Clinical trial NCT02232243
Conditions: Solid Tumor
Keywords: Cancer Surgery Hydroxychloroquine
Sponsor: Peng Wang, MD PhD
Start date: 2015-07-01; Completion date: 2018-12-01
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Baseline levels of PAR-4 secreted by normal cells are generally inadequate to cause massive apoptosis in cancer cells and drugs that bolster the secretion of PAR-4 would constitute an important therapeutic advance.The apoptosis sensitizing features of hydroxychloroquine enhance the anti-tumor effects of a broad range of cancer therapeutics. The investigators hypothesize that hydroxychloroquine will induce at least 2-fold increase in systemic (plasma) PAR-4 levels compared to pre-treatment plasma levels in patients with resectable solid tumors.

Detailed description:

Arms: arm 1: These initial 3 patients received 200mg hydroxychloroquine (HCQ) twice daily (400mg/day total) for 14 days prior to surgery. arm 2: Based on data analysis from the initial patients, these patients received 400mg hydroxychloroquine (HCQ) twice daily (800mg/day total) for 14 days prior to surgery. arm 3: Based on data from the primary and secondary groups, patients received 200mg hydroxychloroquine (HCQ) twice daily (400mg/day total) for 14 days prior to surgery.
Interventions: intervention 1: Hydroxychloroquine, 200mg twice dailiy intervention 2: Hydroxychloroquine, 400mg twice daily
Intervention descriptions: intervention 1: Hydroxychloroquine, 200mg twice daily (400mg/day total) was given to subjects for up to 14 days prior to surgery. intervention 2: Hydroxychloroquine, 400mg twice daily (800mg/day total) was given to subjects for up to 14 days prior to surgery.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Local Protocol #: 
14-Multi-14-MCC 
 
 
TITLE:  A Pilot Study to Determine the Biological Effects of Hydroxychloroquine on PAR-
4 Levels in Patients with Resectable Solid Tumors  
 
Coordinating Center: 
 
 
Markey Cancer Center 
 
*Principal Investigator: 
Peng Wang, MD, PhD 
 
Division of Medical Oncology 
 
University of Kentucky 
 
Phone: 859-323-3179 
 
Email: p.wang@uky.edu 
 
 
 
 
Co-Investigators: 
Vivek Rangnekar, PhD 
 
Department of Radiation Medicine 
 
University of Kentucky 
 
Office: 859-257-2677 
 
Email: vmrang01@uky.edu  
 
 
 
 
 
Markos Leggas, PhD 
 
Department of Pharmaceutical Sciences 
 
University of Kentucky 
 
Office: 859-257-2633 
 
Email: mark.leggas@uky.edu  
 
 
 
John L. Villano MD, PhD 
 
Division of Medical Oncology 
 
University of Kentucky 
 
Phone: 859-257-6006 
 
Email: john.villano@uky.edu 
 
 
Susanne M. Arnold, MD 
 
Division of Medical Oncology 
 
University of Kentucky 
 
Phone: 859-257-9568 
 
Email: susanne.arnold@uky.edu  
 
 
Statistician: 
 
 
 
Heidi Weiss, PhD 
 
 
800 Rose Street, CC441 
 
 
Lexington, KY 40536 
 


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2 
 
 
Telephone: 859-323-0577 
 
 
Fax 
 
 
Email: heidi.weiss@uky.edu  
 
 
 
Commercially Available Agents:  
Hydroxychloroquine  
Protocol Type / Version # / Version Date: Original/v 4.5 / June 20, 2016 
 


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SUMMARY 
 
.  
 
 
 
 
 
 
 
 
 
Dose Schedule 
Dose Level 
Dose 
Hydroxychloroquine (mg/day) 
Level -1 
200 mg/day 
STARTING DOSE: Level 1 
400 mg/day 
Level 2 
800 mg/day 
Level 3 
1200 mg/day 
 
 
 
Oral hydroxychloroquine daily  
for at least 2 weeks 
Surgery 
Follow-up and 
off study 
Off study for 
toxicity 


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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ....................................................................................................................6 
1.1 
Primary Objectives...................................................................................................6 
1.2 
Secondary Objectives...............................................................................................6 
2. 
BACKGROUND ................................................................................................................6 
2.1 
Introduction: PAR-4.................................................................................................6 
2.2 
Hydroxychloroquine ................................................................................................6 
2.3 
Rationale for Studying PAR-4 Expression in subjects treated with 
Chloroquine..............................................................................................................7 
2.4 
Correlative Studies Background ..............................................................................7 
2.5 
Hypothesis................................................................................................................8 
3. 
PATIENT SELECTION ...................................................................................................9 
3.1 
Eligibility Criteria ....................................................................................................9 
3.2 
Exclusion Criteria ....................................................................................................9 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4. 
REGISTRATION PROCEDURES ................................................................................11 
4.1 
Protocol Review and Monitoring Committee and Institutional Review 
Board Review.........................................................................................................11 
4.2 
Enrollment Guidelines ...........................................................................................11 
4.3 
Informed Consent...................................................................................................12 
4.4 
Compliance with Laws and Regulations................................................................12 
5. 
TREATMENT PLAN ......................................................................................................13 
5.1 
Enrollment and Screening Process.........................................................................13 
5.2 
Agent Administration.............................................................................................13 
5.3 
See Statistical Considerations for description of Dose-Escalation Process ...........14 
5.4 
Definition of Dose-Limiting Toxicity ....................................................................14 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................15 
5.6 
Duration of Therapy ...............................................................................................15 
5.7 
Duration of Follow Up ...........................................................................................15 
5.8 
Criteria for Removal from Study ...........................................................................15 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................16 
6.1 
Study Specified Dose Modifications for Non-Hematologic Toxicities .................16 
6.2 
Study Specified Dose Modifications for Hematologic Toxicities .........................17 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................17 
7.1 
Expected Toxicities for Hydroxychloroquine ........................................................18 
7.2 
Precautions .............................................................................................................18 
7.3 
Adverse Reactions .................................................................................................18 


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7.4 
Adverse Event Characteristics ...............................................................................20 
7.5 
Expedited Adverse Event Reporting ......................................................................21 
7.6 
Expedited Reporting to External Agencies ............................................................22 
7.6.1 Expedited Reporting to the Food and Drug Administration (FDA) ......................22 
7.6.2 Expedited Reporting to Hospital Risk Management .............................................23 
7.7 
Routine Adverse Event Reporting .........................................................................23 
8. 
PHARMACEUTICAL INFORMATION ......................................................................23 
8.1 
Commercial Agent: Hydroxychloroquine..............................................................23 
8.2 
Description .............................................................................................................23 
8.3 
Storage requirements .............................................................................................24 
8.4 
Stability: .................................................................................................................24 
8.5 
Route of administration: ........................................................................................24 
8.6 
CONTRAINDICATIONS .....................................................................................24 
8.7 
Precautions: General ..............................................................................................24 
8.8 
Overdose ................................................................................................................24 
8.9 
Symptoms of Overdose: .........................................................................................24 
8.10 
Treatment of Overdose: .........................................................................................25 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ...................................25 
9.1 
Laboratory Correlative Studies ..............................................................................25 
10. 
STUDY CALENDAR ......................................................................................................27 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS .....................................28 
11.1 
Data Reporting .......................................................................................................28 
12. 
STATISTICAL CONSIDERATIONS ...........................................................................28 
12.1 
Study Design/Endpoints.........................................................................................28 
12.2 
Sample Size/Accrual Rate ......................................................................................30 
12.3 
Assessment of Safety .............................................................................................30 
12.4 
Stratification Factors ..............................................................................................31 
12.5 
Analysis of Safety ..................................................................................................31 
12.6 
Pharmacokinetics Modeling and Pharmacodynamics Analysis ............................31 
12.7 
Data Management ..................................................................................................31 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................33 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................34 
APPENDIX C 
ORAL HYDROXYCHLOROQUINE ADMINISTRATION ...................36 
APPENDIX D 
ORAL HYDROXYCHLOROQUINE ADMINISTRATION DIARY .....37 
REFERENCES ..............................................................................................................................38 
 
 
 


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1. OBJECTIVES 
 
1.1 Primary Objectives 
 
1.1.1 To characterize the effects of hydroxychloroquine (HCQ) on plasma PAR-4  levels in 
adults with resectable solid tumors at the time of and after resection and to compare them 
to pre-HCQ treatment plasma levels  
 
1.2 Secondary Objectives 
 
1.2.1 To evaluate the toxicity profile and pharmacokinetics of hydroxychloroquine given in 
this setting  
1.2.2 To assess the ability of hydroxychloroquine to alter PAR-4 expression in tumors. 
 
2. BACKGROUND 
 
2.1 Introduction: PAR-4 
Prostate apoptosis response-4 (PAR-4, also called PAWR) is a tumor suppressor protein that 
induces apoptosis in diverse cancer cells but not in normal cells.1 PAR-4 is ubiquitously 
expressed in normal cells and tissues, but is often inactivated, down-regulated or mutated in 
several types of cancers.2 PAR-4 is located in various cell compartments, including the 
cytoplasm, endoplasmic reticulum (ER), and the nucleus, and both intracellular PAR-4 as well as 
secreted PAR-4 have been shown to play a role in apoptosis induction by caspase-dependent 
mechanisms.3 Moreover, PAR-4 sensitizes cells to the action of diverse therapeutic agents.4 
Accordingly, loss of PAR-4 in tumors contributes to recurrent tumors and a decrease in overall 
patient survival.5 PAR-4 protein is secreted in cell culture-conditioned medium (CM) or 
systemically in mice by normal cells, and extracellular Par-4 binds to its receptor GRP78 on the 
cancer cell surface and induces apoptosis.2,6  By contrast, normal cells express low to 
undetectable levels of cell surface GRP78 and are resistant to apoptosis by extracellular PAR-
4.2,6 Our recent studies have indicated that GRP78 levels can be increased on the surface of 
diverse cancer cells to overcome PAR-4-resistance by inhibition of NF-κB activity, which is 
usually elevated in most cancer cells.6 Recombinant PAR-4 (made in E. coli) induces apoptosis 
of tumor cells and inhibits tumor growth in mice.7 
 
2.2  
Hydroxychloroquine 
Chloroquine [CQ; (RS)-N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine) is 
an antimalarial drug introduced into clinical practice in 1947 for the prophylactic treatment of 
malaria.8 CQ has been repurposed to treat inflammatory diseases such as rheumatoid arthritis 
and lupus. Hydroxychloroquine (HCQ) differs from chloroquine by the presence of a hydroxyl 
group at the N-ethyl substituent is beta-hydroxylated, but has similar pharmacokinetics to CQ, 
with quick gastrointestinal absorption and is eliminated by the kidney with minimal side effects 
on short term treatments.  Side effects of chronic treatment are restricted to the eye.  Overdose 
symptoms, which can occur within a half-hour of taking the medication, include convulsions, 
drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems. 
Both CQ and HCQ are potent inhibitors of autophagy, a cellular survival process during 
starvation to maintain cellular energy by degradation of unnecessary or dysfunctional 


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components through the actions of lysosomes. CQ and HCQ are lysosomotropic agents, 
which inhibit autophagy by raising the lysosomal pH and leads to inhibition of both fusion of 
autophagosome with lysosome and lysosomal protein degradation. Moreover, by inhibiting 
autophagy, CQ activates caspases and sensitizes the cells to apoptosis. These apoptosis 
sensitizing features of HCQ or CQ enhance the anti-tumor effects of a broad range of cancer 
therapeutics.9,10 In fact, CQ prophylaxis against malaria in Tanzania was associated with a 
reduction in the number of cases of Burkitt’s lymphoma.11 Accordingly, HCQ and CQ are being 
studied in a number of clinical trials that use these compounds either pre-operatively or in 
conjunction with chemotherapeutic agents or radiation 
(http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid=12327270) 
 
2.3 Rationale for Studying PAR-4 Expression in subjects treated with Chloroquine 
As the baseline levels of PAR-4 secreted by normal cells are generally inadequate to cause 
massive apoptosis in cancer cells, drugs that bolster the secretion of PAR-4 would constitute an 
important therapeutic advance.  Our recent studies identified several small molecules that show 
robust secretion of Par-4 in cell culture and mouse models, and secreted PAR-4 induces 
apoptosis of cancer cells.12 However, these small molecules are not FDA-approved for human 
use. We therefore sought to identify FDA-approved small molecule drugs that show robust 
secretion of PAR-4 in normal cells and therefore can be repurposed for treatment of cancer. 
These studies (unpublished) identified HCQ as a potent inducer of PAR-4 secretion from normal 
cells under conditions that show no normal cell death.  As normal cells in any patient far 
outnumber cancer cells, FDA-approved PAR-4 secretagogues may play a valuable role in 
elevating systemic and local levels of PAR-4 protein and thereby induce paracrine apoptosis in 
primary and metastatic tumors. Systemic PAR-4 is also expected to induce apoptosis in 
circulating cancer cells that contribute to metastasis. Because PAR-4 produces apoptosis in 
diverse tumors, and HCQ is expected to produce elevated levels of PAR-4 secretion in a broad 
range of patients to prevent the growth of tumors. Thus, our findings will potentially have broad 
clinical significance.  
 
2.4 Correlative Studies Background 
Studies in cell culture and mice indicated that HCQ induced robust secretion of PAR-4 in normal 
fibroblast and epithelial cell cultures, and elevated PAR-4 protein levels in the plasma of 
immunocompetent mice. Moreover, examination of plasma samples from renal cell carcinoma 
patients who were given HCQ (400 mg daily for 2 weeks) prior to surgery indicated that HCQ 
increased the secretion of PAR-4 protein levels in 4 of 5 patients (Figure 1). However, HCQ 
pharmacokinetics is highly variable and we expect an exposure dependent (area under the 
cureve) effect on Par-4 secretion rather than a dose-dependent effect. 
 


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Figure 1. Chloroquine induces Par-4 secretion. 
A and B. Various cell lines such as mouse 
embryonic fibroblasts (MEFs, early passage 4 or 
5), human primary prostate fibroblast cells 
(PrSC), human primary prostate epithelial cells 
(PrEC), human lung embryonic fibroblasts 
(HEL), human bronchial epithelial cells (HBEC) 
(A) or prostate cancer cell lines (B), were treated 
with the indicated amounts of chloroquine 
diphosphate (CQ) or vehicle (V) control for 24 h. 
The conditioned medium (CM), as well as the 
whole-cell lysates were subjected to Western 
blot analysis with the indicated antibodies. 
Collagen (Col1A1) was used as a loading control 
for protein secretion, as it is generally unchanged 
in response to the treatments. The samples were 
also subjected to SDS-PAGE and Coomassie 
blue staining to determine albumin levels in 
serum from the CM as another loading control.  
C. C57/BL6 mice were injected intraperitoneally 
with a single dose (50 mg/kg body weight) of CQ 
and serum samples were collected after 24 h and 
processed by Western blot analysis. 
D. Plasma samples were collected from renal 
cell carcinoma patients who were treated with 
HCQ pre-operatively for 2-weeks at 400 mg/day 
were collected pre- and post-HCQ treatment at 
the University of Pittsburgh as part of a clinical 
trial on HCQ in 2010-2011. The archival (frozen) 
samples were processed by Western blot 
analysis at the University of Kentucky in 2013-
2014. 
 
 
2.5 Hypothesis 
 
That hydroxychloroquine will induce at least 2-fold increase in systemic (plasma) PAR-4 levels 
compared to pre-treatment plasma levels in patients with resectable solid tumors. 
 
 
 
 
 
 
 
 
 
 
 


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3. PATIENT SELECTION 
 
3.1 Eligibility Criteria 
 
3.1.1 Patients must have a histologically confirmed or highly suspected (as determined by 
treating physician) solid tumor that is planned for surgical resection.  
 
3.1.2 Age ≥18 years.   
 
3.1.3 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.4 Patients must be able to ingest oral medications (crushing and administering via PEG 
tube is acceptable). 
 
3.1.5 Patients must have normal organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets  
≥100,000/mcL 
− 
total bilirubin 
Less than 1.5 x ULN 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
creatinine  
less than  institutional ULN 
OR 
− 
Creatinine clearance 
≥60 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. 
 
3.1.6 Patients must be able to undergo surgical resection of their tumor as determined by the 
treating surgeon. 
 
3.1.7 The effects of hydroxychloroquine on the developing human fetus are unknown.  For this 
reason and because anti-malarial agents as well as other therapeutic agents used in this 
trial are known to be teratogenic, women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.  Men treated or enrolled on this 
protocol must also agree to use adequate contraception prior to the study, for the duration 
of study participation, and 4 months after completion of hydroxychloroquine 
administration. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 


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3.2.1 Patients with metastatic cancer and/or cancer that is not amenable to surgery (i.e. must be 
curative intent; locally advanced is acceptable).   
 
3.2.2 Patients with significant malabsorption as determined by the treating physician. 
 
3.2.3 Patients who are receiving any other investigational agents. 
 
3.2.4 Patients with known brain metastases are excluded from this clinical trial because of their 
poor prognosis and because they often develop progressive neurologic dysfunction that 
would confound the evaluation of neurologic and other adverse events.  Patients with 
primary brain tumors amenable to surgery are allowed on this protocol. 
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to hydroxychloroquine. 
 
3.2.6 Caution should be taken with the use of hydroxychloroquine and any drugs known to 
interact with it (Appendix C).  Because the lists of these agents are constantly changing, 
it is important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information.  As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product.  
Appendix C contains a list of known drug interactions with hydroxychloroquine. 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.8 Pregnant women are excluded from this study.  While hydroxychloroquine has not been 
formally assigned to a pregnancy category by the FDA, animal studies have revealed that 
the drug passed rapidly across the placenta, accumulated selectively in the melanin 
structures of the fetal eyes, and was retained in the ocular tissues for five months after the 
drug had been eliminated from the rest of the body. There are no controlled data in 
human pregnancy. Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with hydroxychloroquine, 
breastfeeding should be discontinued if the mother is treated with hydroxychloroquine.  
These potential risks may also apply to other agents used in this study. 
 
3.2.9 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with hydroxychloroquine.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
 


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3.2.10 Patients that are on enzyme-inducing anti-epileptic medications 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
1 
= 
2 
Not Hispanic or Latino 
8 
 
8 
= 
16 
Ethnic Category: Total of all subjects 
9 
 
+ 
9 
 
= 
18 
 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
1 
+ 
1 
= 
2 
Native Hawaiian or other Pacific 
Islander 
 
+ 
 
= 
 
White 
7 
+ 
7 
= 
14 
Racial Category: Total of all subjects 
9 
 
+ 
9 
 
= 
18 
 
 
 
 
 
 
 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Protocol Review and Monitoring Committee and Institutional Review Board Review 
 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by the Markey Cancer Center’s Protocol Review and 
Monitoring Committee and the University of Kentucky Institutional Review Board (IRB). A 
signed and dated statement that the protocol and informed consent have been approved by the 
IRB must be maintained in the Markey Cancer Center Clinical Research and Data Management 
Shared Resource Facility (MCC CRDM SRF) regulatory binder. Any amendments to the 
protocol, other than administrative ones, must be reviewed and approved by the PRMC, study 
sponsor and the UK IRB.   
 
4.2 
Enrollment Guidelines 
 
Eligible patients will be identified by the principal investigator and co-investigators of this study. 
Potentially eligible patients will be screened in the University of Kentucky Markey Cancer Center 
clinics by the investigators, study personnel, and the Principal Investigator (PI). Upon obtaining 
proper consent, patients will be enrolled into the study.   
 


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4.3 
Informed Consent 
 
The goal of the informed consent process is to provide people with sufficient information so they 
can make informed choices about whether to begin or continue participation in clinical research.  
The process involves a dynamic and continuing exchange of information between the research 
team and the participant throughout the research experience.  It includes discussion of the study's 
purpose, research procedures, risks and potential benefits, and the voluntary nature of 
participation. 
The informed consent document provides a summary of the clinical study and the individual's 
rights as a research participant.  The document acts as a starting point for the necessary exchange 
of information between the investigator and potential research participant.  Also, research 
participants and their families may use the consent document as an information resource and 
reference throughout participation in the trial. The informed consent document is often considered 
the foundation of the informed consent process; it does not, however, represent the entirety of the 
process.  Nor is the informed consent document a risk-management tool for the investigator and/or 
institution. 
 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained.  The informed consent form is considered to be part of the protocol, 
and must be submitted by the investigator with the protocol at the time of IRB review. 
 
4.4 
Compliance with Laws and Regulations 
 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, any applicable local health authority, and Institutional Review Board 
(IRB) requirements.  The PI or designee will be responsible for obtaining continuing and not less 
than annual IRB re-approval throughout the duration of the study.  Copies of the Investigator’s 
annual report to the IRB and copies of the IRB continuance of approval must maintained by the 
MCC CRDM SRF.  The PI or designee is also responsible for notifying the Data and Safety 
Monitoring Committee of the MCCC and the UK IRB of any significant adverse events that are 
serious and/or unexpected, as per SOP’s of those entities. The MCC DSMC will review all 


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13 
 
adverse events of this IIT as per its SOP. 
 
 
5. TREATMENT PLAN 
 
5.1 
Enrollment and Screening Process  
 
Prior to any study-required tests, subjects must first provide written informed consent to 
participate in this study.  All lab tests and radiographic studies should be completed within 4 
weeks prior to initiation of treatment. Complete history, physical examination, and evaluation of 
Performance Status. Required lab work will include: complete blood count (CBC) with 
differential; serum chemistry tests to include alkaline phosphatase, glucose, creatinine, 
electrolytes, AST (SGOT), and total bilirubin.  
 
5.2 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
 
 
Dose Schedule 
Dose Level 
Dose 
Hydroxychloroquine (mg/day) 
Level -1 
200 mg/day 
STARTING DOSE: Level 1 
400 mg/day 
Level 2 
800 mg/day 
Level 3 
1200 mg/day 
 
 
Subjects will receive HCQ every day for 14 days, starting at least 14d before planned surgery 
and optimally ending day prior to surgery.  Dosing can be extended 7 days if necessary due to 
unexpected delays. HCQ can be taken at any time of the day with meals. Tablets of HCQ are 
available in 200 mg strengths. HCQ will be administered in divided doses (twice a day) for doses 
above 200 mg/day to minimize nausea. The divided doses should be taken in the AM and at 
night with meals. Subjects will also be required to keep a medication diary and to present this at 
the end of the treatment.  Should a subject have emesis and regurgitate the medication within 30 
minutes of taking it, the dose may be repeated once, but if vomiting occurs longer than 30 
minutes after ingestion, the dose should not be repeated.  Subjects taking antacids, proton-pump 
inhibitors or H2-blockers should not take hydroxychloroquine within 4 hours of these medicines.   
 


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14 
 
5.3 
See Statistical Considerations for description of Dose-Escalation Process  
 
An adaptive, nonparametric, isotonic regression model will be employed in order to determine 
the biological effect of HCQ as well as to assess safety. Patients will be enrolled starting at dose 
level 1.  Dose escalation and de-escalation is described in detail in the Statistical Considerations 
section below.  Briefly, 
 
1. Treat a cohort of 3 patients at dose level 1 
2. Let jt denote the highest level tried thus far.  At the current dose level j, based on the 
observed data, determine the dose j* that has the highest isotonic estimate of biological 
effect probability among the tried doses. 
3. If j* > j, escalate to dose  j+1 
4. If j* < j, de-escalate to dose j-1 
5. If j * = j < jt, stay at dose level j; otherwise if j* = j = jt, escalate to dose j+1 
 
Once the maximum sample size is reached (n = 18), select the lowest dose that has the highest 
estimate of biological effect based on PAR-4 levels.  
 
5.4      Definition of Dose-Limiting Toxicity 
 
Subjects will be evaluated for toxicity according to the Common Terminology Criteria for 
Adverse Events (CTCAE) of the National Cancer Institute (NCI) version 4.0 available 
at: www.ctep.gov.  A DLT is defined as any of the below treatment emergent toxicities with 
attribution (possibly, probably or definitely related) to the study medication that occurs during or 
within 30 days of the last dose of hydroxychloroquine. 
 
Non-Hematologic:  
 > Grade 3 or 4 neuropathy 
 ≥ Any Grade 3 or 4 adverse event (excluding grade 3 nausea, vomiting, diarrhea lasting < 
7 days or grade 3 fatigue). Note: Abnormal non-hematologic laboratory values > grade 3 
will be considered a DLT if they are determined to be clinically significant and possibly, 
probably or definitely related to study drug. If baseline value is elevated (or decreased) 
prior to enrollment, an increase (or decrease) will not be considered a DLT unless it 
worsens by 2 grades and is determined to be clinically significant by the treating 
investigator. 
 ≥ Grade 3 nausea, vomiting, or diarrhea lasting > 7 days despite maximal 
antiemetic/antidiarrheal therapy  
 Grade 5 toxicity  
 
Hematologic:  
 Grade 4 neutropenia (ANC < 0.5 x 109/L) lasting for ≥ 7 days  
 Febrile neutropenia (ANC < 1.0 x 109/L with a fever ≥ 38.3ºC)  
 Grade 4 thrombocytopenia (platelets < 25.0 x 109/L) lasting ≥ 7 days despite dose delay  
 Grade 3-4 thrombocytopenia associated with bleeding  
 Grade 5 toxicity  
 


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15 
 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of hydroxychloroquine with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies.  The 
Principal Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential to affect selected CYP450 isoenzymes.  Appendix B presents guidelines for 
identifying medications/substances that could potentially interact with the hydroxychloroquine.  
While not strictly prohibited, these medications should be avoided if at all possible. 
Hydroxychloroquine should also be used with caution in patients taking medicines which may 
cause adverse ocular or skin reactions. 
 
5.6 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment will continue for 14 days or 
until one of the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s), 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.7 
Duration of Follow Up 
 
Patients will be followed for 30 days after surgery or 30 days after completion of the last dose of 
hydroxychloroquine if no surgery is completed.  Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event.  Follow-
up visit should be combined with subject standard of care post-operative visit.  If that visit occurs 
prior to the 30 days post op, subject should be contacted 30 days or after completion of the last 
dose for adverse event assessment.   
 
5.8 
Criteria for Removal from Study 
 


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16 
 
Patients will be removed from study when any of the criteria listed in Section 5.6 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The following dose levels will be considered: 
 
Dose Schedule 
Dose Level 
Dose 
Hydroxychloroquine (mg/day) 
Level -1 
200 mg/day 
STARTING DOSE: Level 1 
400 mg/day 
Level 2 
800 mg/day 
Level 3 
1200 mg/day 
 
At the discretion of the PI and investigative team, additional dose levels may be considered, 
if the primary endpoint cannot adequately be determined by the dose levels listed above. 
 
 
6.1 Study Specified Dose Modifications for Non-Hematologic Toxicities 
 
Nausea and/or Vomiting 
Management/Next Dose for Hydroxychloroquine 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 or 4 
Hold* until < Grade 2.  Resume at one dose level lower, if 
indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
Diarrhea 
Management/Next Dose for Hydroxychloroquine 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 or 4 
Hold* until < Grade 2.  Resume at one dose level lower, if 
indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  16 mg/24 hours) 


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17 
 
Diarrhea 
Management/Next Dose for Hydroxychloroquine 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Visual Changes 
Management/Next Dose for Hydroxychloroquine 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 or 4 
Hold* until < Grade 2.  Resume at one dose level lower, if 
indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
The methods recommended for early diagnosis of "chloroquine retinopathy" consist of (1) 
fundoscopic examination of the macula for fine pigmentary disturbances or loss of the foveal 
reflex and (2) examination of the central visual field with a small red test object for pericentral 
or paracentral scotoma or determination of retinal thresholds to red. 
 
Pustular or Bullous 
Dermatitis 
Management/Next Dose for Hydroxychloroquine 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 or 4 
Hold* until < Grade 2.  Resume at one dose level lower, if 
indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
6.2 Study Specified Dose Modifications for Hematologic Toxicities 
 
Neutropenia 
Management/Next Dose for Hydroxychloroquine 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 or 4 
Hold* until < Grade 2.  Resume at one dose level lower, if 
indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
Thrombocytopenia 
Management/Next Dose for Hydroxychloroquine 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 or 4 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
All other grade 3 or 4 toxicities should be discussed with the PI. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  


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18 
 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via Medwatch Forms) in addition to 
routine reporting. 
 
7.1 Expected Toxicities for Hydroxychloroquine 
 
7.2 Precautions  
 
Dermatologic reactions to hydroxychloroquine sulfate tablets may occur and, 
therefore, proper care should be exercised when they were administered to any patient 
receiving a drug with a significant tendency to produce dermatitis.  
 
The methods recommended for early diagnosis of "chloroquine retinopathy" consist 
of (1) fundoscopic examination of the macula for fine pigmentary disturbances or loss 
of the foveal reflex and (2) examination of the central visual field with a small red test 
object for pericentral or paracentral scotoma or determination of retinal thresholds to 
red. Any unexplained visual symptoms, such as light flashes or streaks should also be 
regarded with suspicion as possible manifestations of retinopathy.  
 
If serious toxic symptoms occur from overdosage or sensitivity, it has been suggested 
that ammonium chloride (8 g daily in divided doses for adults) be administered orally 
three or four days a week for several months after therapy has been stopped, as 
acidification of the urine increases renal excretion of the 4-aminoquinoline 
compounds by 20 to 90 percent. However, caution must be exercised in patients with 
impaired renal function and/or metabolic acidosis.  
 
7.3 Adverse Reactions  
 
The following Council for International Organizations of Medical Sciences (CIOMS) frequency 
rating is used, when applicable: Very common ≥ 10 %; Common ≥ 1 and <10 %; Uncommon ≥ 0.1 
and < 1 %; Rare ≥ 0.01 and <0.1 %; Very rare < 0.01 %; Not known (frequency cannot be estimated 
from available data).  
 
Blood and lymphatic system disorders  
Not known: Bone marrow depression, anemia, aplastic anemia, agranulocytosis, 
leucopenia, thrombocytopenia.  
 
Cardiac disorders  
Not known: Cardiomyopathy, which may result in cardiac failure and in some cases a 
fatal outcome.  
Chronic toxicity should be considered when conduction disorders (bundle branch block/ 
atrioventricular heart block) as well as biventricular hypertrophy are found. Drug 
discontinuation may lead to recovery.  
 


Protocol #: 14-Multi-14-MCC 
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19 
 
Ear and labyrinth disorders  
Uncommon: Vertigo, tinnitus  
Not known: Hearing loss including cases of irreversible hearing loss.  
 
Eye disorders  
Common: Blurring of vision due to a disturbance of accommodation which is dose 
dependent and reversible.  
Uncommon: Maculopathies which may be irreversible.  
Retinopathy with changes in pigmentation and visual field defects. In its early form it 
appears reversible upon discontinuation of the drug. If allowed to develop however, there 
may be a risk of progression even after treatment withdrawal.  
Patients with retinal changes may be asymptomatic initially, or may have scotomatous 
vision with paracentral, pericentral ring types, temporal scotomas, abnormal color 
visions, reduction in visual acuity, night blindness, difficulty reading and skipping words.  
Corneal changes including edema and opacities. They are either symptomless or may 
cause disturbances such as halos around lights especially at night, blurring of vision or 
photophobia. They may be transient or are reversible upon discontinuation of therapy.  
Not known: Macular degeneration which may be irreversible.  
 
Gastrointestinal disorders  
Very common: Abdominal pain, nausea  
Common: Diarrhea, vomiting  
These symptoms usually resolve immediately upon reducing the dose or upon stopping 
the treatment.  
 
Hepatobiliary disorders  
Uncommon: Abnormal liver function tests  
Not known: Fulminant hepatic failure  
 
Immune system disorders  
Not known: Urticaria, angioedema, bronchospasm.  
 
Metabolism and nutrition disorders  
Common: Anorexia (usually resolves immediately upon reducing the dose or upon 
stopping the treatment).  
Not known: hypoglycemia  
HYDROXYCHLOROQUINE may exacerbate porphyria.  
 
Musculoskeletal and connective tissue disorders  
Uncommon: Sensory motor disorders  
Not known: Skeletal muscle palsies or skeletal muscle myopathy or neuromyopathy 
leading to progressive weakness and atrophy of proximal muscle groups. Depression of 
tendon reflexes, abnormal results of nerve conduction tests. Myopathy may be reversible 
after drug discontinuation, but recovery may take many months.  
 
Nervous system disorders  
Common: Headache  
Uncommon: Dizziness  


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20 
 
Not known: Convulsions  
 
Psychiatric disorders  
Common: Affect lability  
Uncommon: Nervousness  
Not known: Psychosis, suicidal behaviour  
 
Skin and subcutaneous tissue disorders  
Common: Skin rash, pruritus  
Uncommon: Pigmentary changes in skin and mucous membranes, bleaching of hair, 
alopecia. These usually resolve readily upon cessation of therapy.  
Not known: Bullous eruptions (including urticarial, morbilliform, lichenoid, 
maculopapular, purpuric, erythema annulare centrifugum), toxic epidermal necrolysis, 
erythema multiforme, Stevens-Johnson syndrome, Drug Rash with Eosinophilia and 
Systemic Symptoms (DRESS syndrome), photosensitivity, exfoliative dermatitis, acute 
generalized exanthematous pustulosis (AGEP).  
AGEP has to be distinguished from psoriasis, although HYDROXYCHLOROQUINE 
may precipitate attacks of psoriasis. It may be associated with fever and 
hyperleukocytosis. Outcome is usually favorable after discontinuation of drug.  
 
For a comprehensive list of adverse events please refer to the package insert. 
 
7.4 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  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. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
21 
 
7.5 Expedited Adverse Event Reporting 
 
7.5.1 For MCC Investigator-Initiated Trials (IITs), investigators must report to the Overall PI 
any serious adverse event (SAE) that occurs after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment on the local institutional 
SAE form. This applies to the following categories: 
• Grade 3 (severe) Medical Events – Only events that are Unexpected and 
Possibly, Probably or Definitely Related / Associated with the Intervention. 
• ALL Grade 4 (life threatening or disabling) Medical Events – Unless 
expected AND specifically listed in protocol as not requiring reporting. 
• ALL Grade 5 (fatal) Events regardless of study phase or attribution 
 
Note: If subject is in Long Term Follow Up, death is reported at continuing review.  
Note: Abnormal laboratory values are not considered medical events, unless determined 
to be causative of SAE by the investigator or grade 5.   
 
7.5.2 The following table outlines the required forms and reporting structure for clinical trials. 
Study type 
Expedited reporting 
to MCC 
Expedited 
reporting to 
External Agency 
Non-
expedited 
AE 
Form 
IRB 
IIT where 
MCC 
investigator 
holds the IDE 
or IND 
• 
Grade 3 – 
Unexpected AE 
PLUS Possibly, 
Probably or 
Definitely 
Related  
• 
ALL Grade 4 
Unless expected 
AND listed in 
protocol as not 
requiring 
reporting. 
• 
ALL Grade 5 
(fatal) Events 
FDA: 
Suspected AE 
that is serious 
and 
Unanticipated 
(not listed in IDB 
or consent) 
OnCore  and 
DSMC 
reporting 
only 
Mandatory 
Medwatch 
3500a for 
Serious and 
unanticipated 
 
OnCore for all 
AEs, including 
SAEs 
 
 
Yes if it meets 
the IRB 
reporting 
requirements: 
Unanticipated 
Problem and/or 
Serious AE 
(use IRB AE 
reporting form 
for all 
correspondence 
with IRB) 
 
IIT by MCC 
investigator of 
commercially 
available agent 
(non-IND and 
non-IDE)  
• 
Grade 3 –
Unexpected AE 
PLUS Possibly, 
Probably or 
Definitely 
Related  
• 
ALL Grade 4 
Unless expected 
AND listed in 
protocol as not 
requiring 
reporting. 
FDA: 
Suspected AE 
that is serious 
and 
Unanticipated 
(not listed in IDB 
or consent) 
OnCore  and 
DSMC 
reporting 
only 
Voluntary 
Medwatch 
3500 for 
Serious and 
unanticipated 
 
OnCore for all 
AEs, including 
SAEs 
 


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22 
 
• 
ALL Grade 5 
(fatal) Events 
 
 
7.5.3 MCC Expedited Reporting Guidelines for MCC IITs 
 
Investigators within MCC will report SAEs directly to the MCC DSMC per the MCC 
DSMC SOP and the University of Kentucky IRB reporting policy.  
 
 
 
 
Attribution 
MCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event. 
 
 
 
Other investigative sites will report SAEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted 
institutional SAE form should be forwarded to the Overall PI within the timeframes 
detailed in the table above.   
 
The Overall PI will submit SAE reports from outside institutions to the MCC DSMC and 
UK IRB according to IRB policies and procedures in reporting adverse events: 
http://www.research.uky.edu/ori/SOPs_Policies/C2-0350-
Unanticipated_Problems_Adverse_Events_SOP.pdf.  
 
7.6 
Expedited Reporting to External Agencies 
 
The Overall PI will comply with the policies of all external funding agencies and the UK IRB 
regarding expedited reporting, as per the UK IRB’s SOP: 
http://www.research.uky.edu/ori/SOPs_Policies/C4-0150-
Mandated_Reporting_to_External_Agencies_SOP.pdf. 
 
7.6.1  Expedited Reporting to the Food and Drug Administration (FDA) 
 
Include this section and text for investigator-held IDE and IND studies, including gene transfer. 
If this is not an investigator-held IDE or IND study, this section and text should be deleted. 
 


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23 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.   
 
7.6.2 Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to the UK Office of Risk Management any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
OnCore case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 Commercial Agent: Hydroxychloroquine. 
 
8.2 Description 
Hydroxychloroquine sulfate, USP is a colorless crystalline solid, soluble in water to at least 20 
percent; chemically the drug is 2-[[4-[(7-Chloro-4-quinolyl) amino]pentyl] ethylamino] ethanol 
sulfate (1:1). Hydroxychloroquine sulfate, USP has the following structural formula: 
 
Molecular Formula: C18H26ClN3O.H2SO4 
Molecular Weight of 433.95 
Each tablet, for oral administration, contains 200 mg hydroxychloroquine sulfate, USP 
(equivalent to 155 mg base). In addition, each tablet contains the following Inactive Ingredients: 
colloidal silicon dioxide, dibasic calcium phosphate, hypromellose, macrogol/PEG 3350, 
magnesium stearate, polysorbate 80, pregelatinized starch, talc, and titanium dioxide. 
 
Hydroxychloroquine sulfate tablets, USP are white, to off-white, capsule-shaped tablets, 
debossed with "HCQS" on one side and plain on the reverse side and are available in bottles of 
10, 100, 500 and 1000.  


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24 
 
NDC 63304-296-03                                 Bottles of 10 
NDC 63304-296-01                                 Bottles of 100  
NDC 63304-296-05                                 Bottles of 500  
NDC 63304-296-10                                 Bottles of 1000  
 
8.3 Storage requirements 
Dispense in a tight, light-resistant container as defined in the USP/NF. 
Store at 20° - 25°C (68° - 77°F) excursions permitted to 15° - 30°C (59° - 86°F) [See USP 
Controlled Room Temperature].  
 
Store out of the reach of children. 
 
8.4 Stability:   
When stored as listed above and light-resistant containers, hydroxychloroquine is stable for 3 
years from manufacture date. 
 
8.5 Route of administration:   
Hydroxychloroquine is taken orally daily, each dose to be taken with a meal or a glass of milk. 
 
8.6 CONTRAINDICATIONS 
Use of this drug is contraindicated (1) in the presence of retinal or visual field changes 
attributable to any 4-aminoquinoline compound, (2) in patients with known hypersensitivity to 4-
aminoquinoline compounds, and (3) for long-term therapy in children. 
 
8.7 Precautions: General 
Antimalarial compounds should be used with caution in patients with hepatic disease or 
alcoholism or in conjunction with known hepatotoxic drugs. Periodic blood cell counts should be 
made if patients are given prolonged therapy. If any severe blood disorder appears which is not 
attributable to the disease under treatment, discontinuation of the drug should be considered. The 
drug should be administered with caution in patients having G-6-PD (glucose-6-phosphate 
dehydrogenase) deficiency. 
 
8.8 Overdose 
Overdose with the 4-aminoquinolines is dangerous particularly in infants, as little as 1-2 grams 
having proved fatal.  
 
8.9 Symptoms of Overdose:  
The 4-aminoquinoline compounds are very rapidly and completely absorbed following 
ingestion and in accidental overdosage toxic symptoms may occur within 30 minutes. These 
consist of headache, drowsiness, visual disturbances, cardiovascular collapse, hypokalemia 
and convulsions, rhythm and conduction disorders, including QT prolongation, torsade de 
pointes, ventricular tachycardia and ventricular fibrillation, followed by sudden potentially 
fatal respiratory and cardiac arrest. Immediate medical attention is required, as these effects 
may appear shortly after overdose. The ECG may reveal atrial standstill, nodal rhythm, 
prolonged intraventricular conduction time, and progressive bradycardia leading to 
ventricular fibrillation and/or arrest.  


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25 
 
 
8.10 
Treatment of Overdose:  
Treatment is symptomatic and must be prompt with immediate evacuation of the stomach by 
emesis (at home, before transportation to the hospital), or gastric lavage until the stomach is 
completely emptied. If finely powdered activated charcoal is introduced by the stomach tube, 
after lavage and within 30 minutes after ingestion of the tablets, it may inhibit further 
intestinal absorption of the drug. To be effective, the dose of activated charcoal should be at 
least five times the estimated dose of ingested hydroxychloroquine. Convulsions, if present, 
should be controlled before attempting gastric lavage. If due to cerebral stimulation, cautious 
administration of an ultrashort-acting barbiturate may be tried but, if due to anoxia, 
convulsions should be corrected by oxygen administration, artificial respiration or, in shock 
with hypotension, by vasopressor therapy. Because of the importance of supporting 
respiration, tracheal intubation or tracheostomy, followed by gastric lavage, has also been 
advised. Exchange transfusions have been used to reduce the level of 4-aminoquiolines in the 
blood. Consideration should be given to administering diazepam parenterally since studies 
have reported it beneficial in reversing chloroquine cardiotoxicity.  
 
A patient who survives the acute phase and is asymptomatic should be closely observed for 
at least 6 hours. Fluids may be forced, and sufficient ammonium chloride may be 
administered for a few days to acidify the urine to help promote urinary excretion.  
 
If serious toxic symptoms occur from overdosage or sensitivity, it has been suggested that 
ammonium chloride (8 g daily in divided doses for adults) three or four days a week be 11  
administered for several months after therapy has been stopped, as acidification of the urine 
increases renal excretion of the 4-aminoquinoline compounds by 20 to 90 percent. However, 
caution must be exercised in patients with impaired renal function and/or metabolic acidosis. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 Laboratory Correlative Studies 
 
The plasma concentrations of PAR-4 will be measured to assess induction of PAR-4 in each 
patient.  
The plasma concentration of hydroxychloroquine and its metabolites will also be measured to 
establish exposure – response (PAR-4 release) relationships. The extra aliquots of plasma after 
above studies will be stored in −80°C for future biomarker studies if needed.  
 
Blood collection for PAR-4  
 
Collection of Specimens 
 
Blood plasma samples will be collected pre-dosing, and weekly during the preoperative period 
(+/- 1 day), as well as on or after surgery (+/- 1 day).  A total of 8 time points will be required for 
each patient. 4 ml of venous blood will be withdrawn for pharmacokinetics; 4 ml of venous 
blood will be withdrawn for Par-4 and biomarker studies.  Samples will be withdrawn into 


Protocol #: 14-Multi-14-MCC 
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26 
 
sodium heparinized collection tube. 
 
 
Handling of Specimens  
 
After collection, blood and anti-coagulant will be mixed by inverting the tube 8–10 times. Blood 
samples will be placed on ice immediately and centrifuged within 30 min at 7200 g at 4°C for 2 
min. Plasma will be transferred into amber plastic tubes and stored on dry ice prior to 
transferring at −80°C until analysis. Plasma concentrations of PAR-4 will be quantified using 
ELISA (according to manufacturer’s instruction with a kit from CUSABIO).  Moreover, Western 
blot analysis will be performed as described previously2,12 to further confirm the quantitative 
increase in the ~40 kDa PAR-4 band. Aliquots of plasma samples will be subjected to SDS-
PAGE to resolve the plasma proteins. The proteins will be transferred onto nylon membranes, 
and then subjected to Western blot analysis. The blots will be probed with PAR-4 polyclonal 
antibody (from SantaCruz Biotechnology, Inc.) Parallel SDS-PAGE and Coomassie blue staining 
of the albumin in the serum samples will be used as loading control 2,6.  
 
Blood Collection and Handling of Specimens for Pharmacokinetics 
 
Blood samples for pharmacokinetic analysis will be collected prior to the start of HCQ regimen 
and during day 1 of weeks 1 and 2 and on/after day or surgery (+/- 1 day), as specified in the 
Study Calendar. Blood samples (4 mL) will be collected in heparinized tubes. After collection, 
blood and anti-coagulant will be mixed by inverting the tube 8–10 times and samples will be 
placed on ice immediately. Further processing will be carried out in the bioanalytical lab by staff 
in the Center of Pharmaceutical Research and Innovation (CPRI) under the direction of Dr. 
Leggas. Concentrations of HCQ and metabolites will be quantified using a validated 
bioanalytical assay implemented for LC/MS/MS.  
 
Shipping of Specimens for Pharmacokinetics  
 
Samples will be collected by study personnel and will be forwarded to the CPRI for storage, 
processing and analysis. 
 
 
Tumor Collection for Pharmacodynamics 
 
If available, Diagnostic biopsies and paired resected tumor specimen will be store in formalin-
fixed, paraffin-embedded blocks for potential autophagy and apoptosis analysis in the future. 
Each subject will sign the consent form for tissue collection before enrolled in the study.  
 
Shipping of Specimens for Pharmacodynamics  
 
Samples will be collected by study personnel in Dr. Rangnekar’s lab for storage, processing and 
analysis. For PK/Par-4 sample pick up contact Sogol Kangarlou at 859-361-9015.  
 
 


Protocol #: 14-Multi-14-MCC 
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27 
 
Site(s) Performing Correlative Study  
 
University of Kentucky. 
 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2-4 weeks prior to start of protocol therapy.  In 
the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
more frequently, as clinically indicated.  Study drug administration should begin optimally 2 
weeks prior to date of surgery and continue until day prior to surgery. Dosing can be extended 
one week if necessary for any unanticipated delays.  
Studies to be obtained 
Pre-
Study 
Week 1 
(D7)  
Week 2 
(D14) 
 
Day of 
Surgery 
Post-
operative 
visit 
Off study 
History 
X 
X 
X 
 
X 
X 
Physical Exam with 
vital signs 
X 
X 
X 
 
X 
 
Height, Weight 
X 
 
 
 
 
 
Performance Status 
X 
 
 
 
 
 
CBC, differential, 
platelets 
X 
X 
X 
 
X 
 
CMP 
X  
X 
X 
 
X 
 
Pregnancy test (only 
females of 
childbearing potential) 
X 
 
 
 
 
 
Tumor collection for 
Correlative Studies (if 
available) 
X 
 
 
X 
 
 
Correlative Blood 
work* 
X 
X 
X 
 
X 
 
Correlative Par-4, and Hydroxychloroquine levels will be as follows:  
Date 
 
 
Lab Draw  
Tubes 
Pre-study  
 
once 
 
Par-4 (1 tube)  
                                                                                          Hydroxychloroquine (1 tube)                                            
                                                                                           
Week 1 (day 7) 
 
3 samples           
Par-4 (1 tube)  
 
 
 
 
(2 hours apart              HCQ (3 tubes total- two hours apart)    
 
 
 
+/- 15 minutes)  
                                                                         
Week 2 (day 14) 
 
3 samples                   Par-4 (1 tube)  
                                                      (2 hours apart             HCQ (3 tubes total- two hours apart)
 
 
 
+/- 15 minutes) 
 
 
Post-operative clinic visit 
once 
 
Par-4 (1 tube), HCQ (1 tube) 
 
 
 
 
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
28 
 
 
10. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
10.1 
Data Reporting 
 
10.1.1 Method 
 
This study will require data submission and reporting via the OnCore Database, which is 
the official database of the Markey Cancer Center Clinical Research and Data 
Management Shared Resource Facility (CRDM SRF).  Instructions for submitting data is 
listed in Study-Specific Data Management Plans created by CRDM SRF staff. 
 
10.1.2 Responsibility for Data Submission 
 
Study staff is responsible for submitting study data and/or data forms to OnCore as per 
the Markey Cancer Center CRDM SRF SOP’s.  This trial will be monitored by the MCC 
Data and Safety Monitoring Committee (DSMC) on a schedule determined by the 
Protocol Review and Monitoring Committee at the initial PRMC review.  The CRDM 
SRF staff is responsible for compiling and submitting data for all participants and for 
providing the data to the Principal Investigator for review.   
 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design/Endpoints 
 
Based on previous work in renal cell carcinoma (Figure 1, Burikhanov, Rangnekar et al., 
unpublished data), there is on average a 2-fold increase in PAR-4 levels from pre to post plasma 
samples as measured by ELISA and Western Blot.  We are interested in determining the dose 
wherein 70% of patients exhibit a 2-fold increase in PAR-4 levels and with an acceptable 
toxicity rate of no more than 30%.  For calculation of biological effect, we will utilize changes in 
PAR-4 levels from pre-study and the last time point prior to resection.  
 
Given the established safety and minimal toxicity of HCQ in several studies13,14  our choice of 
study design in this pilot trial will be based on determining the dose with the target biological 
effect as well as acceptable toxicity.  Specifically, a nonparametric approach based on a double-
sided isotonic regression will be utilized which can also accommodate non-monotonically 
increasing biological effect rates (Zang, Y., Lee, J. and Yuan, Y. (2014) Adaptive Designs for 
Identifiying Optimal Biological Dose for Molecularly Targeted Agents, Clinical Trials, To appear).  
Simulations were generated for varying scenarios of biological effect rates and dose toxicity 
rates across dose levels to determine the operating characteristics of this design (see Table 1).   
Briefly, the first four scenarios assuming low toxicity indicate close to a 50% selection 
probability for the correct dose with the target biological rate while the next four scenarios 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
29 
 
assuming moderate toxicity also indicate at least a 50% selection probability for the correct dose 
with the target biological rate.  Finally, the last two scenarios indicate good selection probability 
for the dose with the highest biological rate that is closest to the target rate of 70%.   
Furthermore, all scenarios in Table 1 indicate that there is a clear winner (i.e. a much higher selection 
probability for the correct dose compared to the probabilities for the other dose levels).  Finally, the 
simulations also confirmed that more patients will be allocated to the correct dose.  
 
The study will accrue a total of 18 patients with 3 cohorts per dose level. Estimates of biological 
effects as described above will be calculated after every cohort of 3 patients and 
recommendations for the next cohort will be based on these estimates.  Specifically, the study 
will proceed as follows: 
 
1. Treat a cohort of 3 patients at dose level 1 
2. Let jt denote the highest level tried thus far.  At the current dose level j, based on the 
observed data, determine the dose j* that has the highest isotonic estimate of biological effect  
probability among the tried doses. 
3.If j* > j, we escalate to dose  j+1 
4. If j* < j, we de-escalate to dose j-1 
5. If j * = j < jt, we stay at dose level j; otherwise if j* = j = jt, we escalate to dose j+1 
 
6. Once the maximum sample size is reached, we select the lowest dose that 
 
 
has the highest estimate of biological effect based on PAR-4 levels. Decisions on the dose 
 
 
that will be utilized for subsequent trials will be based on biological, clinical and  
 
 
statistical considerations.  
   
Table 1.  Selection Probabilities for Varying Scenarios of Biological Effect and Toxicity Rates 
___________________________________________________________________________  
 
Scenario 1  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.40 
 
 
0.70 
 
 
0.60 
 
 
0.50 
 
Toxicity rates  
 
 
 
0.02 
 
 
0.05 
 
 
0.10 
 
 
0.20 
Selection Probabilities 
 
8.9  
 
 
53.3 
 
 
28.5 
 
 
9.3  
 
 
Scenario 2  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.40 
 
 
0.60 
 
 
0.75 
 
 
0.55 
 
Toxicity rates  
 
 
 
0.02 
 
 
0.05 
 
 
0.10 
 
 
0.20 
Selection Probabilities 
 
15.5    
 
24.0    
 
49.1    
 
11.4   
 
Scenario 3  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.70 
 
 
0.50 
 
 
0.30 
 
 
0.20 
 
Toxicity rates  
 
 
 
0.02 
 
 
0.05 
 
 
0.10 
 
 
0.20 
Selection Probabilities 
 
69.8    
 
24.4    
 
5.2   
 
 
0.6   
 
 
 
Scenario 4  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
30 
 
Biological rates 
 
 
 
0.20 
 
 
0.50 
 
 
0.75 
 
 
0.70 
 
Toxicity rates  
 
 
 
0.02 
 
 
0.05 
 
 
0.10 
 
 
0.20 
Selection Probabilities 
 
9.8   
 
 
13.7    
 
46.9    
 
29.6   
 
Scenario 5  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.20 
 
 
0.50 
 
 
0.70 
 
 
0.70 
 
Toxicity rates  
 
 
 
0.05 
 
 
0.10 
 
 
0.20 
 
 
0.40 
Selection Probabilities 
 
9.9   
 
 
22.2    
 
50.7    
 
17.2   
 
Scenario 6  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.40 
 
 
0.70 
 
 
0.60 
 
 
0.50 
 
Toxicity rates  
 
 
 
0.05 
 
 
0.10 
 
 
0.20 
 
 
0.40 
Selection Probabilities 
 
9.9   
 
 
55.1    
 
30.8    
 
4.2   
 
Scenario 7  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.40 
 
 
0.60 
 
 
0.75 
 
 
0.55 
 
Toxicity rates  
 
 
 
0.05 
 
 
0.10 
 
 
0.20 
 
 
0.40 
Selection Probabilities 
 
15.7    
 
27.2    
 
50.9    
 
6.2   
 
Scenario 8  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.70 
 
 
0.50 
 
 
0.30 
 
 
0.20 
 
Toxicity rates  
 
 
 
0.05 
 
 
0.10 
 
 
0.20 
 
 
0.40 
Selection Probabilities 
 
71.2    
 
23.6    
 
4.5  
 
 
 0.7   
 
Scenario 9  
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.20 
 
 
0.60 
 
 
0.50 
 
 
0.40 
 
Toxicity rates  
 
 
 
0.02 
 
 
0.05 
 
 
0.10 
 
 
0.20 
Selection Probabilities 
 
4.6   
 
 
53.6    
 
31.4    
 
10.4   
 
Scenario 10 
 
 
 
 
Dose -1 
 
Dose 1  
 
Dose 2  
 
Dose 3  
Biological rates 
 
 
 
0.20 
 
 
0.30 
 
 
0.60 
 
 
0.50 
 
Toxicity rates  
 
 
 
0.05 
 
 
0.10 
 
 
0.20 
 
 
0.40 
Selection Probabilities 
 
20.0    
 
16.2    
 
52.6    
 
11.2   
_____________________________________________________________________ 
 
11.2 
Sample Size/Accrual Rate 
 
A total of 18 patients will be enrolled in cohorts of 3 and dose escalation or de-escalation will be 
implemented as described in section 12.1 above.  We expect to enroll 1 patient per month for 
expected study duration of 18 months.    
 
11.3 
Assessment of Safety  
The isotonic regression design as described in 12.1 incorporates toxicity assessment.  The dose 
with the highest selection probability accounts for both the dose with the highest biological effect 
and toxicity that is closest to the target rate of 30%.    
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
31 
 
11.4 
Stratification Factors 
 
Not applicable for this trial  
 
11.5 
Analysis of Safety  
 
All patients who received study drug will be included in the safety analysis of this study.  Adverse 
event data and corresponding toxicity grades during the days of treatment will be summarized in 
each tumor cohort and in the overall patient population.  Incidence tables will be generated to 
summarize incidence of patients reporting at least one episode of each specific adverse event, 
incidence of adverse events causing withdrawal and incidence of serious adverse events. The total 
number of episodes for each event reported (Frequency Table), the severity and attribution to study 
therapy of each episode reported (Severity Table and Attribution Table) will also be displayed.    
 
Listings of adverse events by patients will include the time to onset, the duration of each event, 
the severity of each event, and the relationship of the event to study therapy, whether it was a 
serious event, and whether it caused withdrawal. Safety data will be summarized for the overall 
patient group and by tumor cohort.  Toxicities will be graded according to Common Toxicity 
Criteria (CTCAE) v4.0.   
 
11.6 
Pharmacokinetics Modeling and Pharmacodynamics Analysis 
 
For assessment of biological effect, we will utilize PAR-4 levels from pre-treatment and PAR-4 
from the last time point prior to resection.  Changes in quantitative levels of PAR-4 measured via 
ELISA and Western Blot will be calculated and the proportion of patients exhibiting at least a 2-
fold induction will be estimated overall and in each dose level along with exact 95% binomial 
confidence intervals. Isotonic regression will be fitted for the total sample to obtain estimates of 
biological effect at each dose level. Other exploratory analyses will include: paired tests to 
evaluate changes in PAR-4 quantitative levels from baseline and at each time point of 
measurement; correlations between several biological markers indicated in Section 9.1 for 
Correlative Studies will be estimated using Pearson or Spearman’s correlation coefficient; 
repeated measures modeling of several biomarker measurements over time; and descriptive 
statistics of biomarker levels for each disease group (if there are enough in each disease site).   
Similar analyses plans will be employed for biomarker assessments in tissue specimens.    
 
Population pharmacokinetic studies have previously been conducted 15.  This will allow the use 
of population parameters to be used as priors and thus enable forecasting the HCQ exposure for 
each patient, using a Bayesian approach, despite the limited sampling strategy 16, 17. Data analysis 
will be carried out with ADAPT V 18. 
 
 
11.7 
Data Management 
 
The study statistician and staff from the Biostatistics Shared Resource Facility (BSRF) of the 
Markey Cancer Center will work closely with the study PI and the Clinical Protocol and and 
Data Management (CPDM  SRF) at Markey in the development of eCRFs for the study.  


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
32 
 
Specifically, the statisticians will attend several meetings including the Protocol Initiation 
Meeting (PIM) to address all statistical considerations for this protocol including incorporation 
of dose-escalation and de-escalation plans for the adaptive design in this Phase I trial, 
appropriate and accurate collection of primary and secondary study endpoints and inclusion of 
valid values and range checks for data fields.  The OnCore clinical trial management system, 
managed by Markey’s CPDM, will be the primary database repository of clinical data from all 
patients enrolled into this trial.  Data will be accessed by the study statistical on a regularly-
scheduled basis to perform statistical programming for conduct of data quality control, data 
management, generation of interim reports and statistical analysis.  The BSRF has developed an 
automated mechanism for generating a trigger for assessment of biological response as well as 
dose limiting toxicities based on the dose escalation rules in section 12.1above.  In collaboration 
with the study team, procedures will be developed for timelines for data quality control, 
resolution of data queries, interim reporting and final data analysis.  
 
 
 
 
 
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
33 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
34 
 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
A table with potential drug interaction with HYDROXYCHLOROQUINE is included below. 
HYDROXYCHLOROQUINE should also be used with caution in patients taking medicines 
which may cause adverse ocular or skin reactions.  
 
Drug Interaction:  
Proper Name  
Effect/clinical comment  
Agalsidase  
There is a theoretical risk of inhibition of intra-cellular α-galactosidase 
activity when HYDROXYCHLOROQUINE is co-administered with 
agalsidase.  
 
Aminoglycoside antibiotics  
HYDROXYCHLOROQUINE may also be subject to several of the 
known interactions of chloroquine even though specific reports have not 
appeared including potentiation of its direct blocking action at the 
neuromuscular junction by aminoglycoside antibiotics.  
 
Amiodarone  
There may be an increased risk of inducing ventricular arrhythmias if 
HYDROXYCHLOROQUINE is used concomitantly with other 
arrhythmogenic drugs.  
 
Antacids  
As with chloroquine, antacids may reduce absorption of 
HYDROXYCHLOROQUINE so it is advised that a 4 hour interval be 
observed between HYDROXYCHLOROQUINE and antacid dosing.  
Anti-diabetic drugs  
May enhance the effects of a hypoglycemic treatment, a decrease in doses 
of antidiabetic drugs may be required.  
 
Antiepileptic drugs  
The activity of antiepileptic drugs might be impaired if co-administered 
with HYDROXYCHLOROQUINE.  
 
Antimalarials known to lower the 
convulsion threshold  
HYDROXYCHLOROQUINE can lower the convulsive threshold. Co-
administration of HYDROXYCHLOROQUINE with other antimalarials 
known to lower the convulsion threshold (e.g. mefloquine) may increase 
the risk of convulsions.  
 
Arrhythmogenic drugs  
There may be an increased risk of inducing ventricular arrhythmias if 
HYDROXYCHLOROQUINE is used concomitantly with other 
arrhythmogenic drugs.  
 
Cyclosporine  
An increased plasma ciclosporin level was reported when ciclosporin and 
HYDROXYCHLOROQUINE were co-administered.  
 
Cimetidine  
HYDROXYCHLOROQUINE may also be subject to several of the 
known interactions of chloroquine even though specific reports have not 
appeared including inhibition of its metabolism by cimetidine which may 
increase plasma concentration of the antimalarial. 
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
35 
 
Digoxin  
May result in increased serum digoxin levels; serum digoxin levels 
should be closely monitored in patients receiving concomitant treatment.  
Insulin  
May enhance the effects of a hypoglycemic treatment, a decrease in doses 
of insulin may be required.  
Mefloquine  
HYDROXYCHLOROQUINE can lower the convulsive threshold. Co-
administration of HYDROXYCHLOROQUINE with other antimalarials 
known to lower the convulsion threshold (e.g. mefloquine) may increase 
the risk of convulsions.  
 
Moxifloxacin  
There may be an increased risk of inducing ventricular arrhythmias if 
HYDROXYCHLOROQUINE is used concomitantly with other 
arrhythmogenic drugs.  
 
Neostigmine  
HYDROXYCHLOROQUINE may also be subject to several of the 
known interactions of chloroquine even though specific reports have not 
appeared including antagonism of effect of neostigmine.  
 
Praziquantel  
Chloroquine has been reported to reduce the bioavailability of 
praziquantel. Due to the similarities in structure and pharmacokinetic 
parameters between hydroxychloroquine and chloroquine, a similar effect 
may be expected for HYDROXYCHLOROQUINE.  
 
Pyridostigmine  
HYDROXYCHLOROQUINE may also be subject to several of the 
known interactions of chloroquine even though specific reports have not 
appeared including antagonism of effect of pyridostigmine.  
 
Vaccine: Human diploid cell rabies 
vaccine  
HYDROXYCHLOROQUINE may also be subject to several of the 
known interactions of chloroquine even though specific reports have not 
appeared including reduction of the antibody response to primary 
immunization with intradermal human diploid cell rabies vaccine. 
 
 
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
36 
 
APPENDIX C 
ORAL HYDROXYCHLOROQUINE ADMINISTRATION  
 
Hydroxychloroquine should be taken with a meal or a glass of milk.  Try to take your 
hydroxychloroquine at about the same time every day.  Please record any side effects from the 
medication in the medication diary given to you by your study team. 
 
• Use of nausea medicines (Phenergan, Compazine, or Zofran) may be helpful, and these 
medicines are best given about 30-60 minutes before the hydroxychloroquine. Please 
discuss this with your doctor. 
 
• If you are unable to take the medicine, call your doctor for further instructions 
 
• If you vomit within 30 minutes of taking the medicine, you may take a second dose of the 
medication. Do not take more than two doses of medication in the same day.   
 
• If you vomit longer than 30 minutes after taking the medicine, do not take any more 
hydroxychloroquine that day.   
 
• If you have any questions, call your doctor for further instructions. 
Common hydroxychloroquine side-effects  
What can I do if I experience this? 
Feeling sick, stomach pain, loss of appetite, 
diarrhea 
Remember to take the tablets after food or with a 
drink of milk. Stick to simple foods - avoid spicy 
or rich meals 
Headache 
Ask your doctor or pharmacist to recommend a 
suitable painkiller 
Eye problems (for example, blurred vision or 
sensitivity to light) 
Let your doctor know about this as soon as 
possible 
Skin rash or itching 
If this becomes troublesome, speak with your 
doctor 
 
If you have any other symptoms which you think may be due to this medicine, speak with your 
doctor or pharmacist. 
 
 
 
 
 
 
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
37 
 
APPENDIX D 
ORAL HYDROXYCHLOROQUINE ADMINISTRATION DIARY 
 
Patient Number_______________  
 
Day of 
course 
Date 
Time 
Side effects 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
 
 
 


Protocol #: 14-Multi-14-MCC 
Version Date: 6-20-2016 
 
 
38 
 
REFERENCES 
 
 
 
1. 
Hebbar N, Wang, C., Rangnekar, V. M. . Mechanisms of apoptosis by the tumor 
suppressor Par-4. J Cell Phys 2012;227:3715-21. 
2. 
Burikhanov R, Zhao, Y., Goswami, A., Qiu, S., Schwarze, S. R., and Rangnekar, V. 
M.  . The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 
2009;138:377-88. 
3. 
Bhattarai TaR, V.M. Cancer-selective apoptotic effects of extracellular and 
intracellular Par-4. Oncogene 2010;29:3873-80. 
4. 
El Guendy NaR, V.M. . Apoptosis by Par-4 in cancer and neurodegenerative diseases. 
. Exp Cell Res 2003;283:51-66. 
5. 
Shrestha-Bhattarai T, Hebbar, & Rangnekar, V. M. Par(-4)oxysm in breast cancer. 
Cancer Cell 2013;24:3-5. 
6. 
Burikhanov R, Shrestha-Bhattarai, T., Qiu, S., Shukla, N., Hebbar, N., Lele, S. M., 
Horbinski, C., and Rangnekar, V. M.  . Novel mechanism of apoptosis resistance in cancer 
mediated by extracellular PAR-4. Cancer Res 2013;73:1011-9. 
7. 
Zhao Y, Burikhanov, R., Brandon, J., Qiu, S., Shelton, B.J., Spear B, Bondada, S., 
Bryson, S., and Rangnekar, V.M. Systemic Par-4 inhibits non-autochthonous tumor growth. . 
Cancer Biol Ther 2011;12:152-7. 
8. 
The History of Malaria, an Ancient Disesase. (Accessed January 20, 2014, 
at http://www.cdc.gov/malaria/about/history/.) 
9. 
Maclean KH, Dorsey, F.C., Cleveland, J.L., Kastan, M.B. Targeting lysosomal 
degradation induces p53-dependent cell death and prevents cancer in mouse models of 
lymphomagenesis. J Clin Invest 2008;118:79-88. 
10. 
Kimura T, Takabatake, Y., Takahashi, A., and Isaka, Y. Chloroquine in cancer 
therapy: a double-edged sword of autophagy. . Cancer Research 2013;73:3-7. 
11. 
Geser A, Brubaker, G., Draper, C.C. . Effect of a malaria suppression program on the 
incidence of African Burkitt’s lymphoma. . Am J Epidemiol 1989;129:740-52. 
12. 
Burikhanov R, Shrestha-Bhattarai, T., Hebbar, N.,  Qiu, S., Zhao, Y., Zambetti, 
G.,and Rangnekar, V. M. . Paracrine apoptotic effect of p53 mediated by tumor suppressor Par-4. 
Cell Reports 2014;6:1-7. 
13. 
Jiang P, Mizushima N. Autophagy and human diseases. Cell Res 2014;24:69-79. 
14. 
Rojas-Puentes L, Gonzalez-Pinedo M, Crismatt A. Phase II randomized, double-
blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for 
brain metastases. Radiat Oncol 2013;8:209. 
15. 
Lim HS, Im JS, Cho JY, Bea KS, Klein TA, Yeom JS, Kim TS, CHoi JS, Janq IJ, 
Park JW. Pharmacokinetics of hydroxychloroquine and its clinical implications in 
chemophrophylaxis against malaria coused by Plasmodium vivax. Antimicrob Agents 
Chemother 2009; 53: 1468.  
16. 
Fruit D, Rousseau A, Amrein C, Rolle F, Kamar N, Sebbaq L, Redonnet M, Epailly 
E, Marquet P, Premaud A. Ciclosporin population pharmacokinetics and Bayesian estimation in 
thoracic transplant recipients. Clin Pharmacokinet 2013; 52: 277. 
17. 
Bios FY. Bayesian inference. Methods Mol Biol 2013; 930: 597. 
18. 
D’Argenio, D.Z., A. Schumitzky and X. Wang. ADAPT 5 User’s Guide: 


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39 
 
Pharmacokinetic-Pharmacodynamic Systems Analysis Software. Biomedical Simulations 
Resource, Los Angeles, 2009. 
 
 

ICF_001.pdf: 
IRB#:15-0076-F2L
\Protocol - PI Initiated\14-MULTI-14-MCC
Page 1 of 17
Combined ICF/HIPAA dated 6/20/2016
COMBINED CONSENT AND AUTHORIZATION TO
PARTICIPATE IN A RESEARCH STUDY 
UNIVERSITY OF KENTUCKY
CHANDLER MEDICAL CENTER
MARKEY CANCER CENTER
Study Title: 14-Multi-14-MCC: A Pilot Study to Determine the Biological Effects of 
Hydroxychloroquine on PAR-4 Levels in Patients with Resectable Solid Tumors
INVESTIGATOR INFORMATION:
Peng Wang, MD
Department of lnternal Medicine
University of Kentucky Markey Cancer Center
(859) 323-6522 (Days)
(859) 323-5321 (Evenings and Weekends)
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS RESEARCH?
You are being invited to take part in a research study about a drug called Hydroxychloroquine (HCQ) 
and the effects it has on a tumor suppression protein called Prostate apoptosis response-4 (PAR-4). You 
are being invited to take part in this research study because you have a solid tumor that may be 
surgically removed. If you volunteer to take part in this study, you will be one of about 18 people to do 
so.
WHO IS DOING THE STUDY?
The person in charge of this study is Peng Wang, MD of the University of Kentucky, Department of 
Internal Medicine.  There may be other people on the research team assisting at different times during 
the study. 
WHAT IS THE PURPOSE OF THIS STUDY?
Prostate apoptosis response-4 (PAR-4) is a tumor suppressor protein that induces apoptosis (cell death) 
in cancer cells but not in normal cells. PAR-4 is widely found in normal cells and tissues, but is often 
inactivated, decreased or changed in cancer cells. Usually the amount of PAR-4 secreted by normal cells 
is not enough to cause massive cell death in cancer cells. The drug used in this study, 
Hydroxychloroquine (HCQ), has been approved by the FDA for the treatment of Malaria, lupus 
erythematosus and rheumatoid arthritis. Prior studies suggest that HCQ can increase serum (blood) 
PAR-4 levels so that PAR-4 can induce death of cancer cells and may be able to prevent recurrence after 
surgical resection of the primary tumor. By doing this study, we hope to learn about the effects of HCQ 
on the levels of PAR-4 in patients with resectable (removable) solid tumors at the time of and after 
resection and to compare them to pre-treatment levels. We also hope to learn more about side effects 
related to the use of HCQ. The results of this study will be shared with the company providing financial 
support for the study, the Food and Drug Administration and other federal agencies, if required.
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
\Protocol - PI Initiated\14-MULTI-14-MCC
Page 2 of 17
Combined ICF/HIPAA dated 6/20/2016
ARE THERE REASONS WHY YOU SHOULD NOT TAKE PART IN THIS STUDY?
You should not take part in the study if:
x
You are under the age of 18
x
You are pregnant or nursing a child
x
You are currently taking any other investigational agents
x
You are unable to ingest oral medications
x
You currently have illnesses that would keep you from being in this study and following the 
study requirements such as: an active infection, symptomatic congestive heart failure, unstable 
angina, cardiac arrhythmia, or psychiatric illness/social situations
x
You are HIV-positive and receiving combination antiretroviral therapy
x
You have Porphyria
WHERE IS THE STUDY GOING TO TAKE PLACE AND HOW LONG WILL IT LAST?
The research procedures will be conducted at the University of Kentucky’s Markey Cancer Center. You 
will need to come to the cancer center four times during the study.  Each of those visits will take about 
between 30 minutes and 2 hours. The total amount of time you will be asked to volunteer for this study 
is 8 hours over the next 10 weeks.
WHAT WILL YOU BE ASKED TO DO?
Before you begin treatment (Pre-study visit)…
If not already completed within 2-4 weeks of starting the study: 
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs, height/weight and performance status.
x
Tumor collection for correlative studies (Previous biopsy of primary tumor if available)
x
Blood collection for correlative studies
x
If you are a female, you will have a serum (blood) pregnancy test performed if necessary. 
All laboratory (blood) tests and radiological scans should be completed within 4 weeks prior to 
receiving study treatment.
If the exams, tests and procedures above show that you are able to participate in the study, and 
you choose to take part, then you will be asked to do the following: 
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


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You will receive HCQ every day for 14 days, starting at least 14 days before planned surgery. HCQ can 
be taken at any time of the day with meals. HCQ will be administered in divided doses (twice a day) for 
doses above 200 mg/day to minimize nausea. The divided doses should be taken in the AM and at night 
with meals. You will also be required to keep a medication diary and to present this at the end of the 
treatment.  Should a subject regurgitate (vomit) within 30 minutes of taking the medication, the dose 
may be repeated once, but if vomiting occurs longer than 30 minutes after ingestion, the dose should not 
be repeated.  If you are taking antacids, proton-pump inhibitors or H2-blockers should not take 
hydroxychloroquine within 4 hours of these medicines.  
The starting HCQ dose will be 400 mg/day. If three subjects tolerate a dose level, the dosage will be 
increased to the next dose level. Once the maximum number of subjects (18) has been reached, the 
lowest dose that has shown the greatest biological effect based on Par-4 levels will be used. If you 
experience severe side effects, your dose level will be reduced by one level. 
Week 1 on day 7
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs.
x
You will have a blood sample drawn for routine laboratory tests including complete blood count and 
blood chemistries.  
x
Blood collection for correlative studies 
Week 2 on day 14
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs.
x
Blood and Tumor collection for Correlative Studies (if available)
x
You will have a blood sample drawn for routine laboratory tests including complete blood count and 
blood chemistries.  
x
Blood collection for correlative studies 
Post-operative (inpatient)
x
Tumor collection for correlative studies (Resected primary tumor if available)
x
Blood collection for correlative studies 
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
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Post-operative visit
x
You will be asked questions about your medical history.
x
You will have a physical examination including vital signs.
x
You will have a blood sample drawn for routine laboratory tests including complete blood count and 
blood chemistries.  
x
Blood collection for correlative studies 
Off study 
x
You will be asked questions about your medical history.
Studies to be obtained
Pre-
Study
Week 1 
(Day7)
Week 2 
(Day 14)
Day of 
Surgery
Post-
operative 
visit
Off study
History
X
X
X
X
X
Physical Exam with 
vital signs
X
X
X
X
Height, Weight
X
Performance Status
X
Blood collection for 
complete blood count 
and blood chemistry
X
X
X
X
Pregnancy test (only 
females of childbearing 
potential)
X
Tumor collection for 
Correlative Studies (if 
available)
X
X
Correlative Blood work
X
X
X
X
You will be followed for 30 days after your surgery or 30 days after completion of the last dose of 
hydroxychloroquine if no surgery is completed.  If you are removed from study for unacceptable adverse 
event(s) you will be followed until the event has resolved.
The following procedures will be done as per standard of care and would be performed even if you are 
not in this study: 
x
Medical history (Pre-study, Post-Operative and Off study visit)
x
Physical examination including vital signs and height/weight (Pre-study and Post-Operative visit)
x
Performance status (Pre-study visit)
x
Blood tests including complete blood count and blood chemistries (Pre-study and Post-Operative 
visit).
x
Serum (blood) pregnancy test performed (Pre-study visit)
All other procedures will be performed for the purposes of research. 
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
\Protocol - PI Initiated\14-MULTI-14-MCC
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The effects of hydroxychloroquine on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  If you become pregnant or suspect that your partner has become pregnant, you should 
inform your or your partner’s treating physician immediately.  Men treated or enrolled on this protocol 
must also agree to use adequate contraception prior to the study, for the duration of study participation, 
and 4 months after completion of hydroxychloroquine administration.
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS?
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  Side 
effects may be mild or very serious. Your health care team may give you medicines to help lessen side 
effects. In some cases, side effects can be serious, long lasting, or may never go away. There also is a 
risk of death.
Risks and side effects related to hydroxychloroquine include those which are “Very common”, 
“Common”, “Uncommon”, “rare”, “Very rare” and “not known”. The percentages associated 
with these labels are listed below:
x
9HU\FRPPRQ
x
&RPPRQDQG
x
8QFRPPRQDQG
x
5DUHDQG
x
Very rare < 0.01 %
x
Not known (frequency cannot be estimated from available data)
Blood and lymphatic system disorders 
Not known: Bone marrow depression, anemia (your body makes too few red blood cells), aplastic 
anemia (your body makes too few red blood cells, white blood cells, and platelets), agranulocytosis (a 
condition involving a severe lowered white blood cell count), leucopenia (decreased white blood cells) 
and thrombocytopenia (decreased platelets in the blood).
Cardiac disorders 
Not known: Cardiomyopathy, which may result in cardiac failure and in some cases a fatal outcome. 
Chronic toxicity should be considered when conduction disorders (bundle branch block/ atrioventricular 
heart block) as well as biventricular hypertrophy are found. Drug discontinuation may lead to recovery. 
Ear and labyrinth disorders 
Uncommon: Vertigo (a sensation of rotation or movement of one's self or of one's surroundings),
tinnitus (a buzzing or ringing in the ears)
Not known: Hearing loss including cases of irreversible hearing loss. 
Eye disorders 
Common: Blurring of vision due to a disturbance of accommodation which is dose dependent and 
reversible. 
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
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Uncommon: Maculopathies (a disease of the macula retinae-an area at the center of the retina) which 
may be irreversible. 
Retinopathy (disease of the retina) with changes in pigmentation and visual field defects. In its early 
form it appears reversible upon discontinuation of the drug. If allowed to develop however, there may be 
a risk of progression even after treatment withdrawal. Patients with retinal changes may be not notice 
symptoms at first, or may have scotomatous vision (blind spots), abnormal color visions, reduction in 
visual acuity (clarity of vision), night blindness, difficulty reading and skipping words.  Corneal changes 
including edema (swelling) and opacities (clouding). They are either symptomless or may cause 
disturbances such as halos around lights especially at night, blurring of vision or photophobia
(sensitivity to light). They may be transient or are reversible upon discontinuation of therapy. 
Not known: Macular degeneration (deterioration of a critical region of the retina called the macula)
which may be irreversible. 
Gastrointestinal disorders 
Very common: Abdominal pain, nausea 
Common: Diarrhea, vomiting 
These symptoms usually resolve immediately upon reducing the dose or upon stopping the treatment. 
Hepatobiliary disorders 
Uncommon: Abnormal liver function tests 
Not known: Fulminant hepatic failure (acute liver injury)
Immune system disorders 
Not known: Urticaria (Hives), angioedema (swelling under the skin), bronchospasm (tightening of the 
airways going into the lungs).
Metabolism and nutrition disorders 
Common: Anorexia (Lack or loss of appetite). This symptom usually resolves immediately upon 
reducing the dose or upon stopping the treatment). 
Not known: hypoglycemia 
HYDROXYCHLOROQUINE may exacerbate porphyria (a disorder characterizes by decreased heme 
production).
Musculoskeletal and connective tissue disorders 
Uncommon: Sensory motor disorders 
Not known: Skeletal muscle palsies (paralysis) or skeletal muscle myopathy (weakness) or 
neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups. Depression of 
tendon reflexes, abnormal results of nerve conduction tests. Myopathy may be reversible after drug 
discontinuation, but recovery may take many months. 
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


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\Protocol - PI Initiated\14-MULTI-14-MCC
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Nervous system disorders 
Common: Headache 
Uncommon: Dizziness 
Not known: Convulsions 
Psychiatric disorders 
Common: Affect lability (rapidly changing mood)
Uncommon: Nervousness 
Not known: Psychosis, suicidal behaviour 
Skin and subcutaneous tissue disorders 
Common: Skin rash, pruritus 
Uncommon: Pigmentary changes in skin and mucous membranes, bleaching of hair, alopecia. These 
usually resolve readily upon cessation of therapy. 
Not known: Bullous eruptions (blisters) toxic epidermal necrolysis (a condition where the top layer of 
skin separates from the lower layers), erythema multiforme/Stevens-Johnson syndrome (drug induced 
hypersensitive reaction that results in sores on the skin), Drug Rash with Eosinophilia and Systemic 
Symptoms (DRESS syndrome), photosensitivity (light sensitivity), exfoliative dermatitis (scaling of the 
skin), acute generalized exanthematous pustulosis (AGEP). AGEP has to be distinguished from 
psoriasis, although HYDROXYCHLOROQUINE may precipitate attacks of psoriasis. It may be 
associated with fever and hyperleukocytosis (elevated white blood count). Outcome is usually favorable 
after discontinuation of drug.
Blood Draw: soreness, bruising, pain, infection, possible fainting, bleeding.
Reproductive risks:
You should not become pregnant or father a baby while on this study because the treatment used in this 
study may involve a risks to you (or your embryo or fetus if you become pregnant) which are currently 
unforeseeable. Women should not breastfeed a baby while on this study.  It is important that you 
understand that you need to use birth control while on this study and for 4 months after your last 
treatment.  Check with your study doctor about what kind of birth control methods to use and how long 
to use them. Some methods might not be approved for use in this study.  Some of the drugs used in the 
study may make you unable to have children in the future. 
If you or your partner becomes pregnant anytime during the study or within 4 months after stopping the 
study drug, you MUST immediately tell your study doctor. The study doctor must then report the 
outcome of the pregnancy to the Sponsor (and/or the FDA).
For more information about risks and side effects, ask your study doctor.
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
\Protocol - PI Initiated\14-MULTI-14-MCC
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There is always a chance that any medical treatment can harm you, and the investigational treatment in 
this study is no different.  In addition to the risks listed above, you may experience a previously 
unknown risk or side effect.
WILL YOU BENEFIT FROM TAKING PART IN THIS STUDY?
There may be no direct benefit to you for participating in this study.  The growth of your cancer may be 
slowed as a result of your participation in this study; however, that result cannot be guaranteed. Your 
participation in this study could help advance medical research and the information from this research 
may help other people with cancer.
DO YOU HAVE TO TAKE PART IN THE STUDY?
If you decide to take part in the study, it should be because you really want to volunteer.  You will not 
lose any benefits or rights you would normally have if you choose not to volunteer.  You can stop at any 
time during the study and still keep the benefits and rights you had before volunteering. If you decide 
not to take part in this study, your decision will have no effect on the quality of medical care you 
receive.
IF YOU DON’T WANT TO TAKE PART IN THE STUDY, ARE THERE OTHER CHOICES?
If you do not want to be in the study, you will proceed with surgery as planned. You do not need to 
participate in this study to receive treatment for your cancer.
You may talk with your study doctor about these and other options before you agree to enter the study, 
and about other options that may become available during the study.
WHAT WILL IT COST YOU TO PARTICIPATE?
You and/or your insurance company, Medicare or Medicaid will be responsible for the costs of all care 
and treatment you receive during this study that you would normally receive for your condition. These 
are costs that are considered medically reasonable and necessary and will be part of the care you receive 
if you do not take part in this study.
Medicare, or Medicaid will pay medically necessary costs (if you have any questions regarding 
Medicare/Medicaid coverage you should contact Medicare by calling 1-800-Medicare (1-800-633-4227) 
or Medicaid at 1-800-635-2570.
A co-payment/deductible from you may be required by your 
insurer or Medicare/Medicaid even if your insurer or Medicare/Medicaid has agreed to pay the 
costs. Some health plans will not pay for some costs of people taking part in clinical trials. Check with 
your health plan or insurance company to find out what they will pay for. Taking part in this study may 
or may not cost your insurance company more than the cost of getting regular cancer treatment.  
The University of Kentucky may not be allowed to bill your insurance company, Medicare or Medicaid 
for the medical procedures done strictly for research. You will not be billed for the costs associated with 
the week 1 and week 2 visits or for the blood and tumor correlative collections or for the study drug 
(Hydroxychloroquine). These costs will be paid by the sponsor.
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
\Protocol - PI Initiated\14-MULTI-14-MCC
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WHO WILL SEE THE INFORMATION THAT YOU GIVE?
We will make every effort to keep confidential all research records that identify you to the extent 
allowed by law.
Your information will be combined with information from other people taking part in the study. When 
we write about the study to share it with other researchers, we will write about the combined information 
we have gathered. You will not be personally identified in these written materials. We may publish the 
results of this study; however, we will keep your name and other identifying information private. 
We will make every effort to prevent anyone who is not on the research team from knowing that you 
gave us information, or what that information is. At the University of Kentucky, data is stored at the 
Markey Cancer Center in locked facilities, and with limited access to records by designated research 
staff.
You should know, however, that there are some circumstances in which we may have to show your 
information to other people. For example, the law may require us to show your information to a court or 
to tell authorities if you report information about a child being abused or if you pose a danger to yourself 
or someone else.
Organizations that may look at and/or copy your medical records for research, quality assurance and 
data analysis include:
x
The University of Kentucky Institutional Review Board
x
Representatives of the U.S. Food and Drug Administration as required by law
x
Representatives of the National Cancer Institute (NCI)
x
Representatives of the Kentucky Cancer Registry
x
Authorized representatives of the University of Kentucky, UK Hospital, and the Markey Cancer 
Center 
CAN YOUR TAKING PART IN THE STUDY END EARLY?
If you decide to take part in the study you still have the right to decide at any time that you no longer 
want to continue. You will not be treated differently if you decide to stop taking part in the study.
If you choose to withdraw from the study early, the data collected until that point will remain in the 
study database and may not be removed.
The individuals conducting the study may need to withdraw you from the study, and the study 
medication will no longer be provided by the investigator. This may occur if you are not able to follow 
the directions they give you, if they find that your being in the study is more risk than benefit to you, or 
if the agency funding the study decides to stop the study early for a variety of scientific reasons. 
Certain drugs may harm you if you stop taking them suddenly. To make sure this doesn’t happen, the 
doctor may ask you to gradually reduce the amount of medication you are taking, if you want to stop 
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


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taking part in the study. If you are a female of childbearing potential, your participation in this study 
may be discontinued if you become pregnant or suspect you may have become pregnant.
If you decide to leave the study, please contact Peng Wang, MD or one of the study associates who will 
tell you what you should do before leaving.  You may be asked to return to the clinic for follow-up care, 
if necessary.  You may be asked to have any laboratory tests, or physical examinations that the study 
doctor feels are necessary.  Until your permission is withdrawn, additional information may continue to 
be taken from your medical records for study follow-up purposes.
ARE YOU PARTICIPATING OR CAN YOU PARTICIPATE IN ANOTHER RESEARCH 
STUDY AT THE SAME TIME AS PARTICIPATING IN THIS ONE?
You may not take part in this study if you are currently involved in another research study.  It is 
important to let the investigator/your doctor know if you are in another research study.  You should also 
discuss with the investigator before you agree to participate in another research study while you are 
enrolled in this study.
WHAT HAPPENS IF YOU GET HURT OR SICK DURING THE STUDY?
If you believe you are hurt or if you get sick because of something that is due to the study, you should 
call Peng Wang, M.D. at (859) 323-6522 immediately. If you should have an emergency after 5pm 
during the week or on the weekend, please contact the UK Paging Operator at (859) 323-5321 and ask 
to page Peng Wang, MD.  He will determine what type of treatment, if any, that is best for you at that 
time.
It is important for you to understand that the University of Kentucky does not have funds set aside to 
pay for the cost of any care or treatment that might be necessary because you get hurt or sick while 
taking part in this study. Also, the University of Kentucky will not pay for any wages you may lose if 
you are harmed by this study.  
The medical costs related to your care and treatment because of research related harm will be 
your responsibility. It is possible that these costs may be paid by your insurer if you are insured by a 
health insurance company (you should ask your insurer if you have any questions regarding your 
insurer’s willingness to pay under these circumstances); or may be paid by Medicare or Medicaid if you 
are covered by Medicare, or Medicaid (if you have any questions regarding Medicare/Medicaid 
coverage you should contact Medicare by calling 1-800-Medicare (1-800-633-4227) or Medicaid 1-800-
635-2570.
A co-payment/deductible from you may be required by your insurer or Medicare/Medicaid even if your 
insurer or Medicare/Medicaid has agreed to pay the costs).  The amount of this co-payment/deductible 
may be substantial.
You do not give up your legal rights by signing this form.
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
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WILL YOU RECEIVE ANY REWARDS FOR TAKING PART IN THIS STUDY?
You will not receive any rewards or payment for taking part in the study.
WHAT IF YOU HAVE QUESTIONS, SUGGESTIONS, CONCERNS, OR COMPLAINTS?
Before you decide whether to accept this invitation to take part in the study, please ask any questions 
that might come to mind now.  Later, if you have questions, suggestions, concerns, or complaints about 
the study, you can contact the investigator, Peng Wang, MD at 859-323-6522.  If you have any 
questions about your rights as a volunteer in this research, contact the staff in the Office of Research 
Integrity at the University of Kentucky between the business hours of 8am and 5pm EST, Mon-Fri at 
859-257-9428 or toll free at 1-866-400-9428. We will give you a signed copy of this consent form to 
take with you.
WHAT IF NEW INFORMATION IS LEARNED DURING THE STUDY THAT MIGHT 
AFFECT YOUR DECISION TO PARTICIPATE?
If the researcher learns of new information in regards to this study, and it might change your willingness 
to stay in this study, the information will be provided to you.  You may be asked to sign a new informed 
consent form if the information is provided to you after you have joined the study. 
POTENTIAL FUTURE USE 
Banking biologic material (tissues/specimens) for future use
WHAT IS THE PURPOSE OF THE BANK?
The purpose of the bank is to collect and store leftover samples of tissue and blood along with health 
information for research purposes.  Researchers can then use the stored materials for future research 
studies to learn more about cancer. 
The goal of the study is to ask 18 patients if they would like to participate. Having samples from many 
people allows the researchers to identify trends and discover better ways to diagnose, prevent, and treat 
many conditions.
The researchers who obtain your samples from the may use the genetic material (genes, DNA, RNA) in 
your sample to learn about the role genes play in heath and disease.  Results of genetic studies may also 
reveal information about your family members.  
WHERE WILL SAMPLES AND INFORMATION BE STORED AND FOR HOW LONG?
The samples and information will be stored at the University of Kentucky Markey Biospecimen and 
Tissue Procurement Shared Resource Facility for 5 years or until they are all used up. 
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
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WHAT WILL THE BANK COLLECT AND STORE FOR RESEARCH? 
During the main study about Ten to 30 mL (about 2 tablespoons) of blood and a tissue sample will be 
collected for analysis. Dr. Peng Wang would like to keep some of the blood and tissue that remains after 
this testing has been completed for the purpose of future testing. No additional blood or tissue will be 
taken. 
We also would like to have permission to look at your medical records from time to time. We would 
collect general information related to your health such as test results, treatments, and doctor’s notes. 
Medical records may also include psychiatric, genetic, HIVAIDS, alcohol/substance abuse information.
The confidentiality section below provides details about how we will keep your information private.
WILL YOU BE CONTACTED ABOUT FUTURE RESEARCH?
The researchers who access samples or information related to them will not contact you about future 
research.  If you wish to participate in research studies, you may find information at 
www.ukclinicalresearch.com. 
HOW WILL THE BANK SHARE SAMPLES AND INFORMATION WITH OTHER 
RESEARCHERS?
Your sample or information may be shared with University of Kentucky (UK) researchers and 
researchers outside of UK. 
Researchers may contact the bank to request permission to use samples or information for their studies. 
An oversight committee will review the researcher’s qualifications and proposed research. The 
committee will also determine if any additional review or approval is necessary. 
The bank will remove all information that could identify you such as your name, address, medical record 
number, etc, before sharing with researchers. The bank will use a code to match your samples with your 
medical information without releasing your identity. The researchers will sign an agreement promising 
not to try to use any of the sample or information to identify you. The bank will not share information 
that could identify you without your permission. 
WILL YOU BENEFIT FROM TAKING PART IN THE (BANK)? 
There is no direct benefit to you.  The knowledge gained from research on your sample may help others 
in the future. 
ARE THERE RISKS FROM TAKING PART IN THE (BANK)?
Physical: 
There is no additional physical risk from collecting leftover tissue from a procedure that is being done as 
part of your clinical care.  
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


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Blood draw
Risks associated with blood sampling are generally slight, but may include soreness, bruising, pain, 
infection, possible fainting, bleeding. 
Privacy and Social/Psychological: 
There is a risk that someone could get access to the information stored in the bank. In spite of the 
security measures and safeguards we will use, we cannot guarantee that your identity will never become 
known. 
Even without your name or identifiers, genetic information is unique to you making it possible for 
someone to trace it back to you. The results of genetic research apply to both you and your family 
members. In some cases, it could be used to make it harder for you to get or keep a job or insurance.  
Genetic information could be used in ways that could cause you or your family distress.  
There is a Federal law called the Genetic Information Nondiscrimination Act (GINA).  Generally, GINA 
makes it illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. Be aware that GINA does not protect you against 
discrimination by companies that sell life insurance, disability insurance, or long-term care insurance.  It 
also does not prohibit discrimination on the basis of already known genetic disease.
Unknown:
There may be risks that at this time are unknown.  As technology advances, there may be new ways of 
linking information back to you that we cannot foresee now.
HOW IS YOUR PRIVACY AND CONFIDENTIALITY PROTECTED? 
The bank will take careful steps to keep your information confidential. Electronic records will only be 
accessible to authorized personnel and will require passwords for access.
We will remove information such as your name or other direct identifiers from your sample and medical 
information. We will label your samples and information with a code. The coded samples will be kept in 
locked facilities only accessible by authorized research staff. Data will be store in a password protected 
database.  
Only select bank staff will have access to the list that links the code to you.  The bank staff members 
sign an agreement to keep your identity a secret to the extent allowed by law. In very unusual cases, 
staff at the bank may be required to release your identifiable medical and research information in 
response to an order from a court of law. 
Officials of the Food and Drug Administration, the National Cancer Institute (NCI) and the University 
of Kentucky may look at or copy pertinent portions of records that identify you.
DOES TAKING PART IN THE BANK COST ANYTHING? 
There will be no additional costs or charges to you for taking part in the bank.  You will not need to pay 
for sample collection or blood test done just for the bank.   
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


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WILL YOU RECEIVE ANY REWARDS FOR TAKING PART IN THE BANK? 
You will not be paid for donating your sample or information to the bank. The sample and information 
that you are donating will no longer belong to you.  The research may lead to new medical knowledge, 
tests, treatments, or products. These products could have some financial value. There are no plans to 
provide financial payment to you or your relatives should this occur.
WILL YOU BE GIVEN INDIVIDUAL RESULTS FROM THE RESEARCH TESTS?
Do you give permission for Peng Wang, MD to contact you with information about research results or 
incidental findings that are determined to be important to you/your family’s health? (Incidental findings 
are unforeseen findings discovered during the course of the research that may affect you or your 
family’s health).   
 Yes
 No
_________Initials
You may also withdraw your consent to be contacted with information about research results or 
incidental findings by sending a written request to Peng Wang, MD M.D. c/o Markey Cancer Center 
Clinical Research Organization, cc140 Markey Cancer Center, 800 Rose Street, Lexington, KY. 40536-
0093.
Are there other choices if you do not want to participate in the repository? 
If you do not want to take part in the repository, there are no other choices except not to take part.  Your 
decision will not affect your current or future medical care. 
WHAT IF YOU CHOOSE NOT TO PARTICIPATE OR CHANGE YOUR MIND AND WANT 
TO WITHDRAW FROM TAKING PART IN THE BANK?
Taking part in the bank is voluntary.  Choosing not to take part will not affect your care or cause you to 
lose benefits to which you are entitled.  You may withdraw your permission to continue taking part in 
the bank at any time.  To do so, you must send a written withdraw request to the bank at Peng Wang, 
MD M.D. c/o Markey Cancer Center Clinical Research Organization, cc140 Markey Cancer Center, 800 
Rose Street, Lexington, KY. 40536-0093. The bank will destroy any remaining samples and information 
that has been stored.  In addition, it may be possible for the bank to destroy the code that links you with 
your sample and medical information.  However, the samples and information that has already been 
shared with other researchers or placed in shared databases cannot be withdrawn.  
Please read each sentence below and think about your choice. After reading each sentence, mark “yes” 
or “no”. If you have questions, please talk to the investigator or staff. Remember, no matter what you 
decide to do about the storage, or banking, and future use of your blood and tissue samples, you may 
still take part in the main study. If you answer yes to either choice below you also give your 
authorization for your accompanying health information to be used and disclosed along with the blood.
1. Do you give permission for your blood and tissue to be kept by Dr. Wang in a central 
location/specimen bank at the University of Kentucky Markey Biospecimen and Tissue 
Procurement Shared Resource Facility until they are used up but no longer than 5 years for use in 
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future research to learn more about how to prevent, detect or treat squamous cell carcinoma of 
the head and neck?
Yes
No
_________Initials
2. Do you give permission for your blood and tissue samples to be used for future research about 
other health problems?
Yes
No
_________Initials
The sample(s) (blood and tissue) you are giving will no longer belong to you and might be used in 
studies that lead to new products for research, diagnosis or treatment. These products might have some 
commercial value. There are no plans to provide financial compensation to you should this occur.
WHAT ELSE DO YOU NEED TO KNOW?
There is a possibility that the data/tissue/specimens/blood collected from you may be shared with other 
investigators in the future.  If that is the case the data/tissue/specimen/blood will not contain information 
that can identify you unless you give your consent/authorization or the UK Institutional Review Board 
(IRB) approves the research.  The IRB is a committee that reviews ethical issues, according to federal, 
state and local regulations on research with human subjects, to make sure the study complies with these 
before approval of a research study is issued.
The Markey Cancer Center is providing financial support and/or material for this study.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by U.S. 
Law. This website will not include information that can identify you.  At most, the website will include 
a summary of the results.  You can search this website at any time.
AUTHORIZATION TO USE OR DISCLOSE YOUR IDENTIFIABLE HEALTH 
INFORMATION 
The privacy law, HIPAA (Health Insurance Portability and Accountability Act), requires researchers to 
protect your health information.  The following sections of the form describe how researchers may use 
your health information.  
Your health information that may be accessed, used and/or released includes:
x
Demographic Information (Example:  Sex, race & age, etc.)
x
History and diagnosis of your disease
x
Specific information about treatments you have received
x
Past and present medical records pertaining to your health condition
x
Your entire research record
x
Information about other medical conditions that may affect your treatment
x
Medical data, including physical examinations, laboratory test results, tumor measurements, 
CT scans, MRIs, X-rays, photographs of radiation therapy target areas, and pathology results
x
Information on side effects (adverse events) you may experience, and how these were treated
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


IRB#:15-0076-F2L
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x
Long-term information about your general health status and the status of your disease
x
Tissue and/or blood samples, associated data related to the analysis of the samples
The Researchers may use and share your health information with:
x
The University of Kentucky’s Institutional Review Board/Office of Research Integrity.
x
Law enforcement agencies when required by law.
x
Authorized representatives of the University of Kentucky, UK Hospital, and Markey Cancer 
Center
x
Representatives of the Kentucky Cancer Registry
x
Representatives of the U.S. Food and Drug Administration (FDA)
x
The National Institutes of Health and its affiliates including the for Human Research 
Protections (OHRP) and the NCI (National Cancer Institute) and their affiliates
The researchers agree to only share your health information with the people listed in this document.  
Should your health information be released to anyone that is not regulated by the privacy law, your
health information may be shared with others without your permission; however, the use of your health 
information would still be regulated by applicable federal and state laws.  
If you become pregnant anytime during the study or within 90 days after stopping the study drug, you 
must inform the study doctor.  The study doctor must then report the outcome of your pregnancy to the 
sponsor and/or the FDA.
You may not be allowed to participate in the research study.   If you decide not to sign the form, it will 
not affect your:
x
Current or future healthcare at the University of Kentucky
x
Current or future payments to the University of Kentucky  
x
Ability to enroll in any health plans (if applicable)
x
Eligibility for benefits (if applicable)
After signing the form, you can change your mind and NOT let the researcher(s) collect or release 
your health information (revoke the Authorization). If you revoke the authorization:
x
You will send a written letter to: Peng Wang, MD M.D. c/o Markey Cancer Center Clinical 
Research Organization, cc140 Markey Cancer Center, 800 Rose Street, Lexington, KY. 40536-
0093 to inform him of your decision.
x
Researchers may use and release your health information already collected for this research 
study.
x
Your protected health information may still be used and released should you have a bad reaction 
(adverse event).
The use and sharing of your information has no time limit.
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18


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If you have not already received a copy of the Privacy Notice, you may request one.  If you have 
any questions about your privacy rights, you should contact the University of Kentucky’s Privacy 
Officer between the business hours of 8am and 5pm EST, Mon-Fri at: (859) 323-1184.
You are the subject or are authorized to act on behalf of the subject.  You have read this 
information, and you will receive a copy of this form after it is signed.
_________________________________
____________________________
Signature of research subject 
Date
_________________________________
Printed name of research subject 
________________________________________________________________
_________
Name of [authorized] person obtaining informed consent/HIPAA authorization
Date
_________________________________________
Signature of Principal Investigator or Sub/Co-Investigator
Approval of IRB #15-0076 
Valid from 12/19/17 - 12/18/18