A Phase II Trial of Valproic Acid in Patients With Advanced Thyroid Cancers of Follicular Origin
Phase: PHASE2
Conditions: Thyroid Neoplasm
Sponsor: National Cancer Institute (NCI)

Amendment
Protocol Number:
10C0041-D
Principal Investigator: Electron Kebebew,  MD 
NCI 
EOB 
301.496.5049 
Electron.Kebebew@nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
346736
Protocol Title:
A Phase II Trial of Valproic Acid in Patients with Advanced Thyroid Cancers of Follicular Origin
SIGNATURES
Principal Investigator (*): 
Electron Kebebew,  MD - applied signature on 04/21/2015 7:56 AM EDT
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
Electron Kebebew, MD - applied signature on 04/21/2015 7:57 AM EDT
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
N/A
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 04/24/2015 7:32 AM EDT
Clinical Director:
William Dahut - applied signature on 04/22/2015 1:43 PM EDT
CONCURRENCE
OPS Protocol Specialist:
Signature                                                         Print Name                                              Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at 
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for 
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and 
used solely for those purposes.  Questions may be addressed to the Protrak System Owner. 
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
Expedited
DEC Clearance Date:
NA
Protocol Version Date:04/17/2015
C.Bonds-Beeken   AM D    05/04/15

Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
Abbreviated Title: VPA for Advanced Thyroid Cancer
NCI Protocol #: 10-C-0041D
Version Date: 04/17/2015
Title: A Phase II Trial of Valproic Acid in Patients with Advanced Thyroid Cancers of 
Follicular Origin
Principal Investigator:
Electron Kebebew, M.D.
EOB/CCR/NCI
Bldg 10-CRC Room 4-5952
10 Center Drive
Bethesda, MD 20892
(301) 496-5049
kebebewe@mail.nih.gov
Associate Investigators:
Naris Nilubol, M.D., EOB/CCR/NCI
Monica Skarulis, M.D., DEOB/CES/NIDDK
Craig Cochran, R.N., DEOB/CES/NIDDK
James Reynolds, M.D., NMD/CC/NIH
Seth Steinberg, Ph.D., BDMS/OCD/CCR/NCI
Marina Zemskova, M.D., DEOB/CES/NIDDK
Dan Zlott, PharmD, PHARM/CC/NIH
Samira Sadowski, M.D., EOB/CCR/NCI
Dhaval Patel, M.D., EOB/CCR/NCI
Vladimir Neychev, M.D., EOB/CCR/NCI
Roxanne Merkel, R.N.,
OCD/CCR/NCI
Rachel Aufforth, M.D., EOB/CCR/NCI
Referral Contacts:
Roxanne Merkel, R.N., OCD/CCR/NCI

Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
PRECIS
Background:
x
Patients who have advanced differentiated thyroid cancers (Stage IV) have a five-year 
survival of only 25%. Clinically this results in more aggressive growth, metastasis, 
decreased or loss of iodine uptake in the tumor, and tumors that may be refractory to 
conventional treatment: surgical resection, radioactive iodine treatment and thyroid 
hormone for TSH suppression. 
x
In thyroid cancer, valproic acid, at clinically achievable concentrations, has an 
antiproliferative and differentiating effect. 
x
We hypothesize that valproic acid may inhibit proliferation and induce differentiation 
in thyroid cancer cells so that 131-I may detect residual disease and be more effective 
for radioiodine ablation of thyroid cancer cells of follicular cell origin.  
Objectives:
x
The primary goal of this study is to determine if valproic acid will have an 
antineoplastic and differentiation effect in patients with advanced and or metastatic 
thyroid cancer of follicular cell origin. 
Eligibility:
x
Unresectable advanced and or poorly differentiated thyroid cancers of follicular cell 
origin (excluding anaplastic and medullary thyroid cancer) that have no uptake (<1%) 
on radioiodine scan or are unresponsive to radioiodine therapy.  
x
Elevated serum thyroglobulin (Tg) level (>100ng/ml on thyroid hormone; >10ng/ml 
off thyroid hormone).  
Design:
x
This will be an open label phase II study to assess the efficacy of valproic acid 
therapy as an antiproliferative and differentiation agent in patients with incurable 
differentiated thyroid cancer (unresponsive and/or radioiodine negative and 
unresectable).
x
Oral valproic acid will be administered to reach a therapeutic serum level (50 to 100 
μg/ml).
x
The number of patients to be enrolled is 25 with an interim analysis of response once 
13 patients are evaluable for response. It is anticipated that five patients may be 
enrolled per year.
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
TABLE OF CONTENTS
 
 
1 
INTRODUCTION................................................................................................................. 5 
1.1 
Study Objectives............................................................................................................ 5 
1.2 
Background and Rationale .......................................................................................... 5 
1.3 
Study Design.................................................................................................................. 6 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT.................................................... 7 
2.1 
Eligibility Criteria......................................................................................................... 7 
2.2 
Research Eligibility Evaluation ................................................................................... 9 
2.3 
Registration Procedures............................................................................................... 9 
3 
STUDY IMPLEMENTATION.......................................................................................... 10 
3.1 
Study Design................................................................................................................ 10 
3.2 
Phase 1 – weeks 1-10................................................................................................... 10 
3.3 
Evaluations weeks 1-10 {all evaluations are +/- 3 days}.......................................... 11 
3.4 
Thyrogen RAI Scan .................................................................................................... 12 
3.5 
Phase 2 weeks 11-16.................................................................................................... 13 
3.6 
RAI Ablative Treatment............................................................................................. 15 
3.7 
Research Evaluations.................................................................................................. 15 
3.8 
Follow up for all patients {from week 17} ................................................................ 15 
3.9 
Criteria for Removal from Protocol Therapy and Off Study Criteria.................. 16 
4 
SUPPORTIVE CARE ........................................................................................................ 17 
5 
DATA COLLECTION AND EVALUATION ................................................................. 17 
5.1 
Data Collection............................................................................................................ 17 
5.2 
Response Criteria........................................................................................................ 18 
5.3 
Toxicity Criteria.......................................................................................................... 20 
5.4 
Sample Storage, Tracking, and Disposition ............................................................. 20 
6 
STATISTICAL Considerations......................................................................................... 21 
6.1 
Rates and Types of Responses ................................................................................... 21 
6.2 
Sample Size and Power Analysis ............................................................................... 21 
7 
HUMAN SUBJECTS PROTECTIONS............................................................................ 21 
7.1 
Rationale for Subject Selection.................................................................................. 21 
7.2 
Participation of Children ........................................................................................... 22 
7.3 
Evaluation of Benefits and Risks/Discomforts ......................................................... 22 
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
7.4 
Risks/Benefits Analysis............................................................................................... 22 
7.5 
Consent and Assent Process and Documentation .................................................... 22 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN............................................................................................................................................ 22 
8.1 
Definitions.................................................................................................................... 22 
8.2 
NCI-IRB Reporting .................................................................................................... 24 
8.3 
Data and Safety Monitoring Plan.............................................................................. 25 
9 
PHARMACEUTICAL INFORMATION......................................................................... 26 
9.1 
Valproic Acid - Depakote........................................................................................... 26 
9.2 
Liothyronine sodium, Cytomel .................................................................................. 26 
10 REFERENCES.................................................................................................................... 28 
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
To determine if valproic acid will inhibit thyroid cancer growth, as evidenced by a 
decrease in thyroglobulin level, and tumor size. 
1.1.2
To determine if valproic acid therapy will induce differentiation of thyroid cancer cells 
and therefore increase uptake of radioactive iodine by the tumor cells.  
1.1.3
To determine the effect of valproic acid on differentiation markers of thyroid cancer and 
global gene expression in thyroid tumor tissue.
1.2
BACKGROUND AND RATIONALE
Thyroid cancer is the fastest growing cancer diagnosis in the U.S.1. Approximately 10-15% of 
patients present with aggressive disease and have about a 30% mortality rate at 5-10 years 
following initial treatment 2. Patients with stage IV differentiated thyroid cancer have a five-year 
survival of only 25%. In patients with progressive or recurrent differentiated thyroid cancer, 
one-third of patients develop or have dedifferentiated tumors (loss of differentiation) 3.
Clinically this results in more aggressive growth, metastasis, decreased or loss of iodine uptake 
in the tumor, and tumors that may be refractory to conventional treatment: surgical resection, 
radioactive iodine (RAI) treatment and thyroid hormone for TSH suppression.  In addition, up to 
20% of patients with differentiated thyroid cancer have evidence of residual disease as indicated 
by detectable serum thyroglobulin levels but have negative RAI scans4.  Patients with 
differentiated thyroid cancer are usually treated after total or near total thyroidectomy with RAI
(I-131) in order to ablate any residual thyroid tissue and/or cancer. Loss of iodine uptake makes 
RAI ablation therapy ineffective.  Further dedifferentiation of thyroid cancers of follicular cell 
origin, in about 1% of patients, leads to the formation of anaplastic thyroid carcinoma, which is 
uniformly lethal.
Valproic acid, a histone deacetylase (HDAC) inhibitor, has long been used as an anticonvulsant 
to treat seizures in patients with epilepsy.  It has also been used to treat bipolar disorder.  Recent 
studies have shown that this class of drugs has promising effects in the treatment of cancer by 
inhibiting cancer cell proliferation, inducing apoptosis, cell cycle arrest and differentiation in 
brain, hematologic, endometrial, ovarian and prostate cancers 5-8. Preclinical studies also suggest 
that valproic acid has a similar antiproliferative and differentiating effect in human thyroid 
cancer cells 9-14.
Valproic acid interacts with the catalytic site of histone acetyltransferases to disrupt its activity.  
The post-translational modification process of acetylation is critical to gene transcription, with 
increased acetylation resulting in increased gene transcription.  Because acetylation affects 
chromatin structure and nucleosomal packaging, it affects gene expression through this 
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
mechanism. Approximately 2-5% of transcribed genes are significantly affected after treatment 
with HDAC inhibitors.
In thyroid cancer, valproic acid, at concentrations clinically achievable, has an antiproliferative
and differentiating effect. At concentrations of 0.5 to 2.0mM, valproic acid inhibited growth by 
55 to 80% 9-14. Valproic acid also upregulates sodium-iodine symporter (NIS) gene expression 
in dedifferentiated thyroid cancer cells12-14.  The NIS gene encodes the Na+/I- symporter, located 
on the basolateral membrane of follicular thyroid cells and is responsible for iodide uptake.
Downregulated NIS expression is the predominant mechanism of dedifferentiation in thyroid 
cancer cells of follicular cell origin that makes RAI ablation therapy ineffective.  Treatment with 
valproic acid increases iodide accumulation in poorly differentiated thyroid cancer cells by 
increasing the expression of the NIS gene.
Patients with differentiated thyroid cancers are routinely followed with serial thyroglobulin (Tg) 
levels, ultrasonography and RAI scans.  Recurrent or metastatic thyroid cancer of follicular cell 
origin is suspected by elevated serum Tg in the absence of RAI uptake on a diagnostic scan.  
Such "false negative" RAI scans occur in up to 20% of diagnostic RAI scans in patients with 
detectable Tg levels following thyroid ablation and positron emission tomography (PET) is 
helpful in only a subset of cases for detecting residual disease. The prognosis for patients with 
thyroid cancer is related to the ability of the cancer to accumulate RAI, since well-differentiated 
thyroid cancers usually respond to treatment with RAI.  
We hypothesize that valproic acid may inhibit proliferation and induce differentiation in thyroid 
cancer cells so that 131-I may detect residual disease and be more effective for radioiodine 
ablation of thyroid cancer cells of follicular cell origin (excluding anaplastic and medullary 
thyroid cancer).  If our study demonstrates a tumor response to valproic acid by decreased tumor 
size and/or decreased thyroglobulin and/or increased radioiodine uptake in patients who are 
otherwise no longer amenable to conventional therapy, we will have data to support conducting a 
large, multicenter, trial using valproic acid.
We will also perform correlative studies in tumor tissue biopsy samples to directly determine an 
effect of valproic acid on differentiation markers, cell cycle and apoptosis regulatory genes, and 
genome-wide gene expression analysis.
1.3
STUDY DESIGN
This will be an open label phase II study to assess the efficacy of valproic acid therapy as an 
antiproliferative and differentiation agent in patients with incurable differentiated thyroid cancer 
(unresponsive and/or radioiodine negative and unresectable). Patients with advanced thyroid 
cancers of follicular cell origin who have failed conventional therapy (including total 
thyroidectomy, I-131 ablation, with or without external radiation) who are thyroglobulin-
positive/radioiodine-unresponsive will be eligible to enroll in this study.  The intervention plan 
will be to administer valproic acid to all patients and then to compare serum thyroglobulin levels, 
radioiodine uptake and tumor size, by imaging studies, before and after therapy, as well as, 
perform correlative tumor tissue studies.
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
Valproic acid will be administered at an initial dose of 500 mg daily, titrating to 1500 mg daily 
by week 2 and continuing for 10 weeks. Patients will then undergo imaging for response. 
Depending on the response, patients will proceed to ablation, continue with an increased dose of 
valproic acid or be removed from treatment.  This dose and dosing schedule was chosen to 
obtain a concentration level known to have an antineoplastic effect based on the fact that an oral 
dose of 500 mg twice daily should achieve plasma concentrations of valproic acid typically 
ranging from 0.4-0.6mM. Valproic acid serum trough levels will be obtained for all patients at 
the beginning of week 2 and then weekly thereafter to assess compliance, possible drug toxicity 
and to ensure plasma concentration is 50 to 100 μg/ml.
We will perform tumor tissue biopsy of the target lesions in patients with tumor that is accessible 
to percutaneous biopsy by ultrasound or CT scan guidance. This will allow us to determine if 
valproic acid has effects on differentiation, cell cycle and apoptosis regulatory genes, as well as, 
genome-wide gene expression profile with valproic acid treatment. The correlative studies will 
then be evaluated based on response and therapeutic serum valproic acid levels. (Study Schema 
Appendix 1)
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1 Advanced/poorly differentiated thyroid cancers of follicular cell origin that have no 
uptake (<1%) on radioiodine scan or are unresponsive to radioiodine therapy.  
Unresponsiveness to radioiodine therapy is defined as a patient’s thyroglobulin not 
falling to less than 2ng/ml within 6 months after previous radioiodine ablative 
treatment.
2.1.1.2 Extensive (invasive) loco-regional tumor mass and/or metastatic spread, rendering 
patient inoperable 
2.1.1.3 Thyroglobulin (Tg) levels greater than or equal to 100 ng/ml in the absence of Tg 
antibodies.  Patients who are Tg-antibody (Tg-Ab) positive may be included despite a 
lower Tg level if they have detectable disease on cross sectional imaging.  (The 
presence of Tg-Ab may lead to falsely low Tg levels and therefore render the Tg a less 
sensitive marker of disease.  However, Tg-Ab has been shown to also act as a tumor 
marker, and will be used as an endpoint for the study in patients who are Tg-Ab 
positive.) 
2.1.1.4 Within 18 months of enrollment, patients must have had an RAI scan, showing no or 
therapeutically insignificant RAI uptake .
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
2.1.1.5 Initial therapy must have included total/near-total thyroidectomy and RAI ablation 
therapy.
2.1.1.6 Patients must have had no chemotherapy, radiotherapy, or biologic therapy for their 
malignancy in the month prior to treatment and must have recovered from all side 
effects of therapeutic and diagnostic interventions.
2.1.1.7 Greater than or equal to 18 years of age
2.1.1.8 Must be able to understand and sign the Informed Consent Document
2.1.1.9 Clinical performance status of ECOG less than or equal to 1
2.1.1.10 Life expectancy of greater than three months
2.1.1.11 Women of childbearing potential must have a negative serum beta-HCG within 72 
hours prior to study entry and must be willing to practice effective birth control to 
prevent pregnancy while receiving treatment and for three months after treatment is 
discontinued.  All males of child fathering potential must also be willing to practice 
effective birth control.
2.1.1.12 Laboratory results must be within the following parameters before entry:
o
Absolute Neutrophil Count > 750 cells/mm3
o
Hemoglobin > 8.0 gm/dl
o
Platelet count > 75000/mm3
o
Creatinine < 1.5 times ULN
o
Total protein > 6.4.
o
Total bilirubin should be < 1.5 times ULN.  
o
AST (SGOT), ALT (SGPT) < 1.5 times ULN.
o
Amylase < 1.5 times ULN
o
Ammonia < 1.5 times ULN
2.1.2
Exclusion Criteria
2.1.2.1 Allergy to valproic acid.
2.1.2.2 Current coexisting malignancy other than basal cell carcinoma.
2.1.2.3 Women of child-bearing potential who are pregnant or breastfeeding. Valproic acid is a 
known teratogen, causing primary neural tube defects, facial abnormalities, and skeletal 
malformation; therefore pregnant women will be excluded.  Additionally, patients that
become pregnant while on study protocol will be discontinued immediately.
2.1.2.4 Active systemic infections, coagulation disorders or other major medical illnesses
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
2.1.2.5 Patients taking tolbutamide, warfarin, zidovudine, benzodiazapines, clonazepam, 
diazepam  
2.1.2.6 Seizure disorder
2.1.2.7 Patients with brain metastases
2.2
RESEARCH ELIGIBILITY EVALUATION
Within 4 weeks prior to treatment
x
Ultrasound of the neck 
x
MRI or CT of the Chest
x
Bone scan for patients in whom bone metastases are suspected
x
FDG PET scan
x
Health Related Quality of Life HRQOL) form completion
x
MRI of the brain
Within 2 weeks prior to treatment
x
Laboratory Evaluations
o
Thyroid Stimulating Hormone (TSH)
o
Thyroglobulin (Tg)
o
CBC with differential and platelets
o
BUN, creatinine, total protein, total bilirubin, ALT, AST ALKP, 
amylase, ammonia, albumin
o
24 hour urinary iodine level
o
Tumor biopsy
x
Thyrogen (recombinant TSH) RAI scan (for radioiodine uptake and TSH 
stimulated thyroglobulin levels. See section 3.4)
x
Complete history and physical examination including Height, Weight and 
ECOG status
x
Tumor tissue biopsy of any accessible lesions
Within 3 days prior to treatment
x
Serum or urine beta-HCG (if applicable)
2.3
REGISTRATION PROCEDURES
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and faxed to 301-
480-0757.  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 
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
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. 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN  
Current conventional therapy for patients with thyroid cancers of follicular cell origin after 
thyroidectomy and ablative treatment with 131-I involves only thyroid hormone for TSH 
suppression.  In this study, patients will receive TSH suppression therapy with valproic acid for 
16 weeks. 
The total study period will be 18 weeks, with a one year follow up. Patients who respond to 
treatment as evidenced by decreased Tg level, RAI uptake or decreased tumor size will continue 
treatment of valproic acid for 1 year.
3.2
PHASE 1 – WEEKS 1-10
3.2.1
Drug Administration {all doses are given orally}
x
Week 1 
o
(Days 1-3): Valproic acid  - 500 mg every evening
o
(Day 4-7): Valproic acid  - 500 mg twice daily (morning and 
evening)
x
Weeks 2 through 10
o
Valproic acid – 500 mg every morning and 1000 mg every evening
Drug will be dispensed at each clinic visit and include the number of capsules necessary to be 
administered through the next scheduled clinic visit plus 4 days.  Patients will be instructed to 
take the medications at the same time each day, with or without food.  Prior to discharge from 
the clinic, the research nurse will review the following information with the patient: 
o
The toxicities of the agent and how to treat/prevent them
o
The signs and symptoms to report to the study team
o
How to complete the patient diary
3.2.2
Valproic acid levels
Blood samples will be collected prior to dosing (trough levels) weekly from weeks 2 to 10 and 
week 12 for patients on Schedule 2. The patient will be asked to refrain from taking the morning 
dose of valproic acid and will be instructed to bring in the morning dose along with the rest of 
valproic acid pills for a pill count.  
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Abbreviated Title: VPA for Advanced Thyroid Cancer
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3.2.3
Dose Modification
Based on the serum valproic acid trough level, the dose of valproic acid will be titrated as noted 
below to maintain serum trough levels between 50 and ȝJPl.  Any change of the dose of 
valproic acid will require repeat serum trough levels within 3 days as described above. 
x
,IWKHVHUXPWURXJKOHYHOLV!ȝJPOWKHGRVHZLOOEHUHGXFHGE\125
to 500 mg depending on the serum level
x
,IWKHVHUXPWURXJKOHYHOLVȝJPOWKHGRVHZLOOEHLQFUHDVHGE\125
to 500 mg depending on the serum level
x
For persistent grade 2 toxicities, the dose will be adjusted at the discretion 
of the PI
x
For grade 3 or greater toxicities, the dose will be held until the toxicity has 
resolved to grade 1 or baseline. Following resolution, the dose will be 
reduced
3.2.4
Protocol stopping rules
If more that 15% of patients withdraw from the study due to grade3 toxicity, a safety endpoint 
will be reached and the study will be closed to accrual. The stopping rule applies to all subjects 
during the entire treatment and follow up period of the study.
3.3
EVALUATIONS WEEKS 1-10 {ALL EVALUATIONS ARE +/- 3 DAYS}
x
Week 2-10:
o
Serum valproic acid levels may be performed weekly on all 
patients for at least the first 4 weeks of treatment.  
o
Reports from all evaluations performed at outside institutions will 
be faxed to:
Candice Cottle-Delisle, RN or Roxanne Merkel, RN
301-402-1788
This includes lab values, physical exams, patient diaries, etc.
x
Week 2 (Day 10): 
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin and 
b-HCG (if applicable).  
o
Toxicity assessment, pill count, and review of diary
x
Week 4 – may be performed by their primary physicians
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin and 
b-HCG (if applicable).  
o
Toxicity assessment, pill count, and review of diary
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
x
Week 6: 
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin and 
b-HCG (if applicable).  
o
Toxicity assessment, pill count, and review of diary
x
Week 8 - may be performed by their primary physicians
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein,
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin and 
b-HCG (if applicable).  
o
Toxicity assessment, pill count, and review of diary
x
Week 10:
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin and 
b-HCG (if applicable).  
o
Serum valproic acid levels.
o
Toxicity assessment, pill count, and review of diary
o
Tg, TSH 
o
Thyrogen Scan
o
Health Related Quality of Life HRQOL) form completion
o
Tumor tissue biopsy of any accessible lesions (Section 3.7)
o
24 hour urinary iodine level
3.4
THYROGEN RAI SCAN
All patients will undergo a Thyrogen® (thyrotropin alfa for injection) RAI scan at entry to the 
study and after completion of 10 weeks of valproic acid treatment. Depending on the results of 
the scan, patients will continue valproic acid and prepare for an ablation, or will continue with 
valproic acid.
Procedure:
x
Low iodine diet for 2 weeks
x
Thyrogen 0.9mg intramuscularly (in the buttocks) every 24 hours x 2
doses
x
123-I radioiodine 24 hours following the last dose of Thyrogen
x
Serum Tg and TSH immediately prior to the scan
x
Scan 48 hours after radioiodine administration (72 hours after thyrogen 
administration) 
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Abbreviated Title: VPA for Advanced Thyroid Cancer
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3.5
PHASE 2 WEEKS 11-16
3.5.1
Schedule 1 - Patients who exhibit an increased radioiodine uptake on Thyrogen scan 
post valproic acid therapy at week 10.
x
Week 11:
o
Discontinue Levothyroxine
o
Begin Cytomel for 4 weeks (25 micrograms twice a day)
o
Continue valproic acid for a total of 16 weeks
Note: medication will be dispensed following review of Thyrogen 
scan
x
Week 12 - may be performed by their primary physicians
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP,  amylase, ammonia, albumin 
and b-HCG (if applicable).  
o
Toxicity assessment, pill count, and review of diary
x
Week 14: may be performed by their primary physicians
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP,  amylase, ammonia, albumin 
and b-HCG (if applicable).  
o
Toxicity assessment, pill count, and review of diary
o
Stop Taking Cytomel.
o
Begin low iodine diet.
x
Week 16: 
o
Measure TSH, Tg and 24 hour urinary iodine.  
o
I-131 Ablative treatment {refer to Section 3.6}.
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin and 
b-HCG (if applicable).  
o
Toxicity assessment, pill count, and review of diary
x
Week 17: 
o
Post ablation RAI scan {5 days (+/- 2 days) following 
administration of 131-I}.
 Ultrasound of the neck 
 MRI or CT of the neck and chest
 FDG-PET scan
o
Resume Levothyroxine (pre study dose) .
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Abbreviated Title: VPA for Advanced Thyroid Cancer
Version Date: 04/17/2015
o
Stop valproic acid end of week 17
o
Toxicity assessment, pill count, and review of diary
o
Health Related Quality of Life HRQOL) form completion
3.5.2
Schedule 2 – patients who do not exhibit an increased radioiodine uptake on Thyrogen 
scan post valproic acid therapy at week 10
x
Week 11:
o
Maintain valproic acid dose
Note: medication will be dispensed following review of the Thyrogen 
scan.
x
Week 12:  
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin and 
b-HCG (if applicable).  
o
Serum valproic acid levels.
o
Toxicity assessment and review of diary
x
Week 14:  may be performed by local physician
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP,  amylase, ammonia, albumin 
and b-HCG (if applicable).  
o
Toxicity assessment and review of diary
x
Week 16: 
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP,  amylase, ammonia, albumin 
and b-HCG (if applicable).  
o
Tg, TSH
o
Toxicity assessment and review of diary
o
Ultrasound of the neck and mediastinum
o
MRI or CT of the neck and chest
o
FDG-PET scan
o
Health Related Quality of Life HRQOL) form completion
x
Weeks 17-52
o
Patients who show a response by RECIST criteria or have a 
decreased thyroglobulin level from Day 1 of the treatment 
(registered as a partial response to the treatment) will continue on 
valproic acid at their current dose for a total of 52 weeks.
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o
Stop valproic acid if no response
o
Sixteen weeks or 4 months is significant amount of time to 
measure response to treatment and therefore, if there is a response, 
a patient’s thyroglobulin levels should have decreased by then, as 
well as, by RECIST criteria.
o
Patients who show no response, patients will stop valproic acid 
treatment and continue with routine follow up.
3.6
RAI ABLATIVE TREATMENT
Activity of 131-I will be determined by dosimetry performed during diagnostic study. The 
therapeutic dose will not exceed 600 miCu.
3.7
RESEARCH EVALUATIONS
3.7.1
Tumor tissue biopsy samples
3.7.1.1 Patients who have locoregional or metastatic disease that is amenable to ultrasound 
guided and or CT scan guided needle biopsy will have this done of the target lesion. 
This will be performed at study entry and at week 10.
3.7.1.2 These samples will be processed as described in Section 5.4.
3.8
FOLLOW UP FOR ALL PATIENTS {FROM WEEK 17}
x
3 months
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP,  amylase, ammonia, albumin.  
o
CT and/or MRI of the chest
o
Health Related Quality of Life HRQOL) form completion
o
Ultrasound of the neck as indicated
o
Tg, TSH
x
6 months
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin..  
o
Tg, TSH 
o
Health Related Quality of Life HRQOL) form completion
x
9 months - for patients continuing on valproic acid only-
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin.  
o
Tg, TSH
o
Health Related Quality of Life HRQOL) form completion
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x
12 months
o
Physical exam including ECOG status
o
CBC with differential, platelets, BUN, creatinine, total protein, 
total bilirubin, ALT, AST, ALKP, amylase, ammonia, albumin. 
o
CT and/or MRI of the chest
o
Ultrasound of the and neck 
o
Tg, TSH 
o
Health Related Quality of Life HRQOL) form completion
3.9
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.9.1
Criteria for removal from protocol therapy
x
Patient request
x
PI discretion, if the PI feels it is not in the best interest of the patient to 
remain on treatment
x
Liver Dysfunction (enzyme levels above 1.5 times ULN)
x
Platelet < 50,000
x
Ammonia levels > 65 mol/l
x
Progressive disease
x
Pregnancy
x
Pancreatitis (amylase level above 1.5 ULN)
x
Alcohol consumption
x
Other unacceptable toxicities as determined by the PI
3.9.2
Off-study Criteria
x
Completion of the follow up period
x
Patient request
x
PI discretion ,if the PI feels it is not in the best interest of the patient to 
remain on treatment
Note: Patients must remain on study until all study related adverse events 
have resolved to grade 2 or less or baseline.
3.9.3
Off –Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
faxed to 301-480-0757.
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4
SUPPORTIVE CARE
Appropriate supportive care for any side effects or toxicity may be provided by the Endocrine 
Oncology Branch.  Patients may be admitted as necessary to manage issues related to study 
medication or disease process. 
5
DATA COLLECTION AND EVALUATION
5.1
DATA COLLECTION
Data will be collected using the NCI C3D web based data collection system.
All data will be kept secure. Personal identifiers will not be used when collecting and storing 
data. An enrollment log will be maintained in the regulatory binder/file which is the only 
location of personal identifiers with unique subject identification number.
5.1.1
Routine Data Collection
Following enrollment, all adverse events will be described in the source documents and be 
reviewed by the designated research nurse, and captured in C3D.  
x
For laboratory values obtained at sites other than the NIH Clinical Center: 
only the following values (highest grade per cycle) will be captured in 
C3D:
o
Hemoglobin, total white blood cell count, absolute neutrophil 
count, platelet count
o
Creatinine, ALT, AST, Total bilirubin, Total protein, Albumin, 
Alkaline phosphatase, Amylase, Ammonia and b-HCG (+/-) if 
appropriate.
o
Any unexpected laboratory DEQRUPDOLW\JUDGHSRVVLEO\
probably or definitely related to the research
x
During the follow up period (more than 30 days following the last 
treatment), only those events that are serious, unexpected, and related to 
the treatment will be captured in C3D. 
5.1.2
Exclusions to Routine Data Collection
The following Adverse Events will be captured only in the source documents and will not be 
reported in C3D:
x
Laboratory values that do not support the diagnosis of a reportable event
x
All grade 1 events
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5.1.3
Concomitant medications 
Only those medications that the patient is taking at baseline on a routine basis or medications that 
cause an AE will be captured in C3D.  {Thus onetime medications, PRN medications, and 
medications given to treat adverse events will not be captured in C3D.}
5.2
RESPONSE CRITERIA
RAI uptake and Tg level will be compared pre- and post-valproic acid treatment.  The nuclear 
medicine radiologists using a planar technique will measure the RAI scan uptake.  The post-
valproic acid scan will then be compared side-to-side with the pre-valproic acid scan, using the 
planar technique, and will then be scored as "increased" or "unchanged" compared to 
zero/minimal (<1%) uptake seen on the pre-valproic acid scan.  We will define 4 categories of 
response:
1.
Complete response: increased RAI uptake on post-valproic acid therapy at week 10, 
AND a decrease in Tg level to less than 2 ng/ml (or a decrease in Tg-Ab level to less than 
2.0 IU/ml) at 10 weeks AND disappearance of all lesions at 16 weeks.
2.
Partial response:  increased RAI uptake on post-valproic acid scan at week 10, OR a 
decreased Tg level (or a decrease in Tg-Ab level by more than 20%) at 10 weeks AND 
30% decrease in target lesion at 16 weeks.
3.
Stable disease: no change in RAI uptake AND Tg levels (or Tg-Ab level) AND no 
significant change of lesions 16 weeks.
4.
Progressive disease: tumor mass increases OR Tg levels (or Tg-Ab levels) increases over 
10 weeks OR at least 20% increase in target lesion at 16 weeks.
Target lesions will be evaluated according to the RECIST response criteria outlined below.
5.2.1
Response Criteria RECIST 1.1
5.2.1.1 Evaluation of target lesions*
x
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.
x
Partial Response (PR):  At least a 30% decrease in the sum of 
diameters of target lesions taking as reference the baseline sum 
diameters.
x
Progression (PD):  At least a 20% increase in the sum of diameters 
of target lesions taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study) or the 
appearance of one or more new lesions.
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x
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD taking as references the 
smallest sum diameters while on study.
*
All measurable lesions up to a maximum of 5 lesions (and a maximum of 2 lesions per organ) 
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 organs involved, and be suitable for accurate repetitive 
measurements (either by imaging techniques or clinically).  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.  The baseline sum diameters will be used as reference to 
further characterize the objective tumor response of the measurable dimension of the disease.
5.2.1.2 Evaluation of non-target lesions**
x
Complete Response (CR): Disappearance of all non-target lesions 
and normalization of tumor marker level. All lymph nodes must be 
non-pathological in size (<10mm short axis).
x
Non-CR/Non-PD:  Persistence of one or more non-target lesions 
and/or maintenance of tumour marker level above the normal 
limits.
x
Progression (PD):  Appearance of one or more new lesions.  
Unequivocal progression of existing non-target lesions
**
All other lesions (or sites of disease), including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required, and these lesions should be followed as “present”, “absent ”, or in rare 
cases “unequivocal progression.”
5.2.1.3 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.
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Nor all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
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5.3
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). 
5.4
SAMPLE STORAGE, TRACKING, AND DISPOSITION
Tumor tissue biopsy samples
Patients who have locoregional or metastatic disease that is amenable to ultrasound guided and 
or CT scan guided needle biopsy will have this done of the target lesion. This will be performed 
at study entry and at 10 weeks. 
Immediate cytopathologic review will be performed to confirm the presence of tumor cells. 
The samples will then be stored in -80qC until the immunohistochemistry studies and genome-
wide gene expression analysis.
The Na/I symporter expression level will be determined by quantitative RT PCR and 
immunohistochemistry (11-14). Gene expression levels (differentiation markers, cell cycle and 
apoptosis regulatory genes) changes with valproic acid treatment  will be determine by using 
pathway specific gene expression arrays (12,13).
Blood samples
The laboratory studies will be blinded to the response of patients to therapy.
Samples will be sent to the Endocrine Oncology Laboratory for processing:
NCI Endocrine Oncology Branch Laboratory
CRC Room 4-5840
10 Center Drive, MSC 1201
Bethesda, MD  20892-1201
(301) 435-7891
At the completion of the protocol, the investigator will dispose of all specimens in accordance 
with the environmental protection laws, regulations and guidelines of the Federal Government 
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and the State of Maryland.  Any unintentional loss or destruction of the tissue will be reported to 
the IRB.
6
STATISTICAL CONSIDERATIONS
6.1
RATES AND TYPES OF RESPONSES
Rates and types of responses will be determined and presented with 95% confidence intervals.  
Patient characteristics (demographic and clinical) will be tabulated. Overall survival will be 
summarized using Kaplan-Meier curves.  Toxicities will be tabulated by grade and organ system. 
Summary responses to the quality of life instrument at selected time points will be tabulated; to 
aid in the interpretation of temporal changes in quality of life items, change scores will be 
evaluated using the Wilcoxon signed rank test or McNemar’s test as appropriate.
6.2
SAMPLE SIZE AND POWER ANALYSIS
This is a phase II study aimed at measuring the impact of valproic acid on iodine uptake and on 
tumor response. Response will be defined as complete or partial response as outlined in section 
5.2. The study uses a two-stage Simon optimal design with an interim analysis planned when 13 
patients are evaluable for response. If no complete/partial responses are seen at that time the 
study will close to accrual. The study will proceed to stage II if at least one response is seen 
among the first 13 patients. At the end of study, if the cumulative number of responses among 
the 20 evaluable patients is 3 or more, valproic acid will be considered efficacious, while this 
will not be the case if 1-2 responses are noted.  Under the null hypothesis of a true response rate 
that does not exceed 5% (p0=0.05) , the two-stage design will control type I error (alpha)  to be 
no more than 7.4% , and when the true response rate is at least 25% (p1=0.25), the study has at 
least 90% power (beta=0.10).   The probability of triggering early stopping is at least 51% if the 
true response rate is 5% or less, and less than 2.5% if the true response rate is 25% or more.  If 
the accrual is stopped at the first stage due to futility, the upper bound of a 95% confidence 
interval for the response rate will be less than 25%. We will plan to enroll up to 25 patients with 
the expectation that 20 patients (80%) will be evaluable for response.
The stopping rule for Grade 3 toxicity is set at 15% as the acceptable toxicity rate because the 
study is designed to detect a treatment efficacy rate of 15% or higher. Therefore, if the 
acceptable toxicity rate is higher than the expected efficacy rate the study will be stopped.
7
HUMAN SUBJECTS PROTECTIONS
7.1
RATIONALE FOR SUBJECT SELECTION
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  To date, there is no information which suggests that differences in drug 
metabolism or disease response would be expected in any one patient group. As advanced 
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Abbreviated Title: VPA for Advanced Thyroid Cancer
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thyroid cancers are rare in the pediatric population, study will not include patients < 18 years of 
age. 
7.2
PARTICIPATION OF CHILDREN
As noted above, children under the age of 18 will not be enrolled. 
7.3
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
Treatment with valproic acid may prove to be more effective than current conventional therapy 
(thyroid hormone suppression) for advanced differentiated thyroid cancers.  Patients with a long 
history of unresponsiveness to other treatment modalities (surgical debulking, thyroid hormone 
suppression, radioactive iodine, external beam radiation) may experience an actual therapeutic 
benefit.  Risks include those associated with the agent, and standard imaging procedures for this 
disease entity.  Care will be taken to minimize side effects, but they can be unpredictable in 
nature and severity.  This study may involve risks to patients, which are currently unforeseeable.  
All patients will have laboratory tests to monitor for complications.  If patients suffer any 
physical injury as a result of the participation of this study, immediate medical treatment is 
available at the Clinical Center, National Cancer Institute, Bethesda, Maryland.  Although no 
compensation is available, any injury will be evaluated and treated in keeping with the benefits 
or care to which patients are entitled under applicable regulations.
7.4
RISKS/BENEFITS ANALYSIS
Patients with differentiated thyroid cancer of follicular cell origin have limited options available 
to them. Valproic acid is an approved agent for other indications and the toxicities have been 
well established.  The potential benefits of increased ability to diagnosis and treat residual 
malignancies in this patient population outweigh the risks of treatment with valproic acid. If 
this study demonstrates a tumor response to valproic acid and/or increased radioiodine uptake in 
patients who are otherwise no longer amenable to conventional therapy, a large, multicenter, trial 
using valproic acid in this population of patients will be considered.
7.5
CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The investigational nature and objectives of this trial, the procedures and treatments involved and 
their attendant risks and discomforts, potential benefits and potential alternative therapies will be 
carefully explained to the patient, and a signed informed consent document will be obtained by 
the PI, AI or clinical staff fellow.  
8
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN
8.1
DEFINITIONS
8.1.1
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. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
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laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution. Serious adverse events that occur more 
than 30 days after the last administration of investigational agent/intervention and have an 
attribution of at least possibly related to the agent/intervention should be recorded and reported 
as per section 8.2.
8.1.2
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.
8.1.3
Unexpected Adverse Reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
8.1.4
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.
8.1.5
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:
x
Death,
x
A life-threatening adverse drug experience
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions
x
A congenital anomaly/birth defect.
x
Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug 
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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.
8.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
8.1.7
Life threatening Adverse Drug Reaction
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.
8.1.8
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the approved research protocol.
8.1.9
Protocol 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.
8.1.10 Unanticipated Problem
Any incident, experience, or outcome that:
x
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
x
Is related or possibly related to participation in the research; AND
x
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
8.2
NCI-IRB REPORTING
8.2.1
NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths:
The Protocol PI will report to the NCI-IRB:
x
All deaths, except deaths due to progressive disease 
x
All Protocol Deviations
x
All Unanticipated Problems
x
All serious non-compliance
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Reports must be received by the NCI-IRB within 7 working days of PI awareness via iRIS.
8.2.2
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:
x
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research; 
x
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
x
All Grade 5 events regardless of attribution; 
x
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported. 
8.3
DATA AND SAFETY MONITORING PLAN
Clinical Trial Monitoring Plan
Data will be entered in C3D by the data manager assigned to the protocol. The research nurse 
will verify 100% of the e-CRFs for one of the first 3 patients enrolled. Subsequent monitoring 
will be conducted by the Research Nurse as described in the table below.  Any significant 
discrepancies will be discussed with the PI and the study team and a corrective action plan will 
be drafted and shared with the team.   AEs on all patients are discussed at the weekly team 
meeting to assess over all safety and to ensure that all reporting requirements are met. 
*Based on expected accrual, 25% of enrolled patients will be monitored.
Careful evaluation to ascertain the toxicity and clinical response will be performed.  The 
principal investigator will monitor the data and toxicities to identify trends quarterly.  The 
principal investigator will be responsible for revising the protocol as needed to maintain safety.
Time of year
Evaluation
# of records 
monitored
Quarterly
Compare all fields of  the following e-CRFs to the source 
documentation:
Eligibility, Surgical Procedure, Course Assessment, Adverse 
Events, Off Treatment
3-5 study 
patients
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9
PHARMACEUTICAL INFORMATION
9.1
VALPROIC ACID - DEPAKOTE
Refer to package insert for additional information
9.1.1
Source
Valproic acid will be purchased from commercial sources by the NIH Clinical Center Pharmacy. 
9.1.2
Formulation and preparation
Valproic Acid tablets are for oral administration. Valproic acid tablets are supplied in three 
dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of 
valproic acid.
9.1.3
Stability and storage
Store tablets below 86°F (30°C).
9.1.4
Administration procedures 
Valproic acid will be given orally, twice daily with or without food
9.1.5
Incompatibilities - Potentially significant drug interactions have been reported with 
Amitriptyline/Nortriptyline, Carbamazepine/carbamazepine, Clonazepam, Diazepam, 
Ethosuximide, Lamotrigine, Phenobarbital, Primidone, Phenytoin, Tolbutamide, 
Warfarin, and Zidovudine.  
9.1.6
Toxicity

Hepatotoxicity 

Teratogenicity in the fetus of pregnant women. At high doses (>90mg/kg/day), 
valproic acid has been shown to reduce spermatogenesis and induce testicular 
atrophy in dogs.  

Hyperammonemia has been reported independent of abnormal liver function tests.  

CNS depression and somnolence.  Because of the potential interactions of 
valproic acid with other CNS depressants, alcohol will be prohibited while 
patients are on the study.  If a patient does drink alcohol, he or she will be 
removed from the study.

Nausea, vomiting, anorexia, increases appetite and indigestion

Thrombocytopenia 

Pancreatitis 
9.2
LIOTHYRONINE SODIUM, CYTOMEL
Refer to package insert for additional information
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Version Date: 04/17/2015
9.2.1
Source 
Cytomel will be purchased from commercial sources by the NIH Clinical Center Pharmacy. 
9.2.2
Formulation and preparation 
Cytomel tablets are for oral administration. Cytomel tablets are supplied in three dosage 
strengths 5 mg, 25 mg, or 50 mg.
9.2.3
Stability and storage 
Store tablets between Store between 15° and 30°C (59° and 86°F).
9.2.4
Administration procedures  
Cytomel will be given orally, once daily with or without food
9.2.5
Incompatibilities  
Potential drug interactions have been reported with the drugs listed below.  While administration 
of these are drugs is not an exclusion criteria, care will be taken to carefully monitor  patients 
who are taking any of these medications. 

Oral Anticoagulants 

Insulin or Oral Hypoglycemics 

Cholestyramine 

Estrogen, Oral Contraceptives  

Tricyclic Antidepressants 

Digitalis 

Ketamine 

Vasopressors
9.2.6
Toxicity
Adverse reactions, other than those indicative of hyperthyroidism because of therapeutic
overdosage, either initially or during the maintenance period are rare (see OVERDOSAGE).
In rare instances, allergic skin reactions have been reported with Cytomel (liothyronine sodium)
Tablets.
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10 REFERENCES
1.
Davies, L. and H.G. Welch, Increasing incidence of thyroid cancer in the United States, 
1973-2002. JAMA, 2006. 295(18): p. 2164-7.
2.
Hundahl, S.A., et al., A National Cancer Data Base report on 53,856 cases of thyroid 
carcinoma treated in the U.S., 1985-1995 [see commetns]. Cancer, 1998. 83(12): p. 
2638-48.
3.
Goretzki, P.E., et al., Surgical reintervention for differentiated thyroid cancer. Br J Surg, 
1993. 80(8): p. 1009-12.
4.
Ma, C., J. Xie, and A. Kuang, Is empiric 131I therapy justified for patients with positive 
thyroglobulin and negative 131I whole-body scanning results? J Nucl Med, 2005. 46(7): 
p. 1164-70.
5.
Munster, P., et al., Clinical and biological effects of valproic acid as a histone 
deacetylase inhibitor on tumor and surrogate tissues: phase I/II trial of valproic acid and 
epirubicin/FEC. Clin Cancer Res, 2009. 15(7): p. 2488-96.
6.
Rocca, A., et al., A phase I-II study of the histone deacetylase inhibitor valproic acid plus 
chemoimmunotherapy in patients with advanced melanoma. Br J Cancer, 2009. 100(1): p. 
28-36.
7.
Duenas-Gonzalez, A., et al., Valproic acid as epigenetic cancer drug: preclinical, 
clinical and transcriptional effects on solid tumors. Cancer Treat Rev, 2008. 34(3): p. 
206-22.
8.
Michaelis, M., H.W. Doerr, and J. Cinatl, Jr., Valproic acid as anti-cancer drug. Curr 
Pharm Des, 2007. 13(33): p. 3378-93.
9.
Catalano, M.G., et al., Effects of the histone deacetylase inhibitor valproic acid on the 
sensitivity of anaplastic thyroid cancer cell lines to imatinib. Oncol Rep, 2009. 21(2): p. 
515-21.
10.
de Vries, L., et al., Endocrine effects of valproate in adolescent girls with epilepsy.
Epilepsia, 2007. 48(3): p. 470-7.
11.
Catalano, M.G., et al., Valproic acid, a histone deacetylase inhibitor, enhances sensitivity 
to doxorubicin in anaplastic thyroid cancer cells. J Endocrinol, 2006. 191(2): p. 465-72.
12.
Shen, W.T., et al., Valproic acid inhibits growth, induces apoptosis, and modulates 
apoptosis-regulatory and differentiation gene expression in human thyroid cancer cells.
Surgery, 2005. 138(6): p. 979-84; discussion 984-5.
13.
Catalano, M.G., et al., Valproic acid induces apoptosis and cell cycle arrest in poorly 
differentiated thyroid cancer cells. J Clin Endocrinol Metab, 2005. 90(3): p. 1383-9.
14.
Fortunati, N., et al., Valproic acid induces the expression of the Na+/I- symporter and 
iodine uptake in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab, 
2004. 89(2): p. 1006-9.
Page 28 of 28

MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•
Parent, for Minor Patient
INSTITUTE:
National Cancer Institute
STUDY 
NUMBER:
10-C-0041
PRINCIPAL 
INVESTIGATOR:
Electron Kebebew, M.D.
STUDY TITLE:   
A Phase II Trial of Valproic Acid in Patients with Advanced Thyroid Cancers of Follicular 
Origin
Continuing Review Approved by the IRB on 06/09/14
Amendment Approved by the IRB on 04/24/15 (D)
Date Posted to Web: 05/05/15
Standard
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?
The purpose of this study is to see whether valproic acid can inhibit tumor growth and/or induce 
tumor cell death and/or make tumor cells take up radioiodine.  Although valproic acid is already 
approved by the FDA to treat epilepsy, it is not approved for thyroid cancer and is therefore an 
investigational drug for research purposes.
Why are you being asked to take part in this study?
You are being asked to take part in this study because you have thyroid cancer that is either 
unresponsive or fails to absorb radioiodine.
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•
Parent, for Minor Patient
NIH-2514-1 (7-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent (1)

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:
10-C-0041
CONTINUATION: page 2 of 10 pages
How many people will take part in this study?
About 25 people will take part in this study.
Description of Research Study
Stage
Timeframe
Location
Events
Work up
1-2 weeks
Out patient  
Scans, x-rays, labs, Thyrogen 
scan, other tests as needed
Phase 1
Weeks 1-10
Clinical Center Out-
patient clinic and home 
endocrinologist
Continue thyroid hormone 
suppression therapy, begin 
valproic acid, physician visits, lab 
draws, complete diary
Thyrogen Scan
Schedule 1 –
patients who have 
increased uptake 
on thyrogen scan
Weeks 
11-
16
Clinical Center Out-
patient clinic and home 
endocrinologist
Continue valproic acid, stop long 
acting thyroid suppression 
medication,  add short acting 
medications, physician visits, lab 
draws, scans, complete diary
I-131 ablative 
treatment
Weeks 16-
17
Clinical Center Out-
patient clinic and 
Nuclear Medicine 
Department
I-131 ablative treatment
Scans
Stop valproic acid, resume long 
acting thyroid medication
Schedule 2 -
patients who do 
NOT have 
increased uptake 
on thyrogen scan
Weeks 11-
16
Clinical Center Out-
patient clinic and home 
endocrinologist
Continue valproic acid physician 
visit, lab draws, scans, complete 
diary.
Scans
Follow up
Through 
week 52
Clinical Center Out-
patient clinic
Physician visit, lab draws, scans 
as indicated. Valproic acid for 
patients in Schedule 2 who 
respond to therapy.
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

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:
10-C-0041
CONTINUATION: page 3 of 10 pages
What will happen if you take part in this research study?
Phase 1
Once we have determined that it is safe for you to participate in this trial you will be seen in 
clinic and will begin the first phase of this study.  You will continue on your thyroid hormone 
suppression therapy and you will begin valproic acid.  You will start at a small dose and then 
increase the dose twice over the first week.  You will then have blood drawn to see if the amount 
of valproic acid in your blood is within the correct limits. The research nurse will give you a 
diary to complete – this will include the doses of the medications you will be taking as well as a 
section to write down any side effects and a form for you to complete about how you are feeling. 
You will then be seen every 2 weeks for a total of 10 weeks.  On weeks 4 and 8 you may be seen 
by your local physician if that is more convenient. At each clinic visit (both at home and at the 
NIH Clinical Center) you will have a physical exam, lab work and your diary will be reviewed 
and collected. On weeks 1, 2, 6, you will have additional blood drawn to check the amount of 
valproic acid in your blood and you will receive the valproic acid pills. 
On week 10, you will have another Thyrogen® Scan done to measure radioiodine uptake after 
valproic acid therapy.  Pending the results of the Thyrogen® Scan, you will follow one of two 
schedules. Because valproic acid depresses the nervous system, you may not drink ANY 
alcohol while you are on this study.
Research Samples
If your tumor is easy to biopsy, we would like to take a biopsy and a blood sample before you 
begin treatment and again at week 10 to see if certain characteristics your tumor are changing in 
response to the valproic acid. A biopsy involves inserting a thin needle into your tumor while 
under an X-ray or ultrasound machine and removing a small sample of the tissue.  Your doctor 
will explain the procedure to you and ask you to sign a separate consent.  If you do not want to 
have this biopsy done, you may still participate in this study. 
Schedule 1
If there is increased radioiodine uptake on the post valproic acid Thyrogen ® Scan, you will 
receive treatment on Schedule 1 as described below.  
You will be prepared for radioiodine ablation therapy.  This is the same procedure which you 
have had in the past.  Your doctor will explain the procedure in detail and you will be asked to 
sign a separate consent.  Prior to the treatment you will stop your long acting thyroid hormone
and begin a short acting thyroid hormone. After 4 weeks, you will stop the short acting thyroid 
hormone and begin a low iodine diet.  Foods to avoid in a low-iodine diet include milk and other 
dairy products, commercial baked products (including most breads), seafood, red food dye #3, 
and salt which has iodine added to it. Your research nurse or dietitian will give you additional 
information about this diet.   During this period, you will be seen every 2 weeks either here at the 
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

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:
10-C-0041
CONTINUATION: page 4 of 10 pages
Clinical Center or by your home physician; the same as during the first 10 weeks of the study. 
After 2 weeks off of thyroid medication and a low iodine diet, you will receive radioiodine 
ablation therapy.  One week after therapy you will have a post radioiodine scan.  All the 
necessary blood work to prepare you for the radioiodine ablation therapy will be performed, 
including measuring your urine iodine and a pregnancy test. After the scan, you will start back 
on thyroid hormone therapy at your previous dose.
Schedule 2: 
If there is no increased uptake on the post valproic acid Thyrogen ® Scan, you will receive 
treatment on Schedule 2 as described below. 
You will continue on valproic acid for 7 more weeks. During this period, you will be seen every 
2 weeks either here at the Clinical Center or by your home physician.  Following 16 weeks of 
treatment, your thyroglobulin and TSH will be measured and you will have scans performed. If 
you your thyroglobulin levels have decreased or the scans indicate that your tumor has shrunk, 
you will remain on the valproic acid for 8 additional months. 
Follow up:
At 3, 6, 9 (for patients continuing on valproic acid only) and 12 months, you will have imaging 
studies done (an ultrasound, a CT and/or a MRI scan and PET scan), lab work and a physical 
exam.  This is considered standard follow up care for thyroid cancer.
Birth Control
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
valproic acid may cause harm to your unborn child and valproic acid is excreted in breast milk. If 
you are a woman who can become pregnant, or are the partner of a woman who can become 
pregnant, you will need to practice an effective form of birth control before starting study 
treatment, during study treatment, and for 3 months after you finish study treatment.  If you think 
that you or your partner is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include:
x
Abstinence 
x
intrauterine device (IUD)
x
hormonal [birth control pills, injections, or implants]
x
tubal ligation
x
vasectomy
Alternative Approaches or Treatments
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options:
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

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:
10-C-0041
CONTINUATION: page 5 of 10 pages
x
Getting treatment or care for your cancer without being in a study
x
Taking part in another study
x
Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it 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.
Risks or Discomforts of Participation
What side effects or risks can I expect from being in this study?
The risks of valproic acid are listed in the table below. The risk of somnolence and depression of 
your central nervous system increase greatly if you drink alcohol. Therefore, you may not 
consume any alcohol while you are taking valproic acid. While you are on this study, you 
should consult Dr. Kebebew or the research nurse before taking any prescription or over the 
counter medications.
Likely
Less Likely
Rare but Serious
x
Sleepiness
x
Nausea 
x
Headache
x
Vomiting
x
Anorexia
x
Dizziness
x
Indigestion
x
Muscle weakness
x
Rash
x
Abdominal pain
x
Liver toxicity which 
could be mild to severe
Biopsy
The risks of a biopsy include bruising and discomfort at the biopsy site and rarely bleeding and 
infection.
Radiation
In addition, this research study involves exposure to radiation from 2 CT guided biopsies.
This radiation exposure is not required for your medical care and is for research purposes 
only. The amount of radiation you will receive in this study is 0.290 REM which is below 
the guideline of 5 rem (or 0.5 rem in children) per year allowed for research subjects by the 
NIH Radiation Safety Committee.  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 
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

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:
10-C-0041
CONTINUATION: page 6 of 10 pages
the investigator for a copy of the pamphlet, An Introduction to Radiation for NIH Research 
Subjects.
Potential Benefits of Participation
Are there benefits to taking part in this study?
The aim of this study is to see if this experimental treatment will make your tumor able to 
respond to radioactive iodine therapy or to shrink. Because there is not much information about 
the drug’s effect on your cancer, we do not know if you will benefit from taking part in this 
study, although the knowledge gained from this study may help others in the future who have 
cancer.
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:
x
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.
x
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.
x
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH.
x
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:
x
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.
x
National Cancer Institute Institutional Review Board
x
Qualified representatives from the pharmaceutical company who produces Valproic Acid.
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

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:
10-C-0041
CONTINUATION: page 7 of 10 pages
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. 
Stopping Therapy
Your doctor may decide to stop your therapy for the following reasons:
x
if he/she believes that it is in your best interest
x
if your disease comes back during treatment
x
if you have side effects from the treatment that your doctor thinks are too severe
x
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 the manufacturer of the 
study drug or their designated representatives. 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 generated from the samples that have 
already been distributed to other researchers or placed in the research databases cannot be 
recalled and destroyed.
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. 
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

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:
10-C-0041
CONTINUATION: page 8 of 10 pages
Optional Biopsy 
The biopsy to be performed is exclusively for research purposes and will not benefit you (refer to 
page 3).  It might help other people in the future.  Even if you sign "yes" to have the biopsy you 
can change your mind at any time.  Please read the sentence below and think about your choice. 
After reading the sentence, 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 have the tumor biopsy for the research tests in this study. 
Yes
No
Initials_________
Optional Studies
We would like to keep some of the specimens and data that are collected for future research.  
These specimens and data will be identified by a number and not your name.  The use of your 
specimens and data will be 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 decide now that your specimens and data can be kept for research, you can change your 
mind at any time. Just contact us and let us know that you do not want us to use your specimens 
and/or data.  Then any specimens that remain will be destroyed and your data will not be used 
for future research. 
Please read each sentence below and think about your choice. After reading each sentence, circle 
and initial the answer that is right for you.  No matter what you decide to do, it will not affect 
your care.
1. My specimens and data may be kept for use in research to learn about, prevent, or treat cancer
or other health problems.
Yes
No
Initials_________
2. Someone may contact me in the future to ask permission to use my specimen(s) and/or data in new 
research not included in this consent. 
Yes             No              Initials_________
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (10-84)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•
Parent, for Minor Patient
STUDY 
NUMBER:
10-C-0041
CONTINUATION: page 9 of 10 pages
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 for 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, Electron Kebebew, M.D., Building 10, Room 4-5952, Telephone:
301-496-5049. 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:  301-496-4251.
5. Consent Document.  Please keep a copy of this document in case you want to read it again.
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
(Continuation Sheet)
•
Adult Patient or
•
Parent, for Minor Patient
NIH-2514-1 (7-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•
Parent, for Minor Patient
STUDY 
NUMBER:
10-C-0041
CONTINUATION: page 10 of 10 pages
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
Signature of Parent(s)/ Guardian
Date
Print Name
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 JUNE 9, 2014 THROUGH JUNE 8, 2015. 
Signature of Investigator
Date
Signature of Witness
Date
Print Name
Print Name
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
(Continuation Sheet)
•
Adult Patient or
•
Parent, for Minor Patient
NIH-2514-1 (7-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent