A Phase II Trial to Assess the Efficacy and Toxicity of SGI-110 With DLI for the Treatment of AML or MDS Relapsing After Allogeneic Stem Cell Transplantation
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2015-0117 
Protocol Title 
A Phase II Trial to Assess the Efficacy and Toxicity of SGI-110 with DLI 
for the Treatment of AML or MDS Relapsing After Allogeneic Stem Cell 
Transplantation 
Protocol Version 
12 
Version Date 
January 17, 2019 
 
Protocol PI 
Betul Oran, MD 
Department 
Stem Cell Transplantation and Cellular Therapy 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
121,653 
 

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Protocol Page
A Phase II Trial to Assess the Efficacy and Toxicity of SGI-110 with DLI for the 
Treatment of AML or MDS Relapsing After Allogeneic Stem Cell Transplantation
2015-0117
Core Protocol Information
Short Title 
SGI-110 with DLI for AML or MDS Relapsing Post AlloSCT
Study Chair: 
Betul Oran
Additional Contact:
Glenda Woodworth
Jennifer D. Ramos
Peggy S. LeCompte
Department:
Stem Cell Transplantation and Cellular Therapy
Phone:
713-792-8750
Unit:
423
Study Manager:
Jennifer D. Ramos
Full Title: 
A Phase II Trial to Assess the Efficacy and Toxicity of SGI-110 with DLI for the Treatment of 
AML or MDS Relapsing After Allogeneic Stem Cell Transplantation
Public Description:
The goal of this clinical research study is to learn if giving donor lymphocyte cells and SGI-110 will 
help control acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) (including 
Chronic Myelomonocytic Leukemia [CMML]) in patients who have had an allogeneic stem cell 
transplant (using someone else's stem cells) and have relapsed (the disease has gotten worse). 
Researchers also want to find out if giving SGI-110 after allogenic stem cell transplant in high risk 
AML and MDS patients would help to improve how long they may remain in remission (free of 
disease) after transplant. Researchers also want to learn if SGI-110, when given as maintenance 
therapy for high-risk AML and MDS patients, will reduce the risk of relapse after an allogenic stem 
cell transplantation.  The safety of this treatment will also be studied.
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated 01/25/2019
Version:
12
Submitted by:
Peggy S. LeCompte--1/17/2019 5:14:04 PM
OPR Action:
Accepted by:  Otisia M. Holiday -- 1/23/2019 1:43:46 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

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Protocol Body
1.0 Objectives
1.1 Primary Objective
The primary objectives of the study are:
1.1.1  The primary objective of the study is to determine the complete response (CR) rate 
of SGI-110 with or without donor lymphocyte infusion (DLI) either for the treatment 
of morphologic relapse or the presence of MRD in patients with acute myeloid 
leukemia or myelodysplastic syndrome after hematopoietic stem cell transplantation 
in patients with AML and MDS (cohort 1 and 2).
1.1.2 The primary objective of the study is the  relapse-free survival with the use of 
SGI-110 as maintenance therapy in patients with high risk acute myeloid leukemia 
or myelodysplastic syndrome after hematopoietic stem cell transplantation (cohort 
3).
1.2. Secondary Objectives
The secondary objectives of the study are:
1.2.1 To determine the safety and toxicity of SGI-110 with or without DLI in this subject 
population.
1.2.2 To evaluate overall response and survival. 
1.3 Study Endpoints
1.3.1 Primary Endpoint
The primary endpoint is the CR rate of SGI-110 after enrollment to the clinical trial 
for cohorts 1 and 2.  The primary endpoint is relapse free survival for cohort 3. 
1.3.2 Secondary Endpoints
The secondary endpoints are:
1.3.2.1 Safety (type, frequency, severity of AEs and relationship of AEs to 
SGI-110)
1.3.2.2 Overall response rate
1.3.2.3 Duration of remission
1.3.2.4 Incidence of acute and chronic graft versus host disease (GVHD)
1.3.2.5 Overall survival and disease free survival at one year after study 
enrollment
2.0 Background
Relapse is the major cause of treatment failure after allogeneic hematopoietic transplantation 
for AML or MDS (1, 2) and is associated with a dismal prognosis (3).  Treatment options for 
those patients are mainly restricted to chemotherapy, donor lymphocyte infusion (DLI) or 
second allo-HSCT(4-7). However, remission induction by chemotherapy is challenging because 
of low response rated and high toxicity (4).
A promising strategy is administration of hypomethylating agents with donor lymphocyte infusion 
to augment graft-vs-leukemia effects.   Hypomethylating agents have direct antileukemia effects 
and may also favorably modulate GVL activity.  We and others have reported the activity of 
5-Azacytidine for relapse after allo-HSCT(8). Recently, the safety of 5-Azacytidine in 
combination of DLI as first salvage therapy for relapse after allo-HSCT in AML/MDS patients 
have been shown (9).
SGI-110 is a promising agent for AML and MDS The active metabolite of SGI-110, a 
dinucleotide, is decitabine. SGI-110 is resistant to modification by cytidine deaminase, a 

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common pathway of decitabine metabolism and deactivation. Therefore SGI-110 delivers 
decitabine with a 4-fold longer decitabine half-life and overall exposure up to 8 hours.  Initial 
studies have demonstrated relatively high response rates compared to azacitidine and 
decitabine.  In a phase I study, biologically effective dose (BED) was determined to be 60 
mg/m2 Days 1-5. A recent phase II study in relapsed/refractory or treatment naïve older AML 
patients, overall response rate (including CR+CRp+CRi) was 25.6% and 29.8% in 60 mg/m2 
and 90 mg/m2 dose groups respectively. These early results confirmed the clinical efficacy of 
SGI-110 in AML patients. There has been data that hypomethylating agents may increase the 
immunogenicity of AML blasts by re-expression of important antigens(10-12). Furthermore, 
animal studies suggest an immunomodulatory role of hypomethylating agents that might 
attenuate GVHD after DLI(12, 13). 
Early intervention is important for treatment of relapse post transplant.  The best opportunity to 
improve outcomes would be to identify relapsing patients with minimal residual disease (MRD) 
which has been shown to predict impending hematologic relapse(14, 15). 
In the current study, we aim to investigate the use of SGI-110 in combination with DLI for 
morphologic relapse and presence of MRD in the post allo-HSCT setting. 
It is well known that most relapses tend to occur within a year after transplant and the prognosis 
is poor. Because of this short interval before relapse, it is imperative to focus on post 
transplantation pharmacologic interventions to reduce the relapse risk. The National Cancer 
Institute proposed strategies to prevent relapse at its Second International Workshop on the 
Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation 
(16). Strategies include improving the conditioning regimen by incorporating new drugs with 
stronger antileukemia activity and/or less toxicity, graft manipulation, pre-emptive treatment 
based on detection of minimal residual disease (MRD), early withdrawal of immunosuppression, 
and maintenance therapy. 
There have been studies investigating the role of maintenance therapy in the post-transplant 
setting to improve relapse incidence. The ideal agent for maintenance therapy would have to 
fulfill a number of requirements (16). It should be active against the disease being targeted, 
have acceptable nonhematologic toxicity so that it is tolerated by the patient early after 
transplant, and have tolerable or preferably no myelotoxicity. In addition, the ideal agent should 
be able to be given early after transplant, have manageable drug interactions, should not inhibit 
the graft-versus-tumor effect (GVT), and should not worsen graft-versus-host disease (GVHD). 
A number of agents are being tested as candidates for maintenance therapy after transplant. 
Azacytidine is a DNMT (DNA methyltransferase) inhibitor that has in vitro and in vivo 
demethylating effects. Since its approval by the U.S. Food and Drug Administration on May 19, 
2004, several studies published have shown that DNMT inhibitors have significant anti-tumor 
activity even after HSCT when patients relapsed, with a 20%-40% complete response (CR) rate 
(8,17). These findings led to a phase 1 dose-finding study of azacitidine in the post-transplant 
setting, in which 90 patients were enrolled, but only 45 high-risk patients were actually treated 
with maintenance therapy. In this trial, median age of the patients was 60 years, and 67% of the 
study cohort had active disease at transplant (18). The investigators used a Bayesian adaptive 
method to determine the best dose and schedule combination based on time to toxicity with 
azacitidine. They tested subcutaneous azacitidine at 8, 16, 24, 32, and 40 mg/m2 and showed 
that the ideal combination dose was 32 mg/m2 given for 5 consecutive days every 28 days. 
They gave the drug for 4 cycles, which was chosen arbitrarily. In that study, investigating the 
safety and efficacy of maintenance therapy for the first time in AML after HSCT, 1-year 

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event-free survival (EFS) was 58% and 1-year overall survival (OS) was 77%. Twenty-seven 
percent of patients had grade II-III acute GVHD, and 37% had chronic GVHD. Interestingly, the 
incidence of chronic GVHD did not decrease with azacitidine dose but with the number of 
cycles. The investigators concluded that azacitidine at 32 mg/m2 given for 5 days every 28 days 
for at least 4 cycles was safe in heavily pretreated AML and MDS patients as posttransplant 
maintenance. 
RICAZA study Investigators conducted a study using subcutaneous azacitidine in 27 AML 
patients who had undergone reduced-intensity conditioning (RIC) allogeneic stem cell 
transplantation (19). The conditioning regimen was fludarabine, melphalan, and alemtuzumab, 
and the azacitidine regimen consisted of 36 mg/m2 for 5 consecutive days every 28 days for up 
to 10 cycles. The median time to start of azacitidine treatment was 64 days after the allogeneic 
stem cell transplantation. An additional 19 patients enrolled as the control group, received the 
same conditioning regimen, but no maintenance therapy. The investigators found that 3 of the 
27 patients who received maintenance therapy developed grade 2 acute GVHD, and none 
developed grade 3e4 GVHD. Two patients developed limited chronic GVHD of the skin, and 
none developed chronic extensive GVHD. In comparison, the control group had a higher GVHD 
rate, with 7 of 19 developing grade 2 acute GVHD and 7 of 19 chronic GVHD. Despite these 
encouraging results, 7 of the 27 patients relapsed at a median of 6 months after transplantation. 
Decitabine is another epigenetic therapy that has been investigated in the post-transplant 
maintenance setting (20). The maximum tolerated dose (MTD) was defined as the maximum 
dose at which  25% of people experience dose-limiting toxicities during the first cycle of 
treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were 
completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. 
Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all 
patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them 
remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and 
GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of 
treatment; 1 patient died of acute gut GVHD.  In conclusion, decitabine maintenance is 
associated with acceptable toxicities when given in the post-allo transplantation setting. 
Despite the encouraging results reported, pre-emptive strategies, to prevent relapse, including 
pharmacological, immunological and cellular therapies pose the dilemma of administering 
potentially toxic therapy without evidence of relapse. Therefore patient selection for the right 
group of patients to be included in those studies is very important.
We previously published that proper risk assessment with the use of minimal residual status at 
allogeneic stem cell transplantation in combination with cytogenetics and molecular data could 
overcome this potential problem (21). In our published study, we had shown that even patients 
transplanted in complete remission, had 1- year relapse incidence higher than 40% if they had 
adverse risk characteristics by cytogenetics and molecular studies defined as European 
LeukemiaNet (22) or if they had intermediate risk characteristics with presence of minimal 
residual disease at stem cell transplantation. In contrast patients without those high risk features 
had 1-year relapse incidence <10% and they may not need maintenance treatment beyond 
allogeneic stem cell transplantation. 
Therefore, we also aim to investigate the tolerability and efficacy of SGI-110 as post-transplant 
maintenance treatment in high risk AML and MDS patients (cohort 3).

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2.1  General Information
The active metabolite of SGI-110 (2’-deoxy-5-azacytidylyl-(3’ꞏ5’)-2’-deoxyguanosine sodium 
salt), a dinucleotide, is decitabine. SGI-110 is resistant to modification by cytidine deaminase, a 
common pathway of decitabine metabolism and deactivation. 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. Exploratory preclinical studies demonstrate that unlike decitabine, SGI-110 
can suppress the polycomb repressor complex 2 which is involved in silencing tumor 
suppressor genes. These promising observations suggest that SGI-110 has improved 
pharmaceutical properties and biological activities that expand on 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 promotor region, and 
retarding EJ6 human bladder cancer tumor growth in athymic mice.
2.2  Summary of Nonclinical Data
2.2.1  In Vitro Pharmacology
The ability of SGI-110 to change global methylation status was tested by determining the 
methylation level of long interspersed nucleotide element-1 (LINE-1) and p16 sequences 
(Figure 1). Repetitive DNA elements, such as LINE-1 retro-transposable elements, serve as 
useful markers of genome-wide methylation changes and have previously been shown to be 
demethylated upon treatment with SGI-110 or decitabine (5-Aza-CdR). Both azacitidine and 
decitabine by itself have low objective response rates.

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Figure 1:
Effects of SGI-110 (filled bars) and decitabine (open bars) on LINE-1 and p16 
Gene Methylation Levels in T-24 and HCT116 Cell Lines
In both T-24 and HCT116 cells, the decrease in the level of methylation was dose-dependent 
and comparable for SGI-110 and decitabine after 0.1 mM and 1 mM treatment (Figure 1). In the 
figure noted above and any subsequent places in this document, S110 is the same as SGI-110.  
At 10 mM concentrations, only a small decrease in methylation was noted, probably due to side 
effects of high drug concentrations. In fact, 10 mM treatments may be too cytotoxic for effective 
demethylation to take place as the plating efficiency of T-24 cells indicates. It is well-established 
that the cytotoxic dose of these demethylating agents is not ideal for optimal epigenetic therapy, 
since these drugs inhibit DNA methylation best at low doses in cell lines as well as in the clinic.
Next, the changes in a methylation-silenced tumor suppressor gene, p16 were assayed in both 
cancer cell lines.

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Figure 2:
Effects of SGI-110 (filled bars) and decitabine (open bars) on p16 Gene: 
Expression Levels in T-24 (left) and HCT116 (right) Cells
As shown in Figure 2, untreated T-24 bladder carcinoma cells do not express p16, and dose 
dependent increases in p16 expression were observed after 6 days of continuous treatment with 
SGI-110 or decitabine. After HCT116 colorectal carcinoma cells were treated for six days, a 
dose dependent increase in p16 expression was observed with both SGI-110 and decitabine.
2.2.2 In Vivo Pharmacology
The efficacy and safety of SGI-110 was evaluated in several solid tumor models and HL-60 
promyelocytic leukemia in comparison to equivalent doses of decitabine (Astex Pharmaceuticals
, Inc., data on file). Female nu/nu mice were implanted subcutaneously with HL-60 cells. 
Animals with exponentially growing tumors were randomized into 5 groups of 8 animals each to 
include vehicle, SGI-110 5 mg/kg administered subcutaneously every 7 days and 2.5 mg/kg 
administered intraperitoneally Monday to Friday. Equivalent doses and schedules of decitabine 
12.2 mg/kg and 6.1 mg/kg, respectively, were administered subcutaneously for comparison. 
Results from this study are shown in Table 1 and Figure 3. Both SGI-110 and decitabine 
demonstrated equivalent antiproliferative activity when administered subcutaneously. When 
dosed intraperitoneally, SGI-110 seemed to have a greater effect but at the expense of higher 
toxicity as evidenced by more weight loss and death of 1 animal in the decitabine group.

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Figure 3:
SGI-110 and SGI-110 Activity and Body Weight Loss in HL-60 Promyelocytic Leukemia
2.3
General Safety (Cardiac, CNS, and Respiratory)
SGI-110 was tested to examine the in vitro effects on the human ether-a-go-go related gene 
(hERG) potassium channel current. Whole cell patch clamp recordings were made on human 
embryonic kidney (HEK293) cells that were stably transfected with hERG cDNA. SGI-110 was 
tested at 10 mM and 300 mM.
SGI-110 inhibited hERG current by 1.4 ± 0.3% (mean ± SEM) at 10 mM and by 1.0 ± 1.3% 300 
mM. The half maximal inhibitory concentration (IC50) for the inhibitory effect of SGI-110 on 
hERG current was not calculated but was estimated to be greater than 300 mM.
The potential neurobehavioral toxicity of SGI-110 was studied after a single subcutaneous dose 
of SGI-110 (0, 5, 10, and 20 mg/kg) in 2 repeat dose GLP toxicology studies in rats. Functional 
Observational Battery (FOB) evaluations were conducted on 10 main study animals/group 
pre-dose (Day -1) and 1 hour post-dose on Day 1 of the study [23] [24]. There were no SGI-110 
related changes in any of the FOB measurements in either study. The 
no-observed-adverse-effect level (NOAEL) of SGI-110 on neurobehavioral function is 30 mg/kg.
The potential effects of SGI-110 on respiratory function were studied in a GLP study in rats. 
Pulmonary function (respiratory rate, tidal volume, and minute volume) were monitored 
continuously on 8 animals/sex/group for at least 1 hour pre-dose and at least 4 hours post-dose. 
Test article or vehicle was administered to all groups via a single subcutaneous injection (0, 15, 
30, and 60 mg/kg) SGI-110 did not produce mortality and had no effect on clinical signs, 
respiratory rate, tidal volume, and minute volume. With respect to the basic pulmonary 
endpoints evaluated in this study, a no-observed-effect-level (NOEL) of at least 60 mg/kg has 
been established for SGI-110.
2.4
Summary of Clinical Data

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For the most updated clinical data, please refer to the most recent Investigators’ Brochure.  In a 
Phase I study, 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation part: 44 
patients in the daily x 5 regimen and 34 in the weekly x 3 regimen. There median age was 69 
years. Median number of prior regimens was 3.
The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the 
SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hours) 
compared to Dacogen IV (3-4 hours). At SGI-110 dose range of 60-125 mg/m2, observed mean 
decitabine AUCs (88-231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 
Dacogen IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26-64 ng/mL vs 
146 ng/mL for Dacogen IV). The effective half-life for decitabine after subcutaneous SGI-110 
injection appeared to be prolonged (up to 4-fold or~2.4 hours) compared to Dacogen IV (0.58 
hrs). SGI-110 exposures (AUC) increased in a dose proportional manner regardless of the 
regimen and no accumulation was observed.
Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen 
between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (~25%) was 
evident at higher daily doses (90-125 mg/m2) and therefore the BED for the daily x 5 schedule 
is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably 
with that observed historically after Dacogen IV at the dose of 20 mg/m2 daily x 5. The extent of 
LINE-1 hypomethylation after weekly x 3 SGI-110 was inferior as the maximum average 
hypomethylation plateaued at ~8% from baseline.
Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical 
responses were observed: 2 CRs, 1 CRp, and 1 CRi in heavily pretreated AML patients; 1 mCR 
and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who 
achieved >10% LINE-1 hypomethylation. The most common adverse events (AEs), regardless 
of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site 
pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), 
fatigue (8%), nausea (6%), and thrombocytopenia (5%). The MTD was not reached with the 
weekly regimen up to 125 mg/m2 weekly x 3. With the daily regimen, 125 mg/m2 daily x 5 
resulted in 2 dose-limiting toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 
associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while 
none of the 9 patients with AML had DLT at that dose (14). Since the abstract publication, 
maximum hypomethylation was noted at the 60 mg/m2 dose, while clinical MTD was defined at 
90 mg/m2 dose. Therefore the Phase II study proceeded to compare 60 versus 90 mg/m2 daily 
for 5 days in newly diagnosed MDS and AML. A further arm investigated SGI-110 60 mg/m2 
daily x 10 days in AML salvage. Finally SGI-110 60 mg/m2 daily x 5 is being evaluated in 
patients with MDS and progression on azacitidine/decitabine therapy.
The Phase II randomized study of the biologic effective dose 60 mg/m2 daily x 5 and clinical 
Phase II dose 90 mg/m2 daily x 5 is ongoing. As of June 30, 2013, sixty-seven patients (50 
relapsed/refractory AML, 17 treatment naïve elderly AML) were treated and had a minimum 
follow up of 3 months. Patients were randomized to either 60 mg/m
2 dose (32 patients) or 90 
mg/m
2 dose (35 patients). The median age was 66 years (range, 22–84), 69% were male, and 
ECOG PS of 0/1/2 was reported in 11/47/9 patients respectively. Median number of prior 
regimens was 2 (range, 0–10). Patients’ characteristics were well balanced between the 2 dose 
groups. The primary endpoint of overall remissions (CR, CRp, or CRi) was observed in 17/67 
patients (25% with 95% CI, 16–37%). There were 8 complete remissions (CR, CRp, or CRi) in 
50 patients with relapsed/refractory AML (16% with 95% CI, 7-29%); and 9 complete remissions 

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(CR, CRp, or CRi) in 17 treatment-naïve elderly AML patients (53% with 95% CI, 28-77%). Five 
patients (4 relapsed/refractory, and one treatment-naïve elderly AML) subsequently received a 
stem cell transplant. There was no difference in the complete remission rate between 60 and 90 
mg/m
2 doses (8 remissions in 32 patients at 60 mg/m
2, and 9 remissions in 35 patients at 90 
mg/m
2). LINE-1 DNA methylation data before and after treatment was available in 50 (75%) 
patients enrolled.  LINE-1 demethylation ꞏ 10% post treatment was observed in 83% and 78% in 
the 60 mg/m
2 and 90 mg/m
2, respectively. The median maximum LINE-1 demethylation for 
responders is 25% as compared to 19% for non-responders. The most common adverse events 
(AEs) regardless of relationship to SGI-110 >/= Grade 3 include febrile neutropenia, 
thrombocytopenia, anemia, leukopenia, neutropenia, and pneumonia. The 90 mg/m2 dose 
showed a greater frequency of Grade 3/4 related AEs >/= 10% (anemia, febrile neutropenia, 
leukopenia, neutropenia, and thrombocytopenia) compared to the 60 mg/m2 dose (15).
2.5  Risks of SGI-110 Based on Early Clinical Data 
For the most up-to-date clinical safety information, please refer to the most recent Investigators’ 
Brochure.
The most common risks of SGI-110 are similar to decitabine. These include myelosuppression 
(neutropenia, febrile neutropenia, thrombocytopenia, and anemia) and its consequences such 
as fever, infection, sepsis, bacteremia, or bleeding. While in GLP toxicity studies with SGI-110 
subcutaneous injections, no adverse local site reactions were noted in the multiple-dose rat and 
rabbit studies, clinical data indicate injection site pain, irritation, or inflammation in approximately 
15% of patients. Local pain seems to be ameliorated by the use of ice packs before or after 
injection, injecting SGI-110 slowly instead of a push, and carefully avoiding intradermal 
injections.
2.6  Potential Benefits of SGI-110
Astex Pharmaceuticals has synthesized more stable and potent inhibitors of DNA methylation 
than decitabine, and demonstrated that short oligonucleotides containing an azapyrimidine 
effectively inhibit DNA methylation in living cells. SGI-110 was synthesized by coupling 
decitabine and guanosine into a dinucleotide in an attempt to improve the biological stability and 
thereby increase the in vivo efficacy of decitabine. Unlike decitabine, SGI-110 initially is 
resistant to deamination by cytidine deaminases until it is converted into decitabine as a result 
of cleavage of the phosphodiester linkage by phosphodiesterases.
As such, decitabine is the active metabolite of SGI-110.  SGI-110 is a new chemical entity that 
may possess enhanced pharmacokinetic or pharmacodynamic properties compared to 
decitabine.
The activity of SGI-110 was demonstrated with the same preclinical pharmacodynamics assays 
used to demonstrate the activity of decitabine, e.g., re-expression of p15, p16, and MLH1 and 
induction of fetal hemoglobin, in vivo. In vivo data demonstrate interspecies differences with 
respect to absorption, distribution, and conversion to decitabine. In xenograft studies, SGI-110 
demonstrates promising nonclinical activity in hematologic malignancy and solid tumors.
As such, SGI-110 is an agent that holds promising activity in hematological malignancies given 
decitabine’s proven activity in MDS and AML. The dosage form of SGI-110 developed for use in 
this study as a subcutaneous injection has the potential for a more sustained release effect 

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compared to an IV short infusion which, in addition of being more convenient, may prolong 
efficacy, lower toxicity and change the PK in a beneficial way.
2.7  Potential Benefits of DLI
Although the mechanism by which DLI results in clinical responses is unclear, it is presumed to 
be a T cell-mediated process. Further analysis of larger numbers of patients is critical to fully 
understand the mechanisms involved in this response.
Some data suggest that DLI normalizes the T cell receptor (TCR) repertoire and expands the 
antileukemic cell population. In one study, for example, the TCR repertoire was analyzed before 
and after DLI among four patients with relapsed chronic myeloid leukemia (CML) and 10 normal 
controls (25).  Initially, the patients' repertoire was characterized by a large number of 
oligoclonal and clonal patterns, while all controls had a polyclonal pattern. Following infusion of 
CD4+ lymphocytes, these abnormal patterns slowly normalized over the ensuing several 
months; by one year, all four patients had an almost normal TCR repertoire. In each patient, 
expansion of at least one TCR subfamily coincided with the time of disappearance of 
Philadelphia chromosome-positive cells.
These findings provide evidence of clonal expansion of allogeneic T cells that may be selective 
mediators of the antileukemic effect. In another study, patients with relapsed CML responding to 
DLI generated potent antibody responses to CML-associated antigens, suggesting the 
development of coordinated T and B cell immunity (26).
2.8   Efficacy of DLI
The efficacy of donor lymphocyte infusion (DLI) varies with the underlying malignancy, the dose 
of infused lymphocytes, and the degree of host lymphodepletion. Outcomes are best for patients 
with chronic phase chronic myeloid leukemia (CML) followed by patients with lymphoma, 
multiple myeloma, and acute leukemia (mostly acute myeloid leukemia). Initial studies also 
suggest that the presence of host-derived regulatory T cells decreases the antitumor effect (28). 
Patients who respond to DLI will usually demonstrate a clinical response within two to three 
months, but a full response may take one year or longer(14). Responses can be durable with 
reports of responses lasting up to 20 years.  
Data regarding the efficacy of donor lymphocyte infusions (DLI) come primarily from small case 
series and two large retrospective studies from Europe and North America:
ꞏ
The European Group for Blood and Marrow Transplantation reported the results with DLI 
obtained from 84 patients with chronic myeloid leukemia (CML), 23 with acute myeloid 
leukemia (AML) and 22 with acute lymphoblastic leukemia (ALL) (29). In this retrospective 
analysis, 73 percent of patients with relapsed CML had a complete remission after DLI. 
Remissions, whether defined by molecular or hematologic criteria, were durable. Patients 
with AML and ALL did not respond as well, as only 29 and zero percent developed a 
complete remission, respectively. DLI treatment was associated with substantial toxicity: 41 
percent developed clinically significant GVHD; 41 percent suffered from myelosuppression; 
and 13 percent died of causes other than their underlying malignancy.
ꞏ
A second retrospective analysis (from 25 North American programs) reported the outcomes 
after DLI in 140 allogeneic transplant patients who relapsed (30). A response rate of 60 
percent was observed for patients with CML. The responses were superior in patients with 

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only cytogenetic relapse or for those treated with DLI while in chronic phase, compared with 
those who had progressed to either accelerated or blast phases. As in the European study, 
the results were not as favorable among patients with AML or ALL (15 and 18 percent 
complete response, respectively). Complications included GVHD (60 percent) and 
pancytopenia (19 percent).
The decreased response of relapsed acute leukemia to DLI may be due to the more rapid 
proliferative capacity of malignant cells, since a full response to DLI often requires months. As a 
result, some clinicians have advocated the use of chemotherapy to first debulk the disease prior 
to DLI (31). Other clinicians have advocated the use of DLI in patients with acute leukemia and 
minimal residual disease following HCT (32). As examples:
ꞏ
In one study, 57 patients with AML, CML, or myelodysplastic syndrome (MDS) relapsing 
after allogeneic transplant received cytarabine-based chemotherapy, followed by 
G-CSF-primed DLI without prophylactic immunosuppression (31). Toxicity was appreciable, 
with a 56 percent incidence of GVHD; treatment-related mortality and two-year overall 
survival rates were 23 and 19 percent, respectively. Multivariate analysis indicated that 
those with a post-transplant remission of ꞏ6 months had a relative odds of remission 
following this treatment approach of 3.7 (95% CI: 1.1-12). Patients with a complete response 
or no response to this treatment had one-year survival rates of 51 and 5 percent, 
respectively.
ꞏ
In another study, 814 patients with standard-risk AML, ALL, or MDS who received allogeneic 
HCT in first or second complete remission were assessed for minimal residual disease 
(MRD) to determine eligibility for prophylactic DLI (32). Patients with MRD were eligible for 
DLI if they had a donor available and had no evidence of active GVHD (56 patients). 
Patients with MRD who did not have a donor were treated with interleukin-2 (IL-2, 49 
patients). When compared with IL-2, DLI resulted in superior rates of disease-free (56 
versus 24 percent) and overall (58 versus 28 percent) survival at three years. This 
compared to rates of disease-free and overall survival at three years of 62 and 66 percent, 
respectively, in patients with no evidence of MRD after HCT.
ꞏ
In another study, the combination of azacitidine and donor lymphocyte infusions (DLI) as 
first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 
30 patients with acute myeloid leukemia (AML; n=28) or myelodysplastic syndromes (MDS; 
n=2) within a prospective single-arm multicenter phase-II trial (33). Treatment schedule 
included eight cycles azacitidine (100 mg/m(2)/day, days 1-5, every 28 days) followed by 
DLI (from 1-5 × 10(6) to 1-5 × 10(8) CD3(+)cells/kg) after every second azacitidine cycle. A 
median of three courses azacitidine (range 1-8) were administered, and 22 patients (73%) 
received DLI. Overall response rate was 30%, including seven complete remissions (CRs, 
23%) and two partial remissions (7%). Patients with MDS or AML with 
myelodysplasia-related changes were more likely to respond (P=0.011), and a lower blast 
count (P=0.039) as well as high-risk cytogenetics (P=0.035) correlated with the likelihood to 
achieve CR. Incidence of acute and chronic graft-versus-host disease was 37% and 17%, 
respectively. 
The authors updated their and reported the retrospectively analyzes f 154 patients with acute 
myeloid leukemia (AML, n = 124), myelodysplastic (MDS, n = 28), or myeloproliferative 
syndrome (n = 2) (34). All patients received a median number of 4 courses of Aza (range, 4 to 
14) and DLI were administered to 105 patients (68%; median number of DLI, 2; range, 1 to 7). 
Overall survival (OS) at 2 years was 29% ± 4%. Molecular-only relapse (HR, .14; 95% CI, .03 to 
.59; P = .007), diagnosis of MDS (HR, .33; 95% CI, .16 to .67; P = .002), and bone marrow 
blasts <13% (HR, .54; 95% CI, .32 to .91; P = .021) were associated with better OS. 

2015-0117
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Accordingly, 2-year OS rate was higher in MDS patients (66% ± 10%, P = .001) and correlated 
with disease burden in patients with AML.  These results suggested that Aza and DLI were 
effective and well-tolerated treatment option for patients with relapse after allo-HSCT, in 
particular those with MDS or AML and low disease burden. 
Responses to DLI can be remarkably durable. For example, in an analysis of 66 patients with 
CML who relapsed and received DLI, 67 percent achieved a molecular complete remission (CR) 
(35). For those patients achieving a molecular CR, 95 percent were alive and in continuous CR 
at three years following DLI. Similar results have been reported by others (36-38).
3.0 Patient Eligibility
3.1
Inclusion Criteria
3.1.1
Diagnosis of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome 
(including Chronic Myelomonocytic Leukemia [CMML]) according to WHO 
classification that underwent first allogeneic HSCT with either peripheral blood or 
bone marrow as the source of the hematopoietic stem cells.  
3.1.2
Age 18 to 75 years old.
3.1.3
No more than 1 antigen mismatch at HLA-A, B, C, DRB1 and DQB1 locus for 
either related or unrelated donor.
3.1.4
High risk AML and MDS patients will be included.
3.1.4.1
Cohort 1:  Morphological relapse at least 90 days after stem cell 
transplant:
3.1.4.1.1
MDS patients: Re-appearance of dysplastic changes in the  
bone marrow, with or without increase in bone marrow last 
count, which is pathologically consistent with 
myelodysplastic syndrome.
3.1.4.1.2
AML patients: Bone marrow blast count >/= 5%. 
3.1.4.2
Cohort 2: Persistence or reappearance of minimal residual disease by 
flow cytometry or cytogenetic or molecular testing while being in 
morphological remission after allogeneic stem cell transplantation.
3.1.4.3    Cohort 3: High risk AML and MDS patients who are in complete remission 
morphologically with no evidence of minimal residual disease by flow 
cytometry or cytogenetic or molecular testing after allogeneic stem cell 
transplantation.
3.1.4.3.1  
MDS patients: 
3.1.4.3.1.1  Cytogenetics consistent with poor or very 
poor risk group by 5-risk classification defined 
by Schanz, et al (43).
3.1.4.3.1.2
Cytogenetics consistent with monosomal 
karyotype.
3.1.4.3.1.3 Bone marrow blast count > 5% but less than 
20% at any time during their disease course 
before HSCT.
3.1.4.3.1.4 Peripheral blood blast </=5% at HSCT.
3.1.4.3.1.5
Therapy-related MDS.
3.1.4.3.2 
AML patients
3.1.4.3.2.1 Cytogenetics and molecular features 
consistent with adverse risk group by 
European LeukemiaNet classification for AML 

2015-0117
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(see Appendix G.) (22).
3.1.4.3.2.2 Presence of minimal residual disease by 
multi-color flow cytometry or cytogenetics or 
molecular studies at the time of HSCT.
3.1.4.3.2.3 Presence of active disease defined as bone 
marrow blast count >5% but less than </=10% 
at the time of HSCT.
3.1.4.3.2.4 Peripheral blood blast count </=5% at HSCT.
3.1.4.3.2.5
Therapy-related AML.
3.1.4.3.3 
Be able to start the drug therapy between 42 to 100 days 
following allogeneic SCT.
3.1.4.3.3.1 
No more than 1 prior allogeneic SCT.
3.1.4.3.3.2 
Post-transplant bone marrow consistent with 
complete remission with no evidence of 
minimal residual disease by flow-cytometry or 
cytogenetics or molecular testing.
3.1.4.3.3.3
Adequate engraftment within 14 days prior to 
starting study drug:
ANC >/= 1.0 x 10
9/L without daily use of 
myeloid growth factor; and,
Platelet >/= 50 x 10
9/L without platelet 
transfusion within 1 week.
3.1.5
ECOG performance status of 0, 1, or 2. 
3.1.6
Serum creatinine </=1.5 mg/dL or creatinine clearance greater or equal than 40 
cc/min as defined by the Cockcroft-Gault Equation*.
3.1.6.1
Males (mL/min):(140-age)*IBW(kg) / 72*(serum creatinine(mg/dl))
3.1.6.2
Females (mL/min):0.85*(140-age)*IBW(kg) / 72*(serum 
creatinine(mg/dl)).
3.1.7
Serum bilirubin </= 1.5 x upper limit of normal (ULN).
3.1.8
Aspartate transaminase (AST) or alanine transaminase (ALT) </= 2.5 x ULN.
3.1.9
Alkaline phosphatase </= 2.5 x UL.
3.1.10 No active bleeding.
3.1.11 No uncontrolled GVHD.
3.1.12 No clinical evidence of life-threatening infection.
3.1.13 Capable of understanding the investigational nature, potential risks and benefits of 
the study, and able to provide valid informed consent.
3.1.14 HIV negative and HBs-Ag negative. 
3.1.15 Negative serum or urine pregnancy test for women with reproductive potential.  
The only subjects who will be exempt from this criterion are postmenopausal 
women (defined as women who have been amenorrheic for > 12 months) or 
subjects who have been surgically sterilized or otherwise proven sterile.
3.2
Exclusion Criteria:
3.2.1
Use of any anti-leukemic agents after relapse is documented (note that the use of 
these anti-leukemic agents given as post-transplant maintenance therapy is 
allowed in this study, e.g., subcutaneous or oral 5-Azacytidine or FLT3 inhibitors 
for maintenance) for cohorts 1 and 2.
3.2.2
Bone marrow blast count >60% for cohort 1.
3.2.3    Use of any of the following after transplantation and prior to starting study therapy 
for cohort 3:

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Page 15
3.2.3.1 Investigational agents/therapies. 
3.2.3.2 Anti-leukemic agents given as post-transplant maintenance therapy (e.g., 
subcutaneous or oral 5-Azacytidine or FLT3 inhibitors for maintenance).
3.2.3
Active acute GVHD grade II or higher.
3.2.4
Active chronic GVHD that is extensive.
3.2.5
Concurrent use of systemic immune suppressive other than calcineurin inhibitors 
and sirolimus. 
3.2.6
Active uncontrolled systemic fungal, bacterial or viral infection.
3.2.7
Symptomatic or uncontrolled arrhythmias.
3.2.8
Significant active cardiac disease within the previous 6 months, including:
3.2.8.1
New York Hear Association (NYHA) class III or IV congestive heart 
failure;
3.2.8.2
Unstable angina or angina requiring surgical or medical intervention, 
and/or;
3.2.8.3
Myocardial infarction.
3.2.9  Known active viral infection with Human Immunodeficiency Virus (HIV), Hepatitis B 
Virus (HBV) or Hepatitis C Virus (HCV).
3.2.10 Prior history of solid tumors other than MDS or AML, unless the subject has been 
free of the disease for >/= 1 year. However, subjects with the following 
history/concurrent conditions are allowed:

Basal or squamous cell carcinoma of the skin;

Carcinoma in situ of the cervix;

Carcinoma in situ of the breast;

Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, 
node, metastasis [TNM] clinical staging system).
4.0 Treatment Plan
4.1 This is a single-arm phase II study to determine the efficacy of SGI-110 with or without DLI 
either for the treatment of the morphologic relapse or the presence of MRD in patients with 
acute myeloid leukemia or myelodysplastic syndrome after hematopoietic stem cell 
transplantation and as maintenance therapy without DLI, given after hematopoietic stem 
cell transplantation for high risk AML and MDS patients. 
There will be three patient subgroups (cohorts):
Cohort 1: 
Patients with morphological relapse for AML and MDS as defined in Section 
3.1.4.1.
Cohort 2: 
Patients with minimal residual disease as defined in Section 3.1.4.2.
The protocol specific data will be entered into PDMS/CORe, the electronic 
case report form.
Cohort 3:    High risk AML and MDS patients defined in Section 3.1.4.3
The Investigator or physician designee is responsible for providing source documentation 
and assigning attribution for all AEs.
4.2. Treatment plan of SGI-110 administration (39, 40):
Following confirmation of eligibility, subjects will receive subcutaneous (SC) SGI-110 daily 
for the first 5 days of each 28-day cycle.  
4.2.1. Cohort 1 

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4.2.1.1
The enrolled patients with morphological relapse will start treatment at 
the dose level 3 which is 60 mg/m2 SC daily, days 1 to 5.  The 
treatment will be given with an intent to achieve CR. Treatment delays 
and dose reductions are allowed by discretion of the principal 
investigator and the treating physician on the basis of tolerability.
4.2.1.2
The response assessments schedule will be as follows:
4.2.1.2.1
The first response assessment will be performed after the 
second cycle of SGI-110 given prior to initiation of the third 
cycle.
4.2.1.2.2
For patients who do not achieve CR/incomplete count 
recovery (CRi) after the second cycle of SGI-110 and 
continue to receive SGI-110 with an aim to achieve CR, 
the next assessment will be performed after the fourth 
cycle.
4.2.1.2.3
For patients who do not achieve CR/CRi after the fourth 
cycle of SGI-110 and continue to receive SGI-110 with an 
aim to achieve CR, the next assessment will be performed 
after the sixth cycle.
4.2.1.2.4
Patients may have an earlier disease assessment rather 
than the indicated time point in the study protocol at the 
discretion of the treating physician and principal 
investigator.
4.2.1.3
Patients who do not achieve CR/CRi within the first 2 cycles of SGI-110 
and still have less than 30% bone marrow bone marrow blasts will 
continue to receive SGI-110 with an intent to achieve CR.
4.2.1.4
Patients who do not achieve CR/CRi within the first 4 cycles of SGI-110 
and still have less than 30% bone marrow bone marrow blasts will have 
the option to receive two more cycles of SGI-110 with an intent to 
achieve CR if the patient, treating physician and principal investigator 
determine such an action as the best interest of the patient.
4.2.1.5
Patients who do not achieve CR/CRi after the fourth cycle of SGI-110  
will be taken off the study if the patient, treating physician and principal 
investigator do not determine continuation of SGI-110 for 1-2 more 
cycles with an intent to achieve CR as the best interest of the patient. 
4.2.1.6
Any patient who does not achieve response after a maximum use of six 
cycles of SGI-110 will be taken off the study.
4.2.1.7
Patients who are reported to achieve CR/CRi at any response 
assessment time points will continue the study drug, SGI-110, as 
maintenance therapy at the subsequent treatment cycles.
4.2.1.7.1
The starting maintenance dose will be 40 mg/m2/day 
(dose level 1) for patients who achieved CR/CRi with 
doses higher than 40 mg/m2/day.
4.2.1.7.2
The starting maintenance dose will be at least one dose 
level lower than the treatment dose that led the patient to 
achieve CR/CRi if the patient was on 40 mg/m2/day dose 
or less during treatments with active disease.
4.2.1.8
Patients will not be taken off therapy with SGI-110 prior to completion of 
the first 4 courses unless for unequivocal disease progression while on 
therapy, unacceptable toxicities, or patient request.
4.2.1.9
During the treatment cycles given with the intent to achieve CR (patient 
has active disease), the dose of SGI-110 can be decreased at least by 

2015-0117
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one dose level (presented at Section 4.4.4) at the discretion of the 
treating physician or principal investigator if:
4.2.1.9.1
There are grade 3-4 reversible non-hematological toxicities 
attributable to the drug observed.
4.2.1.9.2       Dose change is considered in the best interest of the 
patient.
4.2.1.10 For patients who achieve CR/CRi, treatment with SGI-110 will be 
continued as maintenance therapy until treatment failure or for a 
maximum of 12 cycles of SGI-110 treatment. 
4.2.1.11 Treatment with SGI-110 will be stopped at any time point if patients 
exhibit evidence of treatment failure, disease progression, experience of 
unacceptable toxicity, or the investigator determines that the 
discontinuation of treatment is in the patient's best interest as provided 
in Section 6.0. 
4.2.2. Cohort 2: Patients without morphological evidence of relapse but with minimal 
residual disease.
4.2.2.1
The enrolled patients will start treatment at the dose level 1 which is 40   
mg/m2 SC daily, days 1 to 5.  Treatment delays up to 70 days are 
allowed.
4.2.2.2
The response assessments schedule will be as follows:
4.2.2.2.1
The first response assessment will be performed after the 
second cycle of SGI-110 given prior to initiation of third 
cycle. 
4.2.2.2.2
For patients who have persistency of detectable MRD after 
the second cycle of SGI-110 and continue to receive 
SGI-110 the next assessment will be performed after the 
fourth cycle.
4.2.2.2.3
For patients who have persistency of detectable MRD after 
the fourth cycle of SGI-110 and continue to receive 
SGI-110 the next assessment will be performed after the 
sixth cycle.
4.2.2.2.4
Patients may have an earlier disease assessment rather 
than the indicated time point in the study protocol at the 
discretion of the treating physician and principal 
investigator.
4.2.2.3
If patients still have detectable MRD even after the fourth cycle of 
SGI-110, further treatment (maximum two more cycles) with SGI-110 
will be given only if the patient, treating physician and principal 
investigator determine such an action as the best interest of the patient.
4.2.2.4
Patients who are documented to have no detectable MRD at any time 
point while treated with SGI-110 will continue the study drug as 
maintenance therapy at subsequent cycles after documentation of MRD 
negative status.
4.2.2.5
The dose level of SGI-110 can be increased at least one dose level at 
the discretion of treating physician and principal investigator if 
persistency of MRD is documented at any time point of disease 
assessment while on study.
4.2.2.6
For patients with detectable minimal residual disease at study entry, 
treatment with SGI-110 will be continued until treatment failure or for a 

2015-0117
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maximum of 12 cycles if they have become negative for minimal 
residual disease at any time point within the first 6 cycles of study drug.
4.2.2.7
Treatment with SGI-110 will be stopped at any time point if patients 
exhibit evidence of treatment failure, disease progression, experience of 
unacceptable toxicity, or the investigator determines that the 
discontinuation of treatment is in the patient's best interest as provided 
in Section  6.0. 
4.2.3. Cohort 3: High risk AML and MDS patients who are in complete remission 
morphologically with no evidence of minimal residual disease by flow cytometry 
or cytogenetic or molecular testing after allogeneic stem cell transplantation.
4.2.3.1
The enrolled patients will start treatment at the dose level -1 which is 30   
mg/m2 SC daily, days 1 to 5 for each 28-day treatment cycle.
4.2.3.2
Treatment delays up to 70 days will be allowed.
4.2.3.3
The response assessments will be performed per departmental 
guidelines which is day +100, 6th month, 1- year after allogeneic stem 
cell transplantation.
4.2.3.4
Disease assessment can be done at any time point after transplantation 
if it is deemed indicated by the treating physician and/or principal 
investigator.
4.2.3.5
The dose level of SGI-110 can be increased at least one dose level at 
the discretion of treating physician and principal investigator if deemed 
in the best interest of the patient by the treating physician and/or 
principal investigator.
4.2.3.6
For patients who remain in remission without detectable minimal 
residual disease at study entry, treatment with SGI-110 will be 
continued until treatment failure or for a maximum of 12 cycles.
4.2.3.7
Treatment with SGI-110 will be stopped at any time point if patients 
exhibit evidence of treatment failure, disease progression, experience of 
unacceptable toxicity, or the treating physician and/or principal 
investigator determines that the discontinuation of treatment is in the 
patient's best interest as provided in Section 6.0. 
4.2.4
Cross-over.  Patients treated on cohort #2 (patients with minimal residual 
disease while in morphological remission and cohort #3 (maintenance treatment 
cohort) will be allowed to receive higher doses of SGI-110 if they progress while 
on therapy with the study drug. Patients who are considered for cross-over to 
another study cohort due to progression of disease with an aim to receive higher 
doses of SGI-110 will be screened for the eligibility of that study cohort prior to 
initiation of higher doses of study drug.  
4.3 SGI-110 Reconstitution and Administration 
See the current Investigator's Brochure Appendix for details.
4.4. SGI-110 Dose Modifications
Subjects will be monitored for hematologic toxicity and non-hematologic toxicity with the 
National Cancer Institute (NCI) Common Terminology Criteria Adverse Events (CTCAE, Version 
4.0) used as a guide for the grading of the severity. 

2015-0117
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4.4.1
Hematologic Toxicity
4.4.1.1
Cohort 1: 
4.4.1.1.1
No dose reductions, delays or modifications are required for 
hematologic toxicities during the treatment cycles given with 
an intent to achieve CR/CRi. It is assumed that low counts 
observed in the presence of active disease (no morphological 
remission) are due to involvement by the disease and require 
treatment for improvement. Patients will not require dose 
modifications for hematological toxicity before they are 
reported to achieve morphological remission.
4.4.1.1.2
For patients who achieve complete morphological remission 
(CR/CRi) on study, they will receive the subsequent cycles 
(given as maintenance therapy) approximately every 28 days, 
provided that their peripheral blood counts have recovered 
(ANC>=1.0 X 10
9 /L and platelet count>=50 X 10
9/L)).  If the 
peripheral count recovery is delayed beyond 42 days from Day 
1 of the prior cycle and the delay is presumed to be secondary 
to therapy (after confirmation of achieving morphological 
remission), the SGI-110 doses may be reduced at least by one 
level for subsequent doses (e.g. from 40 to 30 mg). 
4.4.1.2
Cohort 2:
4.4.1.2.1
No dose reductions, delays or modifications are required for 
hematologic toxicities during the treatment cycles given in the 
continuous presence of MRD. It is assumed that low counts in 
the presence of MRD are due to disease involvement and 
require treatment for improvement. Indeed, the dose level of 
SGI-110 can be increased at least one dose level at the 
discretion of treating physician and principal investigator if 
persistency of MRD is documented at any time point of 
disease assessment while on study independent of 
hematological toxicities observed as indicated at 4.2.2.4.
4.4.1.2.2
After the documentation of MRD negative status with the 
SGI-110 treatment, if the peripheral count recovery is delayed 
beyond 42 days from Day 1 of the prior cycle and the delay is 
presumed to be secondary to therapy, the SGI-110 doses may 
be reduced at least by one level for subsequent doses (e.g., 
from 30 to 20 mg). 
4.4.1.3 Cohort 3:  If  the peripheral count recovery is delayed beyond 42 days 
from Day 1 of the prior cycle and the delay is presumed to be secondary 
to therapy, the SGI-110 doses may be reduced at least by one level for 
subsequent doses (e.g., from 30 to 20 mg). 
4.4.2
Non-hematological toxicity
4.4.2.1
The dose of SGI-110 will be reduced by one level for grade 3-4 reversible 
toxicities attributable to the drug independent of the disease status at the 

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Page 20
time of ongoing treatment with study drug. If toxicity is still present on next 
cycle with one dose level reduction, dose will be reduced with one more 
level again (minimum dose is 20 mg/m2 given for 3 subsequent days).  If 
toxicity is present after 2 dose level reductions, SGI-110 will be 
discontinued. 
4.4.2.2
Dose reduction for grade 2 reversible toxicities and other dose 
modifications can be implemented if in the best interest of the patient, 
after discussion with the primary investigator.   
4.4.2.3
Infections are not considered drug related toxicity.
4.4.3
Patients with uncontrolled GVHD will not be eligible to receive SGI-110. If GVHD 
resolves, patients may receive SGI-110 with at least one level dose reduction in 
the subsequent cycle. If GVHD remains controlled, full dose can be used in the 
subsequent cycles. 
4.4.4
Treatment delays up to 70 days (cohort #2 and #3) are allowed. For cohort #1, 
treatment delays will be decided by the treating physician or principal investigator 
based on the tolerability of the drug taken the best interest of the patient into 
account). 
4.4.5  SGI-110 dose levels allowed in the study
ꞏ
20 mg/m2 SC, Days 1 through 3 (dose level -3)
ꞏ
20 mg/m2 SC, Days 1 through 5 (dose level -2)
ꞏ
30 mg/m2 SC, Days 1 through 5 (dose level -1)
ꞏ
40 mg/m2 SC, Days 1 through 5 (dose level 1)
ꞏ
50 mg/m2 SC, Days 1 through 5 (dose level 2)
ꞏ
60 mg/m2 SC, Days 1 through 5 (dose level 3)
4.5
Criteria to receive SGI-110
4.5.1
Criteria to receive the first cycle
4.5.1.1
Serum creatinine </= 1.5 mg/dL or creatinine clearance greater than 40 
cc/min as defined by the Cockcroft-Gault Equation.
4.5.1.1.1
Males (mL/min):(140-age)*IBW(kg) / 72*(serum 
creatinine(mg/dl))
4.5.1.1.2
Females (mL/min):0.85*(140-age)*IBW(kg) / 72*(serum 
creatinine(mg/dl)).
4.5.1.2
Serum bilirubin </= 1.5 x upper limit of normal (ULN)
4.5.1.3
Aspartate transaminase (AST) or alanine transaminase (ALT) </= 2.5 x 
ULN
4.5.1.4
Alkaline phosphatase </= 2.5 x UL
4.5.1.5
No active bleeding.
4.5.1.6
No uncontrolled GVHD. 
4.5.1.7
No clinical evidence of life-threatening infection.
4.5.1.8
Negative serum or urine pregnancy test for females of childbearing 
potential.  The only subjects who will be exempt from this criterion are 
postmenopausal women (defined as women who have been 
amenorrheic for > 12 months) or subjects who have been surgically 
sterilized or otherwise proven sterile.

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4.5.2
Criteria to receive SGI-110 given as maintenance therapy (first cycle of 
maintenance therapy and beyond for cohorts 1 and 2 and second cycle and 
beyond for cohort 3).  Each cycle is to be started 28-56 days after the previous 
cycle. 
4.5.2.1
ANC >/=1.0 x 10
9 /L without daily growth factor (Intermittent use of 
growth factor is allowed as clinically indicated and platelet count>=50 X 
10
9/L with or without transfusion
4.5.2.2
No clinical evidence of life-threatening infection. 
4.5.2.3
No active bleeding.
4.5.2.4
No active uncontrolled GVHD.
4.5.2.5
Serum creatinine < 2 mg/dL.
4.5.2.6
Serum bilirubin < 1.5 mg/dL.
4.5.2.7
ALT </= 200 IU/ml unless related to patient's malignancy.
4.5.2.8
Negative serum or urine pregnancy test for females of childbearing 
potential.  The only subjects who will be exempt from this criterion are 
postmenopausal women (defined as women who have been 
amenorrheic for > 12 months) or subjects who have been surgically 
sterilized or otherwise proven sterile.
 4.6    Donor Lymphocyte Infusion (for cohorts 1 and 2)
4.6.1    The patients will receive 3 planned DLI infusions after enrollment to the study if 
below criteria is met.
4.6.1.1    No active bleeding.
4.6.1.2    No uncontrolled GVHD. 
4.6.1.3    Patients should be off concurrent of use systemic immune suppressive 
other than calcineurin inhibitors and sirolimus. 
4.6.1.4    No clinical evidence of life-threatening infection
4.6.1.5    No evidence of autologous reconstitution of the hematopoiesis. 
Chimerism studies from peripheral blood and/or bone marrow at study 
entry or at later time points on study will be used to rule out autologous.
4.6.2.  Patients will not receive DLI:
4.6.2.1. If criteria summarized under 4.6.1 is not met.
4.6.2.2 Donor is not available
4.6.2.3. The treating physician and the PI think it is in the best interest of the 
patient not to receive DLI.
4.6.3    For patients eligible to receive the DLI, the first DLI is planned to be given on the 
6th day of the second SGI-110 cycle immediately after the completion of the 5 days 
of SGI-110 administration if no GVHD observed. If the 6th day falls over a weekend 
day or holiday, the DLI will be given on the very first week day following the 6th 
day. 
4.6.4    Additional DLI will be permitted in patients without uncontrolled GVHD on the 6th 
day of the 4th and 6th course of SGI-110 at the discretion of the treating physician. 
If the 6th day falls over a weekend day or holiday, the DLI will be given on the very 
first week day following the 6th day. 
4.6.5    DLI dose:
4.6.5.1    CD3 1 x 10
7/kg for matched related donor; 3 x 10
6/kg for matched 
unrelated and mismatched unrelated donors.  
4.6.5.2    There will be no scheduled dose escalations and CD3+ cells dose of DLI 

2015-0117
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Page 22
can be lower at the discretion of the treating physician on subsequent 
administrations.
4.6.6
Criteria to give DLI
4.6.6.1
No active bleeding.
4.6.6.2
No uncontrolled GVHD. 
4.6.6.3
Patients should be off concurrent of use systemic immune suppressive 
other than calcineurin inhibitors and sirolimus. 
4.6.6.4
No clinical evidence of life-threatening infection
4.6.6.5
No evidence of autologous reconstitution of the hematopoiesis. 
Chimerism studies from peripheral blood and/or bone marrow at study 
entry or at later time points on study will be used to rule out autologous 
reconstitution.
5.0 Evaluation During Study
5.1
Evaluations during SGI-110 cycles
5.1.1
To be done within 72 hours of each cycle and if clinically indicated, on the third day 
of each cycle and once per week in the second and third week of each cycle: CBC, 
differential, platelet, SGPT, bilirubin, creatinine, electrolytes, serum or urine 
pregnancy test for women with reproductive potential.
Other laboratory tests can be performed as medically indicated. 
5.2
Evaluations prior to DLI administration
To be done within 72 hours of each cycle and if clinically indicated, on the third day of 
each cycle and once in the second and third week: CBC, differential, platelet, SGPT, 
bilirubin, creatinine, electrolytes. 
5.3
Response Evaluation:
Disease status evaluations follow standard practice. If clinically indicated, these studies 
may be done at other time points, which can replace the nearest planned time point. 
For cohorts 1 and 2:
5.3.1
To be done after 2nd, 4th, and 6th cycles of SGI-110. 
5.3.2
After the patients are documented to achieve response, further disease status 
evaluation will be performed when it is clinically indicated.
5.3.3
Disease status will include:
5.3.1.1
Bone marrow aspirate and biopsy with cytogenetics, FISH, flow and 
molecular studies.
5.3.1.2
Chimerism studies from peripheral blood 
5.3.4
If a patient shows no evidence of response in the absence of disease progression 
after the second cycle of SGI-110 (Day 28 +/-7 days), further bone marrow aspirate 
and/or biopsy will be scheduled to document response at the end of Cycle 4 (Day 
28 +/-7 days).
5.3.5
If a patient shows no evidence of response in the absence of disease progression 
even after the fourth cycle of SGI-110 (Day 28 +/-7 days), further bone marrow 
aspirate and/or biopsy will be scheduled to document response at the end of Cycle 
6 (Day 28 +/-7 days).
5.3.6
If the patient does not show evidence of response at the end of Cycle 6, the patient 

2015-0117
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Page 23
will be taken off the study with no further follow-up.
5.3.7
Bone marrow evaluations and peripheral blood chimerism studies can be ordered 
more frequently if clinically indicated. 
For cohort 3:
5.3.8   Disease status evaluations follow standard practice with day +100, Month 6, and 1- 
year disease evaluations.
5.3.9   Disease status evaluation will include:
5.3.9.1
Bone marrow aspirate and biopsy with cytogenetics, FISH, flow and 
molecular studies.
5.3.9.2
Chimerism studies from peripheral blood.
5.4
Outside Physician Participation During Treatment
This will be performed only after the patients are documented to show evidence of 
response with the therapy (morphological CR for cohort 1 and MRD negative status for 
cohort 2 respectively). DLI administrations will only be performed at MDACC.
5.4.1
MDACC Physician communication with the outside physician is required prior to 
the patient returning to the local physician. This will be documented in the patient 
record.
5.4.2
A letter to the local physician outlining the patient's participation in a clinical trial will 
request local physician agreement to supervise the patient's care and perform 
certain laboratory tests (see Appendix D.).
5.4.3
Protocol required evaluations outside MDACC will be documented by telephone, 
fax or e-mail.  Fax and/or e-mail will be dated and signed by the MD Anderson 
physician, indicating that they have reviewed it.
5.4.4
A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician.
5.4.5
Documentation to be provided by the local physician will include progress notes, 
reports of protocol required laboratory and diagnostic studies and documentation 
of any hospitalizations.
5.4.6
The home physician will be requested to report to the MDACC physician 
investigator all SAE’s within 24 hours of documented occurrence.
Communication of protocol required evaluations can be by telephone, fax, or e-mail.  
Patients will return to MDACC at least every 3 months for evaluation. The Study Chair or 
treating physician must review the laboratory results, determine clinical significance, and 
sign and date the report. Concomitant medications will be captured in the electronic 
medical record.
5.5
Follow-Up Evaluations
Follow-Up evaluations will be performed per AML or MDS standard of care as appropriate.
6.0 Criteria for Response
6.1
Response definition: 
6.1.1
For patients with documented morphological relapse at study entry:

2015-0117
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6.1.1.1 
Clinical response and hematological improvement for patients with 
myelodysplastic syndrome will be determined according to the 2006 
International Working Group recommendations.
6.1.1.1.1 
Complete remission (CR): Bone  marrow with </= 5% bone 
marrow blasts with normal maturation of all cell lines; a 
peripheral blood granulocyte count >/= 1 X 10
9/L and a 
platelet count >/= 100 x 10
9/L
6.1.1.1.2 
Marrow CR: Bone marrow has </=5% myeloblasts and 
decrease by >/=50% over pretreatment.
6.1.1.1.3 
Partial remission (PR): patients must demonstrate all CR 
criteria if abnormal before treatment except that marrow 
blasts should decrease by 50% or more compared with 
pretreatment levels, or patients may demonstrate a 
less-advanced MDS disease classification category than 
prior to treatment.
6.1.1.2   Clinical response for patients with acute myeloid leukemia will be 
based on revised recommendations of the 2003 International Working 
Group.
6.1.1.2.1 
Morphologic complete remission: Bone marrow with <5% 
blasts in the absence of extramedullary disease in 
addition to a peripheral blood granulocyte count >/= 1 X 
10
9/L and a platelet count >/= 100 x 10
9 /L.
6.1.1.2.2 
Partial remission (PR): This designation requires all of 
the hematologic values for a CR but with a decrease of 
at least 50% in the percentage of blasts to 5% to 25% in 
the bone marrow aspirate.
6.1.1.2.3 
Morphological complete remission with incomplete count 
recovery (CRi): Bone marrow blast count <5%. 
                                
6.1.2
For patients with persistent or recurrent disease by molecular, cytogenetic or flow 
cytometry findings without morphologic remission at study entry; disappearance of 
leukemia clone by repeat studies.
6.1.3    For cohort 3, response will be remaining in morphological remission without 
evidence of minimal residual disease by flow-cytometry, cytogenetics or molecular 
findings. 
6.2.
No response:
6.2.1
Any response less than a partial response.
6.3
Progression:
6.3.1
For patients with documented morphological relapse at study entry; bone marrow 
blast count more than 60% and/or new extramedullary sites.
6.3.2
For patients with persistent or recurrent disease by molecular, cytogenetic or flow 
cytometry findings despite morphologic remission at study entry; evidence of 
morphologic relapse.
6.3.3   For cohort 3, any disease progression with either morphological relapse and/or 

2015-0117
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Page 25
evidence of minimal residual disease with flow-cytometry, cytogenetics or 
molecular testing. 
7.0 Statistical Considerations
This is a single-arm phase IIA activity trial of SGI-110 in combination with or without DLI given 
post allogeneic stem cell transplant for patients with hematologic malignancies.  There will be 
three patient subgroups, patients with minimal residual disease (MRD), and patients who have 
relapsed (REL) and patients who receive SGI-110 as maintenance. The phase IIA design of 
Thall and Sung (41) will be used to monitor the response rate within each subgroup. In the MRD 
subgroup, response will be defined as resolution of MRD with SGI-110. In the REL subgroup, 
clinical response to SGI-110 for patients with myelodysplastic syndrome will be determined 
according to the 2006 International Working Group recommendations and for patients with 
acute myeloid leukemia will be based on revised recommendations of the 2003 International 
Working Group.  For the maintenance cohort (cohort #3), that will be relapse free survival at 
1-year. 
Disease and Treatment Regime. This is a single-arm phase IIA activity trial of SGI-110 in 
combination with or without DLI given post allogeneic stem cell transplant (allosct) for patients 
with hematologic malignancies.  There will be three patient subgroups. The first subgroup will 
be patients with minimal residual disease (MRD). The second subgroup will be patients who 
have relapsed (REL).  The third group will be high risk patients who will receive the intervention 
for maintenance.  The phase IIA design of Thall and Sung (41) will be used to monitor the 
response rate within each subgroup.  The two differences between the subgroups are in terms 
of (i) entry criteria and (ii) definition of response.
7.1  Cohort 1 and 2:  The same phase IIA design will be used for cohort 1 and 2, as follows: A 
response probability of .20 or larger will be considered promising. A maximum of 25 patients 
with will be treated in each group. Accrual will be stopped due to futility if less than or equal to 
0/8 or 1/20 responses are observed. A patient may have therapy temporarily postponed for up 
to 56 days due to toxicity. Any patient whose therapy has been started and later permanently 
discontinued due to the following will be counted as a treatment failure, that is, a non-responder: 
1) progressive disease, or 2) due to death, or 3) dropout, or 4) physician decision that it is futile 
to continue, or 5) severe toxicity prior to achieving disease remission. Patients who do not 
complete the first cycle of treatment will be considered as non-evaluable.  Secondary outcomes 
will include disease-free survival (DFS) time, overall survival (OS) time, graft-versus-host 
disease, safety and duration of remission.  Within each subgroup (MRD and REL), these events 
will be tabulated and the distributions of DFS and OS time estimated using the method of 
Kaplan and Meier (42).  
Patients with MRD.   In this subgroup, response will be defined as resolution of MRD, at any 
time point within the first 6 cycles of SGI-110 treatment.  A response probability of .20 or larger 
will be considered promising. A maximum of 25 patients with MRD will be treated. Denoting p = 
Pr(response), it will be assumed that p follows a beta(.20, .80) prior. Accrual will be stopped due 
to futility if Pr(p > .20 | data)  < .02.  This implies that accrual of patient with MRD will be stopped 
with SGI-110 declared not promising in these patients if less than or equal to 0/8 or 1/20 
responses are observed.  If necessary, accrual will be suspended after 8 or 20 patients have 
been treated in order to apply the stopping rule. For example, if there have been 0/7 responses 
and patient #8 has been treated but not yet been fully evaluated at 4 months, then accrual will 
be suspended until that patient’s outcome has been evaluated. If patient #8 has a response, 
then patients #9 - #20 may be treated. If patient #8 does not have a response, then accrual of 

2015-0117
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Page 26
MRD patients will be terminated. The operating characteristics of this rule are as follows.  
Computations were carried out in Multc99.
Table 1. Operating characteristics of the rule for monitoring response in MRD patients.
True Pr(Response)
Prob(Stop early)
Achieved Sample Size 
Quartiles
.05
.82
8  8  20  
.10
.54
8  20  25  
.15
.32
8  25  25  
.20
.18
25  25  25  
Patients who have relapsed (REL). In this subgroup, response will be defined as disease 
remission at any time point within the first 6 cycles of therapy with SGI-110.  Otherwise, the 
same design as that used in the MRD subgroup will be used.
7.2. High Risk Patients. This cohort will include high risk patients with one-year relapse 
incidence of 35%-45%. They will receive maintenance therapy with SGI for one year. A 
maximum of 40 patients will be enrolled. The primary endpoint for this cohort will be relapse-free 
survival (RFS) time.  The Bayesian method of Thall et al will be used to monitor RFS time in this 
cohort (41).  We denote the standard historical therapy by S and the experimental SGI-110 
therapy by E.  We assume that TS=time to disease progression or death in this cohort 
associated with standard therapy follows an exponential distribution with median mS and that 
TE=time to disease progression or death in these patients associated with the experimental 
SGI-110 therapy follows an exponential distribution with median mE.  We denote the median 
RFS times for the standard and experimental therapies by mS and mE, respectively.  Under a 
Bayesian model, both mS and mE are assumed to follow Inverse Gamma (a, b) priors, denoted 
IG(a, b).  From historical data, Pr(TS > 12 months) = .35, which implies that the historical 
median RFS = 7.9 months in this group under the assumption of exponentially distributed RFS 
times.  For priors, we assume that mS ~ IG (17.6, 131.2), which has mean = 7.9 months and 
variance = 4.0 months.  We assume that mE ~ IG (3, 15.8), which has the same mean = 7.9 
months but a much larger variance = 62.4.  We will monitor possibly right-censored TE 
continuously through the trial and will terminate accrual to this cohort if at any time:
Pr(mS < mE | data) < 0.07.
The accrual rate in this cohort is expected to be 2 patients per month.  We will follow patients 
until all patients in the cohort have been followed for two years after transplant.  We will enroll a 
maximum of 40 patients in this cohort.
Operating Characteristics. The operating characteristics of this stopping rule under the 
assumptions above were obtained by simulating the trial 2000 times each using the program 
One-Arm TTE v 3.0.6.  These are summarized the table below.
Operating Characteristics of the Stopping Rule for Maintenance Patients
True Median RFS 
(months)
True Pr (RFS > 12 
months)
Pr (Stop 
Early)
Mean Sample Size
4.4
.15
.827
21.8

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Page 27
6.0
.25
.339
32.5
7.9
.35
.103
37.3
10.4
.45
.036
39.0
13.9
.55
.009
39.7
Secondary outcomes. Secondary outcomes will include disease-free survival (DFS) time, 
relapse free survival (RFS), overall survival (OS) time, graft-versus-host disease, safety and 
duration of remission.   Within each subgroup, these events will be tabulated and the 
distributions of RFS and OS time estimated using the method of Kaplan and Meier (42).
7.3 Cross-over.  Patients treated on cohort #2 (patients with minimal residual disease while in 
morphological remission and cohort #3 (maintenance treatment cohort) will be allowed to 
receive higher doses of SGI-110 if they progress while on therapy with the study drug. Patients 
who are considered for cross-over to another study cohort due to progression of disease with an 
aim to receive higher doses of SGI-110 will be screened for the eligibility of that study cohort 
prior to initiation of higher doses of study drug.  The subgroup of cross-over patients will be 
followed for evaluation of subsequent outcomes, such as response OS, starting from the date of 
cross-over.
8.0 Adverse Events and Reporting Requirements
8.1  Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study.  It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria below), regardless of etiology.  Any worsening 
(ie, any clinically significant adverse change in the frequency or intensity of a pre-existing 
condition) should be considered an AE.  A diagnosis or syndrome should be recorded on the AE 
page of the eCRF rather than the individual signs or symptoms of the diagnosis or syndrome.
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product (IP) should be reported as an AE.  
If an overdose is associated with an AE, the overdose and AE should be reported as separate 
terms.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring of 
any or all of the following parameters:  the subject’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or other appropriate tests and 
procedures.
Related AEs will be recorded by the Investigator from the time the subject signs informed 
consent to 30 days after the last dose of IP.  The Investigator or physician designee is  
responsible for providing source documentation and assigning attribution for all AEs.  Only 
related adverse events and SAEs will be recorded on the AE page of the eCRF and in the 
subject’s source documents.  
Adverse events and protocol specific data will be entered into PDMS/CORe.  PDMS/CORe will 
be used as the electronic case report form for this protocol.

2015-0117
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All SAEs must be reported to Astex  Drug Safety within 24 hours of the investigator’s knowledge 
of the event by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form.
8.2
Evaluation of Adverse Events and Reporting to Astex Pharmaceuticals
A qualified Investigator will evaluate all AEs as to:
8.2.1 Seriousness
An SAE is any AE occurring at any dose that:
ꞏ
Results in death
ꞏ
Is life-threatening (ie, in the opinion of the investigator, the subject is at immediate risk of 
death from the AE)
ꞏ
Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization 
is defined as an inpatient admission, regardless of length of stay)
ꞏ
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions)
ꞏ
Is a congenital anomaly/birth defect
ꞏ
Constitutes an important medical event
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
ꞏ
A standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be reported as 
an SAE.
ꞏ
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
ꞏ
The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication of such 
transfusion remains a reportable SAE.
ꞏ
A procedure for protocol/disease-related investigations (e.g,, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable SAE.

2015-0117
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ꞏ
Hospitalization or prolongation of hospitalization for technical, practical, or social reasons, 
in absence of an AE.
ꞏ
A procedure that is planned (ie, planned prior to starting of treatment on study) must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
ꞏ
An elective treatment of a pre-existing condition unrelated to the studied indication.
ꞏ
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
Phase I          
Phase II  
Phase III
Phase I          
Phase II  
Phase III
Definitive Phase I          
Phase II
Phase I          
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I          
Phase II  
Phase III
Phase I          
Phase II
Phase I         
Phase II  
Phase III
Phase I          
Phase II  
Phase III
Phase I         
Phase II  
Phase I          
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I          
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Unlikely
Possible
Phase I          
Phase II
Probable
Grade 4
Phase I
Phase I
Phase I
Phase I
Phase I         
Phase II  
Grade 5
Recommended Adverse Event Recording Guidelines 
Unrelated
Phase I          
Phase II  
Phase III
Attribution
Grade 1
Grade 2
Grade 3
8.2.2
Severity / Intensity
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the currently active minor version of Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.0).
AEs that are not defined in the CTCAE should be evaluated for severity according to the 
following scale:
ꞏ
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
ꞏ
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required

2015-0117
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ꞏ
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
ꞏ
Grade 4 = Life threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable
ꞏ
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).  This criterion is not the same as “serious” 
which is
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
8.2.3
Causality
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
The temporal relationship of the AE to IP administration makes
a causal relationship unlikely or remote, or other
medications, therapeutic interventions, or underlying conditions provide 
a sufficient explanation for the observed event.
Suspected:
The temporal relationship of the AE to IP administration makes a 
causal relationship possible, and other medications, therapeutic 
interventions, or underlying conditions do not provide a sufficient 
explanation for the observed event.
8.2.4
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
8.2.5
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(e.g., discontinuation or reduction of IP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event.
8.2.6
Outcome
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered (death due to another 
cause) or death (due to the SAE).
8.2.7
Abnormal Laboratory Values

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An abnormal laboratory value is considered to be an AE if the abnormality:
ꞏ
results in discontinuation from the study;
ꞏ
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
ꞏ
is judged to be of significant clinical importance
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as an SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page/screen of the eCRF. If the 
abnormality was not
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the 
AE.
8.3
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  All SAEs must be reported to 
Astex Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, or 
other appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
The investigator is required to ensure that the data on these forms is accurate and consistent.
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the 
study (from the time the subject signs informed consent to 30 days after the last dose of IP), and 
those made known to the investigator at anytime thereafter that are suspected of being related 
to IP. Serious AEs occurring prior to treatment but after informed consent will be collected.
The SAE report should provide a detailed description of the SAE and include a summary of 
hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Astex Drug 
Safety as soon as these become available. Any follow-up data will be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Astex Drug Safety.
8.4
Discontinuations
The following events are considered sufficient reasons for discontinuing a subject from study 
treatment:
ꞏ
Disease progression and/or no response within the first 6 cycles of SGI-110 in addition to 
DLI as described in sections 4.2 and 6.0.
ꞏ
Related and unexpected serious Adverse event(s)
ꞏ
Development of grade III/IV acute GVHD or severe chronic GVHD 
ꞏ
Subject should receive the subsequent cycle within 70 days after the preceding cycle in 
cohort 2 and 3.  If subject on cohort 2 and 3 cannot receive the subsequent cycle in 70 
days, subject will be discontinued from study treatment.

2015-0117
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ꞏ
For patients on cohort 1, treatment cycles in the presence of disease (morphological 
relapse) can be delayed and subsequent cycles can be given at longer intervals at the 
discretion of treating physician and principal investigator. 
ꞏ        Withdrawal of consent
ꞏ
Death
ꞏ
Lost to follow up
ꞏ
The investigator determines that the discontinuation of treatment is in the best interest of 
the patient. 
ꞏ
60 days after the last cycle.
Although disease recurrence or progressive disease is considered a sufficient reason for 
discontinuing a subject from the study treatment, the investigator should consider continuing to 
treat the subject in attempt to hold the disease until the investigator has alternative therapies 
and considers the study treatment to be no longer beneficial to the subject, or the rapidity of 
change of disease state renders it unacceptable for further treatment in the judgment of the 
investigator.
The reason for discontinuation will be recorded in the eCRF and in the source document for all 
dosed subjects.
All subjects discontinued from study treatment for any reason will be followed further for GVHD 
status, progression to AML, and survival. Every attempt should be made to collect all data 
during the follow-up period unless subjects discontinue from the study.
8.5  
Serious Adverse Event Reporting (SAE)   
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes:
ꞏ
Death
ꞏ
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred in 
a more severe form, might have caused death.
ꞏ
Inpatient hospitalization or prolongation of existing hospitalization
ꞏ
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions.
ꞏ
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
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 (21 CFR 312.32).
ꞏ
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office.

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ꞏ
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”.  
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported 
to the IND Office, regardless of attribution (within 5 working days of knowledge of the event).
ꞏ
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of the 
event to the Safety Project Manager in the IND Office. 
ꞏ
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
ꞏ
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event.
ꞏ
Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy.
Reporting to FDA:
ꞏ
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32.
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy.
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