Clinical trial NCT01794702
Conditions: Leukemia
Keywords: Leukemia Acute Leukemia Acute myelogenous leukemia AML Acute lymphoblastic leukemia ALL Maximum Tolerated Dose MTD Response Rate Decitabine Dacogen Idarubicin Idamycin Cytarabine Ara-C Cytosar DepoCyt Cytosine Arabinosine Hydrochloride
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-02-20; Completion date: 2018-01-11
Enrollment: 65 participants; Allocation: ; Intervention model: SEQUENTIAL

Brief summary:
The goal of Phase I of this clinical research study is find the highest tolerable dose of clofarabine that can be given with decitabine, idarubicin, and cytarabine to patients with acute leukemia.

The goal of Phase II of this study is to learn if decitabine followed by the combination of clofarabine, idarubicin, and cytarabine can help to control acute leukemia. The safety of this drug combination will also be studied.

Decitabine and idarubicin are designed to damage the DNA (the genetic material of cells). This may cause cancer cells to die.

Clofarabine is designed to interfere with the growth and development of cancer cells.

Cytarabine is designed to insert itself into DNA and stop the DNA from repairing itself.

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 based on when you join this study. Up to 3 groups of 6 participants will be enrolled in the Phase I portion of the study. Up to 74 participants will be enrolled in Phase II.

Phase I:

If you are enrolled in the Phase I portion, the number of days of clofarabine you receive will depend on when you joined this study. The first group of participants will receive clofarabine for 4 days. Each new group will receive clofarabine for the same number of days, if no intolerable side effects were seen. The number of days may be reduced to 3. The clofarabine dose per day is the same from group to group.

All participants will receive the same dose level of decitabine, idarubicin and cytarabine.

Phase II:

If you are enrolled in the Phase II portion, you will receive decitabine, idarubicin, and cytarabine. You will receive clofarabine for the highest number of days that was tolerated in the Phase I portion.

All participants will receive the same dose level of decitabine, idarubicin, cytarabine, and clofarabine.

Study Drug Administration:

Each study drug cycle is 33 days. The first cycle of study drugs is called Induction. If the doctor thinks it is needed, you will have up to 2 Induction cycles.

Phase I (Induction):

On Days 1-5 of each cycle, you will receive decitabine 1 time a day by vein over about 1 hour.

On Days 6-10 of each cycle:

* You will receive cytarabine 1 time a day by vein over about 2 hours.
* On Days 6-8 only, you will receive idarubicin 1 time a day by vein over about 30 minutes.
* You will receive clofarabine 1 time a day by vein over about 1 hour on Days 6-8 or 6-9, depending on when you join the study.

If the doctor thinks it is needed, your dose level will be reduced after Induction.

If the doctor thinks it is needed, you may receive fewer days of treatment in the Induction cycle(s).

Phase II (Induction):

On Days 1-5 of each cycle, you will receive decitabine 1 time a day by vein over about 1 hour.

On Days 6-10 of each cycle:

* You will receive cytarabine 1 time a day by vein over about 2 hours.
* On Days 6-8 only, you will receive idarubicin 1 time a day by vein over about 30 minutes.
* You will receive clofarabine 1 time a day by vein over about 1 hour on Days 6-8 or 6-9, depending on the highest number of days clofarabine was tolerated in the Phase I portion of the study.

If the doctor thinks it is needed, your dose level will be reduced after Induction.

If the doctor thinks it is needed, you may receive fewer days of treatment in the Induction cycle(s).

Phases I and II (Consolidation):

If the disease responds to the study drugs, you may receive up to 6 more study drug cycles. This is called Consolidation.

On Days 1-5 of each cycle:

°You will receive decitabine 1 time a day by vein over 1 hour.

On Days 6-8 of each cycle:

* You will receive cytarabine 1 time a day by vein over about 2 hours.
* You will receive clofarabine 1 time a day by vein over about 1 hour.
* On Days 6-7 only, you will receive idarubicin 1 time a day by vein over about 30 minutes.

If the doctor thinks it is needed, you may receive fewer days of treatment in the Consolidation cycles.

Study Visits:

Before the start of each cycle, you will have a physical exam, including measurement of your vital signs.

Every 3-7 days, blood (about 2 teaspoons) will be drawn for routine tests.

On Day 33 of every 2-3 cycles (+/- 7 days), if the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease. To collect a bone marrow aspirate, an area of the hip is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle.

Length of Treatment:

You may continue taking the study drugs for up to 8 cycles. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the long-term follow-up.

Long-term Follow-up:

Every 3 months for 1 year after your last study drug dose, the study staff will call you and ask how you are feeling, about any side effects you may be having, and about any other drugs you may be taking. These calls should last about 5 minutes each.

This is an investigational study. Decitabine is FDA approved and commercially available to treat myelodysplastic syndrome (MDS). Clofarabine is FDA approved and commercially available to treat ALL in children. Idarubicin and cytarabine are FDA approved and commercially available to treat AML. The study drug combination is investigational.

Up to 92 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Phase I - Decitabine 20 mg/m2 by vein over approximately 1 hour daily for 5 days (days 1-5) Idarubicin 10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 6-8) Cytarabine 1 g/m2 by vein over approximately 2 hours daily for 5 days (days 6-10)

Phase II - Clofarabine 15 mg/m2 by vein over approximately 1 hour daily (number of days selected based on Phase I portion).

Decitabine 20 mg/m2 by vein over approximately 1 hour daily for 5 days (days 1-5) Idarubicin 10 mg/m2 by vein over approximately 30 minutes daily for 3 days (days 6-8) Cytarabine 1 g/m2 by vein over approximately 2 hours daily for 5 days (days 6-10)
Interventions: intervention 1: Decitabine intervention 2: Idarubicin intervention 3: Cytarabine intervention 4: Clofarabine
Intervention descriptions: intervention 1: Phase I and II - 20 mg/m2 by vein daily for 5 days (days 1-5) intervention 2: Phase I and II - 10 mg/m2 by vein daily for 3 days (days 6-8) intervention 3: Phase I and II - 1 g/m2 by vein daily for 5 days (days 6-10) intervention 4: Phase I Starting Dose - 15 mg/m2 by vein daily for 4 days (days 6-9)

Phase II Starting Dose - Maximum tolerated dose from Phase I (number of days selected based on Phase I portion).

Protocol documents:
Prot_SAP_000.pdf: 
2012-1064
September 02, 2014
Page 1
Protocol Page
Phase I/II Study of Decitabine (DAC) followed by Clofarabine, Idarubicin, and 
Cytarabine (CIA) in Acute Leukemia
2012-1064
Core Protocol Information
Short Title 
Decitabine followed by Clofarabine, Idarubicin, and Cytarabine in Acute Leukemia
Study Chair: 
Nitin Jain
Additional Contact:
Allison Pike
Jeannice Y. Theriot
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-745-6080
Unit:
428
Full Title: 
Phase I/II Study of Decitabine (DAC) followed by Clofarabine, Idarubicin, and Cytarabine (CIA) 
in Acute Leukemia
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Terminated 01/12/2018
Version:
12
Submitted by:
Jeannice Y. Theriot--4/26/2017 2:13:38 PM
OPR Action:
Accepted by:  Melinda E. Gordon -- 5/1/2017 7:55:15 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2012-1064
September 02, 2014
Page 2
Protocol Body
 


Page 1 of 34 
 
Phase I/II Study of Decitabine (DAC) followed by Clofarabine,  
Idarubicin, and Cytarabine (CIA) in Acute Leukemia 
 
1. OBJECTIVES 
Phase I 
Primary: 
To determine the maximal tolerated dose (MTD) of clofarabine to be used in portion II of the 
study 
 
Phase II 
Primary: 
To determine the response rate of the DAC-CIA regimen 
 
Secondary: 
A) To determine the toxicity of the combination regimen 
B) To determine the disease-free survival (DFS) and overall survival (OS) rates 
 
2. RATIONALE 
2.1 Acute Myelogenous Leukemia 
Acute myelogenous leukemia (AML) is the most common acute leukemia in adults. It is 
estimated that 13,780 men and women will be diagnosed with and 10,200 men and women will 
die of acute myeloid leukemia in the year 2012.1 AML is a disease with a poor prognosis with a 
5-year survival of only around 30%.2,3 Certain subgroups of AML have a particularly worse 


Page 2 of 34 
 
outcome such as patients with relapsed and/or refractory AML and AML arising from antecedent 
myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs).  
Although most patients with AML will achieve remission with induction chemotherapy; many 
patients will relapse, despite the administration of post-remission therapies. Relapses may occur 
weeks to many years later. Up to 10% of patients will be refractory to induction chemotherapy. 
Both of these groups of patients (relapsed/refractory) constitute a particularly poor risk group. 
Although an allogeneic stem cell transplant would be considered a recommended approach for 
most of these patients, it is feasible only in a small number of patients. Many novel drugs and 
approaches are being investigated for this group of patients. However, the CR rates have been, in 
general, less than 30%.4-6 The Eastern Cooperative Oncology Group (ECOG) conducted a 
randomized 3-arm phase II trial where relapsed/refractory AML patients received either 
intermediate-dose cytarabine/gemtuzumab ozogamicin, or intermediate-dose 
cytarabine/liposomal daunorubicin, or intermediate-dose cytarabine/ cyclophosphamide/ 
topotecan.4 The CR/CRp (CR with incomplete platelet count recovery) rates achieved were low, 
ranging from 4% to 12%, depending on the study arm. Cortes et al. performed an exploratory 
study in relapsed/refractory AML patients combining p53 antisense oligonucleotide Cenersen 
with idarubicin either alone or with cytarabine.5 Ten of the 53 (19%) patients achieved CR/CRp. 
These data highlight the need for development of better treatment strategies for this group of 
patients. 
AML arising from antecedent MDS/MPN: In a recent study by Bello and colleagues, outcomes 
of patients who progressed from MDS were studied.7 In the subgroup of patients who had failed 
hypomethylating agents (the current FDA approved standard therapy for MDS), the median 
overall survival (OS) was only 3.7 months from the time of AML diagnosis. Those with poor 


Page 3 of 34 
 
risk cytogenetics (very common for this group of patients) had median OS of only 2.8 months. In 
our experience, the outcomes of these patients remains dismal with CR rate in <20% range 
(Jabbour et al. MDACC, unpublished data). Given these poor outcomes with the conventional 
treatment approaches, we plan to include these patients for frontline treatment of the AML.       
2.2 Combination chemotherapy for AML: Emerging role of purine analogs  
Anthracyclines have been traditionally combined with cytarabine in AML. Two recent 
publications highlighted higher response rates and better disease-free survival in both younger 
and older patients with frontline AML when high-dose daunorubicin (90 mg/m2/dose) was used 
in a “7+3” induction combination highlighting the activity of this class of agents for AML 
therapy.8,9 Pautas et al randomized 468 AML patients ages 50 to 70 years to 3 induction 
anthracycline regimens: idarubicin 12 mg/m2 daily for 3 days, idarubicin 12 mg/m2 daily for 4 
days, and high-dose daunorubicin 80 mg/m2 daily for 3 days.10 The CR rate with idarubicin daily 
for 3 days was higher than with high-dose daunorubicin (83% vs. 70%). A recent report from the 
Polish Acute Leukemia Group provides evidence for adding purine analog cladribine to the 
standard daunorubicin plus cytarabine regimen.11 In a phase III study, 652 untreated patients 
(ages 18 to 60 years) with AML were randomized to receive either daunorubicin plus cytarabine 
(DA), or DA plus fludarabine, or DA plus cladribine. The CR rate was significantly higher in the 
cladribine arm compared to the DA arm (67.5% vs. 56%; p=0.01). The OS was also better in the 
cladribine arm compared to DA arm (3-year OS: 45% vs. 33%, p=0.02). The survival advantage 
of the cladribine arm over the DA arm was observed among patients age 50 years or older 
(p=0.005), those with initial leukocyte count above 50 x 109/L (p=0.03), and those with 
unfavorable karyotype (p=0.03).  
 


Page 4 of 34 
 
2.3 Clofarabine in AML 
Clofarabine (2-chloro-20-fluoro-deoxy-9-b-D-arabinofuranosyladenosine) is a second-generation 
nucleoside analog, which was developed as a hybrid molecule to combine the most favorable 
pharmacokinetic properties of both fludarabine and cladribine and has better stability with higher 
affinity to deoxycytidine kinase, the rate-limiting step in phosphorylation of nucleosides.12 
Clofarabine acts as an inhibitor of both DNA synthesis and the enzyme ribonucleotide reductase 
(RNR). Its structural characteristics render it resistant to deamination by adenosine deaminase 
and phosphorolytic cleavage by bacterial purine nucleoside phosphorylase.13-16 Single agent 
clofarabine has demonstrated activity in phase I-II studies in AML.17,18 As a potent inhibitor of 
ribonucleotide reductase (RNR) and by means of biochemical modulation, clofarabine is more 
ideally suited to be incorporated into combinations such as have been tested and validated with 
cytarabine in AML.19 We have previously conducted a study combining cytarabine with 
clofarabine in patients with relapsed/refractory AML.20 At doses of 1 g/m2 daily x 5 days for 
cytarabine and 40 mg/m2 daily x 5 days for clofarabine, we reported a response rate of 40% 
(28% complete remission) in 29 patients with a median age of 59 years (18 to 84 years). 
Responses extended to patients with primary refractory disease and those with abnormal 
cytogenetics. Other groups have since followed this lead and published comparable results.21 We 
have also reported adaptively randomized study of lower-dose clofarabine (30mg/m2 IV daily 
for 5 days) with or without low-dose cytarabine (20mg/m2 SQ daily for 14 days)  in previously 
untreated older (≥60 years) with AML. CR rate was significantly higher with the combination 
therapy (63% vs. 31%; p=0.025). The combination arm also had improved event free survival 
(7.1 months vs. 1.7 months; p=0.04), but not overall survival (11.4 months vs. 5.8 months; 
p=0.1). No excess toxicity was observed in the combination arm. We have previously explored 


Page 5 of 34 
 
the combination of clofarabine with cytarabine and anthracycline (CIA regimen). In a phase I 
study for patients with relapsed/refractory AML, the following doses were established for further 
evaluation: clofarabine 22.5 mg/m2 daily x 5 days, idarubicin 6 mg/m2 daily x 3 days, and 
cytarabine 0.75 mg/m2 daily x 5 days.22 In a recent update of a phase II study of 63 patients 
treated with CIA regimen,23 the overall response rate was 38% including 21% CR. Median 
overall survival was 34 weeks for all patients and 66 weeks for those patients who achieved 
CR/CRp. Twenty-four patients (38%) were able to proceed with a stem cell transplant. Induction 
mortality was at 8%. Toxicities were manageable.  
 
2.4 The role of Hypomethylating agents in AML 
In the last decade there has been an increasing recognition of the important pathogenetic role of 
epigenetic changes in leukemogenesis.24 Aberrant DNA methylation of tumor suppressor genes, 
leading to their inactivation is an important step in carcinogenesis.25 Thus, drugs such as DNA 
methyltransferase inhibitors which lead to DNA hypomethylation may lead to reexpression of 
tumor suppressor genes. Two such agents, 5-azacytidine and decitabine are currently approved 
by the United States Food and Drug Administration for the treatment of MDS and have 
demonstrated single-agent activity in AML patients.26-29  
Kantarjian et al. performed a multicenter, randomized, open-label, phase III trial comparing the 
efficacy and safety of decitabine with treatment choice (TC, supportive care or cytarabine 20 
mg/m2 per day subcutaneously for 10 consecutive days every 4 weeks) in older patients (age ≥65 
years) with newly diagnosed AML and poor- or intermediate-risk cytogenetics.26 Patients 
(n=485) were randomly assigned 1:1 to receive decitabine 20 mg/m2 per day as a 1-hour 
intravenous infusion for five consecutive days every 4 weeks or TC. The primary analysis 


Page 6 of 34 
 
showed a nonsignificant increase in median OS with decitabine (7.7 months; 95% CI, 6.2 to 9.2) 
versus TC (5.0 months; 95% CI, 4.3 to 6.3; p=0.108). Based on this trial results, on September 
28, 2012, the European Commission approved decitabine for the treatment of adult patients (age 
65 years and above) with newly diagnosed AML, who are not candidates for standard induction 
chemotherapy.  
 
2.5 Combination of hypomethylating agents and chemotherapy in AML 
There is preclinical evidence that DNA hypomethylating agents can sensitize tumor cells to 
cytotoxic chemotherapy.30-34 Studies in the late 1970’s showed that combination of 5-azacytidine 
and cytarabine was synergistic both in vitro and in vivo, when used sequentially whereas 
concurrent administration was antagonistic.35 There studies were, however, done using higher 
doses of 5-azacytidine (600-1500 mg/m2 per course), which led to significant non-hematologic 
toxicities in these earlier clinical trials.36 It is now known that the effects of 5-azacytidine and 
decitabine on DNA hypomethylation occur at a significantly lower dose range; and the standard 
dose of decitabine is 20mg/m2 daily for 5 days.37-40 Qin et al. reported the synergism of 
decitabine at clinically relevant doses with cytarabine in the HL-60 AML cell line.34 The authors 
showed that hypomethylated cells following treatment with decitabine were more likely to 
undergo apoptosis when treated with cytarabine. Scandura et al. recently reported outcomes of 
30 untreated younger (≤60 years old) patients with intermediate/poor risk AML who received 
decitabine as a ‘priming’ agent prior to the conventional ‘7+3’ chemotherapy.41 Overall CR rate 
of 83% was noted (57% with first induction). No excess toxicity was noted with the decitabine 
priming approach and the toxicity profile was similar to the standard induction. Though there 
was a prior concern for potential prolonged myelosuppression with this approach, the authors, on 


Page 7 of 34 
 
the contrary found faster platelet recovery (median 22 days) with the decitabine ‘priming’ 
compared to their prior experience with cytarabine-containing induction regimens.41 The German 
group has reported preliminary results of a dose-finding study in which 5-azacytidine was used at 
2 different dosing regimen (75mg/m2 and 37.5mg/m2) immediately prior to standard induction 
with ‘7+3’.42 In their preliminary analysis, the tolerability of the 2 arms was similar and they 
have selected 75mg/m2 dose (the standard dosing for 5-azacytidine) as the phase II dose.  
 
Based on these observations, we hypothesize that addition of decitabine to our current standard 
chemotherapy regimen (clofarabine, idarubicin, cytarabine), the DAC-CIA regimen, would be 
synergistic and would ultimately lead to an improvement in CR rates and patient outcomes. We 
propose a phase I-II study. The primary endpoint of the phase I study is to determine the 
maximal tolerated dose (MTD) of clofarabine to be used in the phase II portion of the study. The 
primary endpoint of the phase II study is to determine the response rate of DAC-CIA regimen.  
 
2.6 Acute Lymphoblastic Leukemia (ALL) 
Patients with relapsed/Refractory ALL constitute a poor risk group with dismal long-term 
outcomes. Fielding and colleagues analyzed the outcomes of 609 relapsed adult ALL patients 
who were treated on the MRC trial.43 The median OS was only 5.5 months with the 5-year OS of 
only 7%. Similar poor outcomes of relapsed patients with ALL have been reported by the French 
and PETHEMA groups.44,45 Thus, patients with relapsed ALL continue to be a challenging 
subgroup of patient and novel treatment strategies are indicated.  
Epigenetic dysregulation is now thought to play an important role in pathogenesis of ALL.46 
Promoter hypermethylation of cancer related genes such as Wnt, Src and others have been shown 


Page 8 of 34 
 
to be an independent prognostic marker for poor survival in ALL patients.47-49 Preclinical 
evidence supports use of hypomethylating agents such as decitabine in ALL patients.46,50 In the 
proposed clinical trial, all the chemotherapy drugs (clofarabine, idarubicin, cytarabine) have been 
shown to have independent anti-leukemic activity in ALL.17,51,52 Therefore, the proposed 
regimen (decitabine followed by the CIA chemotherapy) deserves evaluation as a treatment 
strategy for relapsed/refractory ALL patients. We plan to enroll ALL patients only in the phase II 
part of the study.  
 
3. BACKGROUND DRUG INFORMATION 
3.1. Idarubicin: 
Idarubicin is commercially available. 
Mechanism of action: 
Similar to doxorubicin and daunorubicin; inhibition of DNA and RNA synthesis by intercalation 
between DNA base pairs 
Adverse effects: 
o 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. 
o Central nervous system: Headache 
o Dermatologic: Alopecia (25% to 30%), radiation recall, skin rash (11%), urticaria 


Page 9 of 34 
 
o Gastrointestinal: Nausea, vomiting (30% to 60%); diarrhea (9% to 22%); stomatitis (11%); 
GI hemorrhage (30%) 
o Genitourinary: Discoloration of urine (darker yellow) 
 
3.2. Cytarabine 
Cytarabine is commercially available. 
Mechanism of action: 
Cytarabine is an antimetabolite. Cytarabine is cell cycle–specific for the S phase of cell division. 
Activity occurs as the result of activation to cytarabine triphosphate in the tissues and includes 
inhibition of DNA polymerase and incorporation of cytarabine into DNA and RNA. 
Adverse effects: 
COMMON 
•  Cardiovascular: Thrombophlebitis 
•  Dermatologic: Rash, conjunctivitis 
•  Endocrine metabolic: Hyperuricemia 
•  Gastrointestinal: Anal inflammation, Diarrhea, Loss of appetite, Nausea, Stomatitis, 
  
Ulcer of anus, Ulcer of mouth, Vomiting 
•  Hematologic: Decreased reticulocyte count, Megaloblastic anemia 
•  Hepatic: Decreased liver function 
• 
 Other: Fever 
SERIOUS 
•  Hematologic: Anemia, Bleeding, Leukopenia, Thrombocytopenia 
•  Immunologic: Anaphylaxis 


Page 10 of 34 
 
•  Neurologic: Neuropathy 
•  Renal: Kidney disease 
•  Other: Infectious disease, Sepsis 
 
3.3. Clofarabine 
Clofarabine is commercially available. 
Mechanism of action: 
Clofarabine potently inhibits DNA synthesis by inhibiting both DNA polymerase and 
ribonucleotide reductase. Clofarabine demonstrated the ability to disrupt mitochondrial integrity 
that results in the release of pro-apoptotic proteins, cytochrome C and apoptosis-inducing factor. 
Adverse effects: 
• Hematologic: Myelosuppression, infections 
• Hepato and Gastrointestinal: Nausea/vomiting, diarrhea, mucositis, stomatitis/ 
pharyngitis, hyperbilirubinemia, increase of SGPT and/or SGOT, abdominal pain or 
cramping, peritonitis, pancreatitis, liver failure 
• Dermatologic: Skin rash with blisters (particularly hand-foot syndrome), alopecia, 
Steven-Johnson's syndrome 
• Systemic: Fatigue, asthenia, anorexia, lethargy, malaise, mental status changes/coma, 
alopecia 
• Allergic reactions: fever, muscle aches, edema, dyspnea 
• Cardiology: Congestive heart failure 
• Nephrology: Kidney failure 
• Autoimmune reactions: antiplatelet antibodies, erythema nodosum 


Page 11 of 34 
 
 
3.4. Decitabine 
Decitabine is commercially available.  
Mechanism of action: 
Decitabine is a nucleoside analog. It is metabolized intracellularly by the enzyme deoxycytidine 
kinase and gets incorporated into DNA. It is believed to exert its antineoplastic effects by 
causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the 
bone marrow. Hypomethylation may restore normal function to genes that are critical for 
differentiation and inhibition of proliferation.  
Adverse effects: 
Myelosuppression, nausea/vomiting, diarrhea, mucositis, skin rash, fatigue, mental status 
changes/coma, allergic reactions (including fever, muscle aches, edema, dyspnea), congestive 
heart failure, liver failure, kidney failure, infections, lethargy, malaise, asthenia, alopecia, 
peritonitis, anorexia, stomatitis/pharyngitis, hyperbilirubinemia, increase of SGPT and/or SGOT, 
abdominal pain or cramping.  
Also reported on decitabine trials, but with the relationship to decitabine still undetermined: 
allergic reaction, allergic rhinitis, GVHD, atrial fibrillation, cardiac ischemia/infarction, 
cardiopulmonary arrest, hypotension, left ventricular systolic dysfunction, right ventricular 
dysfunction, fever, insomnia, rigors/chills, weight loss, pruritus, rash, anal ulcer, ascites, 
constipation, abdominal distention, esophagitis, GI obstruction, ileus, taste alteration, CNS 
hemorrhage, GI hemorrhage, lung hemorrhage, nose hemorrhage, petechiae, urinary hemorrhage, 
cholecystitis, liver failure, infection without neutropenia, opportunistic infection, perianal 
abscess, head/neck edema, alkaline phosphatase, creatinine, hypercalcemia, hyponatremia, 


Page 12 of 34 
 
fracture, agitation, CNS ischemia, confusion, depression, dizziness, extrapyramidal/involuntary 
movement, motor neuropathy, psychosis, seizure, sensory neuropathy, bone pain, headache, 
muscle pain, urinary pain, ARDS, bronchospasm, cough, dyspnea, hiccups, 
pneumonitis/pulmonary infiltrates, cystitis. 
 
4. ELIGIBILITY CRITERIA 
Inclusion criteria: 
• Sign an IRB-approved informed consent document. 
• Age ≥18 to 65 years. 
• Diagnosis of AML [other than acute promyelocytic leukemia] with refractory/relapsed 
disease (Patients must be either primary refractory, in relapse 1, or in relapse 2).  
NOTE: Patients with AML arising from prior MDS or MPN will be eligible even if they 
have not received treatment for the AML.    
NOTE: Patients with relapsed/refractory ALL will also be eligible for the phase II part of 
the study. 
NOTE: Use of hydroxyurea and/or up to 4 doses of cytarabine, for emergent 
cytoreduction is allowed  
• ECOG performance status of ≤2 at study entry. 
• Organ function as defined below (unless due to leukemia): 
o Serum creatinine ≤ 3 mg/dL 
o Total bilirubin ≤ 2.5 mg/dL 
o ALT (SGPT) ≤ 3 x ULN or ≤ 5 x ULN if related to disease 
• Cardiac ejection fraction ≥ 40% (by either cardiac ECHO or MUGA scan) 


Page 13 of 34 
 
• Women of childbearing potential must have a negative serum or urine pregnancy test 
within 7 days. Men must agree not to father a child and agree to use a condom if his 
partner is of child bearing potential. 
 
Exclusion Criteria: 
• Breast feeding women 
• Patients with uncontrolled active infections (viral, bacterial, and fungal are not eligible). 
• Patients with active secondary malignancy will not be eligible unless approved by the PI. 
• NOTE: Prior therapy with decitabine, clofarabine, idarubicin, or cytarabine is allowed, 
unless the prior therapy is identical to the schema/schedule proposed in this study 
 
5. TREATMENT PLAN 
5.1. Study design 
The study will include a phase I portion to determine MTD dose of clofarabine to be used in the 
subsequent phase II portion. Starting with Dose level 1, the patient will be enrolled by cohort of 
3. Once the DLT assessment for the 3 patients is completed, a sequential of another cohort of 3 
patients will be enrolled. If at any time, we see more than 30% patients experiencing DLT, we 
will de-escalate to dose level (-1).  The same above monitoring rule will also be applied to dose 
level -1. A total of 18 patients will be enrolled. Once the phase II dose of clofarabine is 
established, additional patients will be enrolled in the phase II portion of the study.  
 
5.2. Induction 


Page 14 of 34 
 
5.2.1 Phase I (fixed dose of decitabine 20mg/m2 days 1-5, idarubicin 10 mg/m2 days 6-8 and 
cytarabine 1 g/m2 days 6-10) 
Clofarabine 15 mg/m2 IV over approximately 1 hour daily.  
Dose levels and dose escalation schema are described below. 
Dose level 
Clofarabine 15 mg/m2/day IV daily 
-1 
Clofarabine daily for 3 days (days 6-8) 
1 
Clofarabine daily for 4 days (days 6-9) 
 
Decitabine 20 mg/m2 IV over approximately 1 hour daily for 5 days (days 1-5) 
Idarubicin 10 mg/m2 IV over approximately 30 minutes daily for 3 days (days 6-8) 
Cytarabine 1 g/m2 IV over approximately 2 hours daily for 5 days (days 6-10) 
 
Idarubicin will follow clofarabine by 1 to 2 hours and cytarabine will follow clofarabine by 3 to 
6 hours. All chemotherapeutic agents will be dosed, prepared, and administered according to 
MDACC institutional guidelines. BSA will be recalculated prior to each subsequent course. 
 
A DLT is defined as a clinically significant adverse event or abnormal laboratory value assessed 
as unrelated to disease progression, intercurrent illness, or concomitant medications and 
occurring during the first course on study that meets any of the following criteria: 
• CTCAE Grade 3 total bilirubin or AST (SGOT) or ALT (SGPT) for > 7 days 
• CTCAE Grade 4 total bilirubin or AST (SGOT) or ALT (SGPT) of any duration 


Page 15 of 34 
 
• All other clinically significant NCI common terminology criteria that are CTCAE Grade 
3 or 4 
An AE must be clinically significant to define DLT e.g. alopecia, study drug-related fever, 
electrolyte abnormalities (including K, Na, Cl, HCO3, Mg, Ca) that are < Grade 3 will not define 
the DLT. Prolonged myelosuppression, as defined by the NCI criteria specific for leukemia, i.e. 
marrow cellularity <5% on day 42 or later from start of therapy without evidence of leukemia, 
will be considered as DLT. All other prolonged myelosuppressions will also be monitored 
closely. Note: As the patients receive 5-days of decitabine therapy prior to starting the induction 
chemotherapy, extra 5-days will be allowed to assess for prolonged myelosuppression. In 
addition to the above, patient death will be monitored closely. Any death will be submitted to 
discussion by the Department of Leukemia meeting.   
 
Patients, who have not achieved a complete remission following one induction course, can 
receive a second induction course to optimize response if possible. A second induction course at 
the same dose as the previous course or in a dose-reduced fashion should not be given until at 
least 33 days of course 1, unless an earlier administration is judged to be in the best interest of 
the patient by the treating physician. If the bone marrow aspirate and/or biopsy(s) performed 
after the re-induction cycle reveals a remission marrow (CR/CRp/CRi), then the patient may 
proceed with consolidation at the discretion of the treating physician. In addition, any clinically 
significant drug-related, non-hematologic toxicity experienced by a patient should return to ≤ 
grade 2 or the baseline grade before the patient continues treatment. Should the patient not have 
achieved a remission (CR/CRp/CRi) after the reinduction course, he will be taken off study for 


Page 16 of 34 
 
failure to respond, unless the patient has achieved clinical benefit or partial remission, at which 
time further therapy on protocol may be permitted with approval from the PI. 
 
5.2.2 Phase II 
In the Phase II portion, patients will receive the following treatments 
Clofarabine 15 mg/m2 IV over approximately 1 hour daily (number of days selected based on 
Phase I portion).  
Decitabine 20 mg/m2 IV over approximately 1 hour daily for 5 days (days 1-5) 
Idarubicin 10 mg/m2 IV over approximately 30 minutes daily for 3 days (days 6-8) 
Cytarabine 1 g/m2 IV over approximately 2 hours daily for 5 days (days 6-10) 
 
Idarubicin will follow clofarabine by 1 to 2 hours and cytarabine will follow clofarabine by 3 to 
6 hours. All chemotherapeutic agents will be dosed, prepared, and administered according to 
MDACC institutional guidelines. BSA will be recalculated prior to each subsequent course. 
Patients, who have not achieved a complete remission following one induction course, can 
receive a second induction course to optimize response if possible. A second induction course at 
the same dose as the previous course or in a dose-reduced fashion should not be given until at 
least 33 days of course 1, unless an earlier administration is judged to be in the best interest of 
the patient by the treating physician. If the bone marrow aspirate and/or biopsy(s) performed 
after the re-induction cycle reveals a remission marrow (CR/CRp/CRi), then the patient may 
proceed with consolidation at the discretion of the treating physician. In addition, any clinically 
significant drug-related, non-hematologic toxicity experienced by a patient should return to ≤ 
grade 2 or the baseline grade before the patient continues treatment. Should the patient not have 


Page 17 of 34 
 
achieved a remission (CR/CRp/CRi) after the reinduction course, he will be taken off study for 
failure to respond, unless the patient has achieved clinical benefit or partial remission, at which 
time further therapy on protocol may be permitted with approval from the PI. 
 
5.3 Consolidation (for both phase I and phase II portion) 
Patients in CR or CRp or CRi can continue with up to 6 consolidation cycles. 
Decitabine 20 mg/m2 IV over approximately 1 hour daily for 5 days (days 1-5) 
Clofarabine 15 mg/m2 IV over approximately 1 hour daily for 3 days (days 6-8) 
Idarubicin 8 mg/m2 IV over approximately 30 minutes daily for 2 days (days 6-7) 
Cytarabine 1 g/m2 IV over approximately 2 hours daily for 3 days (days 6-8) 
 
Cycles may be repeated every 3 to 10 weeks based on leukemia response and resolution of drug-
related toxicities. Prior to each consolidation cycle, the ANC should be > 1.0 x 109/L, and the 
platelet count should be > 60 x 109/L (except for patients who are considered to have achieved a 
CRp or CRi following induction/reinduction and in whom the platelet count may be lower). 
Patients with borderline values for ANC and platelet count (value up to 10% lower than 
recommended) can still proceed with the next consolidation cycle if this is judged to be in the 
best interest of the patients and after discussion with the principal investigator. In addition, any 
drug-related non-hematologic toxicity experienced by the patient must return to ≤ grade 2 before 
receiving the next cycle. Doses missed or held during a cycle of treatment will not be made up 
and are recorded as being omitted. If patients experience multiple study drug-related toxicities or 
experience significant infections, dose adjustments may need to be made based on the most 
severe toxicity and based on the drug causing the toxicity. 


Page 18 of 34 
 
 
5.4 Dose modifications: 
Drug doses in subsequent consolidation cycles may be modified for drug-related > grade 2 non-
hematologic toxicities. Dose reductions can also be made in other clinical situations where this 
step is considered to be in the best interest for the patient and after discussion with the principal 
investigator. The following table is a suggestion for dose modifications in subsequent treatment 
courses: 
 
Dose level 
Decitabine 
(mg/m2) 
Clofarabine 
(mg/m2) 
Idarubicin 
(mg/m2) 
Cytarabine 
(g/m2) 
0 
20 
15 
8 
1 
-1 
20 
12.5 
8 
0.75 
-2 
20 
12.5 
6 
0.5 
-3 
20 
10 
6 
0.25 
 
Doses of each individual drug can be modified if toxicity is considered due a particular drug. 
Specific Dose Modifications for Organ Function: 
 
 
Decitabine 
(mg/m2) 
Cytarabine 
(g/m2) 
Idarubicin 
(mg/m2) 
Clofarabine 
(mg/m2) 


Page 19 of 34 
 
Creatinine (mg/dL) 
2.1 – 3.0 
(age <65) 
20 
0.75 
10 (induction) 
8 (consolidation) 
75% of current 
dose level 
2.1 – 3.0 
(age ≥65) 
20 
0.5 
8 (induction) 
6 (consolidation) 
50% of current 
dose level 
>3.0 
Discuss with Study PI 
Bilirubin (mg/dL) 
2.6 – 5.0 
20 
1 
5 (induction) 
4 (consolidation) 
Discuss with 
Study PI 
>5.0 
20 
1 
OMIT 
Discuss with 
Study PI 
 
6. PRETREATMENT AND POST-TREATMENT EVALUATION 
Pre-treatment evaluation 
• Medical history, physical examination and concomitant medication within 14 days of 
treatment start 
• CBC, differential, platelet count and chemistry panel (at least including BUN, creatinine, 
SGPT and/or SGOT, total bilirubin, LDH, electrolytes, uric acid) within 7 days of 
treatment start 


Page 20 of 34 
 
• Bone marrow aspirate and/or biopsy with appropriate flow cytometry within 1 month of 
treatment start (and cytogenetic evaluation within 3 months of treatment start). For 
patients with evidence of leukemia in the peripheral blood, the bone marrow may be 
omitted after discussion and approval with the principal investigator. 
• Echocardiography or MUGA scan to assess cardiac ejection fraction within 8 weeks of 
treatment start 
• For women of childbearing age, a negative serum and/or urine pregnancy test is required 
within 7 days of treatment start 
 
Evaluation during study 
• Physical exam prior to every cycle.  
• CBC, differential, and platelet count twice weekly during induction and reinduction then 
at least weekly during consolidation. The differential may be omitted when the WBC 
count is ≤500/uL.  
• Chemistry panel (at least including electrolytes, BUN, creatinine, SGPT and/or SGOT, 
total bilirubin) at least weekly during induction and reinduction then every two weeks 
during consolidation. 
• CBC, differential, platelet count, creatinine, and bilirubin prior to each consolidation 
course 
• Bone marrow aspirate and/or biopsy starting day 33 of induction and reinduction (+/- 7 
days) and every 2 weeks (+/- 7 days) thereafter until remission or non-response (Day 33 
is listed instead of usual day 28 due to 5 days of decitabine treatment prior to 
chemotherapy). No bone marrow is necessary if non-response or progressive disease can 


Page 21 of 34 
 
be diagnosed from peripheral blood evaluation, or, in patients with a WBC ≤ 300/uL, if 
the bone marrow test is considered non-contributory by the Investigator. Cytogenetic 
studies need to be repeated only if abnormal prior to study. Further bone marrow tests as 
indicated by development of peripheral blood counts.  
Marrow aspirates would be repeated every 2-3 cycles during consolidation phase 
Optional procedures for the study 
 
Samples will be collected for potential studies and will be stored in the laboratory of Dr. 
Guillermo Garcia-Manero (pager 713-404-0277) in the Department of Leukemia at MD 
Anderson Cancer Center. Samples will be collected as follows: 
• Bone marrow aspirate: pretherapy (day 0) and on day 33 of first cycle. 
• Peripheral blood (including serum): on days 0, 5, 10, 17, 24 and 33 of the first cycle. 
All samples can be obtained +/- 5 days. Not all research samples may be collected at all time-
points and omissions will not be considered deviations. 
 
Samples could be used, but not limited, to analysis of cytokine profile, genetic and epigenetic 
lesions and molecular characterization of mechanism of action.  
 
Supportive care 
Supportive measures such as prophylaxis for tumor lysis syndrome, erythropoietin, analgesics, 
blood transfusions, antimicrobials and hematopoietic colony stimulating factors for treatment of 
cytopenias are permitted. The administration of anti-leukemia therapies is not permitted, except 


Page 22 of 34 
 
for hydroxyurea which is allowed for up to 7 days each during cycle 1-3 and the use of up to 4 
doses of cytarabine (up to 2 g/m2 each) for emergency use up to 24 hours prior to start of study 
therapy. Intrathecal chemotherapy is allowed for patients with CNS disease. 
 
7. STUDY END POINTS 
Phase I 
Primary: To determine the MTD of clofarabine to be used in portion II of the study 
Phase II 
Primary: To determine the response rate of the DAC-CIA regimen 
Secondary: A) To determine the toxicity of the combination regimen; B) To determine the DFS 
and OS rates 
 
8. CRITERIA FOR WITHDRAWAL 
Reasons for withdrawal include: 
• withdrawal of consent or the subject refuses to continue treatment and/or procedures/ 
observations 
• relapse unless the treating physician determines that the patient has achieved clinical 
benefit, at which time further therapy on protocol may be permitted with approval from 
the PI 
• failure to achieve at least a CRp or CRi after 2 induction courses 
 
9. CRITERIA FOR RESPONSE 
Definitions: 


Page 23 of 34 
 
Complete Response (CR): Disappearance of all clinical and/or radiologic evidence of disease. 
Neutrophil count ≥ 1.0 x 109/L 
Platelet count ≥ 100 x 109/L 
Normal bone marrow differential (≤ 5% blasts) 
No extra-medullary leukemia 
 
Complete Remission without Platelet Recovery (CRp): 
Peripheral blood and bone marrow results as for CR, but with platelet counts of < 100 x 109/L. 
 
Complete Remission without Incomplete Blood Count Recovery (CRi): 
Peripheral blood and bone marrow results as for CR except for ANC < 1.0 x 109/L with or 
without platelet count < 100 x 109/L. 
 
Partial Remission (PR): 
Blood count recovery as for CR, but with a decrease of at least 50% in the percentage of marrow 
blasts to >5% to 25% in the bone marrow aspirate. 
 
Stable Disease (SD): 
In absence of any of the above response criteria, patients will be considered to have stable 
disease if the bone marrow blast percent does not increase compared to pretreatment level. 
 
10. REPORTING REQUIREMENTS 
All adverse and serious adverse events will be recorded and reported according to the 


Page 24 of 34 
 
Department of Leukemia guidelines (appendix A) 
 
11. STATISTICAL CONSIDERATIONS 
 
Phase I 
First, phase I study is performed to assess the safety of different dosing schedules for clofarabine 
combined with fixed dosage of decitabine, idarubicin, and cytarabine. Two dose schedules are 
defined in table 1, and the starting dose schedule is dose level 1. A maximum of 18 AML 
patients will enroll in the phase I study. 
Table 1: dose schedule 
Dose 
level 
Clofarabine 15 mg/m2/day IV daily 
-1 
Clofarabine daily for 3 days (days 6-8) 
1 
Clofarabine daily for 4 days (days 6-9) 
 
Decitabine 20 mg/m2 IV over approximately 1 hour daily for 5 days (days 1-5) 
Idarubicin 10 mg/m2 IV over approximately 30 minutes daily for 3 days (days 6-8) 
Cytarabine 1 g/m2 IV over approximately 2 hours daily for 5 days (days 6-10) 


Page 25 of 34 
 
Dose Escalation Procedures  
Starting with Dose level 1, the patient will be enrolled by cohort of 3. Once the DLT assessment 
for the 3 patients is completed, a sequential of another cohort of 3 patients will be enrolled.  If at 
any time, we see more than 30% patients experiencing DLT, we will deescalate to dose level (-
1). If no dose de-escalation occurs, with a total of 18 patients treated at dose level 1, dose level 1 
will be considered as the MTD for the phase II part. If there is dose de-escalation, a cohort of 3 
patients will be treated, Dose level -1 will be declared as MTD if there are ≤1 out of 6 patients 
experience DLT.   
Phase II 
Phase II part is a single arm study using the dosage schedule recommended from phase I. A 
maximum of 60 AML patients which includes 42 new patients and the 18 patients from phase I 
MTD level, and 20 ALL patients will be enrolled in the study. The trial will be continuously 
monitored regarding efficacy for each cohort, AML and ALL respectively. The toxicity will be 
jointly monitored for AML and ALL patients. The method of Thall, Simon, and Estey will be 
used to perform interim efficacy and safety monitoring.53 The software Multc99.Version 2.1 was 
used to run the simulation.  
Efficacy  
The primary endpoint is the overall response which is defined as the best response (either CR, 
CRp, or CRi) within 56 days.  
11.1 
AML 


Page 26 of 34 
 
For the AML patients, the historical data suggested the overall response rate to current standard 
treatment is 25%. The target response rate is 40%.  The trial will be continuously monitored. The 
study will be stopped early if the data suggest that: 
                                      Pr (π > 0.25|data) < 0.3 
Here π  is the overall response (OR) rate. That is, if at any time during the study we determine 
that there is a less than 30% chance that the average OR rate is greater than 25%, we will 
terminate the study.  The OR rate is assumed to follow a non-informative prior of Beta (0.5, 1.5). 
The study will be stopped early if (The number of overall responses)/ (The number of patients 
evaluated) ≤1/8, 2/11, 3/15, 4/20, 5/24, 6/29, 7/33, 8/37, 9/42, 10/46, 11/50, 12/54, 13/59.  
Table 2: Operating characteristics for monitoring of overall response rate in AML patients 
True Response Rate 
Early Stopping Probability Median Sample size (interquantile) 
0.2 
0.91 
8 (8,20) 
0.25 
0.73 
11 (8, 60) 
0.3 
0.51 
54 (8, 60) 
0.35 
0.33 
60 (15, 60) 
0.4 
0.19 
60 (60, 60) 
 
11.2.   ALL  


Page 27 of 34 
 
For the ALL patients, the historical data suggested the overall response rate to current standard 
treatment is 20%.The target response rate would be 40% after the treatment.  The trial will be 
continuously monitored. The study will be stopped early if the data suggest that: 
                                      Pr (π > 0.2|data) < 0.4 
Here π  is the overall response (OR) rate. That is, if at any time during the study we determine 
that there is a less than 40% chance that the average OR rate is greater than 20%, we will 
terminate the study.  The OR rate is assumed to follow a non-informative prior of Beta (0.4, 1.6). 
The study will be stopped early if (The number of overall responses)/ (The number of patients 
evaluated) ≤1/8, 2/11, 3/17. 
Table 3: Operating characteristics for monitoring of overall response rate in ALL patients 
True Response Rate 
Early Stopping Probability 
Median Sample size (interquantile) 
0.15 
0.85 
8 (8,11) 
0.2 
0.7 
11 (8, 20) 
0.25 
0.54 
17 (8, 20) 
0.3 
0.38  
20 (8,20) 
0.35 
0.26 
20 (17, 20) 
0.4 
0.16  
20 (20, 20) 
 
Monitoring of non-hematological ≥grade 3 toxicities 


Page 28 of 34 
 
With the concern of treatment related toxicity, the non-hematological toxicity (≥grade 3) 
throughout all the cycles of treatment will also be closely monitored during the study for AML 
and ALL together.   
Denote the probability of toxicity by PE. We assume PE ~ beta (0.6, 1.4).  Our stopping rule is 
given by the following probability statement: Pr(PE > 0.3 | data)  > 0.9 . That is, we will stop the 
trial if, at any time during the study, we determine that there is more than 90% chance that the 
toxicity rate is more than 30%. The study will be stopped early if (The number of non-
hematological toxicities being grade 3 or higher)/ (The number of patients evaluated) ≥ 7/13, 
8/15, 9/18, 10/21, 11/23, 12/26, 13/29, 14/32, 15/35, 16/38, 17/41, 18/43, 19/46, 20/49, 21/52, 
22/55, 23/58, 24/61, 25/64, 26/67, 27/70, 28/73, 29/76, 30/79.  The operating characteristics are 
summarized in table 4. 
Table 4: Operating characteristics for monitoring of non-hematological ≥grade 3 toxicities in 
AML or ALL patients 
True Toxicity Rate 
Early Stopping Probability Median Sample size (interquantile) 
0.25 
0.15 
80 (80, 80) 
0.3 
0.35 
80 (27, 80) 
0.35 
0.63 
42 (11, 80) 
0.4 
0.88 
19 (7, 47) 
 
Analysis method 


Page 29 of 34 
 
Data analysis will be performed using SAS or S-plus, as appropriate. The proportion of patients 
having overall response, the mortality rate, and the proportion of patients having grade 3 or 
higher non-hematological toxicities will be estimated by the corresponding posterior mean and 
90% posterior credible interval. 
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