Conditions: Untreated Adult Acute Myeloid Leukemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well guadecitabine with or without idarubicin or cladribine works in treating older patients with previously untreated acute myeloid leukemia. Guadecitabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin and cladribine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether guadecitabine with or without idarubicin or cladribine is more effective in treating older patients with previously untreated acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the complete remission (CR) rate, remission duration, leukemia-free survival, and survival in patients \>= 70 years with previously untreated acute myeloid leukemia (AML) with 4 different guadecitabine (SGI-110) single agent and SGI-110 based combination regimens.

II. To determine the safety profile and tolerability of the 4 SGI-110 single agent and SGI-110 based combination regimens in patients \>= 70 years of age with previously untreated AML.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I:

INDUCTION THERAPY: Patients receive guadecitabine subcutaneously (SC) on days 1-5. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CR with incomplete platelet recovery (CRp) continue on to Maintenance therapy; patients not achieving CR or complete remission with incomplete hematologic recovery (CRi) but deriving clinical benefit may continue to Maintenance therapy at the discretion of the Principal Investigator (PI).

MAINTENANCE THERAPY: Patients receive guadecitabine as in Induction therapy. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

ARM II (CLOSED):

INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-10. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI.

MAINTENANCE THERAPY: Patients receive guadecitabine SC on days 1-5 (days 1-10 of courses 1 and 2). Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

ARM III:

INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-5 and idarubicin intravenously (IV) over up to 1 hour on days 1-2. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI.

MAINTENANCE THERAPY: Patients receive guadecitabine SC on days 1-5 and idarubicin IV over up to 1 hour on day 1. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

ARM IV (CLOSED):

INDUCTION THERAPY: Patients receive guadecitabine SC and cladribine IV over up to 1 hour on days 1-5. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI.

MAINTENANCE THERAPY: Patients receive guadecitabine SC and cladribine IV over up to 1 hour on days 1-5. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every month.

Arms:
arm 1: INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-5. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI.

MAINTENANCE THERAPY: Patients receive guadecitabine as in Induction therapy. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. arm 2: INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-10. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI.

MAINTENANCE THERAPY: Patients receive guadecitabine SC on days 1-5 (days 1-10 of courses 1 and 2). Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. arm 3: INDUCTION THERAPY: Patients receive guadecitabine SC on days 1-5 and idarubicin IV over up to 1 hour on days 1-2. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI.

MAINTENANCE THERAPY: Patients receive guadecitabine SC on days 1-5 and idarubicin IV over up to 1 hour on day 1. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. arm 4: INDUCTION THERPAY: Patients receive guadecitabine SC and cladribine IV over up to 1 hour on days 1-5. Courses repeat every 4-6 weeks for 2-3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a CR or CRp continue on to Maintenance therapy; patients not achieving CR or CRi but deriving clinical benefit may continue to Maintenance therapy at the discretion of the PI.

MAINTENANCE THERAPY: Patients receive guadecitabine SC and cladribine IV over up to 1 hour on days 1-5. Courses repeat every 4-8 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cladribine intervention 2: Guadecitabine intervention 3: Idarubicin
Intervention descriptions: intervention 1: Given IV intervention 2: Given SC intervention 3: Given IV

Protocol document:
Prot_SAP_000.pdf: 
 
 
2013-0843 
 
 
Revised 02-03-2017 
 
1 
 
 
Four-Arm Randomized Phase II Study of SGI-110: 5 days, versus 10 days, versus 
5 days + idarubicin, versus 5 days + cladribine, in Previously Untreated Patients ≥ 
70  Years with Acute Myeloid Leukemia  
 
2013-0843 
 
 
 
Short Title  
4-Arm Randomized Phase II Study of SGI-110 in elderly  AML 
 
Study Chair:  
 
Hagop Kantarjian 
  
Additional Contact: Xuelin Huang, Graciela Nogueras-Gonzalez 
 
Department: 
Leukemia 
Phone: 
713-745-4613 
 
Unit: 
 
428 
Study Co-Chair(s): 
 
Guillermo Garcia-Manero 
 
 
 
 
Protocol Type: 
Standard Protocol 
Protocol Phase: 
Phase II 
 
 
 
Version: 
01 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table of Contents 
1.0  
Objectives ......................................................................................................................... 3 
2.0  
Background ...................................................................................................................... 3 
3.0 
Background Drug Information ......................................................................................... 6 
4.0  
Patient Eligibility ............................................................................................................ 11 
5.0 
Treatment Plan .............................................................................................................. 12 
6.0 
Pretreatment evaluation ................................................................................................ 14 
7.0 
Evaluation during Study ................................................................................................. 14 
8.0 
Criteria for Response ..................................................................................................... 15 
9.0 
Criteria for Discontinuation of Therapy ......................................................................... 16 
10.0 
Statistical Considerations ............................................................................................... 16 
11.0 
Reporting Requirements ................................................................................................ 19 
12.0      References ..................................................................................................................... 22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1.0  
Objectives 
 
1.1 
To determine the complete remission (CR) rate, remission duration, leukemia-free 
survival, and survival in patients > 70 years with previously untreated AML with 4 different 
SGI-110 single agent and SGI-110 based combination regimens.  
 
1.2 
To determine the safety profile and tolerability of the 4 SGI-110 single agent and SGI-110 
based combination regimens in patients > 70 years of age with previously untreated 
AML. 
 
2.0  
Background 
 
2.1  
The Diseases 
 
Acute myeloid leukemia (AML) accounts for approximately 25% of all cases of leukemia 
diagnosed in the Western hemisphere. It is a clonal myelopoietic stem cell disorder characterized 
by the accumulation of neoplastic cells in the bone marrow and in the peripheral circulation. Age-
adjusted incidence ranges from 1 per 100,000 in people < 20 years to 10 per 100,000 in the 
elderly. Current induction chemotherapy protocols combining cytarabine and an anthracycline 
administered as first-line treatment induce complete remissions in a majority (55% to 75%) of 
patients. Standard consolidation therapy with high doses of cytarabine leads to improved survival. 
Between 50% and 70% of patients, however, can be expected to relapse, so that only about 30% 
attain long-term disease-free survival. 
 
Age is a major factor that determines the prognosis of patients with untreated AML. The treatment 
of acute myeloid leukemia (AML) in older patients has not improved significantly in recent years 
when compared with the considerable progress that has been made in younger patients (1-3). 
AML occurring in patients > 60 years of age continues to be associated with an extremely poor 
prognosis. Using a standard induction combination such as the “3+7” regimen (ara-C plus an 
anthracycline), the complete remission (CR) rate is 40% to 50%, the mortality 20% to 40%, and 
remission durations are usually transient and rarely last more than 12 months. The median time 
from treatment with the “3+7” regimen to death is 5 to 10 months and less than 10% of patients 
stay in remission at 3 years (4). Patients who are ≥ 70 years of age in particular tolerate 3+7 
induction regimen very poorly with even worse results [20]). The reasons for this difference in 
outcome when compared to younger patients are multiple. Differences in the biology of AML in 
older patients is reflected by a higher proportion of patients with an unfavorable karyotype, a 
higher rate of  primary drug resistance associated with overexpression of P-glycoprotein (P-gp), 
and an increased frequency of disease evolution from a preexisting and at time probably 
unrecognized myelodysplasia. Poorer tolerance of combination chemotherapy regimens leads to 
the use of less intensive treatment protocols (5). It is clear that several aspects of therapy in this 
group of patients require improvement. The development of new and effective anti-AML agents, 
however, remains a cornerstone of the continued efforts to improve the outcome of poor-
prognosis patients. As the principal cause of treatment failure in older patients is resistant AML 
(manifested by short CR durations or failure to enter CR), investigational strategies should focus 
primarily on this problem and the introduction of new agents is warranted. 
 
2.2 
The Treatment - SGI-110 4-arm study 
 
For the most updated SGI-110 clinical data, please refer to the most recent SGI-110 
Investigators’ Brochure. 
 


 
 
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SGI-110 is a novel second generation hypomethylating agent which has been rationally 
synthesized to increase the half-life of its metabolite, decitabine, and to improve on the 
hypomethylation efficacy. SGI-110 has undergone completed Phase I studies. Phase 2 studies 
using SGI-110 60mg/m2 versus 90mg/m2 daily for 5 days are ongoing in newly diagnosed MDS 
and AML and in MDS salvage. SGI-110 60mg/m2 daily x 10 is undergoing evaluation in AML 
salvage. The results so far appear very encouraging demonstrating longer half-life of the 
decitabine metabolite, better hypomethylation capacity with SGI-110 compared with previous data 
with Dacogen (commercial decitabine), significant anti-MDS and anti-AML efficacy, and minimal 
side effects (6,7). 
 
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 SGI-110 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 60mg/m2 dose, while clinical MTD was defined at 90mg/m2 
dose. Therefore the Phase II study proceeded to compare 60 versus 90mg/m2 daily for 5 days in 
newly diagnosed MDS and AML. A further arm investigated SGI-110 60mg/m2 daily x 10 days in 
AML salvage. Finally SGI-110 60mg/m2 daily x 5 is being evaluated in patients with MDS and 
progression on azacitabine/SGI-110 therapy (6). 
 
The Phase II randomized study of the biologic effective dose 60mg/m2 daily x 5 and clinical 
Phase II dose 90mg/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/m2 dose (32 patients) or 90 mg/m2 
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 


 
 
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Revised 02-03-2017 
 
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(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 (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/m2 
doses (8 remissions in 32 patients at 60 mg/m2, and 9 remissions in 35 patients at 90 
mg/m2).  LINE-1 DNA methylation data before and after treatment was available in 50 (75%) 
patients enrolled.  LINE-1 demethylation ≥ 10% post treatment was observed in 83% and 78% in 
the 60 mg/m2 and 90 mg/m2, 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 (7). 
 
2.3 Rationale for the Proposed Regimen in Elderly AML 
 
Up to 50 patients older than age 65 with newly diagnosed AML were treated in the previously 
described Phase II studies under 2.2. The early results are impressive in terms of CR and marrow 
CR rates. In our institutional experience, 9 of the first 12 patients treated achieved remissions. 
This is significant in this elderly AML population. We are therefore proposing an investigator 
initiated IND study to gain further experience with different SGI-110 regimens. This will help in the 
Phase III design of the potential FDA pivotal trial which will evaluate SGI-110 based therapy 
versus best standard of care in patients who cannot tolerate intensive chemotherapy. We will 
restrict the evaluation in the study to patients 70 years or older, since there is little argument that 
such patients do not benefit from intensive anti-AML therapy. Since we do not know whether 5 or 
10 days of hypomethylator therapy is better, we propose to include 2 arms, one using single-
agent SGI-110 60mg/m2 SQ daily x 5, and the second using SGI-110 60mg/m2 SQ daily x 10. 
We wish also to explore, in this pilot experience SGI combinations. Anthracyclines are historically 
effective in AML; therefore a third arm will evaluate SGI-110 60mg/m2 SQ daily x 5 with idarubicin 
at the low-dose 6mg/m2 daily x 2. Finally, cladribine, an old drug with single-agent efficacy in 
AML, was found to be an effective hypomethylating agent . Therefore combining SGI-110 with 
cladribine at low-doses may improve the anti-AML and hypomethylation efficacy. The fourth arm 
will combine SGI-110 60mg/m2 SQ daily x 5 with cladribine 3mg/m2 daily x 5. 
 
2.4 Update of January 27, 2017 
 
As of February 2017, 34 patients have been treated on study. The complete response in the 4 
treatment arms are as follows: 4 out of 8 patients responded in the SGI-110 for 5 days arm; 5 out 
of 9 patients responded in the SGI-110 for 10 days arm;  7 out of 8 patients responded in the 
SGI+idarubicin arm and 3 out of 9 patients responded in the SGI+cladribine. 
 
In addition, Astex, the sponsoring company, conducted a separate multi-institutional study of SGI-
110 60mg/m2 for 5 and 10 days in older patients with newly diagnosed AML who were not 
candidates for intensive chemotherapy (8). A total of 103 patients were treated, 51 patients were 
treated on the 5-day and 52 patients were treated on the 10-day regimens. The characteristics of 
the 2 study groups were well-balanced. Overall the CR rates were 19/51 = 37% on the 5-day 
regimen and 16/52 = 31% on the 10-day regimen. The overall response rates were 57% and 
48%, respectively. The median survival were 10.5 months on the 5-day regimen and 9.5 months 
on the 10-day regimen (p=0.70). Side-effects, including myelosuppression, were similar in the 2 
study groups. The 60-days all-cause mortality was also similar between the two study groups.  


 
 
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The study concludes that both schedules (SGI-110 given in 5-day and SGI-110 given in 10-day) 
were similar (8). 
 
Based on the above findings, and after discussion with the Biostatistical collaborators, Dr. Xuelin 
Huang and Graciela M. Nogueras-Gonzalez, it was decided to close the 2 arms of SGI-110 for 10 
days (based on the Astex study)and SGI-110 + cladribine (low CR rate),and continue the study, 
with the same Bayesian statistical design, only in the 2 arms of SGI-110 for 5 days and SGI-110 
+idarubicin. 
 
 
3.0 
Background Drug Information 
 
3.1  
SGI-110 
 
Further information is available in the Investigator Brochure. 
 
3.1.1 General Information 
 
The active metabolite of SGI-110 (2’-deoxy-5-azacytidylyl-(3’→5’)-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 decitabine. 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. 
 
 
3.1.2 Summary of Nonclinical Data 
 
a. 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. 
 
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 
 


 
 
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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 μM and 1 μM treatment (Figure 1). In the figure 
noted above and any subsequent places in this document, S110 is the same as SGI-110. At 10 μM 
concentrations, only a small decrease in methylation was noted, probably due to side effects of high 
drug concentrations. In fact, 10 μM 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. 
 
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 


 
 
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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. 
 
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. 
 
Figure 3:  
SGI-110 and decitabine Activity and Body Weight Loss in HL-60 
Promyelocytic Leukemia 
 
 
C. 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 μM 
and 300 μM.  
 
SGI-110 inhibited hERG current by 1.4 ± 0.3% (mean ± SEM) at 10 μM and by 1.0 ± 1.3% 300 μM. 
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 μM. 
 


 
 
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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 unobserved-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. 
 
3.1.3 
Risks of SGI-110 single agent and combination with idarubicin  
 
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.  
 
Risks of idarubicin described below in the subsequent sections.  
 
There is no available clinical data for the combination of SGI-110 with idarubicin but the only 
overlapping toxicity of all 3 agents is myelosuppression which should be well-monitored and 
managed during the first cycle. This is also why the study proposes the use of only a fraction of 
the commercially and clinically full doses of idarubicin in combination with the full dose of SGI-
110.  
 
 
3.1.4  
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 SGI-110.  
 
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. 
 


 
 
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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 
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.  
 
  
  3.2   Idarubicin 
 
 
Idarubicin is commercially available.  Please see package insert for further information. 
 
Synonyms 4-Demethoxydaunorubicin; 4-DMDR, Idarubicin Hydrochloride, IDR: IMI30; NSC-
256439, SC 33428 
 
Use Treatment of acute leukemias (AML, ANLL, ALL), accelerated phase or blast crisis of chronic 
myelogenous leukemia (CML), breast cancer 
 
Contraindications Hypersensitivity to idarubicin, other anthracyclines, or any component of the 
formulation; bilirubin >5 mg/dl; pregnancy 
 
Warnings/Precautions The U.S. Food and Drug Administration (FDA) currently recommends that 
procedures for proper handling and disposal of antineoplastic agents be considered.  Can cause 
myocardial toxicity and is more common in patients who have previously received anthracyclines or 
have pre-existing cardiac disease; reduce dose in patients with impaired hepatic function. 
The Investigator will ensure that any used and unused vials of study drug and other study material 
will be destroyed or returned to the Sponsor on completion of the study. 
 
 
Adverse Reactions 
>10% 
 
Cardiovascular: Transient EKG abnormalities (supraventricular tachycardia, S-T wave changes, 
atrial or ventricular extrasystoles); generally asymptomatic and self-limiting.  Congestive heart 
failure, dose-related.  The relative cardiotoxicity of idarubicin compared to doxorubicin is unclear.  
Some investigators report no increase in cardiac toxicity at cumulative oral idarubicin doses up to 
540 mg/m2; other reports suggest a maximum cumulative intravenous dose of 150 mg/m2.   
 
Central nervous system: Headache  
 
Dermatologic: Alopecia (25% to 30%), radiation recall, skin rash (11%), urticaria 
 
Gastrointestinal: Nausea, vomiting (30% to 60%); diarrhea (9% to 22%); stomatitis (11%); GI 
hemorrhage (30%) 
 
Genitourinary:  Discoloration of urine (darker yellow) 
 
Hematologic: Myelosuppression, primarily leukopenia; thrombocytopenia and anemia.  Effects are 
generally less severe with oral dosing 
Nadir:  10-15 days 
Recovery:  21-28 days 
 


 
 
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Hepactic:  Elevations of bilirubin and transaminases (44%) 1% to 10% 
 
Central nervous system: Seizures 
 
Neuromuscular & skeletal: Peripheral neuropathy <1%: Hyperuricemia 
 
Overdosage/Toxicology Symptoms of overdose include severe myelosuppression and 
increased GI toxicity.  Treatment is supportive.  It is unlikely that therapeutic efficacy or toxicity 
would be altered by conventional peritoneal or hemodialysis. 
 
Drug Interactions Patients may experience impaired immune response to vaccines; possible 
infection after administration of live vaccines in patients receiving immunosuppressants  
 
Stability Store intact vials of solution under refrigeration (2°C to 8°C/36°F to 46°F); protect from 
light.  Solutions diluted in D5W or NS for infusion are stable for 4 weeks at room temperature and 
7 days under refrigeration. 
 
Mechanism of Action Similar to doxorubicin and daunorubicin; inhibition of DNA and RNA 
synthesis by intercalation between DNA base pairs 
 
Extravasation management: Topical cooling may be achieved using ice packs or cooling with 
circulating ice water. Cooling of site for 24 hours as tolerated by the patient.  Elevate and rest 
extremity 24-48 hours, then resume normal activity as tolerated.  Application of cold inhibits 
vesicant's cytotoxicity. Application of heat can be harmful and is contraindicated.  If pain, 
erythema, and/or swelling persist beyond 48 hours, refer patient immediately to plastic surgeon 
for consultation and possible debridement. 
 
4.0  
Patient Eligibility 
 
Inclusion: 
 
4.1 
Previously untreated AML patients, except those who have received prior therapy with 
hydroxyurea, single agent chemotherapy (e.g. decitabine), hematopoietic growth factors, 
biological or targeted therapies are allowed. 
4.2 
Age > 70 years. 
4.3 
ECOG performance status ≤ 2. 
4.4 
Sign a written informed consent form. 
4.5 
Adequate liver function (total bilirubin < 2mg/dL, SGPT or SGOT < x 4 ULN) and renal 
function creatinine clearance of > 50 mL/min (estimated by the Cockroft-Gault [C-G] 
formula). 
4.6 
Male patients must use an effective contraceptive method during the study and for a 
minimum of 8 weeks after study treatment. 
4.7 
Baseline LVEF >/= 40%. 
 
 
Exclusion: 
 
4.8 
Patients with ≥ NYHA grade 3 heart disease as assessed by history and/or physical 
examination. 


 
 
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4.9        Patients who received more than one full course of prior hypomethylating agents 
azacitidine or decitabine 
4.10      Have any other severe concurrent disease, or have a history of serious organ dysfunction 
or disease involving the heart, kidney, liver, or other organ system that may place the 
patient at undue risk to undergo treatment. 
 
4.11  
Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined 
as exhibiting ongoing signs/symptoms related to the infection and without improvement, 
despite appropriate antibiotics or other treatment). 
 
4.12  
Pregnant or lactating patients. 
 
4.13 
Any significant concurrent disease, illness, or psychiatric disorder that would compromise 
patient safety or compliance, interfere with consent, study participation, follow up, or 
interpretation of study results. 
 
4.14 
Any concurrent malignancy (with the exception of exclusion # 4.15) 
 
4.15 
Exceptions to # 4.14: a) Patients with treated non-melanoma skin cancer, in situ 
carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, 
are eligible for this study if definitive treatment for the condition has been completed; b) 
Patients with organ-confined prostate cancer with no evidence of recurrent or progressive 
disease based on prostate-specific antigen (PSA) values are also eligible for this study if 
hormonal therapy has been initiated or a radical prostatectomy has been performed. 
        
 
5.0 
Treatment Plan 
 
 
 
5.1  
Schedule 
 
 
 
Patients are randomized between 2 treatment arms: 
 
 
Induction: 
 
A) SGI-110 60mg/m2 subcutaneously (SQ) daily x 5 
B) SGI-110 60 mg/m2 SQ daily x 5 + idarubicin 6mg/m2 IV daily x 2 
 
 
Cycles will be repeated every 4 to 6 weeks or longer as indicated by leukemia recurrence 
or recovery of normal hematopoiesis. Since efficacy from epigenetic treatment with 
agents such as SGI-110 may take longer to manifest, it is recommended that patients 
receive at least 2 courses of the above regimens regardless of their response. 
  
 
If a patient does not achieve a CR or CRi after a maximum of 3 induction courses, the 
patient will be taken off study unless the patient is deriving clinical benefit at which time 
continuation of protocol therapy will be allowed with prior PI approval. 
 
 
Maintenance: 
 
 
Patients who achieve a CR or CRp during induction may receive up to 24 months of 
maintenance therapy every 4 to 8 weeks. The maintenance arm will be the same as the 
induction arm e.g. patients who are induced on on SGI-110 + idarubicin are also 
maintained with SGI-110 + idarubicin. 


 
 
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A) SGI-110 60mg/m2 SQ daily x 5 
B) SGI-110 60mg/m2 SQ daily x 5 + idarubicin 6 mg/m2 IV on Day 1 
 
 
 
 
Patient may receive follow up laboratory tests from their local physician.  
 
All protocol-specific treatment decisions will be made by MD Anderson physician. 
 
The PI/treating physician must review all outside lab results, determine the clinical 
significance and sign/date the report. 
 
  
 
 
5.2 
Dose Modifications 
 
 
Induction: 
 
 
If a second induction course is considered, doses of each drug should be reduced by 25% for 
grade 3 drug-related non-hematological toxicities. Doses should be reduced by 50% for grade 4 
drug-related non-hematological toxicities and/or life-threatening infections. 
 
 
Maintenance: 
 
 
Prior to each maintenance cycle, the ANC should be > 1.0 x 109/L and the platelet count > 60 x 
109/L, except for patients who are considered to have achieved a CRp following induction and in 
whom a platelet count of < 60 x 109/L will be allowed to continue. In addition, any 
nonhematological toxicity experienced by the patient must return to < grade 2 or baseline before 
the patient continues treatment with the study drugs. Doses missed or held during a cycle of 
treatment will not be made up and are recorded as being omitted. If a patient experiences 
multiple toxicities, dose adjustments will be based on the most severe toxicity. 
 
 
Doses of SGI-110 and idarubicin may be reduced according to the following criteria: 
- 
grade 3-4 (severe) drug-related nonhematologic toxicities (including life-threatening infections), 
or prolonged myelosuppression (hypocellular marrow [<10%] and failure to recover the absolute 
neutrophil count [ANC] ≥1,000 and platelet count ≥ 60,000 by day 42): reduce both drugs by 25-
33% as per Table below. 
 
 
 
 
 
 
Once doses have been reduced for drug-related non-hematologic toxicities, they should not be  
 
increased later on unless it is decided that the toxicity has completely resolved; was not drug- 
 
related; or that the benefit outweigh the risk. 
 
 
Dose reductions are not necessary for alopecia, drug-related fever, fatigue, electrolyte  
 
abnormalities, or nausea/vomiting that can be controlled with supportive care measures. 
 
Left Ventricular Ejection Fraction should be done to monitor for congestive heart failure in 
patients receiving idarubicin following induction. . 
 
 
All other dose modifications outside the above mentioned suggestions and which are 
considered to be in the best interest of the individual patient should be discussed with the 
Principal Investigator. 
 
Dose level 
SGI-110 
 
Idarubicin 
Start-0 
60mg/m2 
 
6mg/m2 
-1 level 
45mg/m2 
 
4mg/m2 
-2 level 
30mg/m2 
 
3mg/m2 


 
 
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In general, in the combination arms, if those reductions are necessitated as described above, 
the doses of idarubicin may be reduced without reducing the SGI-110 doses.  
 
 
Dose reductions other than the above may be considered if judged to be in the best interest of 
the patient. These include reductions in the number of days of SGI-110 or idarubicin if judged 
indicated, such modifications must however be discussed with and approved by the primary 
investigator. 
 
All drug dose modifications will be clearly documented in the medical record to verify 
compliance with the protocol. 
 
 
5.3 
Concomitant Therapy 
 
 
Necessary supportive measures for optimal medical care will be given throughout the study as 
determined by the treating physician and the patient’s medical need. No concomitant 
chemotherapy (with the exception of prophylactic intrathecal therapy), immunotherapy, or therapy 
with monoclonal antibodies will be allowed during this study. Investigational agents that are not 
used for treatment of the leukemia per se (e.g. anti-infective prophylaxis or therapy) will be 
allowed. No concomitant medications will be captured as part of the protocol data. 
 
 
Use of a colony-stimulating factor (e.g., G-CSF, GM-CSF, or erythropoietin) is at the discretion of 
the treating physician and is permitted if judged in the patient’s best medical interest. 
 
 
Prophylactic antibiotics, antifungals, and antiviral agents (e.g., levofloxacin, itraconazole, 
valacylovir, etc.) are recommended; however, the use of these or other drugs will be left to the 
treating physician’s discretion. 
 
6.0 
Pretreatment evaluation  
 
History and physical, CBC with differential and platelets, Chemistry profile (at least creatinine, 
SGOT or SGPT, total bilirubin) within 14 days of therapy start. 
 
Bone marrow aspirate and/or biopsy within 30 days of therapy start. The bone marrow evaluation 
will include cytogenetic studies, if not done in previous 3 months. 
 
Pregnancy (urine or blood) test for women of childbearing potential within two weeks of start of 
therapy. Child bearing potential is defined as not post-menopausal for 12 months or no previous 
surgical sterilization.  
 
Baseline LVEF. 
 
7.0 
Evaluation during Study 
 
 
 
On Day 1 (+/- 7 days) of every cycle, the following tests and procedures will be performed: 
• 
You will have a physical exam, including measurement of your weight 
• 
Vital signs. 
• 
Your performance status will be recorded. 
 


 
 
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CBC with differential and platelet counts at least once a week until remission, then every 2 to 4 
weeks during therapy, and every 4 to 8 weeks thereafter as long as on study. No differential is 
needed if the WBC is < 1.0 x 109/L. 
 
Chemistry profile (at least creatinine, SGOT or SGPT, total bilirubin) at least weekly until 
remission, then every 4 to 8 weeks during therapy. 
 
Bone marrow aspirate and/or biopsy starting on day 28 (± 7 days) of therapy  
and then every 2 weeks (± 7 days) as required by leukemia evolution until  
remission or non-response. Bone marrow tests can be ordered more frequently if  
mandated by development of peripheral blood counts. No repeat bone marrow is  
necessary if non-response or progressive disease can be unequivocally  
diagnosed from peripheral blood tests, or, in patients with a WBC < 0.3 if the  
bone marrow test is considered non-contributory by the investigator at any time  
point (±2 days). 
 
LVEF every 3-4 cycles as indicated. 
 
Optional. Blood 10cc pre-treatment, on Days 1 and 15 (+/- 2 days) of the first course to  
evaluate epigenetic modulation. (This will cover both the 5-day and 10-day regimens) 
 
 
 
Follow-up Visits 
After your last dose of study drug (after completion of all therapies), you will have follow-up visits. 
You will only have these visits if the disease has responded to the study drug. This can be done at 
home through your local cancer doctor as indicated (usually visit + routine CBC and chemistries 
every 2-3 months). Approximately every 6 months, you will return to Houston for a physical exam 
and blood (about 1 tablespoon) will be drawn for routine tests: 
 
 
Chemistry profile (at least creatinine, SGOT or SGPT, total bilirubin). 
 
 
 
8.0 
Criteria for Response 
 
8.1 
Complete Remission (CR):  
 
  . Neutrophil count > 1.0 x 109/L and platelet count > 100 x 109/L, and normal bone 
marrow differential (< 5% blasts) 
 
8.2 
Complete Remission without blood count recovery (CRi): Peripheral blood and bone 
marrow results as for CR, but with platelet counts of < 100 x 109/L or ANC < 1.0 x 109/L  
 
8.3 
Partial Remission (PR): 
 Blood count recovery as for CR, but with both a decrease in marrow blasts of at least 
50% and not more than 6 to 25% abnormal cells in the marrow. 
 
8.4 
Early mortality: Death within 14 days of first dose. 
 
8.5 
Patients who achieve a CR or CRp during induction may receive up to 24 months of 
maintenance therapy every 4 to 8 weeks 
 


 
 
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8.6 
Prior to each maintenance cycle, the ANC should be > 1.0 x 109/L and the platelet count 
> 60 x 109/L, except for patients who are considered to have achieved a CRp following 
induction and in whom a platelet count of < 60 x 109/L will be allowed to continue. 
 
9.0 
Criteria for Discontinuation of Therapy 
 
 
 
Patients can be discontinued from the study under the following conditions: 
 
9.1 
Patient’s physician considers a change of therapy would be in the best interest of the 
patient. 
9.2 
Patient requests discontinuation or withdraws consent. 
9.3 
There is unacceptable toxicity (e.g., grade 4 nonhematologic toxicity), not controlled with 
dose adjustments. 
9.4 
There is a need for any treatment not allowed by the protocol. 
9.5 
Investigator determines that the patient has progressive disease after sufficient induction 
therapy. 
 
 
  
Every 6 months, you will return to Houston for a physical exam and blood (about 1 tablespoon) 
will be drawn for routine tests. 
 
 
10.0 Statistical Considerations 
 
 
 
10.1.1 Update of the General Description/Sample Size February 01, 2017 
 
This is a Phase II with 2 parallel arms study of SGI-110 in patients with newly diagnosed AML >/= 
70 years of age. The primary objective is to obtain an initial assessment of efficacy for the two 
SGI-110 regimens in this patient group: 
 
1) SGI-110 single-agent for 5 days. 
2) SGI-110 for 5 days combination with idarubicin for 2 days. 
 
For each arm, we will enroll 20 patients. When all the arms have 20 patients then to be able to enroll 
more patients after the first 20 patients they have to satisfy the following rules: 1) there is more than 95% 
chance that the grade 3-4 non-hematological toxicity rate doesn’t exceed 30%. 2) there is less than 10% 
chance that the 8-week mortality exceeds 15% and 3) there is more than 2.5% chance that the CR rate 
(CR+CRi) is more than 30%. 
 
The arm or arms with the satisfying monitor rules above will continue to enroll an additional 20 patients. 
This will be decided through an interim analysis discussion with the Leukemia experts and the modality 
experts coordinating the study. 
 
 
Complete Remission monitoring 
 
The primary endpoint is the complete remission rate (CRR) evaluated after at least 2 cycles but 
would also be evaluated after 4 and 6 cycles if the patient is stable or improving.  We have a 
target CRR of 30%, while a CRR of 15% is considered unacceptable. We will monitor complete 
remission using the Bayesian approach of Thall et al. [19].The probability of complete remission 


 
 
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is denoted by PCR. We assume PCR ~ beta (0.6, 1.4).  Our stopping rule is given by the following 
probability statement: Pr (PCR > 0.30 | data) < 0.025. That is, we will stop the study if, at any time 
during the study, we determine that there is less than 2.5% chance that the CRR is more than 
30%. This stopping rule will be applied in each arm.   The stopping boundaries for complete 
remission, based on these assumptions and monitoring conditions are found in Table 1. We will 
apply these stopping boundaries starting from the first patient and in cohorts of 10. For example, 
accrual will cease if only 2 patients experiences complete remission among in the first 20 patients 
treated. The operating characteristics are summarized in Table 2. Both the decision rule and 
operating characteristics were calculated using the stopbound procedure in Stata 
version12.1. 
 
Table 1. Stopping boundaries for Complete Remission (separately for each arm) 
 
The number of patients evaluated for complete remission 
10 
20 
30 
40 
The number of patients with complete remission 
0 
</=2 
</=4 
</=6 
 
Table 2. Operating characteristics for Complete Remission (separately for each arm) 
True Complete  
Remission Rate 
Early  
Stopping  
Probability 
Sample Size 
25th percentile Median 
75th percentile 
0.15 
0.5994 
20 
30 
40 
0.20 
0.3303 
30 
40 
40 
0.25 
0.1528 
40 
40 
40 
0.30 
0.0670 
40 
40 
40 
0.35 
0.0255 
40 
40 
40 
0.40 
0.0087 
40 
40 
40 
Toxicity Monitoring  
 
We will monitor toxicity using the Bayesian approach of Thall et al. [19].  A toxicity is defined as 
grade 3 or higher non-hematological toxicity occurring during the first two cycles. 
Following are the rules for the monitoring of toxicities. The probability of toxicities is denoted by 
PT. We assume PT ~ beta (0.6, 1.4).  Our stopping rule is given by the following probability 
statement: Pr (PT > 0.30 | data) > 0.95. That is, we will stop the study if, at any time during the 
study, we determine that there is more than 95% chance that the toxicity is more than 30%. This 
stopping rule will be applied in each arm. The stopping boundaries for toxicities, based on these 
assumptions and monitoring conditions is found in Table 3. We will apply these stopping 
boundaries starting from the first patient and in cohorts of 5. For example, accrual will cease if 4 
patients experiences toxicities among in the first 5 patients treated. The operating characteristics 
are summarized in Table 4. Both the decision rule and operating characteristics were 
calculated using the stopbound procedure in Stata version12.1. 
 
Table 3. Stopping boundaries for Toxicities (separately for each arm) 
 
The number of patients evaluated  
for toxicities 
5 
10 
15 
20 
25 
30 
35 
40 
The number of patients with toxicities 
4 
6 
8 
10 
12 
14 
16 
18 
 
Table 4. Operating characteristics for Toxicity Monitoring (separately 
for each arm) 
 
True Toxicity Rate 
Early  
Sample Size 


 
 
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Stopping  
Probability 
25th percentile Median 75th percentile 
0.10 
0.0005 
40 
40 
40 
0.20 
0.0149 
40 
40 
40 
0.30 
0.1247 
40 
40 
40 
0.40 
0.4581 
15 
40 
40 
0.50 
0.8272 
10 
15 
40 
 
 
Mortality Monitoring  
 
We will monitor 8-week mortality using the Bayesian approach of Thall et al. [19]. Following are 
the rules for the monitoring of 8-week mortality. The probability of 8-week mortality is denoted by 
PM. We assume PM ~ beta (0.3, 1.7).  Our stopping rule is given by the following probability 
statement: Pr (PM > 0.15 | data) > 0.90. That is, we will stop the study if, at any time during the 
study, we determine that there is more than 90% chance that the 8-week mortality is more than 
15%. This stopping rule will be applied in each arm. The stopping boundaries for 8-week 
mortality, based on these assumptions and monitoring conditions is found in Table 5. We will 
apply these stopping boundaries starting from the first patient and in cohorts of 5. For example, 
accrual will cease if 3 patients died during the first 8 weeks among in the first 5 patients treated. 
The operating characteristics are summarized in Table 6. Both the decision rule and 
operating characteristics were calculated using the stopbound procedure in Stata 
version12.1. 
 
 
 
Table 5. Stopping boundaries for Mortality (separately for each arm) 
 
The number of patients evaluated  
for mortality 
5 
10 
15 
20 
25 
30 
35 
40 
The number of patients died  
during the first 8 weeks 
3 
4 
5 
6 
7 
8 
9 
10 
 
Table 6. Operating characteristics for Mortality Monitoring (separately for each arm) 
 
True Mortality Rate 
Early  
Stopping  
Probability 
Sample Size 
25th percentile Median 
75th percentile 
0.05 
0.0029 
40 
40 
40 
0.10 
0.0298 
40 
40 
40 
0.15 
0.1552 
40 
40 
40 
0.20 
0.3790 
20 
40 
40 
0.25 
0.6341 
10 
25 
40 
 
Statistical Analysis Plan 
 
 
All patients who received at least 1 dose of the agent will be included in the intent-to-treat 
analysis for efficacy and safety.  Demographic/clinical characteristics and safety data of the 
patients will be summarized using descriptive statistics such as mean, standard deviation, median 
and range (i.e. remission duration). Complete remission rates (CRR) will be presented with 95% 
confidence intervals. The association between CRR and patient and clinical characteristics will be 


 
 
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examined by Wilcoxon’s rank sum test or Fisher’s exact test. Survival time will be estimated using 
the Kaplan-Meier method. Patients who drop out of the study will be included in the time to event 
data as “censored data”.  The two-sided log-rank test will be used to assess the differences of 
time to events between groups. 
 
 
10.2 
Treatment Assignment and Stopping Rules 
 
Patients will be assigned to receive either of the 2 regimens. The randomization will be balanced 
1:1 to each of the treatment arms.  
 
 
11.0 Reporting Requirements 
 
             11.1 See Appendix C for guidelines for reporting ADR’s to the IRB. 
 
Adverse events will be graded using CTCAE version 4.03 (Appendix D ) 
 
The investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all subjects 
enrolled on the trial. 
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. 
This study will be monitored by the MD Anderson IND Office and a protocol-specific monitoring 
plan will be followed. 
 
Study Drugs  
The Investigator is responsible for ensuring the study drugs are administered or dispensed only to 
subjects enrolled in the study. The Investigator will ensure that any used and unused vials of 
study drug and other study material will be destroyed locally (by our research pharmacy) or 
returned to the Sponsor on completion of the study. 
 
 
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:  
• 
Death 
• 
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. 
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• 
A congenital anomaly/birth defect. 


 
 
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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). 
• 
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. 
• 
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). 
 
• 
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.  
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
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. 
• 
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: 
• 
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. 
Investigator Communication with Supporting Companies: 
 
11.2 
Reporting to Astex Drug Safety.  The Sponsor-Investigator will notify Astex, as 
designated holder of the global safety database, of any Serious Adverse Event 
(SAE), pregnancy, or infant exposure, including those events reported to the 
Sponsor-Investigator by his/her Investigators, whether related to Study Drug or not, 
within twenty-four (24) hours of being made aware of the SAE. Such notification will 


 
 
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be provided to Astex by faxing the information contained in the exemplar Serious 
Adverse Event Report Form, which is appended to the Protocol, to the Astex Drug 
Safety Department 
Astex Drug Safety SAE Reporting Fax Number 
Local Fax:  925-551-3226  
North America Toll-Free Fax:  800-576-6568 
A copy of the correspondence sent to the FDA [or other controlling regulatory 
authority] shall be sent within twenty-four (24) hours to Astex Regulatory Affairs by 
email or fax: 
Astex Regulatory Affairs email: david.smith@astx.com  
Astex Regulatory Affairs Fax Number: 925.551.6491 
Disputed SAEs. Even if the Sponsor-Investigator decides not to report an event, 
Astex may make its own determination that it is a reportable Serious Adverse 
Event, and may report it. 
Reporting to FDA.  The Sponsor-Investigator shall be responsible for notifying the 
FDA [or other controlling regulatory authority] within fifteen (15) calendar days, or 
seven (7) calendar days if fatal or life threatening, or according to local 
requirements if the local requirements are more strict, of any and all events that are 
both Serious and Unexpected Adverse Events and that are considered related to 
the Study Drug, including those events reported to the Sponsor-Investigator by 
Investigators from his/her Participating Centers.  
 
 


 
 
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12.0   References 
 
 
1. 
Estey E. Prognostic factors in cancer clinical trials. Clin Cancer Res 3: 2591, 1997. 
2. 
Hiddemann W, et al. Management of acute myeloid leukemia in elderly patients. J Clin 
Oncol 17: 3569, 1999. 
3. 
Goldstone AH, et al., on behalf of the Medical Research Council Adult Leukaemia 
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