Conditions: Paraganglioma Gastrointestinal Stromal Tumors Carcinoma, Renal Cell Renal Neoplasms Pheochromocytoma
Keywords: Renal Cancer DNA Hypermethylation Gastrointestinal Stromal Tumors DNA Methyltransferase (DNMT) Inhibitor Succinate Dehydrogenase (SDH) Deficiency
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
Background:

Wild-type gastrointestinal stromal tumor (GIST) is a cancer in the esophagus, stomach, or intestines. It does not respond well to standard chemotherapy or radiation therapy. Most people with GIST are treated with imatinib. But it may not work in many children with GIST. Researchers think the drug SGI-110 may help treat people with GIST, pheochromocytoma and paraganglioma (PHEO/PGL), or kidney cancer related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

Objective:

To learn if SGI-110 causes GIST tumors to shrink or slows their growth. Also to test how it acts in the body.

Eligibility:

People ages 12 and older who have GIST, PHEO/PGL, or HLRCC that has not responded to other treatments

Design:

Participants will be screened with:

* Physical exam
* Urine tests
* Computed tomography (CT) or magnetic resonance imaging (MRI), or fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan: A machine takes pictures of the body.
* Blood tests

Participants will be injected with SGI-110 under the skin each day for 5 days. This cycle will repeat every 28 days. The cycles repeat until their side effects get too bad or their cancer gets worse.

Participants will have tests throughout study:

* Physical exam and blood and urine tests before each cycle
* Blood tests on days 1, 7, 14, and 28 of the first cycle.
* Scans before cycle 1 and then every other cycle.
* Questionnaires about their pain and quality of life
* Tumor biopsy for those 18 and older: A needle removes a small piece of tumor.

After they stop treatment, participants will have a final visit. This includes an evaluation of their health, pain, and quality of life.

...

Detailed description:
Background

* Loss of activity of the Krebs cycle components succinate dehydrogenase (SDH) complex or fumarate hydratase (FH), has been identified as a mechanism of tumorigenesis in subsets of gastrointestinal stromal tumor (GIST), pheochromocytoma and paraganglioma (PHEO/PGL), and renal cell carcinoma.
* Deoxyribonucleic acid (DNA) hypermethylation has been demonstrated in these cancers. Loss of activity of SDH or FH leads to accumulation of the metabolites succinate and fumarate, respectively. Succinate and fumarate act as inhibitors of a broad array of alpha-ketoglutarate dependent dioxygenases. The Ten-eleven Translocation (TET) family of alphaKG-dependent dioxygenase enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine leading to DNA demethylation. Inhibition of these enzymes due to SDH and FH deficiency causes DNA hypermethylation and has been verified in preclinical models.
* Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, resistant to cytotoxic chemotherapy and radiation therapy. KIT and Platelet Derived Growth Factor Receptor Alpha (PDGFRA) mutations have been identified as tumor initiating events in 85% of adult patients with GIST and these tumors are responsive to the tyrosine kinase inhibitor, Imatinib. In pediatric patients, however, 85% of GISTs lack KIT and PDGFRA mutations (wild-type) and imatinib is not effective.
* Recent work in the Pediatric and Wild-Type (wt) GIST Clinic at the National Cancer Institute (NCI) led to the identification of succinate dehydrogenase (SDH) deficiency in approximately 90% of wildtype GIST.
* In addition to wild-type GIST, SDH deficiency is also present in 30% of pheochromocytoma and paraganglioma (PHEO/PGL) and a subset of renal carcinoma. Loss of succinate dehydrogenase complex iron sulfur subunit B (SDHB) protein expression is seen in PHEO/PGL and wtGIST either due to mutation in SDH subunit genes or hypermethylation of the SDHC promoter region.
* Mutations leading to loss of function of FH have been identified in PHEO/PGL as well as type II papillary renal cell carcinoma in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC). An FH-deficient paraganglioma had DNA hypermethylation as demonstrated by array and immunohistochemistry showed increased 5hmC levels in paragangliomas and pheochromocytomas.
* SGI-110 is a small molecule derivative of decitabine that acts as a DNA methyltransferase (DNMT) inhibitor and is resistant to inactivation by cytidine deaminase, hence may thus have a more favorable pharmacokinetic profile compared to decitabine. Subcutaneously administered SGI-110 is gradually converted to decitabine resulting in prolonged exposure with a several fold increase in apparent T1/2 compared to intravenous decitabine. SGI-110 has been demonstrated in preclinical models to induce a dose-dependent decrease in global DNA methylation and up-regulate expression of specific genes including Melanoma-associated antigen 1 (MAGE-A1) and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) through decreased methylation.
* We are proposing a phase II trial with SGI-110 in these SDH-deficient and fumarate hydratase (FH)-deficient tumors.

Objectives:

-To assess the clinical activity of SGI-110 in patients with wt-GIST, SDH-deficient PHEO/PGL, and HLRCC-associated renal cell carcinoma (RCC) using Response Evaluation Criteria in Solid Tumors (RECIST).

Eligibility:

* Adults and children (greater than or equal to 12 years of age) with wt-type GIST, SDH deficient PHEO/PGL, or HLRCC-associated RCC and measurable disease will be eligible.
* Newly diagnosed patients with PHEO/PGL or HLRCC-associated RCC with localized, resectable disease will not be eligible. Patients with PHEO/PGL or HLRCC-associated RCC with unresectable localized disease and/or metastatic disease will be eligible.
* Newly diagnosed patients with wt-GIST with completely resectable disease will not be eligible. Patients with wt-GIST with metastatic disease and/or residual or recurrent tumor following surgical debulking will be eligible
* Patients with wt-GIST or HLRCC-associated RCC who have not previously received systemic therapy are eligible as there are no standard chemotherapy regimens known to be effective for these cancers.
* Must have adequate performance status, may not be pregnant or breastfeeding, and must have adequate major organ function.
* No history of severe or uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic cardiovascular or pulmonary disease will be excluded.

Design:

* This is a single site, open label, phase II study using a small optimal two-stage design to evaluate the clinical response in three groups of patients:

  1. wild-type GIST (GIST without KIT or PDGFRA mutation)
  2. PHEO/PGL in patients with germline SDH subunit mutation, or
  3. RCC associated with HLRCC
* SGI-110 will be administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle to the three groups of patients.
* SGI-110 activity will be assessed by imaging response of measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST)v1.1, using computed tomography (CT), magnetic resonance imaging (MRI) and/or positron emission tomography (PET).
* Patients will be closely monitored for development of toxicity with regular physical examinations and laboratory evaluations. Toxicity will be graded using version 4.0 of the National Cancer Institute (NCI) Common Toxicity Criteria.
* SGI-110 related toxicities greater than or equal to grade 3 will be considered treatment limiting toxicities, unless they are reversible within 72 hours with supportive care. Following recovery from toxicity up to 2 dose reductions will be allowed.
* Initially 7 evaluable patients in each group (strata) will be enrolled and if 0 of the 7 have a response, then no further patients will be accrued in that strata. If 1 or more the first 7 (14.3% or more) have a response, then accrual would continue until a total of 21 patients have enrolled in that strata. If at least 3 responses (at least 14.3%) are observed among the 21 evaluable patients, the agent should be considered worthy of further testing in this disease.
* Enrolling 2 patients/month, it is estimated to require 3 years to complete accrual to a maximum of 70 patients, a maximum of 63 evaluable patients allowing for a small number (7) of inevaluable patients.

Arms:
arm 1: SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Gastrointestinal stromal tumor (GIST) arm 2: SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Pheochromocytoma and Paraganglioma (PHEO/PGL) with succinate dehydrogenase (SDH)-deficient PHE arm 3: SGI-110 administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated Renal Cell Ca

Interventions: intervention 1: SGI-110 (guadecitabine)
Intervention descriptions: intervention 1: SGI-110 will be administered subcutaneously at 45mg/m\^2/day x 5 days on a 28-day cycle. Cycles may be repeated until there is evidence of tumor progression clinically or by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or there is intolerable toxicity that is not alleviated by dose reduction.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title:  Ph II SGI110 in Peds & Adults 
 
1 
Version Date: 07/22/2019 
 
 
Abbreviated Title: PhII SGI110 in Peds & Adults 
CC Protocol #: 17-C-0088 B 
CTEP Protocol #: 10012 
Version Date: 07/22/2019 
NCT Number: NCT03165721 
Title: A Phase II Trial of the DNA Methyl Transferase Inhibitor, SGI-110 (Guadecitabine), 
in Children and Adults with Wild Type GIST, Pheochromocytoma and Paraganglioma 
Associated with Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney 
Cancer  
Principal Investigator:    
 
John Glod, M.D., Ph.D.A-F  
Pediatric Oncology Branch, CCR, NCI 
10 Center Drive, CRC 1-3940 
Bethesda, MD 20982 
Phone: (240) 760-6194 
Email: john.glod@nih.gov 
NIH Associate Investigators:    
Brigitte Widemann, M.D., POB, CCR, NCIA-F 
 
 
 
 
 
Melissa Spencer, R.N., M.S.N., OCD, CCR, NCIA,B,E   
 
 
 
 
 
Joanne Derdak, CRNP, POB, CCR, NCIA,B,E 
Ram Srinivasan, M.D., UOB, CCR, NCIA-F 
Marston Linehan, M.D., UOB, CCR, NCIA-F 
Seth Steinberg Ph.D., CCR, NCIE,F 
Lori Wiener, Ph.D., POB, CCR, NCIA,B,E 
Karel Pacak, M.D., NICHD, NIHA.B,E,F  
Cody J. Peer, PhD, MS, CCR, NCIE,F 
William Figg, Pharm.D, CCR, NCIE,F 
Sima Bedoya, PsyD. POB, CCR, NCIA,B,E 
Jaydira del Rivero, M.D., OCD, CCR, NCIA-F 
Paul Meltzer, M.D., GB, CCR, NCI, NIHE,F 
Donna Bernstein, R.N., OCD, CCR, NCIA,B,E 
Les R. Folio, DO, MPH, DRD, CC, NIHB,E,F 
Referral Contact/  
Study Coordinator:   
Melissa Spencer, R.N., M.S.N. 
 
 
 
 
 
Office Phone: (240) 760-6101  
Email: amayamm@mail.nih.gov 
Investigator Roles: 
A. Obtain information by intervening or interacting with 
living individuals for research purposes 
B. Obtaining identifiable private information about living 
individuals 
C. Obtaining the voluntary informed consent of 
individuals to be subjects 
D. Makes decisions about subject eligibility 


Abbreviated Title:  Ph II SGI110 in Peds & Adults 
 
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E. Studying, interpreting, or analyzing identifiable 
private information or data/specimens for research 
purposes 
F. Studying, interpreting, or analyzing coded, linked data 
or specimens for research purposes 
G. Some/all research activities performed outside NIH 
Investigational Agents:     
Drug Name: 
SGI-110 (guadecitabine) 
IND Number: 
133390 
Sponsor: 
CTEP 
Manufacturer: 
Astex Pharmaceuticals 
Commercial Agents: None 


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PRÉCIS  
Background: 
x Loss of activity of the Krebs cycle components succinate dehydrogenase (SDH) 
complex or fumarate hydratase (FH), has been identified as a mechanism of 
tumorigenesis in subsets of gastrointestinal stromal tumor (GIST), 
pheochromocytoma and paraganglioma (PHEO/PGL), and renal cell carcinoma.  
x DNA hypermethylation has been demonstrated in these cancers.  Loss of activity of 
SDH or FH leads to accumulation of the metabolites succinate and fumarate, 
respectively.  Succinate and fumarate act as inhibitors of a broad array of D-
ketoglutarate-dependent dioxygenases.  The Ten-eleven Translocation (TET) family 
of DKG-dependent dioxengenase enzymes convert 5-methylcytosine to 5-
hydroxymethycytosine leading to DNA demethylation.  Inhibition of these enzymes 
due to SDH and FH deficiency causes DNA hypermethylation and has been verified 
in preclinical models. 
x Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of 
the gastrointestinal tract, resistant to cytotoxic chemotherapy and radiation therapy. 
KIT and PDGFRA mutations have been identified as tumor initiating events in 85% 
of adult patients with GIST and these tumors are responsive to the tyrosine kinase 
inhibitor, Imatinib. In pediatric patients, however, 85% of GISTs lack KIT and 
PDGFRA mutations (wild-type) and imatinib is not effective.  
x Recent work in the Pediatric and Wild-Type (wt) GIST Clinic at the NCI led to the 
identification of succinate dehydrogenase (SDH) deficiency in approximately 90% of 
wild-type GIST1.  
x In addition to wild-type GIST, SDH deficiency is also present in 30% of 
pheochromocytoma and paraganglioma (PHEO/PGL) and a subset of renal 
carcinoma. Loss of SDHB protein expression is seen in PHEO/PGL and wtGIST 
either due to mutation in SDH subunit genes or hypermethylation of the SDHC 
promoter region2-4.   
x Mutations leading to loss of function of FH have been identified in PHEO/PGL as 
well as type II papillary renal cell carcinoma in patients with hereditary 
leiomyomatosis and renal cell cancer (HLRCC)3,5.  An FH-deficient paraganglioma 
had DNA hypermethylation as demonstrated by array and immunohistochemistry 
showed increased 5hmC levels in paragangliomas and pheochromocytomas. 
x SGI-110 is a small molecule derivative of decitabine that acts as a DNA 
methyltransferase (DNMT) inhibitor and is resistant to inactivation by cytidine 
deaminase, hence may thus have a more favorable pharmacokinetic profile compared 
to decitabine.  Subcutaneously administered SGI-110 is gradually converted to 
decitabine resulting in prolonged exposure with a several fold increase in apparent 
T1/2 compared to intravenous decitabine.  SGI-110 has been demonstrated in 
preclinical models to induce a dose-dependent decrease in global DNA methylation 
and up-regulate expression of specific genes including MAGE-A1 and NY-ESO-1 
through decreased methylation. 
x We are proposing a phase II trial with SGI-110 in these SDH-deficient and FH-
deficient tumors. 


Abbreviated Title:  Ph II SGI110 in Peds & Adults 
 
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Version Date: 07/22/2019 
 
 
Objectives: 
To assess the clinical activity of SGI-110 in patients with wt-GIST, SDH-deficient 
PHEO/PGL, and HLRCC-associated RCC using RECIST (v1.1). 
Eligibility: 
x Adults and children (≥12 years of age) with wt-type GIST, SDH deficient PHEO/PGL, 
or HLRCC-associated RCC and measurable disease will be eligible.     
x Newly diagnosed patients with PHEO/PGL or HLRCC-associated RCC with localized, 
resectable disease will not be eligible. Patients with PHEO/PGL or HLRCC-associated 
RCC with unresectable localized disease and/or metastatic disease will be eligible.  
x Newly diagnosed patients with wt-GIST with completely resectable disease will not be 
eligible. Patients with wt-GIST with metastatic disease and/or residual or recurrent 
tumor following surgical debulking will be eligible 
x Patients with wt-GIST or HLRCC-associated RCC who have not previously received 
systemic therapy are eligible as there are no standard chemotherapy regimens known 
to be effective for these cancers.  
x Must have adequate performance status, may not be pregnant or breastfeeding, and 
must have adequate major organ function.  
x No history of severe or uncontrolled inter-current illness including, but not limited to, 
ongoing or active infection, symptomatic cardiovascular or pulmonary disease will be 
excluded. 
Design: 
x This is a single site, open label, phase II study using a small optimal two-stage design 
to evaluate the clinical response in three groups of patients:  
1. wild-type GIST (GIST without KIT or PDGFRA mutation)  
2. PHEO/PGL in patients with germline SDH subunit mutation, or  
3. RCC associated with HLRCC 
x SGI-110 will be administered subcutaneously at 45mg/m2/day x 5 days on a 28-day 
cycle to the three groups of patients. 
x SGI-110 activity will be assessed by imaging response of measurable disease using 
RECISTv1.1, using CT, MRI and/or PET.   
x Patients will be closely monitored for development of toxicity with regular physical 
examinations and laboratory evaluations.  Toxicity will be graded using version 5.0 of 
the NCI Common Toxicity Criteria.  
x SGI-110 related toxicities ≥ grade 3 will be considered treatment limiting toxicities, 
unless they are reversible within 72 hours with supportive care. Following recovery 
from toxicity up to 2 dose reductions will be allowed. 
x Initially 7 evaluable patients in each group (strata) will be enrolled and if 0 of the 7 
have a response, then no further patients will be accrued in that strata. If 1 or more the 
first 7 (14.3% or more) have a response, then accrual would continue until a total of 21 
patients have enrolled in that strata. If at least 3 responses (at least 14.3%) are observed 
among the 21 evaluable patients, the agent should be considered worthy of further 
testing in this disease. 


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x Enrolling 2 patients/month, it is estimated to require 3 years to complete accrual to a 
maximum of 70 patients, a maximum of 63 evaluable patients allowing for a small 
number (7) of inevaluable patients. 


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TABLE OF CONTENTS  
PRÉCIS ............................................................................................................................. 3 
TABLE OF CONTENTS .................................................................................................... 6 
1 
INTRODUCTION .....................................................................................................12 
1.1 
Study Objectives..................................................................................................12 
1.1.1 
Primary Objective .........................................................................................12 
1.1.2 
Secondary.....................................................................................................12 
1.1.3 
Exploratory ..................................................................................................12 
2 
BACKGROUND AND RATIONALE........................................................................12 
2.1.1 
Background ..................................................................................................12 
2.1.2 
Gastrointestinal stromal tumors .....................................................................12 
2.1.3 
Pheochromocytoma and Paraganglioma.........................................................13 
2.1.4 
Renal Cell Carcinoma ...................................................................................13 
2.1.5 
SGI-110 .......................................................................................................13 
2.1.6 
Health-Related Quality of Life and Patient-Reported Symptoms.....................15 
2.1.7 
Rationale ......................................................................................................16 
3 
PATIENT SELECTION.............................................................................................16 
3.1 
Eligibility Criteria ................................................................................................16 
3.1.1 
Inclusion Criteria: .........................................................................................16 
3.1.2 
Exclusion Criteria .........................................................................................18 
4 
RECRUITMENT AND REGISTRATION..................................................................19 
4.1 
Recruitment .........................................................................................................19 
4.2 
Screening Evaluation ...........................................................................................19 
4.2.1 
History and physical examination ..................................................................19 
4.2.2 
Imaging evaluation .......................................................................................19 
4.2.3 
Hematology ..................................................................................................19 
4.2.4 
Chemistries ..................................................................................................20 
4.2.5 
Urine or serum pregnancy test for all females of childbearing potential...........20 
4.2.6 
Pathologic/Tissue Evaluation ........................................................................20 
4.2.7 
For patients with PHEO/PGL ........................................................................20 
4.3 
Registration Procedures .......................................................................................20 
4.3.1 
IWRS ...........................................................................................................20 
4.3.2 
OPEN / IWRS ..............................................................................................20 
4.3.3 
OPEN/IWRS User Requirements ..................................................................21 
4.3.4 
OPEN/IWRS Questions?...............................................................................21 


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4.4 
Local Registration for NCI CCR ..........................................................................21 
5 
STUDY IMPLEMENTATION...................................................................................21 
5.1 
Study Design .......................................................................................................21 
5.2 
Drug Administration ............................................................................................22 
5.3 
Dose Modifications..............................................................................................22 
5.4 
Questionnaires (Appendix III and Appendix IV) ...................................................23 
5.4.1 
PROMIS ......................................................................................................23 
5.4.2 
Distress Rating Tool .....................................................................................23 
5.5 
On-Study Evaluation............................................................................................23 
5.5.1 
Baseline Assessment .....................................................................................23 
5.6 
Study Calendar ....................................................................................................24 
5.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ......................27 
5.7.1 
Criteria for removal from protocol therapy.....................................................27 
5.7.2 
Off-Study Criteria .........................................................................................27 
5.7.3 
Off Protocol Therapy and Off-Study Procedure .............................................27 
6 
CONCOMITANT MEDICATIONS/MEASURES ......................................................27 
6.1 
Injection Site Reactions........................................................................................27 
6.2 
Mucositis.............................................................................................................28 
6.3 
Diarrhea ..............................................................................................................28 
7 
BIOSPECIMEN COLLECTION ................................................................................28 
7.1 
Correlative Studies for Research/Pharmacokinetic Studies ....................................28 
7.1.1 
Pharmacokinetics..........................................................................................28 
7.1.2 
Expression of SDH complex subunits and FH ................................................29 
7.1.3 
DNA hyper-methylation................................................................................29 
7.1.4 
NY-ESO-1 expression...................................................................................29 
7.1.5 
Serum and Urine Concentrations of glycolytic metabolites .............................29 
7.2 
Sample Storage, Tracking and Disposition............................................................31 
7.2.1 
Sample Storage and Destruction ....................................................................31 
8 
MEASUREMENT OF EFFECT .................................................................................32 
8.1 
Definitions...........................................................................................................32 
8.2 
Disease Parameters ..............................................................................................33 
8.2.1 
Methods for Evaluation of Measurable Disease..............................................34 
8.2.2 
Response Criteria..........................................................................................36 
8.2.3 
Duration of Response....................................................................................37 
9 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ..........................38 


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9.1 
Comprehensive Adverse Event and Potential Risk List (CAEPRs).........................38 
9.1.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR for SGI-110 
(NSC 780463)............................................................................................................38 
9.2 
Adverse Event Characteristics ..............................................................................42 
9.3 
Expedited Adverse Event Reporting to CTEP .......................................................42 
9.3.1 
Expedited AE reporting.................................................................................42 
9.3.2 
Distribution of Adverse Event Reports ..........................................................43 
9.3.3 
Expedited Reporting Guidelines ....................................................................43 
9.4 
Routine Adverse Event Reporting to CTEP ..........................................................44 
9.5 
Secondary Malignancy.........................................................................................44 
9.6 
Second Malignancy .............................................................................................45 
10 
NIH Intramural Research Program Reporting..............................................................45 
10.1 
Definitions .......................................................................................................45 
10.2 
OHSRP Office of Compliance and Training/ IRB Reporting ..............................45 
10.2.1 
Expedited Reporting .....................................................................................45 
10.2.2 
IRB Requirements for PI Reporting at Continuing Review .............................45 
10.3 
NCI Clinical Director Reporting .......................................................................45 
11 
STUDY OVERSIGHT AND DATA REPORTING/REGULATORY REQUIREMENTS
 
45 
11.1 
Study Oversight ...............................................................................................45 
11.2 
Data Reporting .................................................................................................46 
11.2.1 
Method.........................................................................................................46 
11.3 
Data Sharing Plans ...........................................................................................47 
11.3.1 
Human Data Sharing Plan .............................................................................47 
11.3.2 
Genomic Data Sharing Plan ..........................................................................47 
12 
STATISTICAL CONSIDERATIONS ........................................................................47 
13 
COLLABORATIVE AGREEMENTS ........................................................................48 
14 
HUMAN SUBJECTS PROTECTIONS ......................................................................49 
14.1 
Rationale For Subject Selection ........................................................................49 
14.1.1 
Gender and Minority Accrual Estimates ........................................................49 
14.2 
Participation of Children...................................................................................50 
14.3 
Participation of Subjects Unable to Give Consent ..............................................50 
14.4 
Evaluation of Benefits and Risks/Discomforts ...................................................51 
14.4.1 
Risks of SGI-110 ..........................................................................................51 
14.5 
Risks/Benefits Analysis ....................................................................................51 


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14.6 
Consent and Assent Process and Documentation ...............................................51 
14.6.1 
Consent for minors when they reach the age of majority.................................52 
14.6.2 
Telephone consent ........................................................................................53 
15 
PHARMACEUTICAL INFORMATION ....................................................................53 
15.1 SGI-110 (Guadecitabine) (NSC 780463) ...............................................................53 
15.1.1 
Agent Ordering and Agent Accountability: ....................................................55 
15.1.2 
Incompatibilities ...........................................................................................56 
16 
APPENDICES ...........................................................................................................57 
16.1 
Appendix I-Performance Status Criteria ............................................................57 
16.2 
Appendix II: Performance Status Scales/Scores in Patients ≤16 years of age ......58 
16.3 
Appendix III: Quality of Life Tools ..................................................................59 
16.3.1 
Pediatric PROMIS Instruments English (6) ....................................................59 


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16.3.2 
Pediatric PROMIS Instruments Spanish (6) 
 
65 
16.3.3 
Parallel Parent Proxy PROMIS Instruments English (6) .................................71 
16.3.4 
Adult Patient PROMIS Instruments English (6) .............................................77 


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16.3.5 
Adult Patient PROMIS Instruments Spanish (6) 
84 
16.4 
Appendix IV: The Distress and Symptom Checklist: The Distress Thermometer 90 
17 
REFERENCES ..........................................................................................................92 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
To assess the clinical activity (CR or PR) of SGI-110 in patients with wt-GIST, SDH-
deficient PHEO/PGL, and HLRCC-associated renal cell carcinoma using RECIST (v1.1). 
1.1.2 Secondary 
1.1.2.1 Evaluate the toxicity, progression-free (PFS) and overall survival (OS), and pain and 
quality of life (QOL) of patients on treatment with SGI-110. 
1.1.2.2 Better define the pharmacokinetics (PK) of SGI-110 in all patients.  
1.1.3 Exploratory 
1.1.3.1 Determine the serum and urine concentration of succinate, fumarate and 2-
hydroxyglutarate in patients with wild-type GIST, pheochromocytoma and 
paraganglioma associated with SDH deficiency and HLRCC-associated kidney 
cancer prior to and on therapy with SGI-110. 
1.1.3.2 Explore changes in DNA methylation and gene expression including SDH, FH, and 
tumor testis antigens in response to treatment with SGI-110. 
1.1.3.3 Assess the global DNA methylation status in tumors by determining LINE-1 
methylation in archival pre-treatment tumor samples and in on-treatment tumor 
samples when available. 
2 
BACKGROUND AND RATIONALE 
2.1.1 Background 
Loss of activity of the Krebs cycle components succinate dehydrogenase (SDH) complex or 
fumarate hydratase (FH), has been identified as a mechanism of tumorigenesis in subsets of 
gastrointestinal stromal tumor (GIST), pheochromocytoma and paraganglioma (PHEO/PGL), 
and renal cell carcinoma.  
DNA hyper-methylation has been demonstrated in these cancers2,6,7.  Loss of activity of SDH 
or FH leads to accumulation of the metabolites succinate and fumarate, respectively.  
Succinate and fumarate act as inhibitors of a broad array of D-ketoglutarate-dependent 
dioxygenases.  The Ten-eleven Translocation (TET) family of DKG-dependent dioxengenase 
enzymes convert 5-methylcytosine to 5-hydroxymethycytosine leading to DNA 
demethylation.  Inhibition of these enzymes due to SDH and FH deficiency causes DNA 
hypermethylation8. It is hypothesized that a methylation inhibitor would impact tumor growth 
by reversing the DNA hypermethylation that is seen in this group of tumors with Krebs cycle 
abnormalities. 
2.1.2 Gastrointestinal stromal tumors 
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the 
gastrointestinal tract, resistant to cytotoxic chemotherapy and radiation therapy. KIT and 
PDGFRA mutations have been identified as tumor initiating events in 85% of adult patients 
with GIST and these tumors are responsive to the tyrosine kinase inhibitor, Imatinib9. In 
pediatric patients, however, 85% of GISTs lack KIT and PDGFRA mutations (wild-type 


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GIST)10 and imatinib is not effective. Recent work in the Pediatric and Wild-Type (wt) GIST 
Clinic at the NCI led to the identification of succinate dehydrogenase (SDH) deficiency in 
88% of pediatric wild-type GIST1,10. Loss of SDHB protein expression is seen in PHEO/PGL 
and wt-GIST either due to mutation in SDH subunit genes or hypermethylation of the SDHC 
promoter region, which was seen in 21 of 95 wild-type GIST tumors examined1,10.   
2.1.3 Pheochromocytoma and Paraganglioma  
In addition to wild-type GIST, SDH deficiency is also present in pheochromocytoma and 
paraganglioma (PHEO/PGL)3,11. Pheochromocytomas (PHEOs) and paragangliomas (PGLs) 
are neuroendocrine tumors arising from the adrenal chromaffin cells and ganglia along the 
sympathetic and parasympathetic chains, respectively. Seventeen underlying germline 
mutations associated with PHEO/PGL have been identified and account for approximately 
35% of PHEO/PGL12. Approximately 10-30% of PHEO/PGL are SDH-deficient13,14 and 
there is an increased risk of more aggressive metastatic disease in patients with SDHB 
mutation. SDHC promoter hypermethyation has also been described in PHEO/PGL as 
mechanisms for SDH deficiency in isolated paraganglioma15 as well as in patients with 
Carney Triad16. However, the percentage of SDH deficient PHEO/PGL with SDHC promoter 
hypermethylation is unknown. Surgical resection is the only curative therapy for patients with 
PHEO/PGL, however both radiation therapy and cytotoxic chemotherapy using 
cyclophosphamide, vincristine, and dacarbazine (CVD) have been used to treat patients with 
metastatic or recurrent disease12. Averbuch and colleagues reported a 57% response rate in 
pateints with malignant pheochromocytoma17. A recent retrospective analysis of 17 patients 
with metastatic PHEO/PGL showed a 47.1% rate of response to CVD18. A meta-analysis of 
patients with metastatic PHEO/PGL treated with CVD chemotherapy showed a 4% CR and 
37% PR rate19. Approximately 60% of metastatic PHEO/PGL are methyl-iodobenzylguanine 
(MIBG) avid and can be treated with 131I-MIBG20. A meta-analysis of patients treated with 
131I-MIBG showed a complete response rate of 3% and PR rate of 27%21. A small number 
of patients with metastatic PHEO/PGL have also been reported to have disease response 
when treated with temozolomide. While CVD chemotherapy has been described as standard 
therapy for PHEO/PGL20 the data supporting this therapeutic approach is limited. 131I-MIBG 
in patients with MIBG avid tumors or cytotoxic chemotherapy (CVD or temozolomide) is 
required prior to enrollment on this trial.  However, patients who have refused cytotoxic 
chemotherapy or for whom treatment on this protocol prior to receiving cytotoxic 
chemotherapy is felt to be in the best interest for the patient by the local investigator will also 
be eligible.   
2.1.4 Renal Cell Carcinoma 
Mutations leading to loss of function of FH have been identified in type II papillary renal cell 
carcinoma in addition to PHEO/PGL6. Hereditary leiomyomatosis and renal cell carcinoma 
(HLRCC) is an autosomal-dominant hereditary syndrome due to mutations in FH5. 
Approximately 93% of patients with HLRCC have detectable mutations in FH4.  While renal 
cell cancer occurs less often than leiomyomas in patients with HLRCC, HLRCC-associated 
kidney cancer is typically clinically aggressive with early development of metastatic disease. 
Nephron-sparing surgical therapy is standard for localized HLRCC-associated renal cancer22. 
While there is currently no standard systemic therapy for metastatic HLRCC-associated renal 
cell cancer, treatments targeting the VEGF and EGFR pathways are being investigated in 
ongoing clinical trials22. 
2.1.5 SGI-110 


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SGI-110 is a small molecule derivative of decitabine that acts as a DNA methyltransferase 
(DNMT) inhibitor and is resistant to inactivation by cytidine deaminase23.  Subcutaneously 
administered SGI-110 is gradually converted to decitabine resulting in prolonged exposure 
with a several fold increase in apparent T1/2 compared to intravenous decitabine.  SGI-110 has 
been demonstrated in preclinical models to induce a dose-dependent decrease in global DNA 
methylation and up-regulate expression of specific genes including MAGE-A1 and NY-ESO-
1 through decreased methylation. 
2.1.5.1 Pharmacokinetics of SGI-110 
Studies were conducted in mice, rats, monkeys and rabbits to examine the PK profile of SGI-
110 available as a sodium salt. Intravenous, bolus, oral, and SC routes of administration were 
evaluated.  Results of these studies are available in the Investigator’s Brochure 
(Guadecitabine: Investigator’s Brochure. Version 6.0, 10September 2015).  In summary, in 
vivo oral bioavailability in rodents was greater than 30%, but in vitro permeability measured 
in human Caco-2-cells was poor. Additionally, SGI-110 degrades rapidly both chemically 
due to hydrolysis and enzymatically due to presence of phosphodiesterases and other 
enzymes (phosphatases, phosphorylases, etc.). These findings substantiate the selection of a 
parenteral route for dosing. Comparative studies indicate close to 100% bioavailability via 
subcutaneous (SC) administration. Once in the biological system, SGI-110 cleaves to 
decitabine, a known active moiety. The rate of this conversion to decitabine varies across 
species and appears to be much higher in rats and rabbits, compared to primates. When 
administered SC to non-human primates, SGI-110 releases decitabine slowly compared to 
other species, possibly prolonging the effect over more sustained periods. Therefore, SC 
route of administration is recommended. 
The recommended safe starting dose of SGI-110 for human studies, [Regimen 1 (Daily x5): 3 
mg/m2/dose, and Regimen 2A (Weekly X3) 6 mg/m2/dose], was based on (1) results from 
repeat-dose toxicology studies in rabbits (the most sensitive species) and rats; (2) results from 
a non-GLP non-human primate toxicology, PD and TK study; (3) the established PK and 
safety profile for decitabine. 
2.1.5.2 Clinical Studies in Humans 
As of 30 June 2015, 5 clinical trials of SGI-110 have been initiated: 3 as monotherapy in 
AML/MDS, 1 as monotherapy in HCC and 1 in combination with carboplatin in ovarian 
cancer.  Three dosing regimens (Daily x 5, Once weekly, and twice weekly) were employed 
in the initial phase I study in adult patients with high-risk myelodysplastic syndrome (MDS) 
or acute myelogenous leukemia (AML).  In a subsequent Phase 2 study doses of 
60mg/m2/day Daily x5 and 90mg/m2/day Daily x5 were used in subjects with MDS or AML.  
An additional cohort in this study was treated with 60mg/m2/day for 10 days.   
In a single agent study, the maximum tolerated dose of the drug for the first cycle when given 
Daily x 5 to patients with MDS was 90mg/m2/dose. Dose limiting toxicities seen at 
125mg/m2/day in this patient population were thrombocytopenia, neutropenia, febrile 
neutropenia, and sepsis.  The MTD was not reached for patients with AML with the highest 
dose administered 125mg/m2/day Daily x5.  In a phase II dose expansion for patients with 
AML and MDS dosing regimens of 60mg/m2/day Daily x5 and 90 mg/m2/day Daily x5 have 
been used.  A total of 202 subjects have been treated using these regimens.  There were no 
significant differences in complete response rates between 60mg/m2/day Daily x5 and 90 
mg/m2/day Daily x5 in relapsed/refractory AML subjects (13% vs 19% respectively) or in 
treatment naïve elderly subjects with AML (54% vs 55%, respectively).  The biologically 
effective dose was determined by assaying LINE-1 demethylation.  In these patients there 


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was also no significant difference in LINE-1 demethylation between patients treated on the 
two different dosing regimens.  A smaller number of patients with AML and MDS have been 
treated using a schedule of 10 days of treatment per cycle (days 1-5 and days 8-12). 
Patients with platinum-resistant ovarian cancer were enrolled on a phase II combination trial 
of SGI-110 and carboplatin (NCT01696032).  In combination with carboplatin a starting dose 
of SGI-110 of 45mg/m2/day Daily x5 was not tolerated and the dose was de-escalated to 
30mg/m2/day.  Dose of SGI-110 of 30mg/m2/day + carboplatin AUC 4 was well-tolerated 
and is being used for stage II of the study.  In patients with HCC, a Phase II study of mono-
therapy with SGI-110 is ongoing (NCT01752933).  Dosing started at 60mg/m2/day on days 
1-5 every 28 days.  This dose was reduced to 45mg/m2/day Daily x5 due to grade >/=3 
hematological toxicity.  Thirty-six subjects received this dose on stage 2 of this study.  
Overall, 22 of 50 subjects (44%) had SAEs in this study. Most subjects had SAEs considered 
not related to study treatment.  No SAE with an outcome of death was considered related to 
study treatment. 
2.1.6 Health-Related Quality of Life and Patient-Reported Symptoms 
2.1.6.1 Study Measures 
Distress and Symptom Checklist (Appendix IV): The Distress Thermometer 24 is a brief 
screening tool endorsed by the National Comprehensive Cancer Network (NCCN) to assess 
for distress in adult cancer patients. The Distress Thermometer (DT) is a visual-analog scale 
similar to those used to assess pain. The DT obtains an overall distress score based on the 
visual analog scale, and includes a “problem list”, or checklist, where patients can identify 
specific physical and emotional symptoms and practical and family concerns that can cause 
their distress.  The DT has been widely validated in adult (>18 years old) cancer patients, and 
has been recognized as a good alternative to many of the longer measures commonly used to 
screen for distress in cancer patients 25-27. 
Whereas the Distress Thermometer was originally written for adult cancer patients, early 
evaluation of the scale shows validity for children and adolescents with cancer 28. In an 
ongoing study at the NIH with 163 pediatric patients ages 7-21 undergoing treatment for 
cancer, NF1, HIV or a primary immune deficiency and their caregivers, an adapted DT has 
shown convergent validity when compared with standardized measures and with specific 
items on the symptom checklist. It has also shown reasonable concordance with parent and 
provider ratings 29. For this study, we will use the DT as a distress and symptom rating tool. It 
is quick to administer and a low burden to patients and their caregivers 29. Whereas most 
patient reported outcome measures utilize a 7–day recall period (including the PROMIS 
measures), the adapted DT utilizes a 30 day recall period which allows problems or 
symptoms that might have been present in the past month, but not necessarily the past week 
to be documented. The distress and symptom rating scales will take approximately 5 minutes 
to complete. 
Patient-Reported Outcomes Measurement Information System (PROMIS) is a health related 
quality of life measurement tool that was developed by NIH to standardize patient-reported 
outcomes for national use by research clinicians. Two versions of PROMIS are available to 
researchers: computer-adaptive tests (CATs) and short forms. The short forms are brief, static 
instruments that have demonstrated similar reliability to the longer, dynamic CATs, which 
provide precise measures for studying populations with widely varied responses and 
longitudinal self-report data 30. Each short form includes 4 to 8 items, measures reported 
health outcomes in the past 7 days on a Likert type scale, and takes approximately 5 minutes 


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to complete.  PROMIS instruments, measuring a broad range of health domains, have been 
validated for adults (>18) with a variety of health conditions 31.  
Early evaluation of PROMIS pediatric instruments indicates validity for children ages 8 to 17 
32, hence this is appropriate for the age group 12-17 years old in this trial. Six pediatric 
PROMIS instruments and six parallel Parent Proxy PROMIS instruments (See Appendix III) 
are available to assess five quality of life health domains (physical function, pain 
interference, fatigue, emotional health, and social health) and are intended for use with both 
healthy and chronically ill pediatric populations. This protocol will utilize pediatric PROMIS 
short forms and the Parent Proxy short forms to assess symptoms that can be associated with 
GIST. These include physical function, anxiety, depressive symptoms, fatigue, pain 
interference, and peer relationships.  
Assessments of Health-Related Quality of Life will be administered at the start of therapy, at 
the end of cycle 4 and then every 4 cycles thereafter, and then at the end of therapy. The 
PROMIS Patient Outcome Measures (6) and patient-reported symptom severity (Distress and 
Symptom Checklist) will provide us with essential information regarding how symptoms may 
change over the course of treatment, and will also provide a more in-depth assessment of the 
known toxicities associated with SGI-110 in this patient population.   
The PI of the study will be notified of participants who have scores 2 standard deviations 
above the mean normative t-score of 50 (so a t-score of 70) on the PROMIS depression short 
form (suggesting high depression), and these participants will be assessed for suicidal 
ideation by a member of the psychosocial team. Those found to have suicidal ideation will be 
referred to the NIH psychiatry service. 
2.1.7 Rationale 
Based on the dosing regimens that have been tolerated in these ongoing trials we propose a 
starting dose for single agent therapy of 45mg/m2/day daily x5 on a 28 day cycle. The 
majority of patients enrolled on our trial will not have had extensive therapy with cytotoxic 
agents and hence would not be expected to experience the degree of bone marrow toxicity 
that was observed in patients on these earlier trials.  Because GIST, RCC, and PHEO/PGL 
are more indolent tumors it may be expected that a more prolonged course of treatment will 
be given to our patients.  In order to facilitate more long-term dosing of the drug two dose de-
escalations of approximately 30% will be allowed.  
3 
PATIENT SELECTION  
3.1 
ELIGIBILITY CRITERIA 
3.1.1 Inclusion Criteria:  
Patients must: 
3.1.1.1 Have recurrent or refractory/unresectable disease for which there is no known 
curative therapy. 
x Wild type-GIST: Patients with recurrent or progressive disease will be eligible.  
Newly diagnosed patients with resectable localized disease will not be eligible. Newly 
diagnosed patients with metastatic disease and newly diagnosed patients with residual 
tumor following surgical debulking will be eligible.  
 


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x PHEO/PGL: Patients with recurrent or progressive disease will be eligible. Newly 
diagnosed patients with PHEO/PGL that is metastatic at diagnosis and/or unresectable 
will be eligible Patients with PHEO/PGL with localized (non-metastatic), resectable 
disease will not be eligible.  
x Renal cell cancer associated with HLRCC: Patients with localized, resectable 
HLRCC-associated renal cell cancer will not be eligible. Patients with metastatic 
and/or unresectable HLRCC-associated renal cell cancer will be eligible. 
3.1.1.2 Have one of the following confirmed histologically, cytologically, or through 
biochemical testing: 
x wild-type GIST (GIST without KIT or PDGFRA mutation); 
x PHEO/PGL with a germline mutation in SDHA, SDHB, SDHC, or SDHD; 
x renal cell cancer associated with HLRCC. 
Testing will be performed in CLIA certified labs using genetic tests for KIT/PDGFRA 
and testing panels developed for patients with PHEO/PGL.  Results from outside labs will 
be accepted. Pathologic diagnosis will be reviewed and verified at the Clinical Center. 
3.1.1.3 Age: be ≥ 12 years of age 
Because there is no dosing or adverse event data currently available on the use of SGI-110 in 
children < 18 year of age, children < 12 years of age will be excluded from this study, but 
may be eligible for future pediatric trials should the results of the study be positive. 
3.1.1.4 Measurable disease:  
Have measurable disease, defined as at least one lesion that can be accurately measured in at 
least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for 
nodal lesions) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.  
See Section 8.2.2 for the evaluation of measurable disease (RECIST v1.1). 
3.1.1.5 Prior Therapy 
3.1.1.5.1 Prior therapy requirements: 
x Wt-GIST:  Because there are no standard chemotherapy regimens known to be 
effective for wt-GIST, previously untreated participants are eligible. 
x PHEO/PGL with germline SDH subunit mutation: 131I-MIBG in patients with MIBG 
avid tumors or cytotoxic chemotherapy (CVD or temozolomide) is required prior to 
enrollment on this trial.  However, patients who have refused cytotoxic chemotherapy 
or for whom treatment on this protocol prior to receiving cytotoxic chemotherapy is 
felt to be in the best interest for the patient by the local investigator will also be 
eligible.   
x HLRCC-associated renal cell cancer: Because there are no standard chemotherapy 
regimens known to be effective for HLRCC-associated renal cell cancer, previously 
untreated participants are eligible. 
3.1.1.5.2 Prior therapy wash-out period requirements 
x Participants must be at least 4 weeks from prior surgical procedures and surgical 
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x Participants must have had their last fraction of external beam radiation therapy at 
least 4 weeks prior to enrollment.  Participants with prior radiation therapy must be at 
least 4 weeks post therapy and have had progression of disease outside the radiation 
port. 
x Participants must have had their last dose of cytotoxic chemotherapy at least 28 days 
prior to enrollment, their last dose of biological therapy, such as biological response 
modifiers (e.g., cytokines), immunomodulatory agents, vaccines, differentiating 
agents, used to treat their cancer at least 28 days prior to enrollment, their last dose of 
a monoclonal antibody at least 28 days prior to enrollment, and their last dose of any 
investigational agent at least 28 days prior to enrollment. 
x Participants must have recovered from the acute toxic effects of prior therapy to a 
grade 1 (CTCAE v.5.0) level prior to enrollment (does not apply to alopecia). 
3.1.1.6 Performance Level: ECOG performance status <2 or Karnofsky >60% in patients > 
16 years of age, Lansky ≥ 60 for patients ≤ 16 years of age (See Appendix I). 
3.1.1.7 Have normal organ and marrow function as defined below:  
 absolute neutrophil count  
>1,500/mcL 
 platelets  
 
 
 
 
 
>100,000/mcL 
 total bilirubin 
 
 
 
 
within normal institutional limits 
 AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of 
normal 
 creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
 creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional 
normal. 
3.1.1.8 Birth Control: 
The effects of SGI-110 on the developing human fetus are unknown.  For this reason and 
because decitabine is 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, and for 6 months following 
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. 
3.1.1.9 Ability of subject or legal guardians (if the patient is <18 years old) to understand 
and the willingness to sign a written informed consent document. 
3.1.2 Exclusion Criteria 
Patients with any one the following will be excluded: 
3.1.2.1 Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, 
immunotherapy, or biologic therapy, including investigational agents for their 
disease. 
3.1.2.2 History of allergic reactions to SGI-110 or decitabine. 
3.1.2.3 Uncontrolled intercurrent illness including, but not limited to, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, symptomatic 


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pulmonary disease or psychiatric illness/social situations that would limit 
compliance with study requirements. 
3.1.2.4 Pregnant or breastfeeding 
Pregnant women are excluded from this study because SGI-110 is a derivative of decitabine 
which has the potential for teratogenic or abortifacient effects.  Because there is an unknown 
but potential risk for adverse events in nursing infants secondary to treatment of the mother 
with SGI-110, breastfeeding should be discontinued if the mother is treated with SGI-110.  
These potential risks may also apply to other agents used in this study. 
3.1.2.5 Any evidence of severe or uncontrolled systemic disease, active infection, active 
bleeding diatheses, or renal transplant, including any patient known to have hepatitis 
B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded. Patients 
with HIV who have adequate CD4 count, not requiring antiretroviral medication, 
may be enrolled. 
3.1.2.6 Patients who, in the opinion of the investigator, may not be able to comply with the 
safety monitoring requirements of the study.   
4 
RECRUITMENT AND REGISTRATION 
4.1 
RECRUITMENT 
In addition to posting this study on clinicaltrials.gov and the NCI website, patients who may 
be eligible will be invited to undergo screening during their participation in CCR Clinical 
studies, i.e. GIST Clinic held by POB, and RCC Clinic held by UOB, and PHEO/PGL Clinic 
held by NICHD.  
4.2 
SCREENING EVALUATION 
Eligibility will be determined during a pre-study evaluation period after subjects have signed 
a consent (either a screening consent or this treatment consent).  Subject information must be 
entered onto a screening log and for subjects not registered (enrolled) on the treatment 
portion of the study, a brief reason will be entered onto the screening log.   
Screening blood tests should be performed within 72 hours and imaging studies within 4 
weeks prior to enrollment on the trial unless otherwise stated.  Any abnormal laboratory 
result that might preclude eligibility can be repeated within 24 hours.   
4.2.1 History and physical examination   
x Complete history, including prior and concurrent therapy; physical examination 
including documentation of measurable disease, performance status, blood pressure, 
height, weight, signs and symptoms.   
4.2.2 Imaging evaluation   
x Assessment of measurable disease sites by appropriate radiological evaluation. This 
may include a CT scan of chest, abdomen and pelvis and primary tumor, MRI scan of 
primary tumor and FDG-PET scan, as clinically indicated. 
4.2.3 Hematology   
x Complete blood count with differential and platelets.  


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4.2.4 Chemistries   
x Electrolytes (including sodium, potassium, chloride, CO2), calcium, phosphorus, 
magnesium, creatinine, BUN, glucose, ALT, bilirubin, urinalysis, total protein, 
albumin, CPK, and chromogranin A. Evaluation of catecholamine production by 
tumor (serum normetanephrine and metanephrine, urine if possible) will be performed 
in patients with PHEO/PGL only. 
4.2.5 Urine or serum pregnancy test for all females of childbearing potential.   
4.2.6 Pathologic/Tissue Evaluation  
x Pathologic diagnosis will be reviewed and verified at the Clinical Center. Expression 
of SDH complex subunits and/or FH will be evaluated by immunohistochemistry in 
available pre-treatment tumor samples in the Clinical Center Laboratory of Pathology.  
GIST without Kit or PDGFRA mutation will be determined using standard approved 
tests. 
4.2.7 For patients with PHEO/PGL  
x Germline SDH subunit mutations will be determined using standard approved testing. 
Approved testing done outside of the Clinical Center will be accepted for these 
patients.  
4.3 
REGISTRATION PROCEDURES 
4.3.1 IWRS 
Patient Enrollment will be facilitated using the Interactive Web Response System (IWRS).  
IWRS is a web-based registration system available to users on a 24/7 basis.  On a successful 
registration, IWRS will assign a patient number and assign the treatment.  Patient enrollment 
data entered by Registrars in IWRS will automatically transfer to the NCI’s clinical data 
management system, Medidata Rave.  IWRS will provide a printable confirmation of 
registration and treatment information.  Please retain a copy of this confirmation for your 
records. 
x Users must have a valid CTEP-IAM account (i.e., CTEP username and password) to 
access the IWRS system. 
x Users defined with the Registrar role will have the ability to register patient in the 
study. 
x Users defined with the Client Administrator role will have the ability to manage 
accrual limits, open and close treatment assignments as well as approve slot 
reservations, if applicable to the study. 
4.3.2 OPEN / IWRS 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It is 
integrated with the CTSU Enterprise System for regulatory and roster data interchange and 
with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 


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OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please retain a copy of this confirmation for your records.  
4.3.3 OPEN/IWRS User Requirements 
OPEN/IWRS users must meet the following requirements: 
x Have a valid CTEP-IAM account (i.e., CTEP username and password). 
x To enroll patients:  Be on an ETCTN Corresponding or Participating Organization 
roster with the role of Registrar. 
x Have regulatory approval for the conduct of the study at their site. 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
x All eligibility criteria have been met within the protocol stated timeframes.   
x If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
4.3.4 OPEN/IWRS Questions? 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.4 
LOCAL REGISTRATION FOR NCI CCR 
Authorized staff must register an eligible candidate with NCI Central Registration Office 
(CRO) within 24 hours of signing consent.  A registration Eligibility Checklist from the 
website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and 
sent via encrypted email to:  NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff 
will call pharmacy to advise them of the acceptance of the patient on the protocol prior to the 
release of any investigational agent.  Verification of Registration will be forwarded 
electronically via e-mail to the research team. A recorder is available during non-working 
hours.  
5 
STUDY IMPLEMENTATION 
5.1 
STUDY DESIGN 
This is a single site, open label, phase II study design using a small optimal two-stage design 
to evaluate the clinical response in three groups of patients:  
1. wild-type GIST (GIST without Kit or PDGFRA mutation)  
2. PHEO/PGL in patients with germline SDH subunit mutation (SDH deficient 
PHEO/PGL), or  
3. RCC associated with HLRCC 
Adults and children (greater than or equal to 12 years of age) with measurable localized or 
metastatic or unresectable wild-type GIST, SDH deficient PHEO/PGL, or HLRCC-associated 


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RCC will be eligible for trial participation.  SGI-110 will be administered subcutaneously at 
45mg/m2/day x 5days on a 28-day cycle.  Cycles may be repeated until there is evidence of 
tumor progression clinically or by RECISTv1.1 or there is intolerable toxicity that is not 
alleviated by dose reduction.     
SGI-110 activity will be assessed by radiographic response of measurable disease using 
RECISTv1.1. Patients will be carefully monitored for toxicity and response.  Time to 
progression, overall survival and quality of life will be evaluated as secondary objectives. 
5.2 
DRUG ADMINISTRATION 
SGI-110 will be administered subcutaneously, preferably in the abdominal area at 
45mg/m2/day x 5 days on a 28-day cycle.  SGI-110 is available in a two-vial system, (1) SGI-
110 for Injection 100 mg, and (2) SGI-110 Diluent for Reconstitution 3 mL.   
SGI-110 drug product admixed with the custom diluent as described in section 15.1. The 
reconstituted SGI-110 solution is stable for 1 week under refrigerated conditions. 
SGI-110 should be injected slowly (up to one minute) as some injection site discomfort or 
pain may be experienced. Care must be taken to avoid intradermal injection as this may result 
in injection site pain.  To prevent injection site pain, patient should be directed to apply ice 
packs to the injection site before and after the injection.  If the injection pain continues 
despite these measures, pre-treatment with topical or systemic analgesics may be considered. 
Patients will be observed in clinic for at least one hour after the first dose of SGI-110.Vital 
signs including blood pressure, heart rate, and respiratory rate will be obtained and injection 
site will be monitored for signs of local reaction every 20-30 minutes in clinic for 1-hour post 
injection after the initial dose of SGI-110. 
5.3 
DOSE MODIFICATIONS 
Although not a phase 1 study, toxicity will be evaluated and treatment limited by the 
toxicities defined below.  This study will utilize the CTEP Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0 for toxicity and Adverse Event grading and reporting.  
An adverse event must be judged to be possibly, probably, or definitely related to SGI-110 to 
be a treatment limiting toxicity. Because it is possible that longer-term administration of the 
drug may be required in these patient populations, two dose reductions of approximately 30% 
will be allowed for patients who develop toxicity determined to be treatment related. 
If a subject misses or skips a dose the dose will be given the next day. When a missed or 
skipped dose occurs, the research team should be notified to provide guidelines to the subject 
on whether to proceed with further doses. 
SGI-110 will be held for treatment-limiting toxicities and re-started at the reduced dose after 
resolution of toxicity to a grade 1 or baseline. 
Treatment-limiting toxicity is defined as: 
x Toxicities that are possibly, probably or definitely related to SGI-110 and are ≥ grade 
3, unless the toxicity resolves/reversible within 72 hours with supportive care.   
x In addition, persistent grade 2 toxicities will be considered dose-limiting if they are 
intolerable to the patient.   
If the patient experiences a treatment limiting toxicity after two dose reductions, SGI-110 will 
be discontinued permanently.   


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Dose Level 
Dose reduction (mg/m2/dose) 
Dose reduction (%) 
Dose -1 
30mg/m2/dose 
~30% 
Dose -2 
20mg/m2/dose 
~30% 
 
5.4 
QUESTIONNAIRES (APPENDIX III AND APPENDIX IV) 
The pediatric PROMIS instruments and the Distress Rating Tool will be administered to all 
consenting patients who speak English or Spanish with parallel Parent Proxy instruments 
administered to parents of patients ages 12-17.  These instruments will be administered at 
baseline, at the end of cycle 4 and every 4 cycles thereafter, and at the time a patient is taken 
off treatment (see Section 5.7).  Since the measures have not been validated in other 
languages, participation in this portion of the study will be limited to subjects who speak 
either English or Spanish.   
5.4.1 PROMIS 
The Patient–Reported Outcome Measurement Information System (PROMIS®), funded by 
the National Institutes of Health to provides clinicians and researchers access to efficient, 
precise, valid, and responsive parent– and child–reported measures of health and well–being. 
5.4.2 Distress Rating Tool 
All patients ages 12 years or older will complete the Distress Thermometer. The Distress 
Thermometer takes less than 5 minutes to complete. 
5.5 
ON-STUDY EVALUATION 
5.5.1 Baseline Assessment 
Laboratory values must be no older than 72 hours from the time of eligibility evaluation and 
starting therapy.  Imaging studies must be no older than 4 weeks of enrollment at enrollment.  
Testing outside of this window must be repeated prior to starting study drug. 
If a post-enrollment/pre-treatment laboratory value is outside of the limits of eligibility, this 
laboratory value must return to the eligibility requirement prior to initiating therapy.  If the 
laboratory value does not return to the limits of eligibility within 14 days, patient may not 
receive protocol therapy.  
The evaluations required prior to starting treatment portion of the study are listed in Section 
5.6, Study Calendar.  Screening labs will be repeated if they are older than 72 hours. 


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5.6 
STUDY CALENDAR 
Procedure 
Screening 
Baseline 
Cycle 1 (± 3 days) 
Subsequent Cycles (± 
3 days) 
Post Therapy 
Follow-up 
(approximately 
30 days after 
final dose of 
study drug) 
Day 1 
Day 2-
5 
Day 7 
Day 
14 
Day 28 
Day 1-5 
Day 28 
 
History  
X 
 
 
 
 
 
 
X 
 
 
Physical Exam 
X 
Xa 
 
 
 
 
 
X 
 
 
Vital signs 
X 
X 
Xi 
 
 
 
 
X 
 
 
Performance Score 
X 
Xa 
 
 
 
 
 
 
 
 
SGI-110 Administration 
 
 
X 
X 
 
 
 
X 
 
 
Labs 
x Complete blood count with 
diff, platelets 
x Electrolytes (including 
sodium, potassium, 
chloride, CO2), calcium, 
phosphorus, magnesium, 
creatinine, BUN, glucose, 
ALT, bilirubin, urinalysis, 
total protein, albumin, and 
CPK 
X 
Xa 
 
 
 
 
 
X 
 
 
Serum normetanephrine 
and metanephrine (if 
possible, urine), and 
chromogranin A (in 
patients with PHEO/PGL 
only) 
X 
 
 
 
 
 
 
Xj 
 
 


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Procedure 
Screening 
Baseline 
Cycle 1 (± 3 days) 
Subsequent Cycles (± 
3 days) 
Post Therapy 
Follow-up 
(approximately 
30 days after 
final dose of 
study drug) 
Day 1 
Day 2-
5 
Day 7 
Day 
14 
Day 28 
Day 1-5 
Day 28 
 
Urine/serum pregnancy test 
for all females of 
childbearing potential 
X 
 
 
 
 
 
 
Xk 
 
 
Biopsies 
Xc 
 
 
 
 
 
 
Xg 
 
 
1) Tumor expression of SDH 
complex subunits and FH 
by IHC 
X 
 
 
 
 
 
 
Xg 
 
 
2) Tumor expression of NY-
ESO-1 by IHC 
 
Xf 
 
 
 
 
 
Xg 
 
 
LINE-1 demethylation 
analysis (Dr. Meltzer 
research)  
 
X 
 
 
 
X 
 
 
 
 
Pharmacokinetic testing 
 
X 
Xd 
Xd 
 
 
 
 
 
 
Pharmacodynamic testinge 
 
X 
 
 
X 
X 
X 
 
 
 
Response evaluation of 
disease b 
X 
Xb 
 
 
 
 
 
 
Xb 
 
Quality of Life (Distress 
thermometer and PROMIS) 
 
X 
 
 
 
 
 
 
Xh 
Xh 
Adverse Events 
 
 
X 
 
 
 
 
 
 
X 
Concomitant Medications 
 
 
X 
 
 
 
 
 
 
X 
a Laboratory tests older than 2 weeks (14 days) at the start of therapy must be repeated.  For abnormal test results, refer to Section 4.2.  
b Imaging studies will be repeated if older than 4 weeks at the start of therapy. Imaging evaluation selection may include CT and/or MRI, and/or FDG-PET 
as clinically indicated.  Staging should be performed prior to the second cycle and then prior to every other cycle. The same imaging strategy will be used 
throughout study participation for tumor evaluation. 


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c when archival tissue is not available.  
d active metabolite (decitabine) will be assayed in plasma prior to first dose in cycle 1 and at 0.5 hour (+/- 15 minutes), 1 hour (+/- 15 minutes), 2 hour (+/- 
30 minutes), 4 hour (+/- 30 minutes), 6 hour (+/- 1 hour) and 24 hours (+/- 2 hours) after the first dose of drug in Cycle 1. 
e LINE-1 demethylation in PBMC using pyrosequencing and urine and plasma glycolytic metabolytes at baseline and day 7, 14, and 28 of cycle 1. 
f pre-treatment tumor samples on archival tissue may be used for initial NY-ESO-1 evaluation. 
g On-treatment biopsy will be performed when a core biopsy may be safely performed in consenting patients ≥ 18 years of age. On treatment biopsy will be 
optional. 
hat the end of cycle 4 and then every 4 cycles thereafter (e.g. at the end of cycle 8, 12, 16, etc.), and at the end of therapy. 
iVital signs will be obtained on day 1 per section 5.2. 
jAt each restaging timepoint 
kPrior to each cycle


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5.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
5.7.1 Criteria for removal from protocol therapy 
Patients participating in this study may be removed for therapy with SGI-110 due to any one of 
the following events: 
x Completed 30-day safety follow-up period 
x Progressive disease 
x Participant requests to be withdrawn from active therapy 
x Unacceptable Toxicity as defined in Section 5.3 
x Investigator discretion 
x Positive pregnancy test 
5.7.2 Off-Study Criteria 
Patients who are removed from treatment permanently for any reason should be monitored until 
resolution or stabilization of toxicity, or until 30 days after the last dose of SGI-110, whichever is 
later.  In addition, the following criteria will result in removal from study: 
x Participant requests to be withdrawn from study 
x Lost to follow up 
x Death 
5.7.3 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 
Note: all minors will be kept on study and followed until the age of 18 to allow for consent. 
6 
CONCOMITANT MEDICATIONS/MEASURES 
There will be no concomitant disease directed therapy allowed while patients are participating in 
this study.   
Supportive standard therapies and preventive measures should be instituted to address known 
toxicities, including the following: 
6.1 
INJECTION SITE REACTIONS 
Care must be taken to avoid intradermal injection, and administer by slow subcutaneous 
injection.  If injection site pain occurs, apply ice packs to the site both before and after injection.  


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If injection site reactions occur despite these measures, pre-treatment with topical or systemic 
analgesic can be considered. 
6.2 
MUCOSITIS 
To prevent mucositis, participants should be directed to increase brushing teeth with the softest 
tooth brush, every 4 hours and at bedtime, and rinse frequently with mouth rinses, to keep the 
mouth moisturized. Patients with a healthy mouth may use non-alcoholic mouthwash 4 to 6 
times daily (e.g. after each meal), or according to the instructions, during the study.  
Saline mouthwashes (Sodium chloride 0.9%) are preferred in cases of stomatitis, and should be 
used at a different time than toothbrushing (e.g. after tea).  
Consider treating stomatitis at an early stage (CTCAE grade 1) or as soon as the patient 
complains of a sore mouth.  Consider using an oral topical analgesic, with or without topical 
steroids, depending on the patient’s clinical condition and the local standard medical practice. 
6.3 
DIARRHEA 
Patients should be made aware that they may experience diarrhea, and should record the number 
of stools and associated symptoms.  Patients should inform the physician if they develop 
diarrhea. The following dietary advice should be considered: BRAT diet (bananas, rice, apple 
sauce, toast, plain pasta), readily digestible food, avoidance of lactose-containing products and 
fried, fatty or spicy foods, increased fluid intake (8-10 glasses of clear fluids/day (including 
water, clear broth, fluids containing salt and sugar).  Patients should be given loperamide to take 
home and should start taking loperamide after the first episode of unformed, loose stool. If 
diarrhea persists and after consulting with the investigator, loperamide can be continued at a dose 
of 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. During the night, the 
patient may take 4 mg of loperamide every 4 hours. Monitor and replace fluid and electrolytes. 
Patients should contact their physician or study nurse if they have persistent diarrhea, diarrhea 
complicated by vomiting or fever, or inability to take oral liquids 
7 
BIOSPECIMEN COLLECTION 
7.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
7.1.1 Pharmacokinetics 
Pharmacokinetic analysis will be performed in patients during cycle 1 according to Section 5.6, 
Study Calendar.  The observed decitabine T1/2 following SC administration of SGI-110 in adults 
is 2.4 hours23. The active metabolite of SGI-110 (decitabine) will be assayed in plasma prior to 
the first dose of drug in cycle 1 and at 0.5 (+/- 15 min), 1 (+/- 15 min), 2 (+/- 30 min), 4 (+/- 30 
min), 6 (+/- 1 hour), and 24 hours (+/- 2 hours).  Blood samples (3mL) will be collected into 6 
mL sodium heparin green top tubes. PK analysis will be performed in the laboratories of Dr. 
Figg.  Plasma levels of decitabine will be determined using a validated liquid chromatography-
mass spectrometry method. 
This PK data will be used to develop a population PK model (using Phoenix NLME®, Certara, 
Cary, NC and RStudio) that will assess the impact of covariates including (but not limited to) 
age, body size (weight, height, surface area), sex, race, PD endpoints, hepatic and renal function.  


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The degree of change in decitabine PK based on the covariates available will be assessed to 
determine if dose adjustments are required. 
7.1.2 Expression of SDH complex subunits and FH 
Expression of SDH complex subunits and FH will be evaluated by immunohistochemistry in 
available pre-treatment and on treatment tumor samples in the Clinical Center Laboratory of 
pathology under the direction of Dr. Marino and Dr. Miettenen.  This analysis will be performed 
in archival tumor tissue and in on-treatment biopsies when available.  Paraffin-embedded tissue 
sections will be utilized for this analysis and staining will be performed using published 
methodology that was developed in the laboratory of pathology for FH, SDHA and SDHB2,33.   
7.1.3 DNA hyper-methylation 
The DNA-methylome will be evaluated for pre-treatment and on-treatment tumor biopsies (when 
available) in the laboratory of Dr. Paul Meltzer.  Methylation assay and methylation data analysis 
will be done using paraffin-embedded samples.  The EZ DNA Methylation kit (Zymo Research) 
will be used for bisulfite conversion of gDNA extracted from paraffin-embedded tumor samples.  
The GoldenGate Cancer Panel Methylation Array 1 (Illumina) will be utilized and data analyzed 
as previously described2.   
7.1.4 NY-ESO-1 expression 
Available pre-treatment tumor samples will be used for initial NY-ESO-1 evaluation and on-
treatment biopsies will be optional for patients >18 years old when core biopsy can be safely 
performed. NY-ESO-1 expression before and on treatment in paired tumor biopsy samples when 
available, using immunohistochemistry in the Laboratory of Pathology at the Clinical Center 
under the direction of Dr. Miettenen and Dr. Marino.  Paraffin-embedded tissue sections will be 
utilized for this analysis and staining will be performed using published methodology that was 
developed in the laboratory of pathology34. NY-ESO-1 staining intensity will be assessed by two 
pathologists using the following scoring system: 1+ = weak, 2+ = moderate, 3+ = strong. 
7.1.5 Serum and Urine Concentrations of glycolytic metabolites 
Impaired activity of the Krebs cycle enzymes SDH complex or FH leads to aberrant cellular 
concentrations of glycolytic metabolites including fumarate and succinate35,36. Systemic levels of 
2-hydroxyglutarate have been investigated as a method of identifying patients with glioblastoma 
with isocitrate dehydrogenase mutation37. In these patients, the plasma/urine ratio of 2-
hydroxyglutarate was significantly different between patients with mutant isocitrate 
dehydrogenase enzymes. Systemic levels of glycolytic metabolites are not well-defined in 
patients with wt-GIST, HLRCC, or PHEO/PGL. We will begin to explore the metabolomic 
profile of patients with tumors related to Krebs cycle defects. Serum and urine 2-
hydroxyglutarate, succinate, and fumarate will be determined at baseline and on treatment.  
Plasma and urine samples will be collected at baseline and on day 7, 14, and 28 of cycle 1.  
Urine samples will be cooled to 4 C, centrifuged, aliquoted and stored at -80 C until analysis. 
Blood samples (3mL) will be collected in EDTA tubes and cooled to 4 C, centrifuged, and 
plasma will be aliquoted and stored at -80 C until analysis. Concentrations of 2-hydroxyglutarate 
succinate and fumarate will be analyzed using liquid chromatography/mass spectrometry 
(LC/MS) as previously described37,38. 


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5.1.6 LINE-1 demethylation analysis of PBMCs 
LINE-1 methylation status in peripheral blood mononuclear cells will be assessed as an estimate 
of global DNA methylation. This analysis will be performed on samples at baseline and on days 
7, 14, and 28 of cycle 1. Analysis will be performed in the laboratory of Dr. Meltzer using a 
previously described quantitative bisulfate pyrosequencing method39. 
 
Study 
Test/Lab Location 
Sample Time 
Points 
Volume/type of blood 
sample 
Tube 
Notes 
PK- analysis of 
decitabine 
Liquid 
Chromatography-mass 
spectrometry method, 
Dr. Figg’s lab  
Pre-dose 1, and 
0.5, 1, 2, 4, 6, 
and 24 hrs post 
dose 1 
3mL blood  
6 mL 
sodium 
heparin 
green top 
Tubes will be 
cooled to 4 
degrees C and 
centrifuged. 
Plasma will be 
aliquoted and 
stored at -80 C 
until analysis. 
Expression of 
SDH complex 
subunits and FH y 
IHC, CC Laboratory 
of Pathology (Dr. 
Marino and Dr. 
Miettenen 
If available: 
prior to dose 1 
and during 
treatment 
Archival samples may be 
used for pretreatment, on 
treatment biopsies 
performed in patients ≥ 18 
years, if safely obtainable. 
NA 
 
 
Block (can be 
same block that 
is used for 
DNA 
hypermethylati
on) or 10 
unstained slides 
Samples will be 
fixed and 
processed by 
the laboratory 
of pathology. 
  
NY-ESO-1 
expression  
IHC, CC Laboratory 
of Pathology (Dr. 
Marino and Dr. 
Miettenen 
If available, 
prior to dose 1 
and during 
treatment 
Archival samples may be 
used for pretreatment, on 
treatment biopsies 
performed in patients ≥ 18 
years, if safely obtainable. 
NA 
DNA 
hypermethylation 
EZ DNA Methylation 
kit (Zymo Research) 
will be used for 
bisulfite conversion of 
gDNA, and The 
GoldenGate Cancer 
Panel Methylation 
Array 1 (Illumina) 
will be utilized in the 
laboratory of Dr. Paul 
Meltzer 
Prior to dose 1 
and during 
treatment 
Archival samples may be 
used for pretreatment, on 
treatment biopsies 
performed in patients ≥ 18 
years, if safely obtainable. 
NA 
 Block (can be 
same block that 
is used for NY-
ESO-1 
expression) 
or10 unstained 
slides of FFPE 
samples will be 
supplied to Dr. 
Meltzer’s 
laboratory for 
processing. 
LINE-1 
demethylation 
analysis 
EZ DNA Methylation 
kit (Zymo Research) 
will be used for 
bisulfite conversion of 
gDNA, and The 
GoldenGate Cancer 
Panel Methylation 
Array 1 (Illumina) 
will be utilized in the 
laboratory of Dr. Paul 
Meltzer 
Prior to dose 1 
and Cycle 1, 
Day 14 (±3 
days) 
10 mL blood 
lavender 
top  
Samples will be 
collected and 
spun by Dr. 
Figg’s Lab and 
then sent to 
Paul Meltzer’s 
lab. PBMC will 
be collected and 
aliquoted and 
stored until 
analysis. 


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Study 
Test/Lab Location 
Sample Time 
Points 
Volume/type of blood 
sample 
Tube 
Notes 
Urine glycolytic 
metabolites (PD) 
LC/MS 
Laboratory of Dr. 
Widemann 
At baseline at 
days 7, 14, and 
28 of cycle 1. 
Urine samples 10-15 ml 
15ml 
Conical 
tube 
Samples will be 
collected. and 
cooled to 4 C. 
Dr. Figg’s lab 
to process:   
spin briefly to 
remove debris. 
Sample will 
then be 
aliquoted and 
stored at -80 C 
until analysis. 
Serum glycolytic 
metabolites (PD) 
LC/MS 
Laboratory of Dr. 
Widemann 
At baseline at 
days 7, 14, and 
28 of cycle 1. 
Blood sample 3mL 
3 ml SST 
Samples will be 
collected and 
cooled to 4 C. 
Dr. Figg’s lab 
to process:    
Spin, and . 
Plasma will 
then be 
aliquoted and 
stored at -80 C 
until analysis. 
 
7.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with data 
entered and stored in the Patient Sample Data Management System (a.k.a LabSamples) utilized 
by the CPP. This is a secure program, with access to LabSamples limited to defined CPP 
personnel, who are issued individual user accounts. Installation of LabSamples is limited to 
computers specified by Dr. Figg. These computers all have a password restricted login screen. 
All CPP personnel with access to patient information annually complete the NIH online 
Protection of Human Subjects course.  
LabSamples creates a unique barcode ID for every sample and sample box, which cannot be 
traced back to patients without LabSamples access. The data recorded for each sample includes 
the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material 
type, as well as box and freezer location, and date samples are sent to the investigator or shipped 
to outside institutions. Patient demographics associated with the clinical center patient number 
are provided in the system. For each sample, there are notes associated with the processing 
method (delay in sample processing, storage conditions on the ward, etc.). 
7.2.1 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at -80qC in accordance to 
stability requirements.  These freezers are located onsite in the CPP and offsite at NCI Frederick 
Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be 
accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LabSamples. All 


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researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the CPP. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. The PI will record any loss or unanticipated destruction of samples as a deviation. 
Reporting will be per the requirements of section 10.2.1.  
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LabSamples. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
The study will remain open and status reported to the NIH Intramural IRB until all samples have 
been analyzed, reported or destroyed.  Unintentional loss or destruction of any samples will be 
reported to the NIH Intramural IRB per the requirements of section 10.2.1.  Any use of these 
samples for purposes not described in this protocol will require prospective NIH Intramural IRB 
review and approval.   
Data from patient reported outcomes and functional endpoints will be sent to POB NCI for data 
analysis.  All data will be identified using the study number; no personal identifying information 
should be sent to NCI.  
8 
MEASUREMENT OF EFFECT 
For the purposes of this study, patients should be re-evaluated for response after the first 4 weeks 
and then every 8 weeks.  In addition to a baseline scan, confirmatory scans should also be 
obtained 4 weeks following initial documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
8.1 
DEFINITIONS 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with SGI-110. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 


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according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
8.2 
DISEASE PARAMETERS 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 


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will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
8.2.1 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and t10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 


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introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 


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c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
8.2.2 Response Criteria 
8.2.2.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
8.2.2.2 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 


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measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “ symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
8.2.3 Duration of Response 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
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Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
  
9 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
9.1 
COMPREHENSIVE ADVERSE EVENT AND POTENTIAL RISK LIST (CAEPRS) 
9.1.1 Comprehensive Adverse Events and Potential Risks list (CAEPR for SGI-110 (NSC 
780463) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 757 patients. Below is the CAEPR for SGI-
110 (Guadecitabine). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.1, May 8, 20191 
 
 Adverse Events with Possible  
 Relationship to SGI-110 (Guadecitabine) 
 (CTCAE 5.0 Term) 
[n= 757] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
Anemia (Gr 2) 
 
Febrile neutropenia 
Febrile neutropenia (Gr 2) 
EYE DISORDERS 


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 Adverse Events with Possible  
 Relationship to SGI-110 (Guadecitabine) 
 (CTCAE 5.0 Term) 
[n= 757] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
Periorbital edema 
GASTROINTESTINAL DISORDERS 
 
Constipation 
Constipation (Gr 2) 
 
Diarrhea 
Diarrhea (Gr 2) 
 
Mucositis oral 
Mucositis oral (Gr 2) 
 
Nausea 
Nausea (Gr 2) 
 
Vomiting 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Edema face 
Fatigue 
 
Fatigue (Gr 2) 
 
Fever 
Injection site reaction 
 
Injection site reaction (Gr 2) 
 
Pain 
INFECTIONS AND INFESTATIONS 
 
Infection2 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Bruising 
Bruising (Gr 1) 
INVESTIGATIONS 
 
Lymphocyte count 
decreased 
Lymphocyte count decreased 
(Gr 4) 
Neutrophil count 
decreased 
 
Neutrophil count decreased 
(Gr 2)  
Platelet count decreased  
Platelet count decreased (Gr 
2) 
 
White blood cell 
decreased 
White blood cell decreased 
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
Anorexia (Gr 2) 
 
 
Tumor lysis syndrome 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
Headache 
PSYCHIATRIC DISORDERS 
 
Insomnia 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 


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 Adverse Events with Possible  
 Relationship to SGI-110 (Guadecitabine) 
 (CTCAE 5.0 Term) 
[n= 757] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
Dyspnea 
 
Epistaxis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Purpura 
 
Rash maculo-papular 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and 
the agent should be included in the e-mail. 
 
2Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS 
SOC. 
Adverse events reported on SGI-110 (Guadecitabine) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that SGI-110 (Guadecitabine) 
caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (agranulocytosis); Blood and lymphatic system disorders - Other (coagulopathy); Blood and 
lymphatic system disorders - Other (febrile bone marrow aplasia); Blood and lymphatic system 
disorders - Other (histiocytosis hematophagic); Blood and lymphatic system disorders - Other 
(lymphadenopathy); Blood and lymphatic system disorders - Other (pancytopenia); Bone marrow 
hypocellular; Leukocytosis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (atrial tachycardia); 
Cardiac disorders - Other (bradycardia); Chest pain - cardiac; Heart failure; Left ventricular systolic 
dysfunction; Palpitations; Sinus tachycardia 
CONGENITAL, FAMILIAL AND GENETIC DISORDERS - Congenital, familial and genetic 
disorders - Other (phimosis) 
EAR AND LABYRINTH DISORDERS - Ear pain; Vertigo  
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Eye disorders - Other (eye/retinal/conjunctival hemorrhage) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Belching; 
Cheilitis; Colitis; Dry mouth; Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; 
Gastritis; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (small intestinal 
hemorrhage); Gastrointestinal disorders - Other (tongue discoloration); Gastrointestinal pain; 


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Gingival pain; Hemorrhoids; Ileus; Lip pain; Lower gastrointestinal hemorrhage; Oral hemorrhage; 
Oral pain; Periodontal disease; Rectal hemorrhage; Rectal pain; Small intestinal mucositis; Small 
intestinal obstruction; Toothache; Typhlitis; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
limbs; Gait disturbance; General disorders and administration site conditions - Other (exercise 
tolerance decreased); General disorders and administration site conditions - Other (general physical 
health deterioration); General disorders and administration site conditions - Other (systemic 
inflammatory response syndrome [SIRS]); Infusion site extravasation; Localized edema; Malaise; 
Multi-organ failure; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Cholecystitis 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase 
increased; Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; Creatinine increased; Ejection fraction decreased; Electrocardiogram QT corrected 
interval prolonged; GGT increased; INR increased; Investigations - Other (elevated c-reactive 
proteins [c-reactive protein increased]); Investigations - Other (klebsiella test positive); 
Investigations - Other (reticulocyte count decreased); Investigations - Other (thrombocytosis); 
Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Alkalosis; Dehydration; 
Hypercalcemia; Hyperglycemia; Hyperkalemia; Hyperphosphatemia; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Metabolism and 
nutrition disorders - Other (gout) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; 
Back pain; Bone pain; Flank pain; Generalized muscle weakness; Joint range of motion decreased; 
Muscle cramp; Musculoskeletal and connective tissue disorder - Other (joint contracture); 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal stiffness); Musculoskeletal 
and connective tissue disorder - Other (pain in jaw); Myalgia; Neck pain; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Ataxia; Dysgeusia; Lethargy; Paresthesia; Presyncope; 
Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Delirium; Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Urinary frequency; 
Urinary tract pain; Urinary urgency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Penile pain; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Atelectasis; Bronchopulmonary hemorrhage; Cough; Hypoxia; Nasal congestion; 
Oropharyngeal pain; Pleural effusion; Pleuritic pain; Pneumonitis; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (oropharyngeal blistering); Rhinorrhea; Sneezing; 
Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Bullous dermatitis; Dry skin; 
Hyperhidrosis; Lipohypertrophy; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - 


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Other (dermal cyst); Skin and subcutaneous tissue disorders - Other (granuloma annulare); Skin and 
subcutaneous tissue disorders - Other (onychoclasis); Skin induration; Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypertension; Hypotension; 
Thromboembolic event 
Note: SGI-110 (Guadecitabine) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
9.2 
ADVERSE EVENT CHARACTERISTICS  
 
x CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
x For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 9.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 9.3.3. 
 
x 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. 
9.3 
EXPEDITED ADVERSE EVENT REPORTING TO CTEP 
9.3.1 Expedited AE reporting  
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP website (https://eapps-ctep.nci.nih.gov/ctepaers).  The reporting 
procedures to be followed are presented in the “NCI Guidelines for Investigators: Adverse Event 
Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be 
downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm).  
These requirements are briefly outlined in the tables below (Section 9.3.3). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 


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notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
9.3.2 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
9.3.3 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via AdEERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 


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Resulting in 
Hospitalization       ≥ 
24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization       ≥ 
24 hrs 
Not required 
NOTE:   Protocol-specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
9.4 
ROUTINE ADVERSE EVENT REPORTING TO CTEP 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
9.5 
SECONDARY MALIGNANCY  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
x Myelodysplastic syndrome (MDS) 
x Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 


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9.6 
SECOND MALIGNANCY 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
unless otherwise specified. 
10 NIH INTRAMURAL RESEARCH PROGRAM REPORTING 
10.1 DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
10.2 OHSRP OFFICE OF COMPLIANCE AND TRAINING/ IRB REPORTING 
10.2.1 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies. 
10.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
 
10.3 NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
11 STUDY OVERSIGHT AND DATA REPORTING/REGULATORY 
REQUIREMENTS 
11.1 STUDY OVERSIGHT  
This protocol is monitored at several levels, as described elsewhere in this section.  The Protocol 
Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, 
including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine 
and serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times. 


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All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via the mechanism described elsewhere in this section.  
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 10.2.1. 
11.2 DATA REPORTING 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding 
Organization or Participating Organization roster at the enrolling site.   
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
11.2.1 Method 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted on an 18-36 month basis as part of routine cancer center site visits. 
More frequent audits may be conducted if warranted by accrual or due to concerns regarding 
data quality or timely submission.  For CTMS monitored studies, after users have activated their 
accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 


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11.3 DATA SHARING PLANS 
11.3.1 Human Data Sharing Plan 
I will share coded, linked human data generated in this research for future research in a NIH-
funded or approved public repository at the time of publication or shortly thereafter. 
11.3.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy 
12 STATISTICAL CONSIDERATIONS   
SGI-110 activity will be assessed by radiographic response of measurable disease using 
RECISTv1.1. The study will be conducted as a small, optimal two-stage phase II trial40, in order 
to rule out an unacceptably low 5% overall response rate (ORR; p0=0.05), in favor of a slightly 
higher response rate of 30% (p1=0.30).  With alpha=0.10 (probability of accepting a poor 
treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), the study will 
initially enroll 7 evaluable patients in each group (strata) and if 0 of the 7 have a response, then 
no further patients will be accrued in that stratum. If 1 or more the first 7 (14.3.1% or more) have 
a response, then accrual would continue until a total of 21 patients have enrolled in that stratum. 
Only complete responses (CR) and partial responses (PR) will be counted towards the overall 
response rate.  As it may take several weeks to months to determine if a patient has experienced 
a response, a temporary pause in the accrual to that stratum in the trial may be necessary to 
ensure that enrollment to the second stage is warranted. If there are 1 to 2 responses in 21 
patients, this would be an uninterestingly low response rate, while if there were 3 or more 
responses in 21 (14.3% or more) patients, then this would be sufficiently interesting to warrant 
further study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 70%.  With three cohorts of up to 21 patients apiece, the maximum number of 
evaluable patients required would be 63. In order to allow for a small number of inevaluable 
patients, the accrual ceiling will be set to 70. 
Descriptive summaries of the secondary outcome variables (toxicity, progression-free survival, 
overall survival, quality of life, pharmacokinetics, pharmacodynamics) will be presented at the 
time of the primary analysis, and will be repeated in subsequent analyses to characterize the 
extent to which changes are maintained over a longer follow-up period.  Each of these secondary 
endpoints will be assessed in a hypothesis generating manner, without formal adjustment for 
multiple comparisons but reported in the context of the number and type of evaluation being 
performed. 
In addition, progression-free survival and overall survival will be reported separately for each 
stratum.  Changes in QOL will be evaluated relative to any degree of response and summary 
statistics will be described over time.  As these evaluations may be performed in a post hoc 
manner based on the response results obtained, the findings will need to be carefully presented in 
the context of the exploratory nature of the analyses undertaken. 


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13 COLLABORATIVE AGREEMENTS 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 


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5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
Email:  ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
14 HUMAN SUBJECTS PROTECTIONS  
14.1 RATIONALE FOR SUBJECT SELECTION 
Patients of both genders, from all racial and ethnic groups are eligible for this trial if they meet the 
eligibility criteria outlined in Section 3.1.  There is no clinical information that suggests differences 
in SGI-110 metabolism or response among racial or ethnic groups or between the genders, 
indicating that results of the trial will be applicable to all groups.  This phase II trial of SGI-110 
will be conducted in children greater than or equal to 12 years of age and adults measurable, 
localized or metastatic or unresectable wild-type GIST, SDH deficient PHEO/PGL, or HLRCC-
associated RCC will be eligible for trial participation.  Patients with PHEO/PGL or RCC must 
have recurrent or refractory disease.  Efforts will be made to extend the accrual to a representative 
group from this population, but with these uncommon diseases and with a planned accrual of 24 
patients, a balance must be struck between completing the trial in a timely fashion on the one hand 
and the need to explore gender, racial, and ethnic aspects of clinical research on the other.  If 
differences in outcome that correlate to gender, racial, or ethnic identity are noted, accrual may be 
expanded or additional studies may be performed to investigate those differences more fully.   
14.1.1 
Gender and Minority Accrual Estimates 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 


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DOMESTIC PLANNED ENROLLMENT REPORT 
American 
Indian/ Alaska 
Native 
1 
1 
 
 
2 
Asian 
1 
3 
 
 
4 
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
0 
 
 
0 
Black or 
African 
American 
4 
5 
 
 
9 
White 
22 
25 
3 
4 
54 
More Than One 
Race 
1 
 
 
 
1 
Total 
29 
34 
3 
4 
70 
 
14.2 PARTICIPATION OF CHILDREN 
Children greater than or equal to 12 years of age will be eligible and the drugs pharmacokinetics 
will be explored in this age group.  The safety of SGI-110 has not been established in children 
and therefore younger age groups will be excluded until more safety data is available in this age 
group.  Children greater than or equal to 12 years of age will be enrolled and the study will be 
conducted by pediatric oncologists who have extensive experience in performing investigational 
drug trials in children.  Patients enrolled at the POB, NCI will be cared for in the POB outpatient 
clinic or day hospital. When patients require hospital admission, they will be cared for on the 
1NW Pediatric Unit by the POB staff. 
14.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 14.5), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP SOP14E for 


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appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed. 
14.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
14.4.1 Risks of SGI-110 
The primary risk to patients participating in this research study is from toxicity of SGI-110.  In 
adults, SGI-110 has been relatively well tolerated.  The dose limiting toxicities observed with 
SGI-110 include grade 4 neutropenia and thrombocytopenia and grade 5 sepsis.  The most 
common toxicities reported with SGI-110 monotherapy include neutropenia, thrombocytopenia, 
fatigue, diarrhea, injection site pain (including pain, burning, irritation, erythema, inflammation, 
bleeding, pain, or subcutaneous nodules), anemia, febrile neutropenia (See Section 9.1).   
14.5 RISKS/BENEFITS ANALYSIS 
Gastrointestinal stromal tumors (GISTs) are resistant to cytotoxic chemotherapy and radiation 
therapy. KIT and PDGFRA mutations have been identified as tumor initiating events in 85% of 
adult patients with GIST and these tumors are responsive to the tyrosine kinase inhibitor, 
Imatinib. In pediatric patients, however, 85% of GISTs lack KIT and PDGFRA mutations (wild-
type) and imatinib is not effective. SDH deficiency is present in the majority of patients with wt-
GIST and guadecitabine may have activity in this population of patients. 
Approximately 10-30% of PHEO/PGL are SDH-deficient13,14 and there is an increased risk of 
more aggressive metastatic disease in patients with SDHB mutation. Surgical resection is the 
only curative therapy for patients with PHEO/PGL, however both radiation therapy and 
cytotoxic chemotherapy using cyclophosphamide, vincristine, and dacarbazine (CVD) have been 
used to treat patients with metastatic or recurrent disease12. While responses can be seen with this 
therapy, complete durable responses are rare and additional therapeutic options are lacking. 
Guadecitabine may have activity in this population of patients with SDH-deficient PHEO/PGL. 
HLRCC-associated kidney cancer is typically clinically aggressive with early development of 
metastatic disease. Nephron-sparing surgical therapy is standard for localized HLRCC-associated 
renal cancer22. While there is currently no standard systemic therapy for metastatic HLRCC-
associated renal cell cancer, treatments targeting the VEGF and EGFR pathways are being 
investigated in ongoing clinical trials22. HLRCC is an autosomal-dominant hereditary syndrome 
due to mutations in FH5. 
All three of these tumors (SDH deficient PHEO/PGL, HLRCC-associated RCC, and wt-GIST) 
have limited treatment options for metastatic and locally recurrent disease and are associated 
with deficiency in the Krebs cycle components SDH and FH. These tumors exhibit global DNA 
hypermethylation and may be responsive to guadecitabine. Therefore, this phase II protocol 
involves greater than minimal risk to children, but presents the prospect for direct benefit to 
individual child-subjects (Category 2). 
14.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The procedures and tests involved in this study and the associated risks, discomforts and benefits 
of these processes, will be carefully explained to the patient or the patient’s parents or guardian if 


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he/she is a child, and a signed informed consent document will be obtained prior to entry onto 
the study.  
The investigators are requesting a waiver from the IRB to allow only one parent to sign the 
treatment informed consent form to enter a child on the protocol.  Because many patients must 
travel to the NIH from long distances at substantial expense, requiring both parents to be present 
for the consent process could be a financial hardship for many families.  The parent who signs 
the consent for a minor must be a legally recognized parent or guardian. When guardianship 
status of the child is uncertain, documentation of custody status must be obtained. 
In situations where there is joint custody of a child, both parents must sign consent. If only one 
parent can be present at NIH, the other parent’s consent can be obtained by telephone via the 
procedure described in section 14.6.1.   
Where deemed appropriate by the clinician and the child’s parent(s) or guardian, the child will 
also be included in all discussions about the trial and age-appropriate language will be used to 
describe the procedures and tests involved in this study, along with the risks, discomforts and 
benefits of participation.  Verbal assent will be obtained as appropriate for children ages 7-11 
and the parent or guardian will sign the designated line on the informed consent attesting to the 
fact that the child has given assent.  Children under the age of 18, but who are age 12 or older 
will be asked to sign an age appropriate assent form. Children under the age of 12 will not be 
required to provide assent as they typically do not have the cognitive ability to fully understand 
the nature of research. The consent/assent process will be documented in the child’s medical 
record, including the assessment of the child’s ability to provide assent (verbal versus written) as 
applicable.  
14.6.1 Consent for minors when they reach the age of majority  
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require consenting of the now 
adult with the standard protocol consent document to ensure legally effective informed consent 
has been obtained. Given the length of time that has transpired for some of the subjects since 
their last visit for this study, we request waiver of informed consent for those individuals who 
become lost to follow up or who have been taken off study prior to reaching the age of majority. 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to 
subjects. 
(2) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects. 
a. Retention of these samples or data does not affect the welfare of subjects.  
(3) The research could not practicably be carried out without the waiver or alteration. 
a. Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again.  A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research.  


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(4) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We only plan to request a waiver of reconsent for those subjects who have 
been lost to follow-up 
14.6.2 Telephone consent 
The following procedure may be used in cases where reconsent is required. This process may 
also be used to obtain initial consent of an absent parent when both parental signatures are 
required. The informed consent document will be sent to the subject.  An explanation of the 
study will be provided over the telephone after the subject has had the opportunity to read the 
consent form.  The subject will sign and date the informed consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented in the medical record. 
 
15 PHARMACEUTICAL INFORMATION   
15.1 SGI-110 (GUADECITABINE) (NSC 780463) 
Chemical Name or Amino Acid Sequence: 
Sodium (2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl)-2-(hydroxymethyl) 
tetrahydrofuran-3-yl ((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-
hydroxytetrahydrofuran-2-yl)methyl phosphate 
Other Names: Guadecitabine 
Classification: DNA methylation inhibitor 
Molecular Formula: C18H23N9NaO10P 
 
 
M.W.: 579.39 Da 
Approximate Solubility:  It is water soluble at about 30 mg/mL over a pH range of 6.0 to 7.0. It 
is unstable in aqueous solutions and is relatively more stable at neutral pH.  SGI-110 is soluble in 
common organic solvent systems such as methanol, dimethylamine (DMA), and dimethyl 
sulfoxide (DMSO). 
Mode of Action: Guadecitabine (SGI-110) is a potent inhibitor of DNA methylation. 
Guadecitabine is a dinucleotide of decitabine and deoxyguanosine linked with a phosphodiester 
bond. Decitabine is the active metabolite. Guadecitabine is a new chemical entity that was 
designed to enhance pharmacokinetic (PK) properties compared with decitabine, with potential 
to improve pharmacodynamics (PD), clinical efficacy, and safety. 
How Supplied:  SGI-110 for Injection is supplied by Astex Pharmaceutical and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as follow: 
x SGI-110 for Injection: 100 mg dry powder lyophile containing free acid equivalent in a 
single-use vial;  


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x Diluents for Reconstitution: Two fill volumes: 3 mL or 1.2 mL 
 3 mL single-use vial containing non-aqueous diluent of propylene glycol, glycerin, 
and ethanol. (Will be phased out around July 2019) 
 1.2 mL single-use vial containing non-aqueous diluent of propylene glycol, 
glycerin, and ethanol.  (Will be available for use around July 2019) 
All vials are packaged in clear glass vials with stoppers made of latex-free rubber stopper and 
capped with an aluminum flip-off seal. 
Preparation: 
1. Allow SGI-110 vial(s) and diluent vial(s) to reach room temperature approximately 60 
minutes. 
2. Next, loosen the lyophilized powder of SGI-110 by gently tapping and rotating the vial on a 
hard surface. 
3. Use a 1 mL syringe and withdraw 0.9 mL of diluent and add it to the SGI-110 vial resulting 
in a final concentration of 100 mg/mL. Manually shake or mechanically vortex the diluted 
vial(s). 
 Manually shake: Intermittently shake the reconstituted vial vigorously 
(approximately 5 minutes).  In general, the shaking process will take 5 to 10 
minutes.  Rotate the vial and inspect the vial contents to ensure that all lyophilized 
SGI-110 powder has dissolved.  After dissolution, allow the vial to rest until all 
bubbles have dissipated (approximately 10 minutes). 
 Mechanically shake (vortex): Before vortexing, rotate or shake the vial to ensure 
that the drug powder is thoroughly wetted with diluent.  Then, vortex for 5-10 
minutes at a speed setting of 5.  Remove the vial from the holder and invert it 2-3 
times.  Place the vial on the vortex and mix for another 10 minutes. Ensure that all 
SGI-110 powder is completely dissolved. Repeat the process if partially 
dissolved.  Once all drug is dissolved, allow the solution rest until all bubbles 
dissipate (approximately 10 minutes). 
4. The final solution of the diluted vial should be colorless to pale yellow. 
5. Withdraw the diluted solution into a syringe. If two or more syringes are needed to deliver 
the total prescribed dose, all dispensed syringes should have equivalent volumes for 
consistency and ease of administration. 
Note:  If SGI-110 powder has not dissolved 60 minutes after completion of manually shaking or 
vortex, do not use the vial(s).  
Vortex: Sites that do not have access to a vortex may request it directly from Astex 
Pharmaceuticals, Inc. 
 
Contact:  Richard Morishige 
 
Phone: (925) 560-2882 
 
Email: Richard.Morishige@astx.com 
Storage:   
 Store SGI-110 lyophilized powder refrigerated between 20 and 80 C (360 and 460 F)   


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 Store 3 mL diluent between 20 and 300 C (360 F and 860 F) 
 Store 1.2 mL diluent between 20 and 80 C (360 and 460 F) 
If a storage temperature excursion is identified, promptly return SGI-110 vials and the diluents to 
the recommended storage temperatures above and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability:  Stability studies of SGI-110 intact vials are ongoing.   
x Upon reconstitution, the diluted drug solution is good for 8 days refrigerated at 2 to 8 C 
Route(s) of Administration: subcutaneous injection 
Method of Administration: Administer by slow subcutaneous injection.  Care must be taken to 
avoid intradermal injection. If injection site pain is reported upon injection, apply ice packs to the 
injection site both before and after injection for 5 – 10 minutes each; however, using icepack for the 
first dosing is not recommended. Pretreatment of topical or systemic analgesics can be considered. 
Potential Drug Interactions: Drug-drug interaction studies have not been conducted with 
guadecitabine or decitabine.  In vitro studies suggested that guadecitabine is unlikely to inhibit or 
induce major P450 enzymes and is not a CYPs substrate.  Furthermore, guadecitabine nor the active 
metabolite decitabine inhibit major human drug transporters. 
Special Handling: SGI-110 is a cytotoxic agent.  Use PPE when preparing the drug.  Direct contact 
of SGI-110 to skin must be washed immediately with soap and copious amount of water.  The drug 
degrades rapidly in soap water.  If SGI-110 contacts the mucous membranes, flush the affected area 
thoroughly with water. 
Drug spilling can be inactivated by either using a 2 N sodium hydroxide solution or water and 
kericide CR Biocide B which consists of a blend of stabilized chlorine dioxide and a quaternary 
ammonium compound 
15.1.1 Agent Ordering and Agent Accountability:   
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application   Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a “current” 
password.  For questions about drug orders, transfers, returns, or accountability, call or email 
PMB any time.  Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final disposition of all 
agents received from the PMB using the appropriate NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page.  Store and maintain separate 
NCI Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
Investigator Brochure Availability – The current versions of the IBs for the agents will be 
accessible to site investigators and research staff through the PMB Online Agent Order 


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Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP Identity 
and Access Management (IAM) account and the maintenance of an “active” account status and a 
“current” password.  Questions about IB access may be directed to the PMB IB coordinator via 
email. 
Useful Links and Contacts: 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/  
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
IB Coordinator: IBCoordinator@mail.nih.gov 
PMB email:  PMBAfterHours@mail.nih.gov 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
15.1.2 Incompatibilities   
Drug-drug interaction studies have not been conducted with SGI-110 or decitabine.  In vitro 
studies in human hepatocytes suggest that SGI-110 is unlikely to inhibit or induct cytochrome 
p450 enzymes.  Thus p450-mediated drug-drug interactions are not anticipated for SGI-110. 
 
 
 
 


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16 APPENDICES 
16.1 APPENDIX I-PERFORMANCE STATUS CRITERIA 
Patient C3D Study ID: _______________________________  Patient’s Age:___________ 
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. 
PERFORMANCE STATUS: 
ECOG Score: ________ 
 
OR 
 
Karnofsky Score: ________ 


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16.2 APPENDIX II: PERFORMANCE STATUS SCALES/SCORES IN PATIENTS ≤16 YEARS OF AGE 
Patient C3D Study ID: _______________________________  Patient’s Age:___________ 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
Karnofsky (> 16 years of age) 
Lansky (≤16 years of age) 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence 
of disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and less time 
spent in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the 
day; no active play, able to participate in 
all quiet play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet 
play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
PERFORMANCE STATUS: 
Karnofsky Score: ________ 
OR 
 
Lansky Score: ________ 
 


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16.3 APPENDIX III: QUALITY OF LIFE TOOLS 
16.3.1  Pediatric PROMIS Instruments English (6)  
 


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16.3.2 Pediatric PROMIS Instruments Spanish (6) 
 


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16.3.3 Parallel Parent Proxy PROMIS Instruments English (6) 
 


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16.3.4 Adult Patient PROMIS Instruments English (6) 
 
 


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16.3.5 Adult Patient PROMIS Instruments Spanish (6) 
 


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16.4 APPENDIX IV: THE DISTRESS AND SYMPTOM CHECKLIST: THE DISTRESS 
THERMOMETER  
 


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17 REFERENCES 
 
1. 
Boikos SA, Pappo AS, Killian JK, et al. Molecular Subtypes of KIT/PDGFRA Wild-
Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health 
Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2016. 
2. 
Kelly L, Bryan K, Kim SY, et al. Post-transcriptional dysregulation by miRNAs is 
implicated in the pathogenesis of gastrointestinal stromal tumor [GIST]. PLoS One 
2013;8:e64102. 
3. 
Favier J, Briere JJ, Strompf L, et al. Hereditary paraganglioma/pheochromocytoma and 
inherited succinate dehydrogenase deficiency. Horm Res 2005;63:171-9. 
4. 
Wei MH, Toure O, Glenn GM, et al. Novel mutations in FH and expansion of the 
spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell 
cancer. J Med Genet 2006;43:18-27. 
5. 
Schmidt LS, Linehan WM. Hereditary leiomyomatosis and renal cell carcinoma. Int J 
Nephrol Renovasc Dis 2014;7:253-60. 
6. 
Waterfall JJ, Killian JK, Meltzer PS. The role of mutation of metabolism-related genes in 
genomic hypermethylation. Biochem Biophys Res Commun 2014;455:16-23. 
7. 
Letouze E, Martinelli C, Loriot C, et al. SDH mutations establish a hypermethylator 
phenotype in paraganglioma. Cancer Cell 2013;23:739-52. 
8. 
Xiao M, Yang H, Xu W, et al. Inhibition of alpha-KG-dependent histone and DNA 
demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH 
tumor suppressors. Genes Dev 2012;26:1326-38. 
9. 
Reichardt P, Joensuu H, Blay JY. New fronts in the adjuvant treatment of GIST. Cancer 
Chemother Pharmacol 2013;72:715-23. 
10. 
Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in 
gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 
2011;108:314-8. 
11. 
Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit 
SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J 
Hum Genet 2001;69:49-54. 
12. 
Martucci VL, Pacak K. Pheochromocytoma and paraganglioma: diagnosis, genetics, 
management, and treatment. Curr Probl Cancer 2014;38:7-41. 
13. 
Kantorovich V, King KS, Pacak K. SDH-related pheochromocytoma and paraganglioma. 
Best Pract Res Clin Endocrinol Metab 2010;24:415-24. 
14. 
Schiavi F, Boedeker CC, Bausch B, et al. Predictors and prevalence of paraganglioma 
syndrome associated with mutations of the SDHC gene. JAMA 2005;294:2057-63. 
15. 
Richter S, Klink B, Nacke B, et al. Epigenetic Mutation of the Succinate Dehydrogenase 
C Promoter in a Patient With Two Paragangliomas. J Clin Endocrinol Metab 2016;101:359-63. 


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16. 
Haller F, Moskalev EA, Faucz FR, et al. Aberrant DNA hypermethylation of SDHC: a 
novel mechanism of tumor development in Carney triad. Endocr Relat Cancer 2014;21:567-77. 
17. 
Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: effective 
treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern 
Med 1988;109:267-73. 
18. 
Tanabe A, Naruse M, Nomura K, Tsuiki M, Tsumagari A, Ichihara A. Combination 
chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant 
pheochromocytoma and paraganglioma. Horm Cancer 2013;4:103-10. 
19. 
Niemeijer ND, Alblas G, van Hulsteijn LT, Dekkers OM, Corssmit EP. Chemotherapy 
with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and 
pheochromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf) 2014;81:642-
51. 
20. 
Fishbein L. Pheochromocytoma and Paraganglioma: Genetics, Diagnosis, and Treatment. 
Hematol Oncol Clin North Am 2016;30:135-50. 
21. 
Yoshinaga K, Oriuchi N, Wakabayashi H, et al. Effects and safety of (1)(3)(1)I-
metaiodobenzylguanidine (MIBG) radiotherapy in malignant neuroendocrine tumors: results 
from a multicenter observational registry. Endocr J 2014;61:1171-80. 
22. 
Menko FH, Maher ER, Schmidt LS, et al. Hereditary leiomyomatosis and renal cell 
cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam Cancer 2014;13:637-44. 
23. 
pharmaceuticals A. SGI-110 Investigator Brochure version number 5.0. 2014. 
24. 
Network DTNCC. http://www.nccn.org/about/news/newsinfo.asp?NewsID=47. 
25. 
Jacobsen PB, Donovan KA, Trask PC, et al. Screening for psychologic distress in 
ambulatory cancer patients. Cancer 2005;103:1494-502. 
26. 
Ransom S, Jacobsen PB, Booth-Jones M. Validation of the Distress Thermometer with 
bone marrow transplant patients. Psycho-oncology 2006;15:604-12. 
27. 
Zwahlen D, Hagenbuch N, Carley MI, Recklitis CJ, Buchi S. Screening cancer patients' 
families with the distress thermometer (DT): a validation study. Psycho-oncology 2008;17:959-
66. 
28. 
Patel SK, Mullins W, Turk A, Dekel N, Kinjo C, Sato JK. Distress screening, rater 
agreement, and services in pediatric oncology. Psycho-oncology 2011;20:1324-33. 
29. 
Wiener L ZS, Battles H, Pao M. . Can an Adapted Distress Thermometer in the Pediatric 
Population be Valid and Clinically Meaningful? Psycho-oncology 2012;21. 
30. 
Cella D, Gershon R, Lai JS, Choi S. The future of outcomes measurement: item banking, 
tailored short-forms, and computerized adaptive assessment. Quality of life research : an 
international journal of quality of life aspects of treatment, care and rehabilitation 2007;16 Suppl 
1:133-41. 
31. 
Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement 
Information System (PROMIS) developed and tested its first wave of adult self-reported health 
outcome item banks: 2005-2008. Journal of clinical epidemiology 2010;63:1179-94. 


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32. 
Varni JW, Stucky BD, Thissen D, et al. PROMIS Pediatric Pain Interference Scale: an 
item response theory analysis of the pediatric pain item bank. The journal of pain : official 
journal of the American Pain Society 2010;11:1109-19. 
33. 
Miettinen M, Killian JK, Wang ZF, et al. Immunohistochemical loss of succinate 
dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA 
germline mutation. Am J Surg Pathol 2013;37:234-40. 
34. 
Lai JP, Robbins PF, Raffeld M, et al. NY-ESO-1 expression in synovial sarcoma and 
other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential 
diagnosis. Mod Pathol 2012;25:854-8. 
35. 
Saxena N, Maio N, Crooks DR, et al. SDHB-Deficient Cancers: The Role of Mutations 
That Impair Iron Sulfur Cluster Delivery. J Natl Cancer Inst 2015;108. 
36. 
Aspuria PJ, Lunt SY, Varemo L, et al. Succinate dehydrogenase inhibition leads to 
epithelial-mesenchymal transition and reprogrammed carbon metabolism. Cancer Metab 
2014;2:21. 
37. 
Lombardi G, Corona G, Bellu L, et al. Diagnostic value of plasma and urinary 2-
hydroxyglutarate to identify patients with isocitrate dehydrogenase-mutated glioma. Oncologist 
2015;20:562-7. 
38. 
Liesenfeld DB, Botma A, Habermann N, et al. Aspirin Reduces Plasma Concentrations of 
the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover 
Trial. Cancer Epidemiol Biomarkers Prev 2016;25:180-7. 
39. 
Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP. A simple method for 
estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic 
Acids Res 2004;32:e38. 
40. 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 
1989;10:1-10. 
 

ICF_003.pdf: 
MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
INSTITUTE:
National Cancer Institute
STUDY NUMBER:
17-C-0088
PRINCIPAL INVESTIGATOR:
John Glod, M.D., Ph.D.
STUDY TITLE: 
A Phase II Trial of the DNA Methyl Transferase Inhibitor, SGI-110 (Guadecitabine), 
in Children and Adults Wild Type GIST, Pheochromocytoma and Paraganglioma 
Associated with Succinate Dehydrogenase Deficiency and HLRCC-Associated Kidney 
Cancer
Continuing Review Approved by the IRB on 02/11/19
Amendment Approved by the IRB on 11/5/19 (B)
Date posted to web: 11/14/19
Standard
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent (1)
INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH).
First, we want you to know that:
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation.
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future.
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study.
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.  


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 2 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
If you are signing for a minor child, “you” refers to “your child” throughout the consent 
document.
What is the usual approach to my diagnosis?
You are being asked to participate in this study because you have one of the following 3 
disorders:

Wild-type gastrointestinal stromal tumor (GIST) (this means there is no mutation in KIT 
or PDGFRA);

Pheochromocytoma and paraganglioma (PHEO/PGL); or 

Kidney cancer related to a disorder called hereditary leiomyomatosis and renal cell 
carcinoma (HLRCC).
GIST is a type of cancer that occurs in the gastrointestinal tract (esophagus, stomach or 
intestines) which does not respond well to standard chemotherapy or radiation therapy.  A 
targeted therapy used to treat most patients with GIST is called imatinib (Gleevec®), but in 
many children with GIST, imatinib may not work.  This may be because children with this type 
of cancer do not have the same permanent alteration in their genes (mutation in KIT or 
PDGFRA) that is often seen in adults with the same cancer. Most GIST in pediatric patients have 
a deficiency in an enzyme called succinate dehydrogenase or SDH.  
This SDH deficiency is also seen in some patients (about 10-30%) with PHEO/PGL.  The only 
treatment to cure PHEO/PGL is surgery, although both chemotherapy and radiation therapy are 
used to treat patients with PHEO/PGL.  
Kidney cancer in patients with HLRCC is often treated with surgery.  If the cancer has 
metastasized outside of the kidney, the most common treatment is chemotherapy.  Many patients 
with HLRCC have mutations in a different enzyme called FH (fumarate hydratase).
SGI-110 is a small molecule that is derived from decitabine that acts as a DNA methyltransferase 
(DNMT) inhibitor.  Its specific properties appear to work in laboratory tests in disorders that 
have the types of enzyme deficiencies seen in GIST, PHEO/PGL or HLRCC. 
What are my other choices if I do not take part in this study?
You will only be eligible for this trial if the other known treatments for your disorder, such as 
surgery, radiation therapy or chemotherapy, have not proven effective treatments for you.  
Alternatives to this experimental regimen may include partial surgical removal of your tumor, 
other experimental therapies, or chemotherapies you have not yet tried, or you may decide not to 
receive any treatment directed at shrinking your tumor(s) at this point in time.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 3 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Please talk to your doctor about these and other options.
Why is this study being done? 
The purposes of this research study are:
1. To assess if SGI-110 is helpful in the treatment of your type of tumor(s) (causes your 
tumor to shrink or slow down the growth).
2. To study how SGI-110 acts in the body (pharmacokinetics, also known as PK) in children 
and adults.
3. To study the DNA methylation (the process that cells use to control gene expression) and 
gene expression in your tumor (the genetic instructions the tumor uses to create proteins) 
in response to treatment with SGI-110.
Studies in animals and other types of cancer have shown that SGI-110 can shrink tumors in some 
types of cancer.  There are several clinical studies using SGI-110 including studies in patients 
with leukemia, liver cancer, ovarian cancer, melanoma, colorectal cancer and myelodysplastic 
syndrome (this refers to a group of bone marrow disorders in which the bone marrow does not 
make enough healthy blood cells). Many of these studies are ongoing.
Up to 70 patients may take part in this study.
What are the study groups?
All study participants will get the same study intervention. There will be three groups of study 
participants based on your tumor type: 

Wild-type gastrointestinal stromal tumor (GIST);

Pheochromocytoma and paraganglioma (PHEO/PGL); or 

Kidney cancer in patients with a disorder called hereditary leiomyomatosis and renal cell 
carcinoma (HLRCC).
You will come to the NIH and be given an injection of SGI-110 under the skin (subcutaneously), 
usually in your abdomen, every day for 5 days.  This will be repeated every 28 days.    
We will help treat any symptoms that you may have as a result of the study medication.  Some 
helpful hints include:

We will inject the study medication slowly (up to one minute) to minimize any 
discomfort.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 4 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent

We will apply ice to the skin where we plan to inject the medication before and after the 
injection.  

If you still have pain, tell your study team and they may give you something to reduce the 
discomfort.
If you experience side effects that are too distressing, the dose of the SGI-110 can be reduced.  
How long will I be in this study?
You will have the injections every day for 5 days, which will be repeated every 28 days as long 
as you do not have unacceptable side effects or your tumor(s) do not get worse.  If you have side 
effects the dose of SGI-110 may be held for a short time and the dose may be reduced to prevent 
return of the side effect.  Two dose reductions are allowed on this study.  If the side effect(s) is 
too severe, or side effect(s) recur after two dose reductions, SGI-110 may need to be stopped.
What extra tests and procedures will I have if I take part in this study?
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer, such as physical examination, laboratory testing and scans and x-rays. However, there 
are some extra tests and procedures that you will need to have if you take part in this study. You 
will not be billed for any extra tests or procedures.
Before you begin the study
You will need to have the following extra tests to find out if you can be in the study:

Pregnancy test (if you are a woman who could have children)

CT Scan, MRI scan and/or FDG-PET scan of your tumor(s).
During the study

Questionnaires to evaluate the effects of SGI-110 on your pain and quality of life at 
baseline and then at the end of cycle 4, and then every 4 cycles thereafter, and at the time 
you stop SGI-110 treatment.  Everyone will be asked to complete a quality of life and 
pain evaluation.

Biopsy of your tumor (take a small piece of your tumor tissue using a large needle) if you 
are 18 years of age and older and a have a tumor that can be safety biopsied (this tumor 
biopsy is optional).  We will ask you to allow us to do one biopsy your tumor at some 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 5 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
point during the treatment with SGI-110.  This tissue will be studied for the effects of 
SGI-110 on your tumor DNA and if your tumor has a protein called NY-ESO-1 or not.

Blood samples for special research tests (mandatory):
o
Pharmacokinetics (called PK studies), to see how much SGI-110 is in your blood.   
About 3 mL of blood (~1/2 teaspoon) will be collected before your first dose of SGI-
110 and then after the first dose at ½ hr, 1, 2, 4, 6, and 24 hours after the first dose.
o
Pharmacodynamics (called PD studies) to study the effects of SGI-110:

A urine sample will be taken to study the metabolites in the urine.  We will ask 
for a urine sample before your first dose, and on days 7, 14 and 28 of cycle 1. 

Blood samples will be taken at the same time as the urine samples to study the 
metabolites in the blood (3 mL of blood or ~1/2 teaspoon), before your first dose, 
and on days 7, 14 and 28 of cycle 1.

Blood samples (3 mL of blood or ~1/2 teaspoon) will be taken to study the 
demethylation activity in response to SGI-110 before the first dose and one 
additional time while you are receiving SGI-110.  
The total volume of blood obtained for the research studies outlined above (PD and PK) 
will be about 40 mL [8 teaspoons] over 1 month. Your doctor will discuss these tests in 
detail with you and make sure that all blood draws combined do not exceed a safe 
volume. 
For specific research tests, your tissue and blood will be sent to other laboratories in the 
NIH for testing.  Your name will not be attached to your tissue or blood; it will be 
identified using a study number.  Only the investigator and research team will have 
access to the information that links your personal information to your tissue and blood 
samples.
When you are finished taking the drugs (treatment)
At the end of treatment with SGI-110 you will have an evaluation at the NIH which will include 
a final evaluation of your pain and quality of life.


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 6 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
A study calendar that shows how often these tests and procedures will be done is attached.
What possible risks can I expect from taking part in this study?
If you choose to take part in this study, there is a risk that the SGI-110 (guadecitabine) may not 
be as good as the usual approach for your cancer or condition at shrinking or stabilizing your 
cancer.
You also may have the following discomforts:

Spend more time in the hospital or doctor’s office. 

Be asked sensitive or private questions about things you normally do not discuss.

May not be able to take part in future studies. 
The SGI-110 (guadecitabine) used in this study may affect how different parts of your body 
work such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood 
and will let you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug/ study approach.
Here are important points things to know about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may make it hard for you to have children.

Some side effects may be mild. Other side effects may be very serious and even result in 
death.
You can ask your study doctor questions about side effects at any time. Here are important ways 
to make side effects less of a problem:

If you notice or feel anything different, tell your study doctor. He or she can see if it is a 
side effect.

Your study doctor will work with you to treat your side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects doctors know about. 
Keep in mind that there might be other side effects doctors do not yet know about. If important 
new side effects are found, the study doctor will discuss these with you.
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving SGI-110 (guadecitabine), more than 20 and up to 100 may have
Tiredness


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 7 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
Swelling and redness at the site of the medication injection
Bruising, bleeding
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving SGI-110 (guadecitabine), from 4 to 20 may have:        
Anemia which may require blood transfusion 
Infection, especially when white blood cell count is low
Constipation, diarrhea, nausea, vomiting
Sores in the mouth which may cause difficulty swallowing
Fever
Pain
Loss of appetite
Dizziness, headache
Difficulty sleeping
Shortness of breath
Nose bleed 
Rash
RARE, AND SERIOUS
In 100 people receiving SGI-110 (guadecitabine), 3 or fewer may have:

Swelling of the eye

Swelling of the face

Kidney damage which may require dialysis
You may experience diarrhea with this treatment and should record the number of stools and 
associated symptoms.  If you develop diarrhea you should inform the study doctor. You may 
take a dose of loperamide after the first episode of unformed, loose stool. After discussion with 
the study doctor, loperamide can be continued until you are diarrhea-free for at least 12 hours.  
You should contact the study doctor or study nurse if you develop persistent diarrhea, diarrhea 
complicated by vomiting or fever, abdominal pain, or inability to take oral liquids.
Reproductive Risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important you understand that you need to use birth control while on 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 8 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
this study.  Both male and female participants must use effective birth control measures while 
participating in this study and for at least six months after the last dose of study drug.  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.  Optional birth control 
methods include, but are not limited to, abstinence, oral birth control pills, an IUD, or condoms 
with spermicide.  If you are a woman and become pregnant or suspect you are pregnant while 
participating in this study, please inform your treating physician immediately.  A patient who 
becomes pregnant while on study drug will immediately be taken off study.
Questionnaires:  You will be asked to complete 2 questionnaires that take 7-12 minutes each to 
complete.  Completion of the questionnaires may become uncomfortable for some participants, 
either due to boredom or due to the personal nature of the questions.  Tell the health care provider 
if you are uncomfortable and do not wish to complete a questionnaire. 
What possible benefits can I expect from taking part in this study?
SGI-110 may cause your tumor(s) to stop growing or shrink or it may lessen the symptoms, such 
as pain, that are caused by the tumor.  However, because there is not much information about the 
drug’s effect on your type of tumor, we do not know if you will benefit from taking part in this 
study, although the knowledge gained from this study may benefit others.  Your samples may be 
helpful to research. The researchers, using the samples from you and others, might make 
discoveries that could help people in the future.
Can I stop taking part in this study?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization helping the investigator run the study.
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study.
The study doctor may take you out of the study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study rules

If the study is stopped by the sponsor, IRB (the Institutional Review Board) or FDA (U.S. 
Food and Drug Administration).  The sponsor is the company or organization, in this 
study it is Cancer Therapy Evaluation Program or CTEP, that is responsible for 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 9 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
overseeing the study.  CTEP works with the drug company making SGI-110 and makes it 
available for this study.
What are my rights?
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights.
What are the costs of taking part in this study? 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH.
What happens if I am injured or hurt because I took part in this study?
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. Please see Other Pertinent Information on page 14 of 15, item 2 
for more information.
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study.
Who will see my medical information?
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 10 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
researchers will do their best to make sure that any information that is released will not identify 
you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database.
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are:

The study sponsor and any drug company supporting the study.

The IRB is a group of people who review the research with the goal of protecting the 
people who take part in the study.

The FDA and the National Cancer Institute in the U.S.
Your individual genomic data and health information will be put in a controlled-access database.  
This means that only researchers who apply for and get permission to use the information for a 
specific research project will be able to access the information.  Your genomic data and health 
information will not be labeled with your name or other information that could be used to 
identify you.  Researchers approved to access information in the database have agreed not to 
attempt to identify you.
Where can I get more information?
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237).
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time.
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH.
Additional Studies Section
Tumor Biopsy (optional)


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 11 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
If you are 18 years of age or older and have a tumor that can be safely biopsied with a needle, we 
will ask that you undergo a biopsy after receiving SGI-110.  This biopsy is optional.
What is involved?
A doctor will use a hollow needle attached to a syringe to enter a tumor, then withdraw (aspirate) 
a small amount of tissue from the tumor.  The doctor may use a scan or ultrasound to guide the 
needle directly to the tumor.  Depending upon the location of the tumor, the doctor may use 
numbing medicine (called local anesthetic) to numb the area before the biopsy.  
What are the possible risks?
Biopsies are very common procedures that have few risks.  The risks will be explained to you 
fully in a different consent.  In general, the risks include bleeding, pain, scarring and infection.  If 
there is bleeding under the skin, a hematoma or collection of blood at the biopsy site may occur. 
Other risks depend on the location of the tumor being sampled.  The doctor will discuss these 
specific risks with you before the procedure.  We have successfully performed hundreds of 
tumor biopsies in the POB without major complications or side effects. 
How will information about me be kept private?
Your tumor samples will be identified and stored using a number and not your name.  Only the 
study investigator and research team taking care of you on this study will have access to your 
name. 
What are the possible benefits?
The use of your biopsy specimens will be for research purposes only and will not benefit you.  
Results of research done on your tumor specimens will not be available to you or your doctor, 
but it will help us better understand how this study drug works on tumors, and it might help 
people who have these types of tumors in the future.
Are there any costs or payments? 
There are no costs to you.  You will not be paid for your tissue.  The cost of storage and testing 
will be paid by the study investigators or collaborators in this study.
What if I change my mind?
If you decide now that you will undergo the biopsy, you can change your mind at any time. Just 
let us know at the time of the biopsy or contact us (office of Dr. Glod, Principal Investigator: 
240-760-6194) and let us know that you do not want to have the biopsy. 


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 12 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
What if I have more questions?
If you have additional questions, please contact the office of Dr. Glod, Principal Investigator: 
240-760-6194.
Use of Specimens and Data for Future Research
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
Study Calendar
Test/Procedure
Pre-
treatm
ent
During Cycle 
1 (28 days)
During Cycles 2 through 
end of treatment
Completion/ 
Stopping 
treatment
Medical history, 
Physical exam, vital 
signs 
X
Before starting 
cycle 1
At the beginning of each 
cycle
Standard blood tests
X
Before starting 
cycle 1
At the beginning of each 
cycle
SGI-110 injection 
under the skin 
(subcutaneously), once 
Day 1 through 
Day 5
Day 1 through Day 5


MEDICAL RECORD
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study
STUDY NUMBER: 17-C-0088
CONTINUATION: page 13 of 15 pages
PATIENT IDENTIFICATION
CONTINUATION SHEET for either:
NIH-2514-1 (07-09)
NIH-2514-2 (10-84)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
a day for 5 days; record 
in the diary
Blood & urine samples 
for special research 
tests
On days 1, 7, 
14 and 28 of 
cycle 1
Tumor biopsy (optional 
if you are 18 years of 
age or older)
During treatment
Pregnancy test (in 
women who can get 
pregnant)
X
At the beginning of each 
cycle
Tumor evaluations may 
include CT scan, FDG 
PET scan and/or MRI
X
Prior to cycle 2, 4, 6, 8, 10, 
12, etc.
Quality of life and 
distress thermometer
X
At the end of cycle 4, and 
then after every 4 cycles (i.e. 
end of cycle 8, 12, 16, etc)
X


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
STUDY NUMBER: 17-C-0088
CONTINUATION: page 14 of 15 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
OTHER PERTINENT INFORMATION
1.
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance.
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations.
2.
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action.
3.
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines.
4.
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, John Glod, M.D., PhD., Building 10, Room 1-3940, Telephone:  240-760-
6194. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have 
any questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5.
Consent Document.  Please keep a copy of this document in case you want to read it 
again.


MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•Parent, for Minor Patient
STUDY NUMBER: 17-C-0088
CONTINUATION: page 15 of 15 pages
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet)
•
Adult Patient or
•Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent
COMPLETE APPROPRIATE ITEM(S) BELOW:
A. Adult Patient’s Consent
B. Parent’s Permission for Minor Patient.
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby 
consent to take part in this study.
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.  
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.)
Signature of Adult Patient/
Legal Representative
Date
Signature of Parent(s)/ 
Guardian
Date
Print Name
Print Name
C. Child’s Verbal Assent (If Applicable)
The information in the above consent was described to my child and my child agrees to 
participate in the study.
Signature of Parent(s)/Guardian
Date
Print Name
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE 
FROM FEBRUARY 11, 2019 THROUGH FEBRUARY 25, 2020. 
Signature of Investigator
Date
Signature of Witness
Date
Print Name
Print Name

ICF_004.pdf: 
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY
   MEDICAL RECORD
 •  Attach to NIH-2514-2, Consent to Participate in a Clinical Research Study
INSTITUTE:
 National Cancer Institute
STUDY NUMBER:
17-C-0088
PRINCIPAL INVESTIGATOR: John Glod, M.D., Ph.D
STUDY TITLE:
A Phase II Trial of the DNA Methyl Transferase inhibitor, SGI-110 (Guadecitabine), in 
Children and Adults Wild Type GIST, Pheochromocytoma and Paraganglioma 
Associated with Succinate Dehydrogenase Deficiency and HLRCC-Associated Kidney 
Cancer
Continuing Review Approved by the IRB on 02/11/19
Amendment Approved by the IRB on 11/5/19 (B)
Date Posted to Web: 11/14/19
Assent
PATIENT IDENTIFICATION
MINOR PATIENT'S ASSENT TO PARTICIPATE IN A CLINICAL
RESEARCH STUDY
NIH-2514-2 (10-09)
P.A.: 09-25-0099
File in Section 4:  Protocol Consent (2)
We would like to invite you to take part in a research study at the National Institutes of Health 
(NIH). Before you decide about taking part in the study, we want you to know why we are doing 
the study and if it will help you. We also want you to know about any risks (what might go 
wrong) and what you will have to do.  You can only be in the study if you and your parent(s) 
agree.
This form gives you information about the study. Your doctor will talk to you about the study 
and answer questions you have.  If you would like to take part in this study, we will ask you to 
sign this form to show that you understand this study.  We will give you a copy of this form to 
keep.  It is important that you know:

You do not have to join the study.

You may change your mind and drop out of the study at any time.
If we make important changes to the study we will tell you about it and make sure you still want 
to be in the study.
Why is this study being done? 
You are being asked to take part in this study because you have one of the following 3 disorders:

Gastrointestinal stromal tumor (GIST) that does not have certain mutations;

Pheochromocyteoma and paraganglioma or 

Kidney cancer related to a disorder called hereditary leiomyomatosis and renal cell 
carcinoma. 
You will only be eligible for this trial if the other known treatments for your disorder, such as 
surgery, radiation therapy or chemotherapy, have not worked for you.


 CONTINUATION SHEET for either:
  MEDICAL RECORDNIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 17-C-0088
CONTINUATION:  page 1  of 4  pages
PATIENT IDENTIFICATIONMINOR PATIENT'S ASSENT TO PARTICIPATE IN A
CLINICAL RESEARCH STUDY
NIH-2514-2 (10-09)
P.A.: 09-25-0099
File in Section 4:  Protocol Consent
The purpose of this study is to learn if SGI-110, an experimental drug, causes your tumor to 
shrink or grow less quickly and to study how SGI-110 acts in the body (pharmacokinetics, also 
known as PK). 
What will I be asked to do? What are my requirements?
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer, such as physical examination, laboratory testing and scans and x-rays. However, there 
are some extra tests. 
Before you begin the Study
You will have these extra tests to find out if you are eligible to participate in the study:

Tests to make sure you are not pregnant (if you are a female and old enough to become 
pregnant)

CT or MRI Scan of your tumors
During the Study
Treatment on this study will require you to come to clinic each day for 5 days in a row. You will 
receive an injection under your skin, usually in the belly of the study drug SGI-110. This will 
occur every 28 days (called a cycle) for as long as you tolerate the drug and if it is effective.
Medical Tests During Treatment
Whether you are on this study or not the following medical tests will be done to monitor for 
response to treatment as well as side effects related to treatment. These include:

Physical exam including checking your blood pressure, pulse, breathing, height and 
weight
o
Blood tests to check how well your organs are working and to make sure you are 
not pregnant if you are a female old enough to become pregnant 

Tumor evaluation that may include a CT or MRI scan
You will have regular medical appointments throughout treatment.
Tests for research purposes
In addition to the routine tests listed above, we would like to do other tests while you are 
enrolled on the study. 
Questionnaires 
These will be used to find out how, if at all, SGI-110 affects your pain and quality of life. You 
will complete two questionnaires that take about 10 minutes each to complete before you have 
taken any SGI-110 and then at the end of cycle 4, and then every 4 cycles thereafter, and at the 
time you stop SGI-110 treatment. T 


 CONTINUATION SHEET for either:
  MEDICAL RECORDNIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 17-C-0088
CONTINUATION:  page 2  of 4  pages
PATIENT IDENTIFICATIONMINOR PATIENT'S ASSENT TO PARTICIPATE IN A
CLINICAL RESEARCH STUDY
NIH-2514-2 (10-09)
P.A.: 09-25-0099
File in Section 4:  Protocol Consent
SGI-110 Drug Levels (Pharmacokinetics)
About a 1/2 teaspoon will be collected before your first dose of SGI-110 and then after the first 
dose at ½ hour, 1, 2, 4, 6, and 24 hours after the first dose. Any leftover blood that is not used for 
this test will be destroyed. 
Pharmacodynamics (called PD studies) to study the effects of SGI-110

We will ask for a urine sample and for about a ½ teaspoon of blood.
Final Study Visit
At the end of treatment with SGI-110 you will have an evaluation at the NIH which will include 
a final evaluation of your pain and quality of life.
What bad effects can happen by being in the study?
This study drug may make you sick. You may feel tired, have swelling and redness at the site 
where the drug is injected, and you may bruise or bleed. 
This drug can also lower the number of your red blood cells, which carry oxygen to your body. 
When your red blood cells are low, you may feel tired or have a headache or feel dizzy. 
You may experience diarrhea with this drug and should record the number of stools and 
associated symptoms.  If you develop diarrhea you should inform the study doctor. The study 
doctor may give you a dose of medicine after the first time you have an unformed, loose stool. 
The doctor may decide to continue this medicine until you have not had diarrhea for at least half 
a day. If your diarrhea gets worse or if you start to vomit, have a fever, your belly hurts or you 
have nausea and can’t keep liquids down you should call the study doctor or the study nurse.
In rare cases, you may have swelling of the eye or face. You may also have kidney damage and 
when the kidneys do not work properly, wastes can build up in your blood. This could become 
severe, requiring dialysis to clean the wastes out of your blood.
This study drug may be harmful to an unborn child.  Birth control measures should be used by all 
girls in this study who can become pregnant and are sexually active.  Sexually active boys in this 
study should also use birth control measures to prevent their partners from becoming pregnant. 
These birth control measures can include not having sex, contraceptive pills, or use of condom 
and spermicide cream. 
We will let you know about any new findings during the study, which may change your 
willingness to continue to participate in the study.


 CONTINUATION SHEET for either:
  MEDICAL RECORDNIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 17-C-0088
CONTINUATION:  page 3  of 4  pages
PATIENT IDENTIFICATIONMINOR PATIENT'S ASSENT TO PARTICIPATE IN A
CLINICAL RESEARCH STUDY
NIH-2514-2 (10-09)
P.A.: 09-25-0099
File in Section 4:  Protocol Consent
What benefit can I expect?
The study drug that you will receive could make your tumor(s) shrink or stop growing for a 
period of time. However, we do not know how likely it is that your tumor(s) will shrink or stop 
growing for a period of time or that you will benefit from this treatment. Information from this 
study will help us find out if this treatment will help patients with y.
Can I refuse to be in the study?
Participation in this study is purely voluntary.  We will discuss with you and your 
parents/guardian about the various options for therapy if you do not want to be in this research 
study. Each alternative therapy has a unique set of benefits and risks and your doctor will discuss 
these options with you.
You will not be paid for any part of your participation in this study. Participating in this study 
will not cost you or your parents any money.
We will keep the records of this study confidential. Only people working on the study at your 
site will know your name. Your name will not appear on the study forms.  Instead, you will be 
assigned a patient identification number.
You may stop being in this any time 
Remember, being in this study is up to you and no one will be upset if you don’t want to take 
part in this study or even if you change your mind later and want to stop.
Re-consenting 
Once you have turned 18, we will contact you to find out if you would still like to participate in 
the study.
You can ask any questions that you have about the study.  
If you have a question later that you didn’t think of now, you can call me at 240-760-6194 or ask 
me next time you see me. You may call me at any time to ask questions about your disease and 
treatment.
Putting your name at the bottom means that you have decided to be in this study.  You and 
your parents will be given a copy of this form after you have signed it.  


 CONTINUATION SHEET for either:
  MEDICAL RECORDNIH 2514-1, Consent to Participate in A Clinical Research Study
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study
STUDY NUMBER: 17-C-0088
CONTINUATION:  page 4  of 4  pages
PATIENT IDENTIFICATIONMINOR PATIENT'S ASSENT TO PARTICIPATE IN A
CLINICAL RESEARCH STUDY
NIH-2514-2 (10-09)
P.A.: 09-25-0099
File in Section 4:  Protocol Consent
I have had this study explained to me in a way that I understand, and I have had the chance to ask 
questions.  I agree to take part in this study.
Signature of Minor Patient:
Date:
Print Name:
Signature of Investigator:
Date:
Print Name: