but the Radiation 
Safety Committee has approved this scan in patients because of the value of the scientific 
information we will obtain. The amount of radiation you will receive in this study in adults 
is 1.1 rem, which is within the NIH Radiation Safety Committee guidelines of 5 rem per 
year.  The average person in the United States receives a radiation exposure of 0.3 rem per 
year from natural sources, such as the sun, outer space, and the earth's air and soil.  If you 
would like more information about radiation, please ask the investigator for a copy of the 
pamphlet, An Introduction to Radiation for NIH Research Subjects. 
While there is no direct evidence that the amount of exposure received from participating in 
this study is harmful, there is indirect evidence it may not be completely safe.  There may 
be a very slight increase in the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care at the NIH or other places/hospitals that use 
radiation.  This way we can make sure that you will not receive too much radiation.  Consider X-
rays taken in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear 
medicine scans in which radioactive materials were injected into your body.  
If you are pregnant or breastfeeding, you will not be permitted to participate in this 
research study.  It is best to avoid radiation exposure to unborn or nursing children since they 
are more sensitive to radiation than adults.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0208 
CONTINUATION: page 17 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
I agree to participate in this research FDG-PET in this study.  
 
Yes              No               Initials_________ 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0208 
CONTINUATION: page 18 of 19 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Brigitte Widemann, M.D., Building 10, Room 1-5750, Telephone:  240-
760-6203. You may also call the Clinical Center Patient Representative at 301-496-2626. If you 
have any questions about the use of your specimens or data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone:  240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0208 
CONTINUATION: page 19 of 19 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby consent to take part in this 
study. 
I have read the explanation about this study and 
have been given the opportunity to discuss it and to 
ask questions.  I hereby give permission for my 
child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/ 
Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the 
study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM DECEMBER 03, 2018 THROUGH DECEMBER 17, 2019. 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name