Clinical trial NCT03075826
Conditions: Myeloproliferative Neoplasms
Sponsor: Weill Medical College of Cornell University
Start date: 2016-03-15; Completion date: 2021-03-31
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
* This is an open label single-arm, single-institution stud to evaluate the efficacy and safety of SGI-110 in Philadelphia chromosome negative (Ph-) Myeloproliferative Neoplasms (MPN) (excluding PV, ET and primary/secondary myelofibrosis). The study will enroll approximately 50 patients at the Weill Cornell Medical College.
* Enrollment onto this clinical study is expected to be completed in approximately 36 months. The total study duration will depend on individual response, evidence of disease progression and tolerance. Participants will be followed monthly for six months after removal from study or until death, whichever occurs first.

Key eligibility:

* Confirmed diagnosis of Ph- MPN and had
* No chemotherapy or radiation treatment within 2 weeks prior to study entry.
* Subjects meet other protocol-defined criteria related to baseline screening procedures.

Detailed description:
The active metabolite of SGI-110 (2'-deoxy-5-azacytidylyl-(3'→5')-2'-deoxyguanosine sodium salt), a dinucleotide, is decitabine, an FDA-approved agent for the treatment of myelodysplastic syndromes. SGI-110 is resistant to modification by cytidine deaminase, a common pathway of decitabine metabolism and deactivation\[1\]. The molecular weight of SGI-110 and decitabine are 580 Da and 228 Da, respectively. Therefore, the molar equivalent dose of 1 mg of decitabine is approximately 2.5 mg of SGI-110. SGI-110's activity was demonstrated with the same preclinical pharmacodynamic assays used to demonstrate decitabine's efficacy e.g., re-expression of p15, p16, and MLH1 and induction of fetal hemoglobin, in vivo. In xenograft studies, SGI-110 demonstrates promising preclinical activity in both hematologic and solid tumors.

In vitro evidence suggests that SGI-110 has a longer half-life than decitabine in the presence of cytidine deaminase. These promising observations suggest that SGI-110 may have improved pharmaceutical properties and biological activities that could extend decitabine's current clinical utility. SGI-110 has shown to be better tolerated in mice than decitabine and is as effective in vivo in inducing p16 expression, reducing DNA methylation at the p16 promoter region, and retarding EJ6 human bladder cancer tumor growth in athymic mice\[2\].

SGI-110 has been developed for subcutaneous administration. SGI-110 is pharmacologically active both in vitro and in vivo in a variety of tumor cells and murine xenograft models when administered subcutaneously. Treatment is well tolerated via the subcutaneous route in murine xenografts. When administered subcutaneously to non-human primates, SGI-110 releases decitabine slowly compared to other species, possibly prolonging the effect over longer periods. SGI-110 has been developed as a non-aqueous formulation to ensure formulation stability.

SGI-110 has been studied in a first-in-human, single-agent study (SGI-110-01).5 This study was a Phase 1/2, dose escalation, multicenter study of two subcutaneous regimens of SGI-110 in subjects with intermediate or high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). This study had two parts, a Dose Escalation Segment and a Dose Expansion Segment. The study evaluated the biological activity, preliminary safety, and efficacy of SGI-110 with two dosing schedules in intermediate to high risk MDS or relapsed or refractory AML subjects, while the Dose Expansion Segment further evaluated safety and efficacy at the recommended dose. The study was based on a 3 + 3 design within each regimen. Eligible subjects were randomized to receive 1 of 2 dosing regimens of SGI-110 with the following starting doses: Regimen 1: 3 mg/m2/day subcutaneously on Days 1-5 of a 28-day course, Regimen 2: 6 mg/m2 subcutaneously Weekly x 3 on Days 1, 8, 15 of a 28-day course. The minimum dose achieving maximal biological activity or biologically effective dose (BED) for the daily regimen was reached at 60 mg/m2 daily on Days 1-5.

Study disease: MPN

Philadelphia chromosome negative Myeloproliferative Neoplasms (PHN-MPN) comprise a group of myeloid neoplasms with varying clinical, morphologic and laboratory features and a wide range of survival. According to 2008 World Health Organization (WHO) classification, the MDS/MPN overlap syndromes include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia(JMML) and myelodysplastic/myeloproliferative neoplasm unclassifiable (MDS/MPN-U). In a recent retrospective study from MD Anderson Cancer Center, the median survival of patients with a diagnosis of MDS/MPN unclassifiable was 12.4 months\[3\] .There is no effective therapy for PHN-MPN and this represents an unmet medical need.

The MDS/MPN overlap syndromes can present with a wide range of hematological and clinical manifestations and individual patients may exhibit a combination of features characteristic of both MDS and MPN. For example, while transfusion-dependent anemia is generally present, other hematological laboratory abnormalities can range from leukopenia to leukocytosis and from thrombocytopenia to thrombocytosis. Unlike with MDS, significant splenomegaly is often present in patients with PHN-MPN. Also, patients may have a constellation of constitutional findings, including fatigue, weight loss, anorexia, night sweats and other unpleasant symptoms that lead generally to poor quality of life. Thus, while improving overall survival is a critical goal of therapy, effective therapy for this group of patients will include also agents that can be demonstrated to improve as many of the disease-related clinical issues as possible.

Overall Study Design

This is a single arm, open-label study of SGI-110 in patients with MPN. SGI-110 will be administered subcutaneously at a dose of 60 mg/m2 on days 1-5, repeated every 28 days. Toxicity will be evaluated using the NCI Common Terminology Criteria for Adverse Events Active Version 4. The frequency of toxicities per organ system will be tabulated using descriptive statistics. All patients who receive any amount of the study drug will be evaluable for toxicity.

Screening and pre-treatment criteria Screening Procedures Screening procedures and tests will be performed within 14 days before treatment administration with the exception of informed consent, bone marrow biopsy which may be performed within 28 days of the first dose of study drug.

* Provision of written informed consent. The ICF must be signed and dated by the subjects before collection of any samples or performance of any study-specific evaluations.
* Complete medical history, including demographics (date of birth, sex, race). A disease history, including the date of initial diagnosis and list of prior treatments and responses to these treatments, also will be recorded. Concurrent medical signs and symptoms must be documented to establish baseline conditions.
* Record concomitant medications.
* Record all study-procedure related AEs from the time of informed consent and then treatment-emergent AEs after the start of study drug administration (Course 1, Day 1) through 30 days after the last dose of study drug.
* Investigator's confirmation of eligibility. Perform all necessary procedures and evaluations to document that the subject meets each eligibility criterion.
* Complete physical exam including weight and examination
* Vital signs include resting systolic/diastolic blood pressure, resting heart rate, resting respiration rate, body temperature and pulse oximetry. Assess after the subject has rested in the sitting position for at least three minutes.
* ECOG performance status.
* 12-lead ECG (rhythm, atrial rate, ventricular rate, PR interval, QRS duration, and QT/QTc (QtcF), morphology and overall interpretation).
* Height.
* Sample collection for clinical laboratory tests (hematology, chemistry and urinalysis).
* Serum or urine pregnancy test: for female subjects of child-bearing potential only. Results must be negative for the subject to be eligible for enrollment into the study.

Agent Administration

• SGI-110 administered at dose level of 60 mg/m2 SC daily on Days 1-5 of a 28-day cycle. However, treatment delays are allowed per section 6.3.1 SGI-110 is administered by SC injection preferably in the abdominal area. The total amount (in mg) of SGI-110 to be administered will be determined based on the body surface area (BSA). In calculating the BSA, actual heights and weights should be used. There will be no adjustments to "ideal" body weight. The institutional standard for calculating BSA is acceptable. Dose adjustment should be made for a +/- 10% weight change at the beginning of each cycle The site(s) of SGI-110 SC injections will be captured on the dosing CRF. Investigators are prohibited from supplying SGI-110 to any subjects not properly enrolled in this study or to any physicians or scientists except those designated as sub-investigators on Food and Drug Administration (FDA) Form 1572. The investigator must ensure that subjects receive SGI-110 only from personnel who fully understand the procedures for administering the study treatment.

Duration of Therapy

Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In the absence of treatment delays due to adverse events, treatment may continue until one of the following criteria applies:

* Disease progression to acute leukemia unless, in the opinion of the principal investigator, the subject is experiencing clinical benefit from SGI-110 despite laboratory evidence of progression to acute leukemia.
* Intercurrent illness that prevents further administration of treatment,
* Unacceptable adverse event(s)
* Participant demonstrates an inability or unwillingness to comply with the medication regimen and/or documentation requirements
* Participant decides to withdraw from the study
* General or specific changes in the participant's condition render the participant unacceptable for further treatment in the opinion of the treating investigator.

Duration of Follow Up

Participants will be followed monthly for six months after removal from study or until death, whichever occurs first. Participants removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. Post-study case report forms will capture information including subsequent treatments, response to subsequent therapy, and survival.

Anticipated Toxicities

Adverse Event List(s) for SGI-110

The most common AEs suspected by the investigators in Study SGI-110-01 to be related to the drug and observed to date in the MDS/AML population are: injection site pain, fatigue, nausea, thrombocytopenia, anemia and diarrhea. Based on the mechanism of action of the drug and its active form decitabine, myelosuppression (neutropenia, thrombocytopenia, and anemia) and the related consequences such as infection (e.g. pneumonia), sepsis, and bleeding are the most likely risks for the drug. Mucositis has also been reported.

Pain and burning at the injection site has been reported that are related to dose and volume of injection as well as the speed of injection. Care must be taken to avoid intradermal injection. Ice packs will be applied prior to injection of SGI-110 and the drug will be injected slowly, over 30-60 seconds. If the injection site events are reported at subsequent injections despite slow injection and the use of ice packs, pre-treatment with topical or systemic analgesics can be considered.

Arms: arm 1: This is a single arm, open-label study of SGI-110 in patients with MPN. SGI-110 will be administered subcutaneously at a dose of 60 mg/m2 on days 1-5, repeated every 28 days. Toxicity will be evaluated using the NCI Common Terminology Criteria for Adverse Events Active Version 4. The frequency of toxicities per organ system will be tabulated using descriptive statistics. All patients who receive any amount of the study drug will be evaluable for toxicity
Interventions: intervention 1: SGI-110
Intervention descriptions: intervention 1: subcutaneously at a dose of 60 mg/m2

Protocol documents:
Prot_SAP_000.pdf: 
November 22, 2016 
Protocol Version Date: November 22, 2016 Version 3 
 
Local Protocol #: IST-ASTX-SGI 110-MPN  
 
Title: A phase II study of SGI-110 in Philadelphia-negative myeloproliferative neoplasms 
 
Principal Investigator: Pinkal Desai, MD 
 
Coordinating Center: Weill Cornell Medical College and The New York Presbyterian Hospital 
 
Co-Investigators:  Gail J. Roboz, M.D.; Ellen K. Ritchie, M.D.; Sangmin Lee, M.D., Jeffery 
Ball M.D.; Michael Samuel, M.D. 
 
Statistician:   
 
Paul Christos  
 
 
 
 
 
Cornell Study Coordinator: Jill Kleczko jmk2008@med.cornell.edu  
 
Cornell Research Nurse:  Tania Curcio, NP    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IST-ASTX-SGI 110-MPN November 22, 2016 
 
 
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Table of Contents 
1. 
OBJECTIVES ....................................................................................................................... 1 
1.1 
Study Design .................................................................................................................................................... 1 
1.2 
Primary Objectives .......................................................................................................................................... 1 
1.3 
Secondary Objectives ...................................................................................................................................... 1 
2. 
BACKGROUND ................................................................................................................... 1 
2.1 
SGI-110 ........................................................................................................................................................... 1 
2.4 
Study disease: MPN ........................................................................................................................................ 4 
2.5 
Rationale ......................................................................................................................................................... 5 
3. 
PARTICIPANT SELECTION ............................................................................................ 5 
3.1 
Eligibility Criteria ........................................................................................................................................... 5 
3.2 
Exclusion Criteria ........................................................................................................................................ 6 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................... 7 
4. 
REGISTRATION PROCEDURES ..................................................................................... 7 
4.1 
General Guidelines ......................................................................................................................................... 7 
4.2 
Registration Process ....................................................................................................................................... 8 
4.3  Patient assignment and randomization procedure for second cohort ............................ 8 
5. 
TREATMENT PLAN ........................................................................................................... 8 
5.1 
Overall Study Design ...................................................................................................................................... 8 
5.2 
Screening and pre-treatment criteria ........................................................................................................... 9 
5.3 
Agent Administration ................................................................................................................................ 9 
5.4 
General Concomitant Medication and Supportive Care Guidelines  Error! Bookmark not defined. 
5.5 Duration of Therapy  .................................................................................................................................. 10 
5.6 Duration of Follow Up  ............................................................................................................................. 11 
5.7 Criteria for Removal from Study Treatment  ......................................................................................... 11 
 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ...... 12 
6.1 
Anticipated Toxicities .................................................................................................................................... 12 
6.2 
Dose Modifications/Delays ........................................................................................................................... 13 
7. 
DRUG FORMULATION AND ADMINISTRATION .................................................... 13 
7.1 
SGI-110 ......................................................................................................................................................... 13 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................ 15 


IST-ASTX-SGI 110-MPN November 22, 2016 
 
 
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9. 
STUDY CALENDAR ......................................................................................................... 15 
10. MEASUREMENT OF EFFECT ....................................................................................... 17 
11. ADVERSE EVENT REPORTING REQUIREMENTS ................................................. 23 
11.1 
Definitions ................................................................................................................................................ 23 
11.2 
Procedures for AE and SAE Recording and Reporting ............................................................................ 24 
11.3 
Reporting Requirements ........................................................................................................................... 25 
11.4 
Reporting to the Study Sponsor ................................................................................................................ 25 
11.5 
Reporting to the Institutional Review Board (IRB)................................................................................... 26 
11.6 
Reporting to the Food and Drug Administration (FDA) .......................................................................... 27 
11.7 
Reporting to Hospital Risk Management .................................................................................................. 27 
11.8 
Monitoring of Adverse Events and Period of Observation ....................................................................... 27 
12. DATA AND SAFETY MONITORING ............................................................................ 28 
13. REGULATORY CONSIDERATIONS ............................................................................ 29 
13.1 
Protocol Review and Amendments ........................................................................................................... 29 
13.2 
Informed Consent ..................................................................................................................................... 29 
13.3 
Ethics and Good Clinical Practice (GCP) ............................................................................................... 30 
13.4 
Study Documentation ................................................................................................................................ 30 
13.5 
Records Retention ..................................................................................................................................... 30 
13.6 
Data Collection ........................................................................................................................................ 31 
14. STATISTICAL CONSIDERATIONS .............................................................................. 32 
14.1 
Study Design/Endpoints ............................................................................................................................ 32 
14.2 
Reporting and Exclusions ......................................................................................................................... 33 
15. REFERENCES .................................................................................................................... 35 


November 22, 2016 
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1 
1. OBJECTIVES 
 
1.1 Study Design: Open label single-arm, single-institution study to evaluate the efficacy 
and safety of SGI-110 in Philadelphia chromosome negative (Ph-) Myeloproliferative 
Neoplasms (excluding PV, ET and primary/secondary myelofibrosis). While this study 
would begin as a single institution study, it may be open later as a multi institutional 
study.  
 
1.2 Primary Objective: Determine the efficacy of SGI-110 in improving hematological 
and/or quality of life outcomes in patients with Ph- MPN 
 
 
1.3 
Secondary Objectives:  
Determine whether SGI-110 has increased efficacy in specific morphologic, cytogenetic 
and/or molecular subgroups of MPN  
Perform correlative scientific studies to assess potential epigenetic or other biomarkers 
predictive of response  
 
2. BACKGROUND 
 
2.1 SGI-110 
 
2.1.1  SGI-110 Background 
 
For further information on SGI-110 please refer to the most up to date version of the Investigator’s 
Brochure (IB). 
 
The active metabolite of SGI-110 (2’-deoxy-5-azacytidylyl-(3’→5’)-2’-deoxyguanosine sodium 
salt), a dinucleotide, is decitabine, an FDA-approved agent for the treatment of myelodysplastic 
syndromes. SGI-110 is resistant to modification by cytidine deaminase, a common pathway of 
decitabine metabolism and deactivation[1]. The molecular weight of SGI-110 and decitabine are 
580 Da and 228 Da, respectively. Therefore, the molar equivalent dose of 1 mg of decitabine is 
approximately 2.5 mg of SGI-110. SGI-110’s activity was demonstrated with the same preclinical 
pharmacodynamic assays used to demonstrate decitabine’s efficacy e.g., re-expression of p15, p16, 
and MLH1 and induction of fetal hemoglobin, in vivo. In xenograft studies, SGI-110 demonstrates 
promising preclinical activity in both hematologic and solid tumors. 
 
In vitro evidence suggests that SGI-110 has a longer half-life than decitabine in the presence of 
cytidine deaminase. These promising observations suggest that SGI-110 may have improved 
pharmaceutical properties and biological activities that could extend decitabine’s current clinical 
utility. SGI-110 has shown to be better tolerated in mice than decitabine and is as effective in vivo 
in inducing p16 expression, reducing DNA methylation at the p16 promoter region, and retarding 
EJ6 human bladder cancer tumor growth in athymic mice[2]. 


IST-ASTX-SGI 110-MPN November 22, 2016 
 
 
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2 
 
SGI-110 has been developed for subcutaneous administration. SGI-110 is pharmacologically 
active both in vitro and in vivo in a variety of tumor cells and murine xenograft models when 
administered subcutaneously. Treatment is well tolerated via the subcutaneous route in murine 
xenografts. When administered subcutaneously to non-human primates, SGI-110 releases 
decitabine slowly compared to other species, possibly prolonging the effect over longer periods. 
SGI-110 has been developed as a non-aqueous formulation to ensure formulation stability. 
 
2.1.2 Nonclinical pharmacokinetics 
 
The overall pharmacokinetic characteristics of SGI-110 are summarized as follows. The relative 
bioavailability of SGI-110 dosed subcutaneously in rats is close to 100%. Circulating SGI-110 
levels were very low in the mice, rats and rabbits. However, higher levels were observed in 
monkeys post subcutaneous dosing. Rapid decline in systemic exposure of SGI-110 with 
elimination plasma half-life (T1/2) in the range of 0.4-1 hours in rats and monkeys was observed. 
High levels of decitabine were observed after a subcutaneous dose of SGI-110 in  mice, rats, and 
rabbits (maximum in rat, 54 μg/mL). Levels in monkeys (maximum 463 ng/mL) were substantially 
lower. Rapid decline in systemic exposure of decitabine with elimination plasma T1/2 of 3.7 hour 
in rats and 1 hour in monkeys was observed. 
 
In monkeys, pharmacokinetic parameters were similar on Day 1 and Day 15 of a study in which 
they were dosed once weekly for three consecutive weeks suggesting no significant accumulation 
of the parent or the active metabolite, decitabine. 
 
The metabolic characteristics of SGI-110 are summarized as follows. SGI-110 was more stable in 
humans, dogs and mice and was less stable in rats and rabbit plasma. Incubation of SGI-110 with 
liver microsomes from mouse, rats, rabbits, dogs and humans showed little apparent metabolism 
of the compound. Incubation of SGI-110 with human hepatocytes also showed little apparent 
metabolism of the compound, based on disappearance of the parent. SGI-110 does not significantly 
bind to human plasma proteins; in vitro unbound fraction was estimated to be 91%. SGI-110 has 
poor in vitro bidirectional permeability which correlates well with its poor oral absorption in vivo. 
SGI-110 shows no appreciable induction of CYP1A1/2, CYP2C9 and CYP3A4 in human 
hepatocytes. SGI-110 does not have any CYP450 inhibitory effect on CYP1A2, CYP2C9, 
CYP2C19, CYP2D6 and CYP3A4. 
 
 
 
2.1.4 Nonclinical safety of SGI-110 
 
SGI-110 toxicity findings in rat and rabbit studies are similar to the non-clinical study findings of 
decitabine in New Drug Application (NDA) supporting Good Laboratory Practices (GLP) 
toxicology studies. Myelosuppression, decreases in thymus weight, and testicular atrophy, the 
main study findings of the SGI-110 studies, were also observed as the main study findings in repeat 
dose toxicity studies with decitabine in mice, rats, rabbits, and dogs. As with SGI-110, 
myelosuppression and thymus toxicities after decitabine administration were reversible during 
recovery periods while testicular atrophy persisted. Myelosuppression, particularly neutropenia, 
has been reported as a dose-limiting toxicity for decitabine in human clinical studies. Signs of 


IST-ASTX-SGI 110-MPN November 22, 2016 
 
 
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3 
testicular toxicity have not been observed in any of the published clinical studies of decitabine to 
date. 
 
No studies have been performed to evaluate the genotoxic, mutagenic, carcinogenic or 
reproductive and developmental toxicity of SGI-110. Decitabine may have genotoxic potential; 
decitabine is mutagenic and in preclinical studies in mice and rats, decitabine was teratogenic, 
fetotoxic, and embryotoxic. 
 
 
 
2.1.5 SGI-110 Clinical Data 
 
SGI-110 has been studied in a first-in-human, single-agent study (SGI-110-01).5 This study was a 
Phase 1/2, dose escalation, multicenter study of two subcutaneous regimens of SGI-110 in subjects 
with intermediate or high-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia 
(AML). This study had two parts, a Dose Escalation Segment and a Dose Expansion Segment. The 
study evaluated the biological activity, preliminary safety, and efficacy of SGI-110 with two 
dosing schedules in intermediate to high risk MDS or relapsed or refractory AML subjects, while 
the Dose Expansion Segment further evaluated safety and efficacy at the recommended dose. The 
study was based on a 3 + 3 design within each regimen. Eligible subjects were randomized to 
receive 1 of 2 dosing regimens of SGI-110 with the following starting doses: Regimen 1: 3 
mg/m2/day subcutaneously on Days 1-5 of a 28-day course, Regimen 2: 6 mg/m2 subcutaneously 
Weekly x 3 on Days 1, 8, 15 of a 28-day course. The minimum dose achieving maximal biological 
activity or biologically effective dose (BED) for the daily regimen was reached at 60 mg/m2 daily 
on Days 1-5. 
 
2.1.6 Human pharmacokinetics 
 
The PK of SGI-110 and decitabine are being evaluated in Study SGI-110-01. Decitabine forms 
from SGI-110 as it undergoes cleavage by phosphodiesterase (PDE) enzymes. SGI-110 after SC 
injection undergoes efficient conversion to decitabine and delivers decitabine exposures as 
measured by AUC that are equivalent or higher than those achieved by IV decitabine infusion at 
20 mg/m2, while maintaining significantly lower decitabine Cmax. It is hypothesized that lower 
Cmax may be associated with less toxicity. 
 
Due to slower release of decitabine from SGI-110, the effective half-life of decitabine after SC 
SGI-110 is prolonged and the observed decitabine exposure window is longer (8+ hrs) compared 
to IV (3-4 hrs). At Cohort 6, doses of 90 mg/m2 for the daily regimen and 125 mg/m2 for weekly, 
the observed decitabine AUCs were approximately 1.41 and 1.77 fold higher than with IV 
decitabine at the approved dose of 20 mg/m2 IV, whereas Cmax levels were only at 0.35 and 0.44-
fold for the daily and weekly regimens, respectively. It is hypothesized that longer exposure to 
decitabine may allow more drug to be incorporated into the DNA thus resulting in better 
hypomethylation and better biological activity. Clinical drug-drug interaction studies have not 
been conducted with SGI-110. In vitro, SGI-110 does not inhibit the activity nor induce levels of 
major human CYP enzymes, hence, the likelihood of CYP-mediated drug-drug interactions with 
SGI-110 is remote. 
 
2.1.7 Clinical efficacy and biological activity of SGI-110 


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Based on PD assessment of global hypomethylation from the first 7 cohorts in Study SGI-110-01 
Dose Escalation Segment, the LINE-1 demethylation data show dose dependent hypomethylation 
induction in the daily schedule reaching a plateau at 60 mg/m2 SC dailyx5. The hypomethylation 
of the weekly schedule was inferior to the daily schedule and plateaued early (Figure 1). The 
Biologically Effective Dose or BED was therefore established as 60 mg/m2 dailyx5. 
 
 
 
 
 
 
Figure 1: LINE-1 Demethylation 
 
 
 
There have been 5 documented major responses (2 CRs and 2 CRi, 1 CRp) all in heavily-pretreated 
refractory AML subjects regardless of  prior hypomethylating agents (HMA) treatment : 1 CR and 
CRp with weekly (60 mg/m2 and 125mg/m2, respectively) and 2 CRi and 1 CR with daily (36/60 
mg/m2 and 60 mg/m2 respectively). The major responses were observed in 5/19 refractory AML 
patients when adequate hypomethylation (>10%) was achieved. Five MDS patients who all 
received prior treatment with HMAs had hematological improvements or marrow CR. Since these 
initial data were reported, SGI-110 has shown further responses in patients with MDS and acute 
myeloid leukemia, phase II data have been reported and the agent is currently being  tested in a 
phase III trial compared to decitabine in older patients with acute myeloid leukemia. 
2.4 
Study disease: MPN 
 
Philadelphia chromosome negative Myeloproliferative Neoplasms (PHN-MPN) comprise a 
group of myeloid neoplasms with varying clinical, morphologic and laboratory features and a 
wide range of survival. According to 2008 World Health Organization (WHO) classification, the 
MDS/MPN overlap syndromes include chronic myelomonocytic leukemia (CMML), atypical 
chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia(JMML) and 
myelodysplastic/myeloproliferative neoplasm unclassifiable (MDS/MPN-U). In a recent 
retrospective study from MD Anderson Cancer Center, the median survival of patients with a 


IST-ASTX-SGI 110-MPN November 22, 2016 
 
 
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5 
diagnosis of MDS/MPN unclassifiable was 12.4 months[3] .There is no effective therapy for 
PHN-MPN and this represents an unmet medical need.  
 
 
The MDS/MPN overlap syndromes can present with a wide range of hematological and clinical 
manifestations and individual patients may exhibit a combination of features characteristic of 
both MDS and MPN. For example, while transfusion-dependent anemia is generally present, 
other hematological laboratory abnormalities can range from leukopenia to leukocytosis and 
from thrombocytopenia to thrombocytosis.  Unlike with MDS, significant splenomegaly is often 
present in patients with PHN-MPN. Also, patients may have a constellation of constitutional 
findings, including fatigue, weight loss, anorexia, night sweats and other unpleasant symptoms 
that lead generally to poor quality of life. Thus, while improving overall survival is a critical goal 
of therapy, effective therapy for this group of patients will include also agents that can be 
demonstrated to improve as many of the disease-related clinical issues as possible. 
 
2.5 
Rationale 
 
2.5.1 Both decitabine and SGI-110 have demonstrated safety and efficacy in patients with 
MDS, AML and CMML. Based on these data, substantial clinical experience and the 
lack of an effective treatment option in PHN-MPN, we hypothesize that treatment 
with SGI-110 will result in improved hematological and quality of life outcomes in 
patients with these diseases. SGI-110 will be administered subcutaneously at the 
dose level of 60mg/m2 for 5 days to be repeated every 28 days. If the treating 
physician feels that SGI-110 needs to be started before 28 days for subsequent 
cycles, SGI-110 can be started before the 28 days in those clinical situations after 
getting permission from the study PI. To capture the potential ability of SGI-110 to 
improve both hematological and QOL measures, we will utilize a recently published 
composite endpoint for response assessement based on IWG-MDS, IWG-
myelofibrosis and MFSAF (Myeloproliferative Neoplasm Symptom Assessment 
Form) tools: Savona et al., An international consortium proposal of uniform 
response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in 
adults. Blood,125(12):1857-65. 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Participants must have confirmed diagnosis of Philadelphia chromosome negative 
MPN neoplasm based on WHO classification [5] including Chronic Neutrophilic 
Leukemia (CNL), atypical Chronic Myeloid Leukemia (aCML), Chronic 
Myelomonocytic Leukemia (CMML), Myelodysplastic/myeloproliferative 


IST-ASTX-SGI 110-MPN November 22, 2016 
 
 
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6 
neoplasm unclassifiable  , accelerated phase myelofibrosis and MPN unclassifiable 
(defined as peripheral and or bone marrow blasts of 10-19%). Patients with early 
stages of Polycythemia Vera or Essential Thrombocytosis will be excluded from 
the study. 
 
 
3.1.2  Age minimum of 18 years.  
Because no dosing or adverse event data are currently available on the use of SGI-
110 in participants <18 years of age, children are excluded from this study but may 
be eligible for future pediatric trials. 
 
3.1.3 ECOG performance status <3 
  
3.1.4 Participants must have normal organ function as defined below: 
• Total bilirubin < or = 1.5 X institutional upper limit of normal unless 
attributable to underlying disease, hemolysis or documented Gilbert’s syndrome 
• AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal 
unless attributable to underlying disease 
•   Creatinine < 1.5add < or = 1.5X institutional upper limit of normal or 
creatinine clearance add  using Cockcroft Gault > 50 mL/min/1.73 m2 for 
subjects with creatinine levels above institutional normal. 
• LVEF < 40 % is allowed as long as there is no NY class III/IV heart failure or 
uncontrolled arrhythmias. 
3.1.5 The effects of SGI-110 on the developing human fetus are unknown. For this 
reason and because oncological agents are known to be teratogenic, women of 
child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and 
for the duration of study participation. Should a woman become pregnant or suspect 
she is pregnant while participating in this study, she should inform her treating 
physician immediately. 
 
3.1.6 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 
 
3.2.1 Participants who have had any chemotherapy (investigational or FDA approved) 
(hydroxyurea is permitted) or radiotherapy within 2 weeks prior to study entry or 


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7 
those who have not recovered from adverse events due to agents administered 
more than 2 weeks earlier.  
 
3.2.2 Participants may not be treated with any other investigational agents while on this 
study unless approved by the principal investigator AND the sponsors of BOTH 
investigational agents. 
 
3.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to decitabine or SGI-110. 
 
 
3.2.4 Uncontrolled intercurrent illness including, but not limited to, infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
Pregnant women are excluded from this study because SGI-110 is a hypomethylating 
agent with the potential for teratogenic or abortifacient effects. Because there is an 
unknown but potential risk of adverse events in nursing infants secondary to 
treatment of the mother with SGI-110, breastfeeding should be discontinued.  
 
3.2.5 Individuals with a history of a different malignancy are ineligible except for the 
following circumstances. Individuals with a history of other malignancies are eligible 
if they have been disease-free for at least 3 years and are deemed by the investigator 
to be at low risk for recurrence of that malignancy. Individuals with the following 
cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer 
in situ, and basal cell or squamous cell carcinoma of the skin. 
 
 
 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Both men and women of all races and ethnic groups are eligible for this trial.  
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
 Eligible patients will be entered on study centrally at Weill Cornell Medical College 
by the Lead Study Coordinator. A record of patients who fail to meet entry criteria (i.e. 
screen failures) will be maintained.  Patient consent must be obtained prior to 
performing any study-related activities and registration must be completed prior to 
treatment.  
 


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Following registration, patients should begin protocol treatment within 14 days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be cancelled.   
 
 
4.2 
Registration Process 
 
To register a patient, the following documents should be completed by the research 
nurse or data manager and sent to the Weill Cornell Medical College Joint Clinical 
Trials Office (JCTO). Email the following documents to the JCTO regulatory 
coordinator: 
 
• Signed patient consent form 
• HIPAA authorization form 
• WCMC registration form 
• Eligibility Checklist signed and dated by investigator and research nurse/study 
coordinator 
• Source documentation to confirm eligibility, including pathology disease 
confirmation 
• Documentation of any granted eligibility waivers 
 
4.3  
Patient assignment  
Each subject who satisfies the eligibility criteria and is accepted for the study will be 
assigned a unique identification number. The subject number will be used to identify the 
subject throughout the study and will be entered on all study documents.  Once the subject 
identification number has been assigned, a confirmation email will be sent to all site 
personnel.  
This is an open-label study. There will be no blinding of treatment assignment.  
 
 
 
5. TREATMENT PLAN  
 
5.1 
Overall Study Design 
 
This is a single arm, open-label study of SGI-110 in patients with MPN. 
SGI-110 will be administered subcutaneously at a dose of 60 mg/m2 on days 1-5, repeated every 
28 days. Toxicity will be evaluated using the NCI Common Terminology Criteria for Adverse 
Events Active Version 4.  The frequency of toxicities per organ system will be tabulated using 
descriptive statistics. All patients who receive any amount of the study drug will be evaluable for 
toxicity. 


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5.2 
Screening and pre-treatment criteria 
 
5.2.1 
Screening Procedures 
Screening procedures and tests will be performed within 14 days before treatment administration 
with the exception of informed consent, bone marrow biopsy which may be performed within 
28 days of the first dose of study drug. 
• Provision of written informed consent. The ICF must be signed and dated by the subjects before 
collection of any samples or performance of any study-specific evaluations.  
• Complete medical history, including demographics (date of birth, sex, race). A disease history, 
including the date of initial diagnosis and list of prior treatments and responses to these 
treatments, also will be recorded. Concurrent medical signs and symptoms must be 
documented to establish baseline conditions. 
• Record concomitant medications. 
• Record all study-procedure related AEs from the time of informed consent and then treatment-
emergent AEs after the start of study drug administration (Course 1, Day 1) through 30 days 
after the last dose of study drug.   
• Investigator’s confirmation of eligibility. Perform all necessary procedures and evaluations to 
document that the subject meets each eligibility criterion. 
• Complete physical exam including weight and examination  
• Vital signs include resting systolic/diastolic blood pressure, resting heart rate, resting 
respiration rate, body temperature and pulse oximetry. Assess after the subject has rested in 
the sitting position for at least three minutes.  
• ECOG performance status.  
• 12-lead ECG (rhythm, atrial rate, ventricular rate, PR interval, QRS duration, and QT/QTc 
(QtcF), morphology and overall interpretation).  
• Height. 
• Sample collection for clinical laboratory tests (hematology, chemistry and urinalysis).  
• Serum or urine pregnancy test: for female subjects of child-bearing potential only. Results must 
be negative for the subject to be eligible for enrollment into the study. 
 
5.3 Agent Administration  


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10 
 
5.3.1 SGI-110 
 
• SGI-110 administered at dose level of 60 mg/m2 SC daily on Days 1-5 of a 28-day cycle. 
However, treatment delays are allowed per section 6.3.1 
SGI-110 is administered by SC injection preferably in the abdominal area. The total amount (in 
mg) of SGI-110 to be administered will be determined based on the body surface area (BSA). In 
calculating the BSA, actual heights and weights should be used. There will be no adjustments to 
“ideal” body weight. The institutional standard for calculating BSA is acceptable. Dose adjustment 
should be made for a +/- 10% weight change at the beginning of each cycle  
The site(s) of SGI-110 SC injections will be captured on the dosing CRF.  
Investigators are prohibited from supplying SGI-110 to any subjects not properly enrolled in this 
study or to any physicians or scientists except those designated as sub-investigators on Food and 
Drug Administration (FDA) Form 1572. The investigator must ensure that subjects receive SGI-
110 only from personnel who fully understand the procedures for administering the study 
treatment. 
 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
In general, concomitant medications and therapies deemed necessary for the supportive care and 
safety of the subject are allowed, provided their use is documented in the subject records and on 
the appropriate case report form. If toxicity occurs, the appropriate treatment will be used to 
ameliorate signs and symptoms (including antiemetics for nausea and vomiting, anti-diarrheals for 
diarrhea and anti-pyretics and anti-histamines for drug fever). All supportive measures for optimal 
medical care will be given during the period of study.  
5.5.1 Antibiotics 
Antibiotics may be utilized to prevent or manage febrile neutropenia based on institutional 
standard practice. Febrile neutropenia is defined as temperature at least 38.5ºC when the ANC is 
< 1000 µL. Febrile subjects should be evaluated by physical examination, complete blood count 
(CBC) with differential, and blood culture. Subjects with febrile neutropenia or suspected sepsis 
on the basis of the physical examination are to be hospitalized for appropriate broad spectrum 
antibiotic coverage, consistent with local pathogen sensitivities.  
5.4.2 Hematopoietic Growth Factors 
Granulocyte-colony stimulating factor (GCSF) may be administered per ASCO guidelines.25 Use 
of other white blood cell stimulating factors after Course 1 can be employed according to accepted 


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11 
practice or institutional guidelines, at the discretion of the treating physician. RBC transfusions 
can be administered at the discretion of the treating physician. 
5.4.3 Prohibited Medications 
The administration of any other anticancer agents including chemotherapy and biologic agents is 
NOT permitted, with the exception of hydroxyurea. Similarly, the use of other concurrent 
investigational drugs is not allowed unless specific approval has been obtained from the principal 
investigator AND the sponsors of BOTH investigational products. Red cell and platelet stimulating 
agents are not allowed on protocol. In life threatening situations, these can be given after 
permission from study PI. 
5.5 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse events, 
treatment may continue until one of the following criteria applies: 
• Disease progression to acute leukemia unless, in the opinion of the 
principal investigator, the subject is experiencing clinical benefit from SGI-
110 despite laboratory evidence of progression to acute leukemia.  
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s) 
• Participant demonstrates an inability or unwillingness to comply with the 
medication regimen and/or documentation requirements 
• Participant decides to withdraw from the study  
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
5.6 
Duration of Follow Up  
 
Participants will be followed monthly for six months after removal from study or 
until death, whichever occurs first. Participants removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event.  
Post-study case report forms will capture information including subsequent treatments, 
response to subsequent therapy, and survival. 
  
 
5.7 
Criteria for Removal from Study Treatment 
 
Participants will be removed from study treatment for: 
• Unacceptable adverse events that the in the opinion of the investigator is 
harmful to the participant 
• Violation of the study plan or for administrative and/or other safety reason 
after discussion with the sponsor 


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• Progression to Acute Myeloid Leukemia unless patient is deriving clinical 
benefit and it is in the opinion of the treating physician that the subject 
continue on the drug after discussion with the study PI. 
• Progression of underlying disease (without transformation to AML) as 
specified in table 3.  
The reason for study removal and the date the participant was removed must be 
documented. Alternative care options will be discussed with the participant. 
 
When a subject discontinues/withdraws prior to study completion, all applicable 
activities for the final study visit should be performed at the time of discontinuation (after 
28 days from last day or drug administration or before starting alternative treatment, 
whichever happens first). Any adverse experiences which are present at the time of 
discontinuation/withdrawal should be followed. 
 
If a patient withdraws for non-medical reasons the following procedures will be followed: 
  
• Physical examination will be performed. 
• Safety assessment (physical examination, vital signs, hematology and serum 
chemistry), performed 30 days after last treatment  
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE). 
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheal, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
  
 
6.1 
Anticipated Toxicities 
 
6.1.1 Adverse Event List(s) for SGI-110 
 
The most common AEs suspected by the investigators in Study SGI-110-01 to be 
related to the drug and observed to date in the MDS/AML population are: injection 
site pain, fatigue, nausea, thrombocytopenia, anemia and diarrhea. Based on the 
mechanism of action of the drug and its active form decitabine, myelosuppression 
(neutropenia, thrombocytopenia, and anemia) and the related consequences such as 


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13 
infection (e.g. pneumonia), sepsis, and bleeding are the most likely risks for the 
drug. Mucositis has also been reported.  
Pain and burning at the injection site has been reported that are related to dose and 
volume of injection as well as the speed of injection. Care must be taken to avoid 
intradermal injection. Ice packs will be applied prior to injection of SGI-110 and 
the drug will be injected slowly, over 30-60 seconds. If the injection site events are 
reported at subsequent injections despite slow injection and the use of ice packs, 
pre-treatment with topical or systemic analgesics can be considered. 
 
6.2 
Dose Modifications for adverse events 
  
All adverse events should be reported and considered as part of the overall safety evaluation of 
SGI-110. The Investigator should try to the best of his/her ability to assess whether an adverse 
event is related or unrelated to SGI-110. Dose modifications are not required for hematologic 
toxicities, but may be considered at the investigator’s discretion, in collaboration with the Sponsor. 
In general, SGI-110 should be held for any: 
1. Grade ≥ 3 non-hematologic toxicity (except nausea/vomiting, diarrhea) that fails to resolve to < 
grade 2 within 72 hours despite appropriate management. 
2. Persistent grade ≥ 3 neutropenia or thrombocytopenia beyond day 56 of cycle 1 in the setting 
of a hypocellular bone marrow biopsy and absence of residual disease  
3. Other clinically significant adverse event which, in the opinion of the Safety Review Committee 
(SRC), would place subjects at undue safety risk. 
After resolution of toxicity, treatment with SGI-110 may be resumed at dose level of 45 mg/m2.  
Retreatment at the original dose level may be considered, depending on the nature of the AE, and 
after discussion with the principal investigator. If the same toxicity that led to the dose reduction 
occurs again at this dose level, SGI 110 can be resumed at 30mg/m2 after the toxicity has resolved 
to Grade ≤ 2 or baseline levels. Missed doses will be replaced at the investigator’s discretion. Dose 
modifications for drug-related hematological toxicities will be managed on a case-by-case basis, 
depending on the patient’s disease status and response to growth factor support, in collaboration 
with theprincipal investigator. There is no mandatory dose reduction or delay for hematological 
toxicity, but delays up to 14 days and dose reductions down to 30 mg/m2 will be permitted 
depending on clinical circumstances, after discussion with the principal investigator. Additional 
delays or dose reductions may be considered after discussion with the principal investigator at 
Weill Cornell Medical Center. 
7. DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
SGI-110 
 


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14 
7.1.1 Description 
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 
7.1.2 Form 
SGI-110 product is supplied in a two-vial configuration. 
SGI-110 for Injection, 100 mg is a 5 mL glass vial containing lyophilized SGI-110 
drug powder for reconstitution and subcutaneous injection using the custom diluent 
supplied in a separate vial. Each vial is stoppered with fluropolymer coated butyl 
rubber closure and sealed with a blue flip-off cap. SGI-110 for Injection, 100 mg 
vial is individually packaged in a heat-sealed aluminum foil pouch with a single 
desiccant bag to protect from moisture. 
SGI-110 Diluent for Reconstitution, 3 mL is a 5 mL glass vial with 3 mL of 
custom diluent. Each vial is stoppered with fluropolymer coated butyl rubber 
closure and sealed with a white flip-off cap. 
 
7.1.3 Storage and Stability 
 
SGI-110 for Injection, 100 mg vial is stored at refrigerated condition of 2–8ºC in 
the original packaging until use. SGI-110 Diluent for Reconstitution, 3 mL can be 
stored at 2–30ºC in upright position until use. Both vials are preservative free and 
for single use only. SGI-110 must be stored in a secure, locked facility accessible 
only to authorized study personnel. 
OSHA Guidelines for handling cytotoxic drugs outlined in the American Journal 
of Hospital Pharmacy must be followed.22 As with other potentially toxic anti-
cancer agents, care should be exercised in the handling and preparation of SGI-110. 
The use of gloves and protective garments is recommended. Preparation should 
occur in a vertical laminar flow biological hood using proper aseptic technique. If 
SGI-110 contacts the skin, it should be immediately be treated with borax buffer 
solution pH 10 followed by washing immediately and thoroughly with soap and 
water. If SGI-110 contacts the mucous membranes, flush thoroughly with water. 
Drug spilling can be inactivated by 2 N sodium hydroxide solution.  
7.1.4 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment. 


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15 
 
7.1.5 Availability 
 
SGI-110 is an investigational agent and will be supplied free-of-charge from 
Astex Pharmaceuticals. 
 
7.1.6 Ordering and accountability 
 
An initial supply of SGI-110 will be shipped to the investigational pharmacy when 
all the initiation documents, including IRB approvals and IRB approved ICF, have 
been received and reviewed by Astex Pharmaceuticals.  Thereafter, it is the 
responsibility of the trial pharmacist to order a resupply. 
SGI-110 must be kept in a locked limited access room. The study drug must not be 
used outside the context of the protocol. Under no circumstances should the 
Investigator or other study center personnel supply SGI-110 to other Investigators, 
subjects, or clinics or allow supplies to be used other than as directed by this 
protocol.  
An accurate accounting of the study drugs and investigational devices must be 
maintained. These records must show dates, lot numbers, quantities received, 
dispensed, and returned and must be available for monitoring. SGI-110 
accountability records must be maintained and readily available for inspection by 
regulatory authorities at any time. 
7.1.7 Destruction and Return 
 
At the end of the study, unused supplies of SGI-110 should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
 
8. CORRELATIVE/SPECIAL STUDIES  
 
Bone marrow aspirate and peripheral blood will be collected for correlative scientific studies at 
the time of routine study assessments as detailed in the study calendar. Experimental work will 
be performed in the laboratories of Monica Guzman, Ph.D. and Joseph Scandura, M.D, Ph.D. 
The samples would consist of peripheral blood and bone marrow aspirate. Approximately 10mL 
of bone marrow aspirate (in a syringe with heparin) and up to 20mL of peripheral blood in purple 
or green top tubes will be collected at time points as indicated in the study calendar. The study 
samples will be stored indefinitely unless the study participant requests in writing that the study 
samples be destroyed. 
 
9. STUDY CALENDAR 
 


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16 
Baseline evaluations are to be conducted within 2-week prior to start of protocol 
therapy with the exception of informed consent and bone marrow biopsy which may be 
performed within 28 days of first dose of study drug. In the event that the participant's 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior 
to initiation of the next cycle of therapy 
All assessments must be performed prior to administration of any study 
medication. All study assessments and medications should be administered within 
+ 5 days of the protocol-specified date, unless otherwise noted.  
 
Assessment 
Screening 
Course 1 
Day 1 
(+/- 5 days) 
Course 1 
Day 14 
(+/- 5 
days) 
Course ≥ 2 
Day 1 
(+/- 5 days) 
Course ≥ 2 
Day 14 
(+/- 5 days) 
Final Safety 
Evaluation 
Visit 
(28 days +2 
after last study 
drug) 
Physical examination1 
X 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
X 
CBC including manual differential 
X 
X 
 
X 
X 
X 
Blood chemistry8 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
X 
ECG3 
X 
 
 
 
 
X 
LVEF4 
       X 
          
 
 
 
 
Concomitant medication/non-drug 
therapies 
X 
X 
X 
X 
X 
X 
Bone marrow aspiration or biopsy5 
     
           X 
 
           X 
Adverse events 
 
X 
X 
X 
X 
X 
Spleen measurement6 
      X 
          
 
 
 
X 
QOL measurements7 
       X 
 
X 
 
X 
Research Studies ( bone marrow 
aspirate, peripheral blood) 9 
X 
 
Xpb 
Xpb 
 
 
1. Examinations will include assessment of extramedullary disease. 
2. Vital signs will include weight, body surface area, body temperature (°C), pulse rate, and systolic and diastolic blood pressures. 
3. Single ECGs will be obtained prior to first cycle only, repeat measurements based on clinical indication 
4. Echocardiography or MUGA to be performed at baseline and repeated based on clinical indication. The same method that was used for 
Baseline LVEF determination will be used on repeat measurements. 
5. Bone marrow samples will only be taken at baseline and the end of each cycle 3, 6 and 12.  A confirmatory bone marrow will be needed 1 month 
after a CR/CRp is first detected by peripheral blood assessment confusing. Cytogenetics and molecular markers will be assessed only if a CR/CRp 
is obtained. Molecular marker assessment may be omitted if no molecular markers were detected at screening. Cytogenetics, immunophenotype 
and molecular markers may be obtained from the peripheral blood in the event of a dry tap.   
6. Spleen size will be measured at baseline using US, MRI or CT at baseline and the end of cycle 3, 6 and 12. The same modality of imaging that 
was used at baseline will be used will be used for subsequent measurements (IF NO SPLENOMEGALY PRESENT AT BASELINE EXAM 
AND NO SPLENOMEGALY ON PHYSICAL EXAM, US, MRI, CT MAY BE OMITTED AT SUBSEQUENT TIMEPOINTS) 
7. QOL measurements will be done using MFSAF scores at baseline and at beginning of every cycle. 
8. Blood chemistry includes comprehensive metabolic panel, magnesium, phosphorus and uric acid, LDH 
9. Research studies sample to be collected at baseline (Bone marrow) and day 14 of cycle 1 and then day 1 prior to each cycle from peripheral 
blood (pb). Research study samples from bone marrow (b) to be collected at the end of cycle 3, 6 and 12 as well as at the time of CR/CRp if the 
bone marrow biopsy is done outside the scheduled bone marrow biopsies per study guidelines. 


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17 
 
 
10. MEASUREMENT OF EFFECT  
 
As epigenetic agents may take many months to show their benefit as seen in MDS/AML studies, 
subjects receiving SGI-110 may continue receiving their assigned treatment if their disease 
progresses to leukemia or progression as discerned by the clinical investigator criteria if 1) the 
patient is clinically stable, 2) the patient is informed of their clinical results and agrees to 
continue therapy, and 3) the patient provider agrees that remaining on study would be 
appropriate for the patient. 
10.1.1 Response Criteria: from Savona et al., An international consortium proposal of 
uniform response criteria for myelodysplastic/myeloproliferative neoplasms 
(MDS/MPN) in adults. Blood,125(12):1857-65. 
 
 
• CR (presence of all of the following improvements)* 
•  Bone marrow: ≤5% myeloblasts (including monocytic blast equivalent in case of CMML) with 
normal maturation of all cell lines and return to normal cellularity* 
•  Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” (≤grade 1 fibrosis)† 
•  Peripheral blood‡ 
•   WBC ≤10 × 109 cells/L 
•   Hgb ≥11 g/dL 
•   Platelets ≥100 × 109/L; ≤450 × 109/L 
•   Neutrophils ≥1.0 × 109/L 
•   Blasts 0% 
•   Neutrophil precursors reduced to ≤ 2% 
•   Monocytes ≤1 × 109/L 
•  Extramedullary disease: Complete resolution of extramedullary disease present before therapy (eg, 
cutaneous disease, disease-related serous effusions), including palpable hepatosplenomegaly 
• Provisional category of CR with resolution of symptoms:‡ CR as described above, and complete 
resolution of disease-related symptoms as noted by the MPN-SAF TSS 
• Persistent low-level dysplasia is permitted given subjectivity of assignment of dysplasia* 
• Complete cytogenetic remission 
•  Resolution of previously present chromosomal abnormality (known to be associated with 
myelodysplastic, syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic 
karyotyping with minimal of 20 metaphases or FISH§ 
• Partial remission 
•  Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and blast 
equivalents) reduced by 50%, but remaining >5% of cellularity except in cases of MDS/MPN with 
≤5% bone marrow blasts at baseline 
• Marrow response 
•  Optimal marrow response: Presence of all marrow criteria necessary for CR without normalization of 
peripheral blood indices as presented above. 


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•  Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but remaining 
>5% of cellularity, or reduction in grading of reticulin fibrosis from baseline on at least 2 bone 
marrow evaluations spaced at least 2 mo apart 
• Clinical benefit 
•  Requires 1 of the following in the absence of progression or CR/partial response and independent of 
marrow response (cord blood response must be verified at ≥8 wk) to be considered a clinical 
benefit 
•  Erythroid response 
•   Hgb increase by ≥2.0 g/dL 
•   TI for ≥ 8 wk for patients requiring at least 4 packed red blood cell transfusions in the previous 8 
wk 
•   Only red blood cell transfusions given based on physician’s judgment for a pretreatment Hgb of 
≤8.5 g/dL will count in the red blood cell TI response evaluation|| 
•  Platelet response 
•   Transfusion independence when previously requiring platelet transfusions of at least a rate of 4 
platelet transfusions in the previous 8 wk 
•   Pretreatment ≤20 × 109/L: increase from <20 × 109/L to >20 × 109/L and by at least 100% 
•   Pretreatment >20 × 109/L but ≤ 100 × 109/L: absolute increase of ≥30 × 109/L|| 
•  Neutrophil response 
•   Pretreatment ≤0.5 × 109/L at least 100% increase and an absolute increase ≥0.5 × 109/L 
•   Pretreatment, >0.5 × 109/L and ≤1.0 × 109/L At least 50% increase and an absolute increase ≥0.5 × 
109/L|| 
•  Spleen response 
•   Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at 
baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpable 
•  Symptom response 
•   Improvement in symptoms as noted by decrease of ≥50% as per the MPN-SAF TSS scoring <20 
were not considered eligible for measuring clinical benefit.¶ 
 
 
 ↵* Presence of dysplastic changes, which may be interpreted within 
the scope of normal range of dysplastic changes, may still exist in the 
presence of CR as allowed in MDS IWG. Marrow should exhibit age-
adjusted normocellularity in CR. 
 
 
 ↵† If there is no significant fibrosis present on the initial bone 
marrow biopsy, a second biopsy is not required to prove resolution of 
fibrosis. Grading of fibrosis in measurement of treatment response 
should be according to the European Consensus System.67 
 
 
 ↵‡ Given the current lack of a validated tool to assess complete 
resolution of symptoms in MDS/MPN, “CR with resolution of 
symptoms” (a complete resolution of disease-related symptoms as 
noted by the MPN-SAF TSS in presence of CR) will be a provisional 
category of disease response. 
 
 
 ↵§ Loss of cytogenetic burden of disease by (via FISH or classic 


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19 
karyotyping) known to adversely affect prognosis is required to reach 
complete cytogenetic remission. Decrease in the cytogenetic burden 
of disease must be by ≥50% (via FISH or classic karyotyping) to be 
indicative of a partial cytogenetic response. Given variability of 
fluorescent probes used in FISH, cytogenetic normalization via FISH 
will depend on the performance characteristics of the specific probes 
used. 
 
 
 ↵|| Resolution of abnormal peripheral blood counts must persist for 
at least 2 separate analyses over at least 8 wk. In the case of 
proliferative MDS/MPN, CR will include resolution of 
thrombocytosis to a normal platelet count (150-450 × 109/L) and 
resolution of leukocytosis to WBC ≤10 × 109 cells/L but ≥1.5 × 
109/L. Hgb should be maintained >11 g/dL and platelets ≥100 × 109/L 
without the support of transfusions. Clinical benefit may occur when 
these changes occur in absence of other changes required for CR or 
marrow response. Platelet and packed red blood cell TI would be 
considered for clinical benefit, and duration of TI should be 
monitored. Reduction in myeloid precursors (promyelocytes, 
myelocytes, metamyelocytes, nucleated red blood cells) to less than 
appreciable levels (≤2-3%) and/or 1 × 109/L monocytosis in the 
absence of infection, cytokine treatment, or other reactive causes. 
 
 
  
•      
• Table 3 Proposed criteria for measurement of disease progression in adult MDS/MPN   
• Combination of 2 major criteria, 1 major and 2 minor criteria, or 3 minor criteria from list 
• Major criteria 
•  Increase in blast count* 
•   <5% blasts: ≥50% increase and to >5% blasts 
•   5-10% blasts: ≥50% increase and to >10% blasts 
•   10-20% blasts: ≥50% increase and to >20% blasts 
•   20-30% blasts: ≥50% increase and to >30% blasts† 
•  Evidence of cytogenetic evolution‡ 
•   Appearance of a previously present or new cytogenetic abnormality in complete cytogenetic 
remission via FISH or classic karyotyping 
•   Increase in cytogenetic burden of disease by ≥50% in partial cytogenetic remission via FISH or 
classic karyotyping 
•  New extramedullary disease 
•   Worsening splenomegaly 
•    Progressive splenomegaly that is defined by IWG-MRT: the appearance of a previously absent 
splenomegaly that is palpable at >5 cm below the left costal margin or a minimum 100% increase 
in palpable distance for baseline splenomegaly of 5-10 cm or a minimum 50% increase in palpable 


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distance for baseline splenomegaly of >10 cm 
•   Extramedullary disease outside of the spleen 
•    To include new/worsening hepatomegaly, granulocytic sarcoma, skin lesions, etc. 
• Minor criteria 
•  Transfusion dependence§ 
•  Significant loss of maximal response on cytopenias ≥50% decrement from maximum 
remission/response in granulocytes or platelets 
•  Reduction in Hgb by ≥1.5g/dL from best response or from baseline as noted on complete blood count 
•  Increasing symptoms as noted by increase in ≥50% as per the MPN-SAF TSS|| 
•  Evidence of clonal evolution (molecular)¶ 
 
 
 ↵* Blasts as measured from the bone marrow. 
 
 
 ↵† Patients with development of acute myeloid leukemia from 
MDS/MPN; 20-30% blasts may be allowed on some clinical trials for 
patients with MDS/MPN. 
 
 
 ↵‡ Increase in cytogenetic burden of disease by ≥50% (via FISH or 
classic karyotyping). Given variability of fluorescent probes used in 
FISH, cytogenetic normalization via FISH will depend on specific 
probes used. 
 
 
 ↵§ Transfusion dependency is defined by a history of at least 2 U of 
red blood cell transfusions in the past month for a hemoglobin level 
<8.5 g/dL that was not associated with clinically overt bleeding. 
Cytopenias resulting from therapy should not be considered in 
assessment of progression. 
 
 
 ↵|| MPN-SAF TSS validation among patients with MDS/MPN is 
currently under way (R.A. Mesa, personal communication, 2014). 
 
 
 ↵¶ The identification of new abnormalities using single nucleotide 
polymorphism arrays or sequencing or a clearly significant increase in 
mutational burden of a previously detected abnormality. Precise 
criteria for defining new abnormalities and what exactly constitutes a 
significant increase in mutational burden are open to interpretation; 
we suggest that this criterion should be used conservatively based on 
current evidence. 
 
 
 
 
 
 
 


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Myelofibrosis Symptom Assessment Form (MF-SAF) [4] 
 
 
 


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23 
11. ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 Definitions 
11.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
11.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at 
least a 24-hour hospitalization or prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior to 
study entry are not considered SAEs if the illness or disease existed before 
the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 


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24 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
• respite care 
 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
11.1.3.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of the agent. For the purposes of this study, 
an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   
 
Refer to Section 7 for a listing of expected adverse events associated 
with the study agent(s). 
11.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows:  
 
• Related – There is reasonable evidence that the AE is related to the study 
treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 


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All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
11.3 Reporting Requirements 
 
 Each participating investigator is required to abide by the reporting requirements. The 
study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to 
report serious adverse events to the PI of this study, Dr. Desai, and/or others as 
described below.  
11.4 Reporting to the Study Sponsor 
11.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the Principal Investigator, Dr. Desai, on the local institutional SAE form. This 
includes events meeting the criteria outlined in Section 11.1.2, as well as the 
following: 
 
• Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and related with the intervention. 
 
• All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
 
• All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time 
of continuing review.  


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Participating investigators must report each serious adverse event to the Principal 
Investigator Dr. Desai within 24 hours of learning of the occurrence. In the event 
that the participating investigator does not become aware of the serious adverse 
event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and 
document the time of his or her first awareness of the adverse event. Report 
serious adverse events by telephone, email or facsimile to: 
 
 
 
Dr. Pinkal Desai 
 
 
c/o  
 
 
 Jill Kleczko jmk2008@med.cornell.edu   
 
 
 
                        435 E 70 St 
 
 
Room 4F 
 
 
New York, NY 10021 
 
 
212-746-0284 
 
 
 
 
The participating investigator must provide follow-up information on the serious 
adverse event as soon as possible. Follow-up information should describe whether 
the event has resolved or continues, if and how the event was treated, and whether 
the participant will continue or discontinue study participation. 
 
11.4.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the Principal Investigator Dr. 
Pinkal Desai on the toxicity Case Report Forms.   
11.5 Reporting to the Institutional Review Board (IRB) 
 
Other investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events. A 
copy of the submitted institutional SAE form should be forwarded to: 
 
 
 
Dr. Pinkal Desai 
 
 
c/o Jill Kleczko jmk2008@med.cornell.edu  
 
 
 
 
 
435 E 70 St 
 
 
Room 4F 
 
 
New York, NY 10021 
 
The Principal Investigator Dr. Desai will submit SAE reports from outside institutions, 
if applicable, to the Cornell IRB per their policies and procedures in reporting adverse 
events.  


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11.6 Reporting to the Food and Drug Administration (FDA) 
 
The Principal Investigator Dr. Desai, as holder of the IND, will be responsible for all 
communication with the FDA. Dr. Desai will report to the FDA, regardless of the site 
of occurrence, any adverse event that is serious, unexpected and related  to the study 
treatment (Suspected Unexpected Serious Adverse Reactions or SUSARs) according 
the regulatory-defined timelines (7-day or 15-day reports). Dr. Desai will copy Astex 
pharmaceuticals (SGI-110 manufacturer) on any such reports. 
 
  
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the 
adverse events and progress of the investigation. All IND annual reports will be 
submitted to the FDA by the IND Sponsor. 
 
Events will be reported to the FDA using Form FDA 3500A (Mandatory Reporting 
Form for investigational agents) or FDA Form 3500 (Voluntary Reporting Form for 
commercial agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm.  
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
investigational agent.  Such reports are to be telephoned or faxed (301- 796-9845) to the 
FDA within 7 calendar days of first learning of the event.   
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any serious adverse event that is 
unexpected and possibly related to the investigational agent in a written IND Safety 
Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND 
concerning similar events should be analyzed.  The new report should contain comments 
on the significance of the new event in light of the previous, similar reports.  Written IND 
safety reports with Analysis of Similar Events are to be submitted to the FDA within 15 
calendar days of first learning of the event.  
11.7 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
11.8 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 


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28 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the Overall Principal Investigator and their respective IRB of any unanticipated 
death or adverse event occurring after a participant has discontinued or terminated 
study participation that may reasonably be related to the study.   
 
12. DATA AND SAFETY MONITORING 
 
12.1 
Data Reporting 
 
 
12.1.1 
Data monitoring of this protocol will occur on a regular basis with the frequency 
dependent on the rate of subject accrual and the progress of the study. The protocol will be 
monitored internally at Cornell by Dr. Pinkal Desai and externally by the Cornell CRO QA Office 
and the Coordinating Center in accordance with the Cornell Data Safety Monitoring Plan. All trial 
monitoring and reporting will be done through the Safety Monitoring Committee (SMC) at Cornell. 
Authorized representatives of the Coordinating Center may visit the site to perform audits or 
inspections, including source data verification. The purpose of these audits or inspections is to 
systematically and independently examine all trial-related activities and documents to determine 
whether these activities were conducted and data were recorded, analyzed, and accurately reported 
according to the protocol, Good Clinical Practice (GCP), and any applicable regulatory 
requirements. 
 
 
12.1.2 
Dr. Desai will be holding the IND for this study.  She will comply with all 
regulated reporting requirements to the FDA. 
 
 
Weill Cornell Medical College requires that all research approved by the WCMC IRB 
include an appropriate plan for the monitoring of data to ensure the safety of human subjects. 
Research supported by Federal agencies will be monitored according to all regulations and 
guidelines of the relevant Federal agency. The WCMC Data and Safety Monitoring Board 
(DSMB) will review the IRB approved protocol, informed consent documents, and data and 
safety monitoring plan prior to study initiation. After the first fifteen patients have been treated 
and observed for 28 days, the DSMB will perform an initial safety analysis. After the initial 
safety analysis period, the DSMB will review the cumulative study data semiannually to evaluate 
safety, efficacy, study conduct, and scientific validity and integrity of the trial. Due to the nature 
of the underlying diseases of the subjects on this study and the prolonged duration of therapy that 


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29 
may be required in order to observe clinical benefit with the proposed treatment, there will be no 
assessment of efficacy until at least 25 patients have been treated for at least 4 cycles of therapy. 
If, at that point, there are fewer than 10% responses, as defined in the protocol, the study will be 
stopped for futility. The WCMC DSMB may also convene as needed if stopping criteria are met 
or other safety issues arise that the Principal Investigator and/or IRB would like the WCMC 
DSMB to address. 
 
Stopping criteria also include: 
- 
The early death of more than three of the first ten subjects, as defined by death within 
28 days of beginning therapy. 
- 
If there is an unacceptable rate of Grade 4 toxicities, as judged by the investigation 
team, study sponsor, or the WCMC DSMB. 
 
 
The study PI will submit all written DSMB recommendations to the IRB upon receipt. 
 
 
13. REGULATORY CONSIDERATIONS 
 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) and 
any other necessary documents must be submitted, reviewed and approved by a 
properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The Overall Principal Investigator (or Protocol Chair) will 
disseminate protocol amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
13.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, using 
the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and 
by the person obtaining the consent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent 
document must be retained in the medical record or research file.  


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13.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf 
link does not work,  error message  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB according to the local reporting policy.  
13.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5 Records Retention 
 


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All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
13.6   Data Collection 
Data will be collected and reported on either paper case report forms (CRF) or through 
an internal data monitoring system, which will be determined prior to the start of the 
study. 
 
 


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14. STATISTICAL CONSIDERATIONS  
 
The hypothesis of this study is that SGI-110, a demethylating agent, will lead to at least a 25% 
response rate in any one or more of the following response assessments: IWG-MDS, IWG-MF 
criteria or MF-SAF scores. Based on historical data, there is approximately a 10% hematological 
response rate with standard therapies and there is no precedent for quality of life response with 
any current therapy 
 
14.1 Study Design/Endpoints 
 
This is an open-label, single-arm phase II study designed to explore the clinical activity of SGI-
110, a demethylating agent, in patients with MPN.  The hypothesis of this study is that SGI-110 
will lead to at least a 25% response rate in any one or more of the following response assessments: 
IWG-MDS, IWG-MF criteria, or MF-SAF scores.  Based on historical data, there is approximately 
a 10% hematological response rate with standard therapies and there is no precedent for quality of 
life response with any current therapy. 
 
Sample size considerations: 
 
This is a phase II trial with 50 patients in the study arm; a 95% confidence interval for the 
hematological response rate can be constructed to be within ± 12.0% of the observed response rate.  
This calculation assumes a hematological response rate of 25%. The primary endpoint is the 
hematological response proportion, as measured by any one or more of the following response 
assessments: IWG-MDS, IWG-MF criteria or MF-SAF scores.  Based on historical data, the 
hematological response proportion based on standard therapies is approximately 10%.  Sample 
size recommendations for the current design are determined according to A’Hern’s exact single-
stage phase II design (A’Hern, RP, 2001).  We project a hematological response proportion of 
10%, below which the regimen will be unacceptable, and a hematological response proportion of 
25%, above which the regimen will be considered worthy of further exploration.  The null 
hypothesis that the hematological response proportion is less than or equal to 10% will be tested 
against the alternative hypothesis that the hematological response proportion is greater than or 
equal to 25%.  The sample size computations were performed assuming a 5% level of significance 
and 85% power.  Patients will be continuously accrued throughout the study up to a maximum of 
47 patients.  The new regimen will be declared effective and worthy of further testing if 9 or more 
patients respond among the 47 patients entered into the study.  This exact single-stage design yields 
a ≥ 0.85 probability of a positive result if the true hematological response proportion is ≥ 25%.  It 
yields a ≥ 0.95 probability of a negative result if the true hematological response proportion is ≤ 
10%.   A one-sided 95% confidence interval constructed around the expected hematological 
response proportion of 25% will extend 10.4% from the observed hematological response 
proportion.  Assuming that approximately 5% of patients will be unevaluable/ineligible, we 
anticipate that a total of 50 patients will be enrolled in the study (Reference:  A’Hern AP. Sample 
size tables for exact single-stage phase II designs. Statistics in Medicine 2001;20:859-866.) 
 
 
Analysis Plan: 


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33 
 
The primary endpoint of the hematological response proportion will be calculated and a 95% 
confidence interval will be estimated via binomial proportions.  Descriptive statistics will be 
utilized to describe the parameter proportion defined above (i.e., frequency, percent).  Estimated 
differences in the hematological response proportion between categories of demographic and 
treatment variables of interest (evaluated by the two-sample t-test, Wilcoxon rank-sum test, 
Fisher’s exact test, and chi-square test, as appropriate) will serve as preliminary data (i.e., 
hypothesis-generating) for future studies.  Similar analyses will be conducted for secondary 
outcomes of quality of life.  Exploratory analyses of the hematological response rate and quality 
of life outcomes will be also be stratified by specific cytogenetic and/or molecular subgroups of 
MPN. 
 
All p-values will be one-sided with statistical significance evaluated at the 0.05 alpha level.  One-
sided ninety-five percent confidence intervals will be calculated to assess the precision of the 
obtained estimates.  All analyses will be performed in SAS Version 9.3 (SAS Institute, Inc., Cary, 
NC) and Stata Version 13.0 (StataCorp, College Station, TX). 
 
Safety Analyses: 
 
The frequency of subjects experiencing toxicities will be tabulated.  Toxicities will be assessed 
and graded according to CTCAE v. 4.0 terminology.  Exact 95% confidence intervals around the 
toxicity proportions will be calculated to assess the precision of the obtained estimates. 
 
14.2 Reporting and Exclusions 
 
14.2.1 Evaluation of toxicity. All participants will be evaluable for toxicity from the time 
of their first treatment. 
14.2.2 Evaluation of response.  All participants included in the study must be assessed 
for response to treatment.  Each participant should be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database. 
 
 


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Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
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. 
 
 


 
 
 
35
15. REFERENCES 
 
1. 
Yoo, C.B., et al., Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides. 
Cancer Res, 2007. 67(13): p. 6400-8. 
2. 
Chuang, J.C., et al., S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an 
effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer 
Ther, 2010. 9(5): p. 1443-50. 
3. 
Dinardo, C.D., et al., Myelodysplastic/myeloproliferative neoplasms, unclassifiable 
(MDS/MPN, U): natural history and clinical outcome by treatment strategy. Leukemia, 
2014. 
4. 
Mesa, R.A., et al., The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-
based brief inventory to measure quality of life and symptomatic response to treatment in 
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