Clinical trial NCT01498445
Conditions: Leukemia
Keywords: Leukemia Chronic myelogenous leukemia Chronic myeloid leukemia CML Accelerated phase Blastic phase Dasatinib BMS-354825 Sprycel Decitabine Dacogen
Sponsor: M.D. Anderson Cancer Center
Start date: 2012-06-12; Completion date: 2019-09-24
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if combining Sprycel (dasatinib) and Dacogen (decitabine) can help to control Chronic Myeloid Leukemia (CML). The dose level of decitabine will also be studied.

Dasatinib is designed to block the protein that is responsible for chronic myeloid leukemia.

Decitabine is designed to affect the mechanism that cells use to control the expression of certain genes, some of which are important in the progression of CML.

This is an investigational study. Dasatinib is FDA approved and commercially available for the treatment of patients with certain types of CML.

Decitabine is FDA approved for the treatment of patients with myelodysplastic syndrome.

The combination of these drugs to treat CML is investigational.

Up to 84 patients will take part in this study. All will be enrolled at MD Anderson.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group and dose level based on when you join this study and the side effects that are seen. Your doctor will discuss this with you in more detail.

There will be up to 5 doses of dasatinib tested in Phase 1. The first 3 participants will receive a lower dose of therapy. If no major side effects are seen in these participants, the next participants will receive a higher dose. Once a dose is identified that is well-tolerated for most participants, that dose will be used for all new participants. If you are in Phase 2, you will receive a dose level tested in Phase 1.

You will receive one of 2 doses of decitabine. What dose you receive is determined by chance (like a coin toss).

Study Administration:

Each cycle is 28 days.

You will take dasatinib by mouth 1 time a day.

You will receive decitabine by vein for 10 days of each cycle. If the doctor thinks it is in your best interest, you may receive decitabine for fewer days each cycle (5 days instead of 10 days). Your doctor will decide how many doses you will take based on side effects you may have and the status of the disease.

If you have severe side effects from the study drug, the study doctor may decide to stop drug dosing until your side effects improve.

You will be asked to keep a study diary that will be reviewed at scheduled study visits. In the diary, you will record when you take the study drug.

Study Visits:

At every visit, you will be asked about any side effects you may have had and to list any drugs you may be taking.

Every week for the first 3 cycles and then every 2-4 weeks after that, blood (about 1 tablespoon) will be drawn to check your blood cell counts.

About 1 week after your first dose, you will have an ECG.

Every 1-2 weeks for the first 3 cycles and then every 4-8 weeks after that, blood (about 1 tablespoon) will be drawn to test your kidney and liver function.

Every 1-3 months, blood (about 1 tablespoon) will be drawn for genetic testing.

Before the start of Cycle 2, every 2-4 cycles after that for the first year, and then every 6 cycles after that, you will have a complete physical exam.

Before the start of Cycle 2, every 3 cycles after that during the first year, then every 4-6 cycles (as needed) you will have a bone marrow aspirate to check the status of the disease.

After Cycle 6, the number of blood draws and bone marrow collections may be changed.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Arms: arm 1: Less Intensive, Schedule A1 Dasatinib 100 mg daily by mouth ; Decitabine 10 mg/m\^2 by vein over 1 hour daily for 10 days; 28 day cycle. arm 2: More Intensive, Schedule A2: Dasatinib 100 mg daily by mouth ; Decitabine ose 20 mg/m\^2 by vein over 1 hour daily for 10 days; 28 day cycle. arm 3: Less Intensive, Schedule B1 Dasatinib 140 mg daily by mouth ; Decitabine 10 mg/m\^2 by vein over 1 hour daily for 10 days; 28 day cycle. arm 4: More Intensive, Schedule B2 Dasatinib 140 mg daily by mouth ; Decitabine 20 mg/m\^2 by vein over 1 hour daily for 10 days; 28 day cycle. arm 5: Less Intensive, Schedule B1 Dasatinib 140 mg daily by mouth; Decitabine e 10 mg/m\^2 by vein over 1 hour daily for 10 days; 28 day cycle. arm 6: More Intensive, Schedule B2 Dasatinib140 mg daily by mouth; Decitabine 20 mg/m\^2 by vein over 1 hour daily for 10 days; 28 day cycle.
Interventions: intervention 1: Dasatinib intervention 2: Decitabine intervention 3: Decitabine
Intervention descriptions: intervention 1: Starting Dose: 100 mg by mouth once daily of a 28 day cycle. intervention 2: Starting Dose (less intensive group) Schedule A: 10 mg/m2 by vein daily for 10 days of a 28 day cycle. intervention 3: Starting Dose (more intensive group) Schedule B: 20 mg/m2 by vein daily for 10 days of a 28 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
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AN OPEN-LABEL, PHASE I/II STUDY OF TWO DIFFERENT SCHEDULES 
OF DASATINIB (SPRYCEL) AND DECITABINE (DACOGEN) USED IN 
COMBINATION FOR PATIENTS WITH ACCELERATED OR BLASTIC 
PHASE CHRONIC MYELOGENOUS LEUKEMIA (Protocol CA180357) 
PI: Jorge Cortes 
Department of Leukemia 
The University of Texas, MD Anderson Cancer Center 
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1.0 
OBJECTIVES AND ENDPOINTS 
 
 
1.1 
Objectives 
 
1.1.1 Primary Objectives  
a) For phase I: To define the maximally tolerated dose (up to the target 
dose) of the combination of dasatinib (Sprycel) and decitabine (5-
aza-deoxycitidine; Dacogen) in patients with chronic myelogenous 
leukemia (CML) in the accelerated (AP) or blastic (BP) phases. 
 
b) For phase II: To assess the efficacy, measured as the response to 
therapy during the first 3 months of therapy, of the combination of 
dasatinib and decitabine in patients with CML in AP or blastic BP 
phases.  
 
1.1.2 Secondary Objectives  
a) To determine the duration of response and survival with the 
combination of dasatinib and decitabine in advanced phase CML. 
 
b) To establish the toxicity of the combination of dasatinib and 
decitabine therapy.  
 
c) To determine the effects on gene methylation of decitabine given in 
combination with dasatinib. 
 
 
1.2 
Endpoints 
 
1.2.1 Primary Endpoints 
a) Phase I: To determine the MTD (up to the target dose) with the 
combination of dasatinib and decitabine in CML-AP or CML-BP. 
 
b) Phase II: To determine the hematologic response (HR) rate with the 
combination of dasatinib and decitabine in CML-AP or CML-BP.  
 
1.2.2 Secondary Endpoints  
a) To document the rate of major cytogenetic response (MCyR), 
duration of response, and survival (overall survival and progression-
free survival) of patients with CML-AP or CML-BP treated with 
dasatinib and decitabine. 
 
b) To determine the nature, incidence, and severity of adverse events, 
as determined by physical exam and laboratory assessment, of the 
combination of dasatinib and decitabine.  
 
c) Assessment of decitabine-induced demethylation of p15, H19, and 
ABL1 genes in peripheral blood and/or marrow leukemic cells 
obtained from patients enrolled in the present study. 
 
2.0 
BACKGROUND 
 
 
2.1 
The Disease 
 
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CML is a fatal disease characterized by clonal expansion of myeloid progenitor 
cells.  The worldwide incidence of CML is 1-2 cases per 100,000, and CML 
accounts for one-fifth of all leukemias.1  In the United States there are almost 
5000 new cases annually.  The median age of diagnosis is between 45-55 years 
of age with approximately 10% of cases occurring before the age of 20.  
However one-third of patients are over the age of 60 making some treatment 
options more difficult.  CML is slightly more prevalent in males than in females 
(1.3:1).1-5 
 
As a consequence of the translocation of chromosomes 9 and 22 (the 
Philadelphia chromosome), the BCR (breakpoint cluster region) gene on 
chromosome 22 is fused to the ABL1 gene on chromosome 9. The result is the 
generation of the hybrid BCR-ABL1 oncogene, which encodes the fusion BCR-
ABL1 oncoprotein. BCR-ABL1 acts as a constitutively activated tyrosine kinase 
whose activity is central in the pathogenesis of CML. In addition, the subcellular 
localization of this hybrid Abl tyrosine kinase is altered, resulting in its 
cytoplasmic location. The BCR breakpoint site varies creating fusion proteins of 
variable sizes.  The p210BCR-ABL1 fusion protein is seen mainly in CML with a 
minority of CML patients having a p230BCR-ABL protein. A smaller p190BCR-
ABL1 protein is found in Philadelphia chromosome-positive acute lymphoblastic 
leukemia (Ph+ ALL). 2, 6, 7 
 
Most patients with CML, about 85%, are diagnosed during the chronic phase 
(CML-CP) of the disease. Clinical presentation during this phase includes 
fatigue, weight loss, bleeding, purpura, splenomegaly, leukocytosis or 
thrombocytosis, and anemia.   Left untreated, CML-CP lasts 3 to 5 years.8, 9 
Over time, cells bearing the BCR-ABL1 fusion gene acquire additional genetic 
abnormalities (i.e., genomic instability) and undergo clonal expansion, thus 
setting the stage for CML progression. Whilst most patients may progress quite 
rapidly to CML-BP, most do somewhat more gradually, through an accelerated 
stage of the disease (i.e., CML-AP), which may last for months or years, before 
a CML-BP ensues.  
  
During CML-AP, patients increase the percentage of blastic cells in both bone 
marrow and peripheral blood, and they become more symptomatic and 
frequently present with fever, bone pain, and hepatosplenomegaly.  The 
duration of CML-AP is variable but frequently short-lived, lasting an average of 
6 to 18 months. The clinical importance of CML-AP is that it quickly proceeds 
into blast crisis, the final aggressive stage of the disease.  About a quarter of 
patients may rapidly progress from diagnosis of CML to CML-BP without 
evidence of AP.3, 8 
 
CML-BP is defined by the presence of >30% blasts in the bone marrow and/or 
peripheral blood.  Patients suffer from increasing symptoms of anemia, 
bleeding, infections, lymphadenopathy and leukostasis. Patients with CML-BP 
have an extremely poor prognosis with a median survival of only 3-6 months.  
CML-BP is clinically similar to acute leukemia, including a remarkable resistance 
to standard chemotherapeutic agents. In CML-BP, the bone marrow is 
hypercellular with blast cells. Interestingly blast crisis can have a myeloid 
(50%) phenotype, lymphoid (25%), or mixed phenotype (25%).3, 8 
 
 
2.2  
Treatment of CML 
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There are multiple treatment options for CML-CP. Hydroxyurea (500-2000 
mg/day PO) or busulfan (2000-6000 mg/day PO) have been used for many 
years as oral chemotherapy to control high white blood cell counts, and prolong 
survival in patients with CML.  Neither of these agents can prevent the 
progression from CML-CP to CML-BP.    
 
Interferon-alfa-2a (IFN-α) has been shown in many trials to be effective in the 
treatment of CML. The exact therapeutic mechanism of IFN-α is not known.  It 
is speculated that it may have an antiproliferative effect on CML progenitor cells 
or it may restore normal regulatory control of CML cells. IFN-α appears to be 
superior to chemotherapy. The 5-year survival of patients with CML treated 
with IFN-α was 57% and only 42% for those who received chemotherapy. In 
addition 80% of patients achieve a complete hematological response (CHR), 
50% of patients achieve a cytogenetic response, and >25% of patients 
complete disappearance of Philadelphia chromosome-positive cells.1, 10, 11 In 
CML-AP, IFN-α appears to have no added benefit. Hence, attempts have been 
made to combine IFN-α with ara-C for better efficacy, but unfortunately these 
have led to increased toxicity.1, 10, 11 
 
Stem cell transplantation or bone marrow transplantation is another effective 
treatment for CML. In selected cases, it represents a curative treatment, but 
its use is associated with significant morbidity and mortality. Transplantation-
related mortality varies from 5% to 50% depending on several factors including 
the age of the patient, CML phase, degree of compatibility, CMV status, and the 
experience of the center where the transplantation is performed. Most patients 
with CML are ineligible for transplantation, as a matched related or unrelated 
donor is not available. In addition, transplantation is less effective when used 
in advanced phase CML (i.e., CML-AP or CML-BP).2, 12 
 
Imatinib mesylate (Gleevec) is a tyrosine kinase inhibitor (TKI) that specifically 
targets BCR-ABL1 kinase and results in remarkable clinical response rates.13-15  
While the drug is highly active in CML-CP, being associated with a >90% 
response rate, fewer responses are seen in CML-AP or CML-BC, with most of 
these responses being often transient in nature. In CML-BC, for example, 1-
year survival is only 25% in patients treated with imatinib alone.16 These data 
suggest that the drug is relatively ineffective in advanced phase CML, likely as 
a result of additional genetic and epigenetic changes. 
 
Dasatinib (Sprycel) and Nilotinib (Tasigna) are second generation TKIs which 
are 300- and 30-fold respectively more potent than imatinib against BCR-ABL1 
kinase.17 Phase II studies of dasatinib and nilotinib have shown that most 
patients with CML-CP resistant or intolerant to imatinib therapy respond to 
second generation TKI therapy.18, 19 In addition, therapy with either nilotinib or 
dasatinib has been associated with higher response rates compared with single-
agent imatinib in patients with CML-AP and CML-BP.20, 21  
 
 
 
2.2.1 Dasatinib in CML 
 
Dasatinib is a multityrosine kinase inhibitor with activity against BCR-
ABL1, the SRC family of kinases (SFKs), c-KIT, EPHA2, and platelet-
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derived growth factor (PDGFR-β) at nanomolar concentrations.17 
Dasatinib was tested in phase I study in 84 patients with any phase of 
CML or Ph+ ALL and hematologic resistance or intolerance to imatinib.22 
Of these, 63 were dosed on a twice a day schedule with total daily doses 
ranging from 50 to 240 mg, and 21 received dasatinib once daily, with 
doses ranging from 15 to 180 mg. Over 40% of all treated patients 
attained major hematologic and/or cytogenetic responses, with most 
responses occurring at doses between 100 and 140 mg daily. The MTD 
was not defined, and the phase II dose (70 mg twice daily) was based 
primarily on efficacy rather than safety criteria.22  
Four different ongoing single-arm phase II studies of dasatinib have 
enrolled a total of 445 patients. Most patients had received prior 
cytotoxic chemotherapy and were imatinib resistant. Therapy consisted 
of dasatinib 70 mg twice daily given continuously. The FDA Drug 
Application was based on interim analyses from these phase II studies, 
in which all patients had a minimum follow-up of 6 months.23 Median 
duration of treatment ranged from 5.6 months for patients with CML-CP 
to 2.8 months for those with lymphoid CML-BP.  The primary efficacy 
end-point for CML-CP was major cytogenetic response (MCyR), which 
comprises 
complete 
cytogenetic 
response 
(CCyR) 
and 
partial 
cytogenetic response (PCyR). The primary efficacy end-point for CML-
AP, CML-BP, and Ph+ ALL was major hematologic response (MHR), 
which comprises CHR and no evidence of leukemia (NEL). In CML-CP, 
the MCyR rate was 45% with a CCyR rate of 33%. MCyR rates were 
59%, 32%, 31%, and 42% in patients with CML-AP, myeloid CML-BP, 
lymphoid CML-BP, and 42% in Ph+ ALL, respectively. 
Table 1. Efficacy of dasatinib in phase II single-arm trials 
  
CP       
(n=186) 
AP       
(n=107) 
Myeloid 
BP 
(n=74) 
Lymphoid 
BP 
(n=42) 
Ph+ 
ALL    
(n=36) 
Response 
rate 
  
  
  
  
  
CHR (95% 
CI) 
90     (85-
94) 
33    (24-
42) 
24    
(15-36) 
26       (14-
42) 
31   (16-
48) 
MCyR (95% 
CI) 
45    (37-
52) 
31    (22-
41) 
30    
(20-42) 
50       (34-
66) 
58  (41-
74) 
CCyR (95% 
CI) 
33    (26-
40) 
21    (14-
30) 
27    
(17-39) 
43       (28-
59) 
58  (41-
74) 
Despite the high response rate achieved in all phases, the duration of 
response is short for patients treated in accelerated or blast phase. 
While progression-free survival for patients in chronic treated with 
dasatinib is 80% at 2 years, it is only 46% for those treated in 
accelerated phase, and the median is only 3 to 6 months for those 
treated in blast phase. 
The 
most 
common 
treatment-related 
adverse 
events 
were 
gastrointestinal (e.g., diarrhea, nausea, vomiting, anorexia, and 
abdominal pain), constitutional (e.g., pyrexia, headache, fatigue, and 
asthenia), fluid retention, and bleeding events. Myelosuppression was 
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common in all patient populations. Baseline grade 3-4 neutropenia and 
thrombocytopenia were reported in 7% to 31% and 1% to 58% of 
patients, respectively. Forty percent of the safety population 
experienced bleeding events of any type, and 10% experienced grade 3 
or 4 bleeding. Fatal brain hemorrhages tended to occur in patients with 
blast-phase disease in the setting of grade 4 thrombocytopenia. 
Approximately 50% of the patients experienced fluid retention, which 
was grade 3-4 in 9%. Pleural effusion was reported in 22% of patients 
across all studies and was grade 3-4 in 5%. Grade 3-4 pericardial 
effusion, pulmonary edema, ascites, and generalized edema were each 
reported in 1%.  
The FDA granted dasatinib accelerated approval for the treatment of 
adults with CML in all phases with resistance or intolerance to prior 
therapy including imatinib. The approval was based on cytogenetic or 
hematologic responses.23  
 
2.2.2  Decitabine 
 
Decitabine is a deoxycytidine analog with demonstrated antineoplastic 
activity against murine leukemias, which is more potent than ara-C, 
against murine leukemias.  Decitabine is phosphorylated to its 
nucleotide prior to DNA incorporation.24 Once incorporated, it produces 
marked DNA hypomethylation (superior to Azacytidine in this effect) via 
inhibition of DNA methyltransferase. At high doses, it appears to cause 
DNA 
synthesis 
arrest 
due 
to 
covalent 
linkage 
with 
DNA-
Methyltransferases (Mtase), which results in cytotoxicity and apoptosis. 
At low doses, however, minimal cytotoxicity is observed, and the treated 
cells exhibit marked reduction in Mtase activity, reduced overall and 
gene-specific DNA methylation and reactivation of silenced genes. This 
is associated with tumor suppressor gene activation, induction of cellular 
differentiation, and inhibition of clonogenic growth of leukemia 
progenitors. Decitabine also 1) induces a stable increase of HLA-class I 
RNA transcripts and 2) interacts additively or synergistically with several 
biological modifiers such as IFN-α and retinoic acid in induction of 
differentiation and loss of clonogenicity. 
 
Clinical Experience with Low-Dose Decitabine at M.D. Anderson 
Cancer Center 
 
Based on in vitro data suggesting greater hypomethylating activity at 
lower doses, a phase I biological study of decitabine was initiated at 
M.D. Anderson Cancer Center that accrued 48 patients with myeloid 
malignancies (35 AML, 7 MDS, 5 CML, 1 ALL) over a period of two 
years.25 In order to maximize the hypomethylating effects of decitabine, 
multiple low dose schedules in patients with relapsed/refractory myeloid 
malignancies were tried.  Initially, patients were treated at 5 mg/m2 IV 
over 1 hour daily for 10 days (dose 30 folds lower than the reported 
MTD). The dose was then escalated to 10, 15 and 20 mg/m2 daily for 
10 days. Finally, a group of patients received 15 mg/m2 daily for 15 days 
then 20 days. Of the 39 patients enrolled onto the study, 3 did not 
complete the first course (one due to sepsis and death on day 2 and two 
due to rapidly rising counts) and therefore were excluded from analyses. 
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Responses were seen at all dose levels, but 15 mg/m2 appeared to 
induce the most responses, with no further benefit for increasing the 
dose or duration of administration. The overall response rate was 32%, 
including 9 complete remissions (CR; 18%) and 1 partial remission (PR; 
2%). Seven additional patients had significant reductions in peripheral 
and/or bone marrow blasts but did not recover normal hematopoiesis. 
Responses were seen in refractory/relapsed acute myeloid leukemia 
(AML; 10/30), myelodysplastic syndrome (MDS; 3/4), and CML (2/2). 
These responses were confirmed in an additional cohort of 10 patients 
treated at 15 mg/m2 in the phase II component of the study. Overall, 5 
patients with CML were treated. Two were in BP, refractory to imatinib, 
and one of these had a CHR and PCyR after one cycle. Of the other three 
patients (previously untreated with imatinib), one had a partial 
response, one had a CHR and CCyR and one was taken off study early 
and is not evaluable for response. In most patients who responded, 
there was a very gradual diminution of blasts over 2-4 weeks, and 
eventual recovery of normal hematopoiesis at 4-5 weeks, suggesting a 
non-cytotoxic mode of action for this regimen Response duration ranged 
from 2 months to 10+ months. Of the 6 patients who achieved a clinical 
response and had baseline and on-treatment samples available, only 2 
were methylated (1 had a CR, 1 had a PR), and these had not changed 
methylation at days 5 or 12 after therapy. Therefore low-dose decitabine 
is an effective agent in myeloid malignancies. The effective low dose 
administration schedule derived from this phase I study is 15 mg/m2 IV 
over 1 hour daily for 10 days. 
 
In a recent study, three different schedules of decitabine aimed at 
delivering a dose of 100 mg/m2 have been investigated in 95 patients 
with MDS following a Bayesian adaptive design: (1) 10 mg/m2 
intravenously over 1 hour daily for 10 days; (2) 20 mg/m2 intravenously 
over 1 hour daily for 5 days; and (3) 20 mg/m2 subcutaneously daily for 
5 days. In this study, decitabine was given every 4 weeks (rather than 
6 to 8 weeks) regardless of counts, as long as there was persistent 
disease and no significant myelosuppression-associated complications. 
Importantly, therapy was continued for at least 3 courses before 
evaluating response or failure on therapy. The 5-day IV schedule was 
selected as the optimal single-agent dose, with 39% of patients 
achieving a complete remission, compared with 21% in the 5-day 
subcutaneous arm and 24% in the 10-day IV arm (p<0.05). The high 
dose-intensity arm was also superior at inducing hypomethylation at day 
5 and at activating p15 expression. Grade 3-4 drug-related 
extramedullary toxicities were uncommon, and included transient liver 
toxicities (mostly elevations of liver enzymes) in 4 patients (4%) and 
other in 1 patient (1%). Myelosuppression-related complications 
occurred in approximately 15% of patients. 
 
Clinical Experience with Decitabine in CML at M.D. Anderson 
Cancer Center 
 
A phase II trial of decitabine was conducted in 123 with Ph-positive CML 
(64 BP, 51 AP, 8 CP) and 7 with Ph-negative CML at M.D. Anderson 
Cancer Center.26 Initially, patients were treated at 100 mg/m2 q12h for 
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5 days (1000 mg/m2 per course) but the dose had to be reduced initially 
by 25% and eventually by 50% (100 mg/m2) because of prolonged 
myelosuppression.  
 
Table 2. Number of patients treated at each dose schedule of 
decitabine by CML phase (n=130) 
 
Decitabine        
(mg/m2 IV over 6 
hrs q12hrs for 5 
days) 
No. treated 
BP 
AP 
CP 
Ph-
negative 
Total 
100 
9 
4 
0 
0 
13 
75 
13 
17 
0 
3 
33 
50 
42 
30 
8 
4 
84 
 
Most patients (n=84) received decitabine at 50 mg/m2, including 42 
patients with CML-BP and 30 CML-AP. Table 3 illustrates the responses 
obtained with decitabine by CML phase. 
 
Table 3.  Response to decitabine by CML phase in a phase II 
clinical trial 
 
Response 
CML Phase 
AP 
BP 
No. (%) 
No. (%) 
Complete hematologic 
response 
12 (24) 
6 (9) 
Cytogenetic response 
 
 
Complete 
3 (6) 
0 (0) 
Partial 
3 (6) 
2 (3) 
Minor 
3 (6) 
3 (5) 
Partial hematologic 
response 
1 (2) 
2 (3) 
Hematologic 
improvement 
10 (20) 
7 (11) 
Second chronic phase 
3 (6) 
3 (5) 
Induction death 
3 (6) 
3 (5) 
Primary resistance 
0 (0) 
20 (31) 
Secondary resistance 
7 (14) 
23 (36) 
 
Unique features of decitabine in this setting were (1) a slow pattern of 
reduction of blasts, (2) a rapid rise in platelets following therapy and (3) 
occasional responses late into therapy (after 2 cycles). These suggested 
that responses to decitabine might involve a differentiation component, 
similar to what was observed with other differentiating agents in 
leukemia. A subset analysis of older (>50) patients in CML-BP showed 
that decitabine therapy resulted in a better survival than historical 
controls treated with combination chemotherapy.  
In a subsequent phase II study, a low-dose of decitabine (15 mg/m2 IV 
over 1 hour daily, 5 days a week for 2 weeks) was administered to 35 
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patients with imatinib-resistant or –intolerant CML (12 CP, 17 AP, and 6 
BP).27 CHR was reported in 12 (34%) patients and partial hematologic 
response in 7 (20%) patients, for an overall hematologic response rate 
of 54% (83% in CP, 41% in AP, and 34% in BP). McyR was observed in 
6 (17%) patients, and mCyR in 10 (29%) patients, for an overall 
cytogenetic response rate of 46%. Median response duration was 3.5 
months (range, 2 to 13+ months). Neutropenic fever was reported in 
28 (23%) of 124 decitabine courses. LINE1 methylation decreased from 
71.3% ±1.4% to 60.7% ±1.4% after 1 week, 50.9% ±2.4% after 2 
weeks, and returned to 66.5% ±2.7% at recovery of counts (median, 
46 days). At day 12, the decrease in methylation was 14.5% ±3.0% vs 
26.8% ±2.7% in responders vs nonresponders (p= .007).27 
In an attempt to improve on the response rates obtained with decitabine 
as single-agent, a phase II study was conducted in which low-dose 
decitabine was combined with the BCR-ABL1 kinase inhibitor imatinib 
mesylate.28 Twenty-eight patients were treated (25 with imatinib 
resistance; 18 in AP, 10 in BP) with decitabine 15 mg/m2 IV daily, 5 days 
per week for 2 weeks and imatinib 600 mg orally daily. A median of 2.5 
cycles per patient were administered. Hematologic responses were 
observed in 43% of patients (32% with CHR), with a median duration 
of response 18 weeks (range, 4 to 107). A major cytogenetic response 
was attained by 18% of patients. A decrease in methylation assessed 
by long interspersed nucleotide element (LINE) bisulfite/pyrosequencing 
assay tended to be greater in nonresponders than in responders on days 
5 and 12.28 Hematologic responses were significantly more frequent in 
patients with no BCR-ABL1 kinase mutations (53%) than in those with 
mutations (14%), suggesting that synergy between decitabine and 
imatinib may depend on residual sensitivity to imatinib. 
 
2.2.3  Rationale for the Combination Use of Dasatinib and Decitabine 
 
In previous studies we have shown that single-agent decitabine is an 
active therapy in CML-AP and CML-BP.26 We have also shown that 
responses to decitabine in advanced phase CML are accompanied by 
demethylation and reactivation of the p15 cyclin-dependent kinase 
inhibitor. Furthermore, these responses can be achieved with low-dose 
decitabine.26 The activity of dasatinib, a potent BCR-ABL1 and SFKs, is 
currently being investigated in phase II and III studies in patients with 
CML in all phases. Dasatinib has proved the most effective single agent 
in patients with CML-BP.21 In addition, synergy has been reported 
between dasatinib and TKI (particularly imatinib) in imatinib-resistant 
cell lines.29  Based on these data, we propose the hypothesis that the 
combination of dasatinib and decitabine will be a more effective regimen 
in CML-AP and CML-BP than either drug alone, by targeting different 
aspects of the biology of advanced phase CML simultaneously. We 
propose that decitabine is active in advanced phase CML through its 
ability to demethylate and reactivate genes silenced during disease 
progression, while dasatinib is most effective against CML cells whose 
proliferation is highly dependent on the activity of the BCR-ABL1 kinase. 
Furthermore, dasatinib has shown remarkable activity against CML-AP 
and CML-BP (particularly in patients with lymphoid CML-BP), and it is 
possible that its potent inhibitory effect against SFKs may play a role.21 
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In addition, decitabine may cause epigenetic (DNA demethylation) 
changes, which may enhance the sensitivity of CML cells to TKIs such 
as dasatinib. We then propose to combine the two drugs and test the 
hypothesis that the combination will result in a higher response rate and 
more durable responses than either drug alone. We will also measure 
toxicity and induction of demethylation as well as gene reactivation by 
this combination. In the clinical trial of decitabine + imatinib in imatinib 
resistant patients, the greatest clinical benefit was seen in those patients 
without mutations, suggesting that residual sensitivity to the TKI greatly 
enhances the response rate to the combination. Because dasatinib is 
more active in most patients with BCR-ABL mutations, the combination 
of decitabine + dasatinib would be predicted to be particularly effective. 
 
3.0 
BACKGROUND DRUG INFORMATION 
 
3.1 
Dasatinib 
 
Dasatinib is manufactured and distributed by Bristol-Myers Squibb.  It has been 
approved by the FDA for the treatment of all phases of CML after failure of 
imatinib therapy, and for patients in chronic phase as initial therapy. 
 
Pharmaceutical Data: dasatinib is provided by Bristol-Myers Squibb as 70 mg, 
50 mg, and 20 mg capsules packaged in bottles.  Medication labels will comply 
with the legal requirements of each country and will be printed in the local 
language 
 
Stability and Storage Requirements: the storage conditions for dasatinib will be 
described on the medication label.  Bottles must be stored in a safe, secure 
location at 25°C (77°F). 
 
Route of Administration: Oral. 
 
Special Precautions:  dasatinib is a local irritant and must be taken in a sitting 
position with a large (250 mL) glass of water.  This direction is noted on the 
medication label. 
 
Known Side Effects and Toxicities: dasatinib was generally well-tolerated in 
phase II studies involving patients with CML in all phases. The most frequently 
encountered side effects include fluid retention syndromes, diarrhea, headache, 
skin rash, nausea, hemorrhage, fatigue, dyspnea, bone and joint aches, and 
vomiting. 
 
Drug Disposal:  Unused/expired drug will be disposed of onsite following 
institutional guidelines. 
 
 
Table 4.  Adverse effects reported in more than 10% of all patients in 
clinical studies of dasatinib 
 
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3.2 
Decitabine 
 
Decitabine is manufactured by MGI Pharma, Inc. It has been approved by the 
FDA for the treatment of myelodysplastic syndrome. 
 
Description:  decitabine is an analog of 2'-deoxycytidine with a nitrogen atom 
substituted for carbon at the 5-position of the ring. 
 
Other Names:  deoxyazacytidine; 5-aza-2'deoxycytidine, DAC. 
 
How Supplied: freeze-dried power for injection, 50 mg in 20 ml vials. 
 
Solution Preparation: when reconstituted with 10 mL of sterile water for 
injection each ml will contain 5mg of decitabine and 6.8 mg of KH2PO4.  The 
reconstituted solution can be further diluted in 0.9% sodium chloride 
intravenous infusion B.P., which has been cooled to a temperature of 4-8°C.   
 
Adverse reaction 
All patients  
(n=2182) 
CP  
(n=1150) 
AP  
(n=502) 
Myeloid 
BP 
(n=280) 
Lymphoid 
BP and 
Ph+ALL 
(n=250) 
All 
grades 
Grade 
3-4 
Grade   3-
4 
Grade   
3-4 
Grade 3-4 
Grade 3-4 
Fluid retention 
37 
8 
6 
7 
13 
7 
      Local superficial edema 
20 
<1 
<1 
1 
1 
<1 
      Pleural effusion 
22 
5 
4 
5 
10 
6 
      Other fluid retention 
10 
3 
3 
3 
6 
2 
           Generalized 
3 
<1 
<1 
1 
<1 
1 
           Congestive heart failure 
2 
1 
2 
<1 
2 
1 
           Pericardial effusion 
3 
1 
1 
1 
2 
0 
           Pulmonary edema 
2 
1 
1 
1 
1 
1 
           Ascites 
<1 
<1 
0 
0 
1 
<1 
           Pulmonary hypertension 
1 
<1 
<1 
0 
1 
1 
Diarrhea 
31 
3 
3 
4 
5 
4 
Headache 
24 
1 
1 
1 
1 
2 
Skin rash 
22 
1 
1 
1 
1 
1 
Nausea 
22 
1 
1 
1 
2 
2 
Hemorrhage 
21 
6 
2 
11 
12 
8 
           Gastrointestinal 
7 
4 
1 
8 
9 
5 
           CNS 
1 
<1 
0 
<1 
<1 
2 
Fatigue 
21 
2 
2 
3 
1 
2 
Dyspnea 
20 
4 
5 
4 
5 
2 
Musculoskeletal pain 
14 
1 
2 
1 
1 
<1 
Pyrexia 
13 
1 
1 
2 
3 
1 
Vomiting 
13 
1 
1 
1 
1 
2 
Abdominal pain 
10 
1 
1 
<1 
1 
2 
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Decitabine will be administered at a dose of 15 mg/m2 (or the modified dose 
as per protocol) infused over approximately 1 hour daily for 10 days.  
 
Storage:  Vials should be stored at 25°C (77°F); excursions permitted to 15°C 
to 30°C (59°F to 86°F).  After reconstitution, use decitabine within 15 minutes.  
If diluted with cold (2°C to 8°C) fluids, the diluted solution is stable for up to 7 
hours if stored between 2°C and 8°C (36°F and 46°F). 
 
Pharmaceutical data 
Decitabine sterile powder is a freeze-dried preparation. Each 20 ml vial contains 
50 mg decitabine. The vials should be stored at 2-8°C and are stable for at 
least 2 years. Chemical instability of decitabine is a major problem encountered 
in the clinical formulation, leading to drug solutions of a decreasing potency 
upon storage. Reconstitution of the powder results in a rapidly decomposing 
solution. The concentration of decitabine decreases by about 10% after 4 hours 
at 25°C and by about 10% after 24 hours at 4°C. Thus the solution should be 
prepared at least twice a day and kept in a refrigerator (4-8°C), for a maximum 
period of 11 hours, until administration. The solution can be infused over 
maximally 3 hours if kept in the refrigerator for less than 10 hours. The solution 
can be infused over maximally 2 hours if kept in the refrigerator for more than 
10 hours.  
 
Precautions 
Drug handling precautions will be strictly followed. Skin contact with the 
solution should be avoided and protective (chemotherapy) gloves should be 
worn. Drug spilling can be inactivated by 2 M sodium hydroxide solution. The 
skin should be treated with a borax buffer solution pH 10 and after that 
thoroughly washed with water and soap. 
 
Drug supply and distribution 
Both dasatinib and decitabine are commercially available.  
 
The supply of vials for the treatment of patients should be available and kept 
up to date. 
 
3.1.5 Human Toxicology 
 
 
In the Phase I and Phase II studies of solid tumors the primary toxic 
reaction has been hematologic.  Leukopenia has, in general, been more 
pronounced than thrombocytopenia.  The median WBC nadir was day 
21 (range 7-31) and median day to recovery was day 34 (range 13-50).  
No cumulative myelosuppression was documented in these studies.  
Other common toxicities have included mild to moderate nausea and 
vomiting.  Rare occurrences of diarrhea, fever, mucositis and peripheral 
neuropathy have been recorded.  At the higher dose schedules in 
leukemia neurotoxicity and gastrointestinal toxicity were a problem. In 
a randomized open-label, multicenter, phase III trial, 170 patients with 
International Prognostic Scoring System (IPSS) high-risk, intermediate-
2, and intermediate-1 MDS were randomized to receive decitabine (15 
mg/and best supportive care (n=89) or to receive best supportive care 
alone (n=81).  The most commonly occurring adverse reactions were 
neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, 
cough, petechiae, constipation, diarrhea, and hyperglycemia. The 
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adverse reactions most frequently resulting in treatment discontinuation 
included thrombocytopenia, neutropenia, pneumonia, Mycobacterium 
avium complex infection, cardio-respiratory arrest, increased blood 
bilirubin, intracranial hemorrhage, and abnormal liver function tests. 
 
4.0 
PATIENT ELIGIBILITY 
 
4.1 
Inclusion Criteria 
 
4.1.1 Patients age 18 years of age or older with CML-AP, CML-BP or 
Philadelphia chromosome-positive acute myeloid leukemia defined as 
follows: 
o 
CML-AP is defined by the presence of 15-29% blasts in peripheral 
blood (PB) or bone marrow (BM), >20% basophils in PB or BM, 
>30% blasts plus promyelocytes (with blasts <30%) in PB or BM, 
<100 x109/L platelets unrelated to therapy, or by clonal cytogenetics 
evolution (i.e., the presence of cytogenetic abnormalities other than 
the Philadelphia chromosome).  
 
o 
CML-BP is defined by the presence of ≥30% blasts in the bone 
marrow and/or peripheral blood or the presence of extramedullary 
disease. 
 
4.1.2 Patients are eligible whether they have received or not prior TKI 
therapy. For the phase I portion of the study, patients who had received 
prior therapy with dasatinib should have been able to tolerate the dose 
equivalent to the starting dose of dasatinib in the dose level at which 
the patient is being entered.  Patients who previously received dasatinib 
but never at the dose being proposed are eligible provided they tolerated 
the maximum dose they were prescribed with no grade 3-4 toxicity not 
responding to optimal management. 
 
4.1.3 ECOG performance status 0-3.  
 
4.1.4 Men and women of childbearing potential should practice 2 methods of 
contraception; 1 method must be highly effective and a second method 
must be either highly effective or less effective. .  Men and women of 
childbearing potential are defined as: a male that has not been surgically 
sterilized or a female that has not been amenorrheic for at least 12 
consecutive months or that has not been surgically sterilized.  Patients 
must use birth control during the study and for 3 months after the last 
dose of study drug if they are sexually active. 
 
4.1.5 Women of childbearing potential must have a pregnancy test at 
screening.   
 
4.1.6 Signed informed consent. 
 
4.1.7 Patients must have been off all prior therapy for CML for 2 weeks prior 
to start of study therapy and recovered from the toxic effects of that 
therapy.  Exceptions to these are hydroxyurea and TKIs (including but 
not limited to imatinib, nilotinib, and bosutinib) which should be 
discontinued ≥24 hrs prior to the start of therapy. Patients who are 
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receiving dasatinib prior to enrollment do not have to discontinue this 
agent prior to start of study therapy.  
 
4.1.8 Adequate organ function:  
o 
Serum creatinine ≤2.0 mg/dl or creatinine clearance ≥60 mL/min 
 
o 
Total bilirubin ≤1.5xULN (unless considered due to Gilbert’s 
syndrome or hemolysis)  
 
o 
Alanine aminotransferase (ALT) ≤3xULN unless considered due to 
leukemic involvement.  
 
4.2 
Exclusion Criteria 
 
4.2.1 NYHA cardiac class 3-4 heart disease. 
 
4.2.2 Cardiac disease including:  
o 
Uncontrolled angina within 3 months. 
 
o 
Diagnosed or suspected congenital long QT syndrome. 
 
o 
Any history of clinically significant ventricular arrhythmias (eg, 
ventricular tachycardia, ventricular fibrillation, or Torsades de 
pointes). 
 
o 
Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) 
on the Fridericia’s correction. 
 
o 
Uncontrolled hypertension (defined for this protocol as sustained 
systolic BP ≥150 and diastolic ≥100). 
 
o 
Patients currently taking drugs that are generally accepted to have 
a risk of causing Torsades de Pointes (see Appendix F).  
 
4.2.3 Serious uncontrolled medical disorder or uncontrolled active systemic 
infection or current unstable or decompensated respiratory or cardiac 
conditions which makes it undesirable or unsafe for the patient to 
participate in the study. 
 
4.2.4 Patients with known, clinically significant pericardial or pleural effusion. 
 
4.2.5 History of significant bleeding disorder unrelated to cancer, including 
diagnosed congenital bleeding disorders (e.g., von Willebrand’s 
disease), or diagnosed acquired bleeding disorders within one year 
(e.g., acquired anti-factor VIII antibodies).   
 
4.2.6 Subject is receiving potent inhibitors of CYP3A4; for such medications, 
a wash-out period of >/= 7 days is required prior to starting dasatinib 
unless discontinuation or substitution of such an inhibitor is not in the 
best interest of the patient as determined by the investigator. These 
include 
the 
following 
medications: 
itraconazole, 
ketoconazole, 
miconazole, voriconazole; amprenavir, atazanavir, fosamprenavir, 
indinavir, nelfinavir, ritonavir; ciprofloxacin, clarithromycin, diclofenac, 
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doxycycline, enoxacin, isoniazid, ketamine, nefazodone, nicardipine, 
propofol, quinidine, telithromycin. In instances where use of these 
agents is felt to be required for the best management of the patients, 
inclusion of such a patients should be discussed with PI and the rationale 
documented. 
 
4.2.7 Females who are pregnant or are currently breastfeeding. 
 
4.2.8 Patients that are eligible for (including having available donor) and 
willing to receive an allogeneic stem cell transplant within 4 weeks.   
 
5.0 
TREATMENT PLAN 
 
5.1 
Therapy with decitabine may be administered on an outpatient or inpatient 
basis.   Decitabine may be administered by local doctor or at MD Anderson.  
The maximum number of patients to be enrolled in this study is 84.   
 
 
Outside Physician Participation During Treatment 
 
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 
 
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 
(Appendix K) 
 
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 
MDACC physician, indicating that they have reviewed it. 
 
4. Changes in drug dose and/or schedule must be discussed with and approved 
by the MDACC physician investigator, or their representative prior to 
initiation, and will be documented in the patient record. 
 
5. A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician. 
 
6. Documentation to be provided by the local physician will include drug 
administration records, progress notes, reports of protocol required 
laboratory 
and 
diagnostic 
studies 
and 
documentation 
of 
any 
hospitalizations. 
 
7. The home physician will be requested to report to the MDACC 
physician investigator all life threatening events within 24 hours of 
documented occurrence. 
 
8. Patients will return to MDACC every month for 1-2 months, then 
every 2-4 cycles for evaluation. 
 
9. For patients who receive the first cycle at home, a phone call will 
be placed to the patient on day 14 (+/- 5 days) of the first cycle to 
assess toxicity. 
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10.  Patients receiving therapy at home will return to MDACC for 
assessment before the start of each cycle for the 1st 3 cycles, then 
every 3 cycles (+/- 1 cycle) until 1 year from start of therapy, then 
every 6 months (+/- 1 month). 
 
 
5.2 
The first 3 patients will be treated on schedule A, dose level 0 (See Table on 
section 5.3.4). If DLT is identified in 0 of 3 or ≤1/6 patients, the next 3 patients 
will be assigned to schedule B. If DLT is identified in 0 of 3 or ≤1/6 of these 
patients, patients will be accrued to dose level +1 (ie, Target dose), first to 
Schedule A, and then to Schedule B using the same algorithm. If no MTD is 
identified at this dose level, phase II will start and all subsequent patients will 
be randomized to schedules A and B as described under statistical section. The 
initial dose is per dose level 0, and the target dose is dose level +1. If MTD has 
not been defined after completing dose level +1 for one or both arms, all 
subsequent patients will be randomized to this dose level, or the MTD for each 
dose level if lower than +1. If MTD is exceeded at dose level 0, dose levels -1, 
-2 and -3 will be explored. If dose level -3 exceeds MTD, additional dose levels 
might be explored after discussion with sponsor and approval of amendment 
by IRB. The phase II portion of the study will commence once an MTD is defined 
for both schedules or, if no MTD is identified, when 0/3 or ≤1/6 patients treated 
at the Target Dose have experienced DLT with each schedule where MTD has 
not been determined at a lower level. The dose to be used for the phase 2 
portion of the study is the one declared as MTD or the target dose (dose level 
+1) if no MTD was defined at a lower dose, whichever is lowest. 
 
For the phase I aspect of the protocols:  Subjects will not be enrolled into a 
higher dose level until all subjects in the current cohort have completed the 
first cycle of treatment.  Prior to changing dose levels a cohort summary will 
be completed and submitted to the Clinical Research monitor in the IND Office. 
 
5.3 
Dose Schedules:  
 
*Dasatinib and Decitabine administration will start at the same time. 
 
5.3.1 Dasatinib will be administered at a starting dose of 100 mg once daily. 
During the first cycle, dasatinib will be administered for the first 2 weeks 
only.  Patients with rapidly proliferative disease and/or a high peripheral 
blood blast count (e.g. >2 x 109/L) may continue dasatinib 
uninterrupted.  In subsequent cycles, dasatinib may continue 
uninterrupted in the absence of adverse events that require treatment 
interruption. 
 
5.3.2 The starting dose of decitabine for Schedule A will be 10 mg/m2 IV over 
approximately 1 hour daily for 10 days.  The starting dose of decitabine 
for Schedule B will be 20 mg/m2 IV over approximately 1 hour daily for 
10 days. Administration of decitabine can be divided into 5 days weekly 
for two consecutive weeks if weekend administration or other logistical 
issues prevent administration in 10 consecutive days.  
 
5.3.2.1 
Decitabine will be dosed based on actual body weight. 
However, at the treating physician’s discretion an adjusted 
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body weight may be used, if actual body weight is >40% over 
ideal body weight. Adjusted body weight = ((Actual body 
weight – Ideal body weight) 0.4) + Ideal body weight 
 
5.3.3 Treatment will be repeated every 28 days (±7 days). Patients with 
rapidly proliferating disease may have therapy started earlier (but not 
earlier than day 14). The start of subsequent cycles may be delayed to 
allow for recovery of any adverse events as specified below. Patients 
with rapidly proliferating disease may start subsequent cycles early, but 
not earlier than day 14. In such instances, the observation period for 
DLT will be until the start of cycle 2. 
 
5.3.4 Dose Adjustment Levels*: 
 
 
 
 
 
 
 
 
 
 
* Dose levels are described for induction. For maintenance, the daily 
dose is unchanged but decitabine will be administered for only 5 days.  
** Dose level +2 to be used only for dose escalation as described in 
section 5.3.8 
 
5.3.5 Definition of Dose-Limiting Toxicity (DLT) 
 
5.3.5.1 
DLT will be defined by events that are clinically significant 
and at least possibly related to study drug occurring during 
the first 4 weeks (1 cycle) of therapy. In patients with rapidly 
proliferating disease who start cycle #2 early, the 
observation period to determine DLT will be until start of cycle 
2. 
 
5.3.5.2 
Non-hematologic DLT is defined as ≥ grade 3 (NCI common 
criteria, version 4.0) that is clinically significant and 
considered to be at least possibly related to the study drug. 
Grade 3 or 4 nausea, vomiting and diarrhea will be considered 
DLT only if not controlled by optimal therapy. 
 
 
Decitabine 
Dose 
level 
Dasatinib 
Schedule A 
Schedule B 
+2** 
140 mg PO 
QD 
40 mg/m2 IV over 
1 hour daily for 5 
days 
40 mg/m2 IV over 1 
hour daily, 5 
days/week for two 
consecutive weeks 
+1 
(Target 
dose) 
140 mg PO 
QD 
10 mg/m2 IV daily 
for 10 days 
20 mg/m2 IV daily 
for 10 days 
0 
(Starting 
dose) 
100 mg PO 
QD 
10 mg/m2 IV daily 
for 10 days 
20 mg/m2 IV daily 
for 10 days 
-1 
 
70 mg PO 
QD 
7.5 mg/m2 IV daily 
for 10 day  
15 mg/m2 IV daily 
for 10 days 
-2 
50 mg PO 
QD 
5 mg/m2 IV daily 
for 10 day 
10 mg/m2 IV daily 
for 10 days 
-3 
20 mg PO 
QD 
5 mg/m2 IV daily 
for 5 days 
7.5 mg/m2 IV daily 
for 10 days  
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5.3.5.3 
Grade 3 or greater biochemical abnormalities (e.g., lipase or 
bilirubin 
elevation) 
will 
only 
be 
considered 
DLT 
if 
accompanied by clinical consequences.  Grade 3 or greater 
electrolyte abnormalities will only be considered DLT if at 
least possibly related to study drug and not corrected by 
optimal replacement therapy. 
 
5.3.5.4 
Hematologic DLT is defined as grade ≥3 neutropenia and/or 
thrombocytopenia with a hypocellular bone marrow with 
<5% bone marrow blasts lasting for 6 weeks or more after 
the start of a course.  Hypocellular bone marrow with <5% 
blasts has to be confirmed with another bone marrow 
aspiration and/or biopsy within 7 -14 days to be counted as 
DLT.  Once one bone marrow study is obtained that meets 
this criteria, dasatinib should be stopped and a repeat bone 
marrow aspiration and/or biopsy done within 7-14 days.  If 
this bone marrow is confirmed hypocellular and with <5% 
blasts, a DLT is defined.  The confirmation bone marrow 
aspiration and/or biopsy might occur after the 6 week 
threshold. (In case of a normocellular bone marrow with <5% 
blasts, 8 weeks with pancytopenia will be considered DLT). 
Anemia will not be considered for the definition of DLT. 
 
5.3.6 Definition of Maximally Tolerated Dose (MTD) 
 
5.3.6.1 
MTD will be defined as the highest dose at which 0 of 3 or 
≤1/6 patients experience a first cycle DLT. If no MTD is 
identified at dose level +1 (ie, the Target dose) for each arm, 
this dose will be explored further in the phase II portion of 
the study and no further exploration of an MTD will be 
pursued.  
 
5.3.7 For the phase II portion of the study, patients who had received prior 
dasatinib and have demonstrated non-hematologic toxicity to a dose of 
140mg daily (or lower) requiring dose reductions, will be treated at the 
highest dose they had tolerated before. 
 
5.3.8 If no significant anti-leukemic effect is observed after the first cycle of 
therapy and in the absence of grade 3 or higher clinically significant non-
hematologic toxicity that is related to the study drugs, patients may be 
dose-escalated to the next dose level, provided it has been already 
deemed safe according to the phase I dose escalation rules. Dose level 
+2 is provided only for the purposes of dose escalation during the phase 
II portion of the study. For phase II portion of the study, if at any time 
patients need to be escalated to dose level +2, if at any time 33% or 
more of patients experience DLT at this dose level during the first cycle 
they receive at this dose, this would be considered to have exceeded 
MTD and should not be used any further.   
 
5.3.9 Dose adjustments of only one of the two agents is allowed if judged in 
the best interest of the patient (e.g., in patients with risk factors for 
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pleural effusion secondary to dasatinib or grade 1 or 2 pleural effusion 
at lower doses) 
 
5.4 
Treatment cycles with decitabine will start every 28 days (± 7 days).  Dasatinib 
will be continued uninterrupted. One cycle is defined as 28 days of therapy or 
until the start of the next course of decitabine in instances where this occurs 
before day 28. 
  
5.4.1 Subsequent cycles will be started once neutrophils recover to ≥1 x109/L 
and platelets to ≥70 x109/L (if above these levels before the start of the 
cycle).  
 
5.4.2 Patients with persistent leukemia (eg, blasts >5% in peripheral blood or 
bone marrow) may start the next cycle in the absence of full recovery 
of the bone marrow and/or peripheral blood counts provided they have 
recovered from non-hematologic toxicity as discussed below. 
 
5.4.3 Delays in beginning the next course of therapy for other reasons might 
be acceptable. The rationale should be discussed with the principal 
investigator and documented. 
 
5.4.4 Subsequent courses may be instituted early if there is evidence of early 
recovery of neutrophils (to ≥1 x109/L) and platelets (to ≥70 x109/L) 
and/or increasing blast count, but not earlier than 14 days from the start 
of the prior cycle.  
 
5.4.5 In instances where it is considered appropriate to delay therapy with 
one agent, administration of the other agent may continue as planned 
(eg, pleural effusion due to dasatinib) 
 
5.5 
Maintenance Therapy: Patients that achieve a major hematologic response 
or are back to chronic phase may receive maintenance chemotherapy as 
follows: 
 
5.5.1 Dasatinib: 100 mg daily or the highest dose tolerated before. 
 
5.5.2 Decitabine: at the maximum dose tolerated before but for 5 days only.  
 
5.5.3 Patients that show increased proliferative activity (eg, increase blasts, 
rapid increase of WBC, etc) can revert back to the induction schedule.  
 
5.5.4 Dose adjustments for the maintenance therapy can be made following 
the same principles detailed below. 
 
5.6 
Dose Adjustments  
 
5.6.1 Patients who exhibit no significant anti-leukemic effect (e.g., failure to 
decrease the WBC count by at least 50% if initial WBC >10x109/L, or 
failure to decrease the peripheral blood blast percentage by at least 50% 
if initial WBC <10x109/L) after 6 courses of therapy will be taken off 
study. 
 
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5.6.2 Patients who develop grade 3 or 4 drug-related clinically significant non-
hematologic toxicity [except for a) nausea, vomiting or diarrhea unless 
uncontrolled by optimal therapy, or b) electrolyte abnormalities, unless 
uncontrolled by optimal supplementation or associated with clinical 
consequences] possibly related to the study drugs may have therapy 
interrupted until resolution of toxicity to grade ≤1, then therapy can be 
reinitiated at the next lower dose.  
 
5.6.2.1 
If toxicity is clearly attributable to one of the drugs (eg, 
pleural effusion with dasatinib, arthralgias with decitabine) 
interruptions may apply to that drug alone while continuing 
the other agent. Resumption of the drug responsible for the 
toxicity will follow the guidelines mentioned above.  
   
5.6.2.2 
Missed doses will not be made up.  
 
5.6.3 Patients with neutropenia or thrombocytopenia as a consequence of the 
disease prior to the start of therapy do not require treatment 
interruptions for myelosuppression. Dose-reductions and treatment 
interruptions in these patients should be considered in an individual case 
and discussed with the PI. The following guidelines can be used for these 
patients: 
 
5.6.3.1 
Patients with a response and pre-course counts of neutrophils 
>1x109/L and platelets >50 x109/L who have sustained low 
counts of neutrophils <0.5 x 109/L or a platelet count <25 x 
109/L for more than 2 consecutive weeks in the current cycle, 
with <5% blasts in the bone marrow, may receive a 
subsequent course at 1 dose level reduction.  A reduction of 
2 dose levels may be considered if the myelosuppression was 
deemed severe and life threatening by the treating physician, 
and if it is in the patient's best interest. 
 
5.6.3.2 
If WBC >10 x 109/L and/or absolute blast count >2 x 109/L, 
may continue treatment regardless of neutrophil and platelet 
count and give transfusion and other support as needed. 
 
5.6.3.3 
If WBC is 5 to 10 x 109/L or absolute blast 0.5 to 2 x 109/L 
and platelet count ≤20 x 109/L, may continue treatment at 
same dose unless platelet count represents a decrease of 
>50%. If platelets <20 x 109/L and <50% from baseline, 
may decrease dose by 1 dose-level. 
 
5.6.3.4 
If WBC is <5 x 109/L and absolute blast <0.5 x 109/L and 
platelet count ≤20 x 109/L, may interrupt therapy until 
platelets ≥50 x 109/L. Then re-start therapy with a dose 
reduction by 1 dose-level. If WBC increases to >10 x 109/L 
or blasts to ≥5 x 109/L before platelets recover, may re-start 
therapy with a 1 dose level reduction. 
 
5.6.4 Since the effect of decitabine may be delayed for up to 4 weeks, patients 
with high WBC counts (i.e., >10x109/L) may receive hydroxyurea prior 
to study entry. The use of hydroxyurea will be allowed during the first 4 
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cycles of therapy if necessary to control rapidly proliferating disease.  
The use of hydroxyurea will not be permitted after the first 4 cycles of 
therapy.  
 
5.6.5 Treatment interruptions and dose modifications other than the ones 
mentioned above can be considered after discussion with the PI and 
proper documentation of the rationale. 
 
5.6.6 Dose Escalation: Patients with persistent disease (ie, not hematologic 
response after 1 cycle or no CCyR after 3 cycles) that are showing no 
evidence of unacceptable toxicity may have their dose escalated by one 
dose level per cycle up to dose level +2.  
 
5.6.6.1 
Dose escalation of only one of the drugs is allowed if it is 
considered, based on the outcome with prior cycles that 
higher doses of one agent are not likely to be tolerated.  
 
5.7 
Duration of Therapy 
 
5.7.1 Patients achieving hematologic remission may continue receiving 
therapy with decitabine and dasatinib for as long as the treatment is 
judged to be beneficial to the patient, that is, if they maintain a response 
in the absence of intolerable toxicity. 
 
5.7.2 If needed, subsequent courses of decitabine will be adjusted to the 
immediate lower dose level to try to maintain granulocyte count 
approximately >0.5x109/L and platelet count approximately >20x109/L 
for most of the 28 days of each cycle. 
 
5.8 
A minimum of 2 full courses will be required for a patient to be considered as 
having received an adequate trial to evaluate efficacy. Patients who fail to 
complete 2 full courses of therapy will be replaced to reach the planned patient 
accrual. All patients receiving at least one dose of decitabine will be considered 
evaluable for toxicity.  Patients achieving a partial response or with stable 
disease may continue on therapy until definite evidence of disease progression.  
 
5.9 
Concurrent Administration of Other Medications. Hematopoietic growth 
factors will not be routinely used. However, their use is permitted when 
clinically indicated. Other approved medications to treat concurrent medical 
problems and/or infections are allowed as clinically indicated. 
 
5.9.1 The use of investigational medications is not allowed during study. 
 
5.9.2 Concurrent administration of intrathecal chemotherapy is allowed for 
patients with evidence of CNS disease as clinically indicated.  
 
5.9.3 Caution is warranted when administering dasatinib to subjects taking 
drugs that are highly dependent on CYP3A4 for metabolism and have a 
narrow therapeutic index.  Systemic exposures to these medications 
could be increased while receiving dasatinib.  In in vitro studies, 
dasatinib is a strong inhibitor of the human CYP3A4 enzyme and a weak 
inhibitor 
of 
CYP1A2, 
CYP2D6 
and 
CYP2C19. 
dasatinib 
shows 
time-dependent inhibition of CYP3A4; however, there appears to be a 
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low probability for drug-drug interactions due to metabolism-dependent 
CYP3A4 inactivation.  Results from an in vitro hPXR trans-activation 
study suggest that dasatinib has little potential to induce CYP3A4 
through the activation of hPXR. 
 
5.9.4 CYP3A4 inhibitors and inducers should be used with caution (but are not 
prohibited) since they could alter the systemic exposure to dasatinib.  
Incubations with recombinant human CYP450 isozymes suggest that 
dasatinib is primarily metabolized by the CYP3A4 enzyme.  Many other 
enzymes appear capable of metabolizing dasatinib, including CYP1A1, 
2C9, 2E1, FMO3, 1B1, 2B6, 2A6, 2C8, and 4A1; however, it is unknown 
at this time what contributions these enzymes may have to the total 
metabolic clearance of dasatinib. A list of drugs that are inducers, 
inhibitors 
or 
substrates 
of 
CYP3A4 
can 
be 
found 
at 
http://medicine.iupui.edu/clinpharm/ddis/.  
 
 
6.0 
METHYLATION STUDIES (Optional) 
 
Gene-specific methylation assays: in vitro, decitabine efficiently inhibits gene-specific 
(promoter CpG island) methylation allowing for gene reexpression. This methylation 
can be quantitatively measured using either Southern blot analysis or bisulfite 
treatment of DNA followed by PCR and restriction enzyme digestion, or 
pyrosequencing. We have previously shown that decitabine therapy is associated with 
demethylation and reexpression of p15, which appears to be associated with response 
to the drug. Some degree of demethylation was also observed for ABL1, but no 
demethylation was observed for H19, a gene frequently found methylated in CML. In 
the present trial, we will measure the methylation status of p15, H19, and ABL1 (as 
well as other disease specific genes) before or on the first day of treatment (day 0 or 
day 1) in blood and/or bone marrow, at the end of the first 5 doses of decitabine (day 
5) in blood, at the end of the treatment course (day 12) in blood, and at recovery of 
counts in blood by pyrosequencing (Cycle 1 only). For all patients, we will also measure 
methylation at either complete remission, or at exit from the protocol if the regimen 
did not provide substantial benefit. When more than one gene is used (and methylated 
at baseline), each gene will be considered separately for all correlative endpoints. 
Global DNA methylation will also be measured by the LINE1 bisulfite pyrosequencing 
assay. In addition to methylation, we will also measure expression of p15 and p21 at 
these same time-points by real-time polymerase chain reaction (qPCR). The values 
obtained will be compared to our experience with single-agent decitabine and will also 
be correlated with response. All these studies will be performed by Dr. Jean-Pierre Issa 
at Temple University – Fels Institute. 
 
Optional samples will also be obtained for decitabine pharmacokinetics and stored for 
subsequent analysis. Samples will be obtained at 0, 1, 4, 8, and 24 hours on Cycle 1 
Day 1 and baseline only on Cycle 2 Day 1.  All samples will be collected in the Leukemia 
Department clinic by accredited personnel. All pharmacokinetic studies will be 
performed at M.D. Anderson Cancer Center. 
 
 
7.0 
PRETREATMENT EVALUATION  
 
All pretreatment evaluations with the exception of the Cytogenetics should be 
completed within 14 days (+/- 2 days) prior to start of protocol treatment. 
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7.1 
A complete history, physical, concomitant medications and performance status.   
 
7.2 
CBC, platelet count, differential, SGPT, creatinine, bilirubin, HBV screening, 
potassium, magnesium. 
 
7.3 
Bone marrow aspirate. 
 
7.4 
Bone marrow cytogenetics if not done in previous 3 months. 
 
7.5 
Urine pregnancy test for women of childbearing potential. 
 
7.6 
EKG. 
 
7.7 
Optional blood sample (12 cc) for methylation studies, to be sent to Dr. Jean-
Pierre Issa’s laboratory (215-707-4307).  Optional samples will also be 
obtained for Decitabine pharmacokinetics. 
 
8.0 
EVALUATION DURING STUDY 
 
8.1 
Physical exam, review of toxicity and concomitant medications before the start 
of cycle 2, and then every 2-4 cycles for the first year, then every 6 cycles.  
 
8.2 
Patients will keep a study diary that will be reviewed at scheduled study visits. 
 
8.3 
CBC, platelet count and differential (if WBC >1x109/L) weekly for the first 3 
cycles, then Q2-4 weeks. 
 
8.4 
SGPT, creatinine, bilirubin, potassium, magnesium Q1-2 weeks for the first 3 
cycles then every 4-8 weeks.  
 
8.5 
EKG approximately 1 week after the start of therapy. 
 
8.6 
Bone marrow aspiration (to include cytogenetics) before the start of cycle 2 
and every 3 cycles during the first year, then every 4-6 cycles as clinically 
indicated.  
 
8.7 
Peripheral blood for PCR for bcr/abl every 1-3 months. 
 
8.8 
Optional: Blood sample (12 cc) on days 0 (same sample as described in section 
7.7), 5 and 12 (all days +/- 2 days) of treatment for methylation studies.   The 
samples from days 5 and 12 will be collected during the first course of 
treatment.  Samples to be sent to Dr. Jean-Pierre Issa’s laboratory (215-707-
4307).*  
 
8.9 
Optional: Blood sample (12 cc) from all patients at either complete remission 
or when taken off study (if possible) (+/- 2 days). Samples to be sent to Dr. 
Jean-Pierre Issa’s laboratory (215-707-4307).* 
 
8.10 
Patients that remain on study with no significant toxicity for more than 6 
months, subsequent evaluation during study may be modified after discussion 
with the principal investigator.  These include a decrease in the frequency of 
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bone marrow aspirations to every 6-12 months (or as clinically indicated), and 
laboratory tests once with every cycle. 
 
8.11 
Optional:  Blood sample (about 1 teaspoon) for Decitabine pharmacokinetics at 
0, 1, 4, 8, 24 hrs on Cycle 1 Day 1 and baseline only on Cycle 2 Day 1. 
 
* Missing occasional samples of optional correlative studies and for Decitabine 
pharmacokinetics will not be considered a protocol deviation.  
 
9.0 
CRITERIA FOR RESPONSE AND TOXICITY 
 
9.1 
Major Hematologic Response (HR) 
 
9.1.1 
Complete Hematologic Response (CHR):  
 
9.1.1.1 WBC ≤ institutional upper limit of normal (ULN). 
 
9.1.1.2 Absolute neutrophils count (ANC) ≥1 x109/L. 
 
9.1.1.3 Platelets >100 x109/L. 
 
9.1.1.4 No blasts or promyelocytes in peripheral blood. 
 
9.1.1.5 < 5% myelocytes plus metamyelocytes in peripheral blood 
 
9.1.1.6 Peripheral blood basophils <5% 
 
9.1.1.7 No extra-medullary involvement including no splenomegaly or 
hepatomegaly 
 
9.1.1.8 ≤5% blasts in bone marrow 
 
9.1.2 No Evidence of Leukemia (NEL) - meet the same criteria as CHR 
except for: 
 
9.1.2.1 WBC ≤ institutional upper limit of normal (ULN). 
 
9.1.2.2 No blasts or promyelocytes in peripheral blood. 
 
9.1.2.3 < 5% myelocytes plus metamyelocytes in peripheral blood 
 
9.1.2.4 Peripheral blood basophils <5% 
 
9.1.2.5 No extra-medullary involvement including no splenomegaly or 
hepatomegaly 
 
9.1.2.6 ≤5% blasts in bone marrow 
 
9.1.2.7 At least one of the following:  
 
9.1.2.7.1 
20 x109/L ≤ Platelets <100 x109/L 
 
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9.1.2.7.2 
0.5 x109/L ≤ ANC <1 x109/L 
 
9.2 
Minor Hematologic Response (MiHR) - meet all of the following: 
 
9.2.1 
< 15% blasts in BM and PB 
 
9.2.2 
< 30% blasts + promyelocytes in BM and PB 
 
9.2.3 
< 20% basophils in PB 
 
9.2.4 
No extra-medullary disease other than spleen and liver 
 
9.3 
Overall Hematologic Response (OHR) is defined as CHR, NEL or 
MiHR 
 
9.4 
A confirmed HR is obtained when all above criteria are fulfilled at least 28 days 
after they are first met. 
 
9.5 
Cytogenetic Response (CyR): classified according to suppression of the 
Philadelphia chromosome (Ph) by cytogenetics (FISH if cytogenetic analysis not 
informative, e.g., insufficient metaphases) 
 
9.5.1 No cytogenetic response - Ph positive >95%  
 
9.5.2 Minimal cytogenetic response - Ph positive 66-95%  
 
9.5.3 Minor cytogenetic response - Ph positive 36-65%  
 
9.5.4 Partial cytogenetic response - Ph positive 1-35% 
 
9.5.5 Complete cytogenetic response - Ph positive 0% 
 
9.5.5.1 *Major cytogenetic response = complete + partial (Ph positive 
≤35%) 
 
9.6 
Molecular Response  
 
9.6.1 Major (MMR): BCR-ABL/ABL ratio < 0.1% (IS). Currently, results form 
the MDACC laboratory can be converted to the IS by multiplying the 
BCR-ABL1/ABL1 ratio by 0.35. 
 
9.6.2 Complete: Undetectable BCR-ABL 
 
9.7 
Duration of Response will be measured frome the date the given response is 
achieved to the date the response is first known to be lost. 
 
9.8 
Overall survival will be measured from the date treatment is started to the date 
of death or last follow-up. 
 
9.9 
Toxicities will be reported on a scale of 1-4 according to the NCI criteria 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4 
 
10.0 
CRITERIA FOR REMOVAL FROM STUDY 
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10.1 
Patients with clinically significant progressive disease 
 
10.2 
Unacceptable (grade 3-4) toxicity in the absence of significant antileukemic 
effect. 
 
10.3 
Patient’s request. 
 
10.4 
If the patient does not derive any appreciable benefit and/or has better 
treatment options as judged by the investigator. 
 
10.5 
Poor compliance with treatment or protocol procedures. 
 
11.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
11.1 
Regulatory and Reporting Requirements 
 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the CTEP Version 4.0 of the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) will be utilized for AE reporting.  The CTEP Version 
4.0 of the CTCAE is identified and located on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All appropriate treatment areas should have access to a copy of the CTEP 
Version 4.0 of CTCAE. 
 
Refer to Section  11.2 for Leukemia-Specific Adverse Event Recording 
Guidelines.  The Principal Investigator will sign the PDMS/CORe  Case Report 
Form toxicity pages per each patient at the completion of each course for the 
first 3 courses, then every 3-6 courses.  The attribution of toxicity will be 
determined by the PI.  Following signature, the Case Report Form will be used 
as source documentation for the adverse events. 
 
11.2 
Leukemia-Specific Adverse Event Recording and Reporting Guidelines 
 
These guidelines serve to bring the Department of Leukemia in compliance with 
the institutional policy on Reporting of Serious Adverse Events-definition of 
expected AE-“ All clinical protocols should include a list of the expected and 
anticipated events or hospitalizations relating to the study treatment” and 
Guideline for Good Clinical Practice 4.11.1 “All serious adverse events (SAEs) 
should be reported immediately to the sponsor except for those SAEs that the 
protocol or other document  (e.g., Investigator’s Brochure) identifies as not 
needing immediate reporting”. 
 
Adverse event is any untoward medical occurrence that may present during 
treatment with a pharmaceutical product but which does not necessarily have 
a causal relationship with this treatment. 
 
Adverse drug reaction is a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for the modification of physiologic function. 
 
Assessing causal connections between agents and disease is fundamental to 
the understanding of adverse drug reactions. In general, a drug may be 
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considered a contributory cause of an adverse event if, had the drug not been 
administered, 1) the event would not have happened at all, 2) the event would 
have occurred later than it actually did, or 3) the event would have been less 
severe. 
 
Adverse Events (AEs) will be evaluated according to current CTC version in each 
protocol. Only unexpected AEs will be recorded in the Case Report Form (CRF). 
Expected events during leukemia therapy are: 
 
 
1. Myelosuppression related events (due to disease or leukemia therapy) 
a. febrile or infection episodes not requiring management in the 
intensive care unit 
 
b. epistaxis or bleeding except for catastrophic CNS or pulmonary 
hemorrhage 
 
c. anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia, 
leukocytosis 
 
2. Disease related events 
a. symptoms associated with anemia 
i. 
fatigue 
ii. 
weakness 
iii. 
shortness of breath 
 
b. electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, 
magnesium) 
 
c. chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, 
albumin, uric acid, alkaline phosphatase, glucose) 
 
d. coagulation abnormalities 
 
e. disease specific therapy (induction, maintenance, salvage, or stem 
cell therapy) 
 
f. 
alopecia 
 
g. bone,  joint, or muscle pain 
 
h. liver function test abnormalities associated with infection or disease 
progression 
 
i. 
disease progression 
 
3.  General therapy related events 
a. catheter related events 
 
b. renal failure related to tumor lysis syndrome or antibiotic/ antifungal 
therapy 
 
c. rash related to antibiotic use 
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4. Hospitalization for the management of any of the above expected events 
 
Abnormal hematologic values will not be recorded on the CRF. For abnormal 
chemical values grade 3 or 4, the apogee will be reported per course in the 
CRF. 
 
11.3 
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. 
 
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.  
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• 
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: 
 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
Phase I Stage 
A 3+3 design for dose escalation scheme will be used.    For purposes of estimating 
the MTD, up to 2 schedules of combination Dasatinib/Decitabine treatment will be 
considered.  These schedules are listed in the table below.   Schedule A is a less 
intensive schedule of the combination while Schedule B is a more intensive schedule.  
To minimize the risk to patients we will proceed in a sequential manner using a 3+3 
algorithm and starting the first cohort patients at Schedule A.    The starting dose is 
defined by dose level 0 on section 5.3.4, with the target dose being dose level +1 for 
both schedules. If no MTD is identified at this dose level, the phase II stage will begin 
with this dose, or at the maximum dose resulting in <2/6 patients with DLT for each 
cohort. The phase II portion of the study will commence once and MTD is defined for 
both schedules, or when 0/3 or ≤1/6 patients treated at dose level +1 have been 
treated without experiencing DLT. Treatment escalation will be based on toxicities 
observed through 28 days of drug administration.   
1 
Schedules 
 
Schedule 
Fixed Dose Dasatinib/Variable Decitabine 
A (less intensive) 
Dasatinib 100mg daily; Decitabine 10 mg/m2 
IV daily for 10 days 
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B (more 
intensive) 
Dasatinib 100mg daily; Decitabine 20 mg/m2 
IV daily for 10 days 
 
Patients will be treated in cohorts of 3 using a 3+3 algorithm.  The probability of 
escalating from one dose to the next dose given the true probability of toxicity is given 
in the table below.  We can see that for low probabilities of toxicity we are likely to 
escalate while for high toxicity probabilities we are unlikely to escalate. 
2 
Dose Escalation  
 
Probability 
of Toxicity 
Probability of Dose Escalation  
0.01 
0.999 
0.10 
0.906 
0.20 
0.709 
0.30 
0.494 
0.40 
0.309 
0.50 
0.172 
0.60 
0.082 
0.70 
0.032 
0.80 
0.009 
 
 
Phase II Stage 
 
Gehan Augmented Selection Design 
 
2.1 
In this trial we will randomize patients to two treatment arms.  The goal of this 
study is to evaluate the activity of the two arms.  In the Gehan Stage of the 
design we will initially enroll 14 patients per arm and evaluate each arm 
independently for activity.  An arm will be deemed active if we observe at least 
1 of 14 patients with hematologic response (any hematologic response observed 
during the first 3 months of treatment) in a given arm.  If we observe activity in 
both arms then the goal will be to accrue a total of 30 patients per arm and 
“select” the best arm, where the best arm is the arm in which more patients 
respond.  We justify our power calculation below. 
 
The test statistic to select treatment s over treatment t at the end of a trial is: 
 
ˆ
ˆ
`
(1
)
(1
)
s
t
s
s
t
t
s
s
t
t
p
p
Z
p
p
p
p
m
n
m
n
−
=
−
−
+
+
+
   
 
 
Where 
ˆ
 
ˆ
 
s
s
s
s
s
t
t
t
s
s
x
X
p
m
n
x
X
p
m
n
+
=
+
+
=
+
 
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The variable xs is the data accumulated at the Gehan interim look for group s and Xs 
is the future data that will accrue for group s.  Note that xs is observed thus fixed. 
 
The quantity xt is the accumulated data at the Gehan interim analysis for group t and 
Xt is the future data that will accrue for group t. Note that xt is observed thus fixed. 
 
Now define  
'
ˆ (
)
 
'
ˆ (
)
 
s
s
s
s
s
s
t
t
t
t
s
s
x
x
p x
m
n
x
x
p x
m
n
+
=
+
+
=
+
 
 
ˆ
ˆ
ˆ
(
)
(
)
s
s
t
t
p x
p x
θ =
−
 
 
Given these definitions the probability of both arms advancing past the first stage of 
the Gehan design and then at the end of the trial declaring treatment s superior to 
treatment t is given as 
 
(
)
1
1
'
0
'
0
'
'
'
'
(1
)
(1
)
ˆ
        
(1
)
(1
)
0
'
s
t
s
t
s
s
s
t
t
t
s
t
s
t
s
s
s
t
t
t
m
m
n
n
s
t
x
m
x
x
m
x
s
s
t
t
x
x
x
x
s
t
s
t
x
n
x
x
n
x
s
s
t
t
s
t
m
m
p
p
p
p
x
x
n
n
p
p
p
p
I
x
x
θ
−
−
=
=
=
=
−
−




−
−












×
−
−
<








∑∑∑∑
. 
 
Based on these probabilities the chance of selecting s over t if the response rate is 
25% in for treatment s and 5% for treatment t is 97.0%.  The chance of selecting s 
over t if the response rate is 40% in the s arm and 25% for the t arm the power is 
86.8%. 
 
If only one arm proceeds to the second stage of the Gehan design, we will accrue a 
total of 20 patients in the second stage.  For example if treatment s stops in stage 1 
because of 0 of 14 patients experienced hematologic response, then treatment t will 
accrue only 7 more patients. 
 
Toxicity Monitoring 
 
An arm will stop if unexpected grade 3-4, treatment-related toxicity exceeds 33% at 
any time in the trial.  
 
13.0 REFERENCES 
 
1. 
Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of 
chronic myeloid leukemia. New England Journal of Medicine 1999;341(3):164-72. 
2. 
Sawyers CL. Chronic myeloid leukemia. [see comments]. New England Journal of 
Medicine 1999;340(17):1330-40. 
3. 
Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology 
and therapy. Ann Intern Med 1999;131(3):207-19. 
4. 
Hill JM, Meehan KR. Chronic myelogenous leukemia. Curable with early diagnosis and 
treatment. Postgraduate Medicine 1999;106(3):149-52. 
Proprietary Information of MD Anderson


2011-0333 
November 15, 2016 
Page 32 of 33 
 
5. 
Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review. American 
Journal of Medicine 1996;100(5):555-70. 
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