Phase I/II Randomized Study of Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome
Phase: PHASE1
Conditions: Leukemia
Sponsor: M.D. Anderson Cancer Center

2010-0788
October 10, 2013
Page 1
Protocol Page
Phase I/II Randomized Study of Clofarabine, Idarubicin, and Cytarabine (CIA) 
versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous 
Leukemia and High-Risk Myelodysplastic Syndrome
2010-0788
Core Protocol Information
Short Title 
Clofarabine, Idarubicin, and Cytarabine (CIA) versus Fludarabine, Idarubicin, and Cytarabine 
(FLAI) in AML and High-Risk Myelodysplastic Syndrome
Study Chair: 
Elias Jabbour
Additional Contact:
Vicky H. Zoeller
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-4764
Unit:
428
Full Title: 
Phase I/II Randomized Study of Clofarabine, Idarubicin, and Cytarabine (CIA) versus 
Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous Leukemia and High-Risk 
Myelodysplastic Syndrome
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 02/14/2017
Version:
20
Submitted by:
Vicky H. Zoeller--1/4/2017 4:09:06 PM
OPR Action:
Accepted by:  Julie Arevalo -- 1/10/2017 10:00:37 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

2010-0788
October 10, 2013
Page 2
Protocol Body
 

 
 
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Phase I/II Randomized Study of Clofarabine, Idarubicin, and Cytarabine (CIA) 
versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous 
Leukemia and High-Risk Myelodysplastic Syndrome 
 
 
I. OBJECTIVES 
Phase I 
Primary:   
Determine the MTD of clofarabine to be used in portion II of the study. 
Phase II  
Primary: 
Compare the response rates of two different regimens CIA versus FLAI  
Secondary: 
Evaluate the durability of response, the overall and event-free survival rates, and the 
safety profile of 2 different regimens. 
 
II. RATIONALE 
Treatment options for relapsed and refractory AML and high-risk MDS are limited. 
Retreatment with a high-dose cytarabine (HDAC) containing regimen is considered 
standard for patients relapsing after an initial complete remission (CR) lasting for a year 
or more. Once a second remission is achieved, these patients can proceed to stem cell 
transplant if appropriate donors are available. For patients relapsing after a shorter 

 
 
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remission or with primary refractory disease no true standard options exist and 
investigational therapy is considered appropriate. 
 
We have been using fludarabine and ara-C (FA) combination chemotherapy since 1989 
for relapsed AML, and since 1991 for newly diagnosed AML/MDS. We have reported 
that FA is superior to ara-C in relapsed AML, if disease is sensitive to ara-C as 
manifested by a relatively long first remission. 1 In patients with newly diagnosed 
disease, the use of FA- containing regimens was associated with higher complete 
response rates (50-60%) than with standard chemotherapy.2 The effectiveness of FA is 
believed due to the ability of fludarabine to modulate the pharmacologic behavior of ara-
C. Specifically, at intracellular concentrations of ≥10 μM, F-ara-ATP, the active 
metabolite of fludarabine, increases accumulation of ara-CTP in AML cells beyond that 
possible with dose escalation of ara-C.3 Once above 10 μM F-ara-ATP, ara-CTP 
formation plateaus. 
 
Single agent clofarabine has demonstrated activity in phase I studies in AML.4 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 fludarabine and cytarabine in AML in the past.5 
We have previously conducted a study combining cytarabine with clofarabine in patients 
with relapsed/refractory AML.6 At doses of 1 g/m2 daily x 5 for cytarabine and 40 mg/m2 
daily x 5 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 

 
 
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patients with primary refractory disease and those with abnormal cytogenetics.  Other 
groups have since followed this lead and published comparable results, albeit doses of 
cytarabine and clofarabine varied throughout the different studies.7 
 
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 “3+7” induction combination highlighting the activity of this 
class of agents for AML therapy.8-9 Pautas et al randomized 468 patients ages 50 to 70 
years on Acute Leukemia French Association studies 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. The CR rate with idarubicin daily 
for 3 days was higher than with high-dose daunorubicin (83% vs 70%), as was the 3-
year event-free survival rate (23% vs 16%).10 
 
The combination with nucleoside analogs synergizes the anthracyclines activity by 
inhibiting DNA repair damage. Holowiecki et al from Poland randomized 673 patients 
(ages 18 to 60 years) to receive either daunorubicin plus cytarabine (DA), or DA plus 
fludarabine, or DA plus chlorodeoxyadenosine (DAC). The authors reported significantly 
higher CR rates after 1 course of induction and overall and reported better 3-year 
survival rates with the addition of the DAC regimen.11 
 

 
 
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We have previously explored the combination of clofarabine, idarubicin, and cytarabine 
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, idarubicin 6 mg/m2 
daily x 3, and cytarabine 0.75 mg/m2 daily x 5.12 In a recent update of a phase II study 
of 63 patients treated with CIA,13 the overall response rate was 38% including 21% with 
complete remission. 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. 
 
In view of this experience and in light of above data of the possible usefulness of higher 
doses of anthracyclines, and the synergistic activity of the combination of anthracyclines 
with nucleoside analogues, we propose to evaluate in a phase II Bayesian design the 
CIA combination at higher doses than established versus the FLAI combination in 
patients with relapsed/refractory and newly diagnosed AML (not fit for any protocol) and 
high-risk MDS. 
 
III. BACKGROUND DRUG INFORMATION 
A. 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. 

 
 
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Adverse effects: 
 Cardiovascular: Transient EKG abnormalities (supraventricular tachycardia, S-T 
wave changes, atrial or ventricular extrasystoles); generally asymptomatic and self-
limiting. Congestive heart failure, dose-related. The relative cardiotoxicity of 
idarubicin compared to doxorubicin is unclear. Some investigators report no increase 
in cardiac toxicity at cumulative oral idarubicin doses up to 540 mg/m2; other reports 
suggest a maximum cumulative intravenous dose of 150 mg/m2. 
 Central nervous system: Headache 
 Dermatologic: Alopecia (25% to 30%), radiation recall, skin rash (11%), urticaria 
 Gastrointestinal: Nausea, vomiting (30% to 60%); diarrhea (9% to 22%); stomatitis 
(11%); GI hemorrhage (30%) 
 Genitourinary: Discoloration of urine (darker yellow) 
 
B. 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 

 
 
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• 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 
• Neurologic: Neuropathy 
• Renal: Kidney disease 
• Other: Infectious disease, Sepsis 
 
C. Fludarabine 
Fludarabine is commercially available. 
Mechanism of action: 
Fludarabine phosphate is fluorinated nucleotide and analog of antiviral agent 
vidarabine, that is relatively resistant to adenosine deaminase deamination. It is actively 
dephosphorylated to 2-fluoroara-A and phosphorylated further by deoxycytidine kinase 
to 2-ribonucleotide reductase and DNA primase resulting in DNA synthesis inhibition. 
Adverse effects: 
COMMON 

 
 
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• Endocrine metabolic: Shivering 
• Gastrointestinal: Loss of appetite, Nausea, Vomiting 
• Neurologic: Asthenia 
• Other: Fatigue, Malaise 
SERIOUS 
• Cardiovascular: Edema (frequent) 
• Dermatologic: Aplasia of skin (rare) 
• Hematologic: Autoimmune hemolytic anemia, Graft versus host disease, Transfusion-
associated, with non-irradiated blood (rare), Myelosuppression (frequent) 
• Neurologic: Neurotoxicity 
• Respiratory: Pneumonia (frequent) 
• Other: Fever (frequent), Infectious disease 
 
D. 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 

 
 
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 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), Steven-
Johnson's syndrome, alopecia, conjonctivitis 
 Systemic: Fatigue, asthenia, anorexia, lethargy, malaise, mental status 
changes/coma, alopecia  
 Allergic reactions: (including fever, muscle aches, edema, dyspnea)  
 Cardiology: Congestive heart failure  
 Nephrology: Kidney failure  
 Autoimmune reactions:  (antiplatelet antibodies, erythema nodosum) and/or 
chemical imbalances in the blood. 
 
IV. Eligibility criteria 
Inclusion criteria: 
 Sign an IRB-approved informed consent document. 
 Age 18 to 60. Patients above the age of 60 only with PI approval 
 Diagnosis of newly diagnosed AML [other than acute promyelocytic leukemia (APL)]. 
Prior therapy with hydrea and the use of a single or a two day dose of cytarabine (up 
to 3 g/m2) for emergency use up to 24 hours prior to start of study therapy is 
allowed.  Prior therapy for MDS or other AHD is not allowed. 
 ECOG performance status of ≤ 3 at study entry. 
 Organ function as defined below (unless due to leukemia): 

 
 
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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 
 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. 
 Cardiac ejection fraction ≥ 40% (by either cardiac echo or MUGA scan). 
Documentation of recent (≤ 6 months from screening) outside reports is acceptable. 
 
Exclusion Criteria: 
 Breast feeding females 
 Patients with uncontrolled active infections (viral, bacterial, and fungal are not 
eligible). 
 Patients with active secondary malignancy will not be eligible. 
 
IV. Treatment plan 
1. Study design  
The study will include a phase I portion to determine MTD dose of clofarabine to be 
used in the subsequent randomized phase II portion. Patients will be randomized to 
either arm on an even basis at the beginning, then, based on efficacy and following a 
Bayesian design, patients will be assigned to the superior arm.  
 
2.  Induction 

 
 
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2.1 Phase I (fixed dose of idarubicin of 10 mg/m2 day 1-3 and cytarabine 1 g/m2 
day 1-5) 
Clofarabine IV over approximately 1 hour daily for 5 days (days 1-5). Dose levels and 
dose escalation schema are described below. 
Idarubicin 10 mg/m2 IV over approximately 30 minutes daily for 3 days (days 1-3) 
Cytarabine 1 g/m2 IV over approximately 2 hours daily for 5 days (days 1-5) 
 
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 will be entered sequentially to each dose level. If none of the first 3 patients at  
 
a dose level experience first cycle dose-limiting toxicity (DLT), new patients may be 
  
entered at the next higher dose level. If 1 of 3 patients experience first cycle DLT, up to 
 
 3 more patients are started at that same dose level. If 2 or more experience first cycle 
 
 DLT, no further patients are started at that dose and clofarabine’s dose will be reduced  
 
to -1 level, which is 10 mg/m2  IV daiy for 5 days. The MTD is the highest dose level in 
 
 which <2 patients of 6 develop first cycle DLT. New dose levels may begin accrual only 
 
 if all patients at the current dose level have been observed for a minimum of 4 weeks.  
 
Dose escalation schedules are as follows:  
 

 
 
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Dose level  
Clofarabine  
(mg/m2  IV daiy for 5 days)  
-1  
10 
1 Starting  
15  
2  
20  
3  
25  
4  
30  
 
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 AST (SGOT) or ALT (SGPT) for > 7 days  
 
 
CTCAE Grade 4 AST (SGOT) or ALT (SGPT) of any duration 
  
 
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. Drug-related Grade 3-4 nausea and vomiting not controlled with adequate 
 
 therapy and Grade 3-4 hyperbilirubinemia will be considered DLTs. Only prolonged 
 
 myelosuppression, as defined by the NCI criteria specific for leukemia, i.e. marrow 
 
 cellularity <5% on day 42 or later (6 weeks) from start of therapy without evidence of  
 
leukemia, will be considered in defining the MTD and DLT.  
 
 
 
 

 
 
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2.2 Phase II 
In the Phase II portion, patients will randomized to receive 
a. Clofarabine (dose selected based on Phase I portion) IV over approximately 1 hour 
daily for 5 days (days 1-5) 
b. Idarubicin 10 mg/m
2 IV over approximately 30 minutes daily for 3 days (days 1-3) 
c. Cytarabine 1 g/m
2 IV over approximately 2 hours daily for 5 days (days 1-5) 
Idarubicin will follow clofarabine by 1 to 2 hours and cytarabine will follow clofarabine 
by 3 to 6 hours. 
or 
a. Fludarabine 30 mg/m2 IV over approximately 30 minutes daily for 5 days (days 1-5) 
b. Idarubicin 10 mg/m2 IV over approximately 30 minutes daily for 3 days (days 1-3) 
c. Cytarabine 1 g/m2 IV over approximately 2 hours daily for 5 days (days 1-5) 
Idarubicin will follow fludarabine by 1 to 2 hours and cytarabine will follow 
fludarabine by 3 to 6 hours. 
 
The induction or reinduction may be given over 4 days (Fludarabine, Clofarabine and 
Cytarbine) in patients ≥ 65 years, or at the discretion of the treating physician and over 
3 days (Fludarabine, Clofarabine and Cytarbine) in patients with PS ≥ 2, or at the 
discretion of the treating physician. Idarubicin 8-10 mg/m2 will be given for 2 days in 
these situations. 
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 

 
 
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should not be given until at least 28 days of course 1. If the bone marrow aspirate 
and/or biopsy(s) performed after the re-induction cycle reveals a remission marrow 
(CR/CRp), then the patient may proceed with consolidation at the discretion of the 
treating investigator. 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 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. 
 
Consolidation 
Patients in CR or CRp can continue with up to 6 consolidation cycles.  
 
Clofarabine (dose selected based on Phase I portion) IV over approximately 1 hour 
daily for 3 days (days 1-3) 
Idarubicin 8 mg/m2 IV over approximately 30 minutes daily for 2 days (days 1-2) 
Cytarabine 1 g/m2 IV over approximately 2 hours daily for 3 days (days 1-3)Or  
Fludarabine 30 mg/m2 IV over approximately 30 minutes daily for 3 days (days 1-3) 
Idarubicin 8 mg/m2 IV over approximately 30 minutes daily for 2 days (days 1-2) 
Cytarabine 1 g/m2 IV over approximately 2 hours daily for 3 days (days 1-3) 
 
The consolidation may be given over 2 days in patients ≥ 65 years and/or with PS ≥ 2. 
 

 
 
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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 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. 
 
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 
Fludarabine 
(mg/m2) 
Clofarabine 
(mg/m2) 
Idarubicin 
(mg/m2) 
Cytarabine 
(g/m2) 
-1 
22.5 
15 
8 
0.75 
-2 
20 
15 
6 
0.5 

 
 
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-3 
15 
10 
6 
0.25 
Doses of each individual drug can be modified if a toxicity is considered due this 
particular drug. 
Specific Dose Modifications for Organ Function: 
 
Fludarabine 
(mg/m2) 
Cytarabine 
(g/m2) 
Idarubicin 
(mg/m2) 
Clofarabine (mg/m2) 
Creatinine 
(mg/dL) 
 
2.1 – 3 
 (age < 65) 
22.5 
0.75 
10 * 
8 ** 
75% of current dose 
level 
2.1 – 3  
(age ≥ 65) 
15 
0.5 
8 * 
6 ** 
50% of current dose 
level 
Above 3 
Discuss with study principal investigator 
Bilirubin (mg/dL) 
 
 
 
 
2.6 – 5 
30 
1 
5 * 
4 ** 
Current dose level 
Above 5 
30 
1 
OMIT 
Current dose level 
*Induction/Re-Induction          **Consolidation 
V. PRETREATMENT AND POST-TREATMENT EVALUATION 
Induction Treatment (Pre-treatment) 
1. CBC, diff, platelet count.  
2. Creatinine, bilirubin, ALT or AST, marrow aspirate with cytogenetics (if bone 
marrow not done within 1 month or cytogenetics within 3 months. For patients 
with evidence of leukemia in the peripheral blood, the bone marrow may be 
omitted after discussion and approval with the principal investigator.) 
Pretreatment Evaluation 
 
Procedure 
Comments 
Schedule 
Informed Consent 
Obtain standard informed consent approved by IRB 
Within 14 days 
of therapy 
Medical History 
History of present illness, known allergies, prior cancer history as 
far as traceable, and past medical/ surgical history as far as 
relevant. 
Within 14 days 
of therapy 
Physical 
Examination 
Vital signs (temperature, heart rate, respiratory rate, blood 
pressure) and performance status. 
Within 14 days 
of therapy 
Concomitant 
Document concomitant medications 
Within 14 days 

 
 
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Procedure 
Comments 
Schedule 
Medications 
of therapy 
Hematology 
CBC with differential and platelet count 
Within 14 days 
of therapy 
Biochemistry 
Creatinine, total bilirubin, SGPT or SGOT 
Within 14 days 
of therapy 
Bone marrow 
Aspirate and/or biopsy*  
Cytogenetics 
Within 30 days 
of therapy 
Within 90 days 
of therapy 
Pregnancy test 
Serum or urine, if female and of child-bearing potential only 
Within 7 days of 
therapy 
 
For patients with evidence of leukemia in the peripheral blood, the bone marrow may be 
omitted after discussion and approval with the PI. 
 
During therapy 
1. CBC, differential, and platelet count every 3-7 days (the differential may be 
omitted when the WBC is < 500.) 
2. Creatinine, bilirubin, ALT or AST once weekly.  
3. Marrow aspirate to confirm complete remission. 
During Therapy 
 
Procedure 
Comments 
Schedule 
Hematology 
CBC with differential and 
platelet count 
Every 3-7 days (the differential may be omitted 
when WBC is ≤500) 
Biochemistry 
Creatinine, total bilirubin, SGPT 
or SGOT 
Once weekly 
Physical 
Examination 
Focused physical examination 
Prior to each treatment course 
Bone marrow 
Aspirate and/or biopsy  
On day 28 +/- 7 days  
 
 
During Post-Remission Therapy 
CBC, diff, platelet count, creatinine, and bilirubin prior to each post-CR course. Marrow 
aspirates every 2-3 cycles. 
 
 

 
 
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Targeted Therapy 
Patients with AML may harbor FLT3/ITD mutations. We have previously explored the 
use of sorafenib in these patients and was found to be safe and therefore we can allow 
patients with FLT3/ITD mutations to receive concomitant sorafenib therapy at a dose of 
400 mg orally twice daily continuously at the discretion of the treating physician. 
 
In addition patients with Acute Myeloid Leukemia may evolve from Myeloid Fibrosis 
where JAK2 inhibitors such as ruxolitinib was found to be effective therefore we will 
allow the concomitant use of ruxolitinib @ 20 mg BID at the discretion of the treating 
physician. 
 
Patients with the presence of BCR/Abl or the Philadelphia chromosome may receive 
concomitant therapy with any approved TKI. TKI therapy will be given orally and should 
be given continuously. The choice and the dose will be at the discretion of the 
investigator. 
 
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 for hydroxyurea which is allowed for up to 7 days 
each during cycle 1-3 and the use of a single or a two day dose of cytarabine (up to 3 
g/m2) for emergency use up to 24 hours prior to start of study therapy. Intrathecal 
chemotherapy is allowed for patients with CNS disease. 
 
VI. STUDY END POINTS 
Primary: 
1. Complete remission rates with the 2 different regimens 
Secondary: 
1. Event free survival at 2 years (events defined as death and relapses) 

 
 
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2. Overall survival 
3. Remission duration 
4. Predictive factors for response and outcome 
5. Safety profile 
 
VII. 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 CRi after 2 induction courses 
 
VIII. CRITERIA FOR RESPONSE 
The response criteria recommended by the NCI and the MDS International Working 
Group. 
Definitions: 
Complete Response (CR): 
Neutrophil count ≥ 1.0 ×109/L 
Platelet count ≥ 100 ×109/L 
• Bone marrow aspirate </= 5% blasts 
No extramedullary leukemia 

 
 
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CRi: 
• Response as in CR but platelets <100 ×109/L 
Partial response (PR): 
Neutrophil count ≥ 1.0 ×109/L 
Platelet count ≥ 100 ×109/L 
≥ 50% reduction in bone marrow blasts over baseline 
Clinical benefit:  
In addition to IWG criteria, in AML, a decrease in bone marrow blasts to <5% will also 
be considered clinical benefit. 
Stable Disease:  
In addition to IWG criteria and 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. 
Relapse: 
Increase of bone marrow blasts to > 10% after an initial response. 
 
IX. REPORTING REQUIREMENTS 
All adverse and serious adverse events will be recorded and reported according to the 
Department of Leukemia guidelines (appendix D) 
 
X. STATISTICAL CONSIDERATIONS 

 
 
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This is a phase I/II study of CIA and FIA in patients with relapsed/refractory and newly 
diagnosed AML (not fit for any other protocol) and high-risk MDS. The objective of the 
phase I study is to determine the safety profile and MTD of the combination therapy of 
CIA. The Objective of the phase two study is to compare the response rate of the two 
combination regimens CIA and FLAI. 
Phase I 
First, phase I study is performed to assess the safety of the combination therapy of CIA. 
Four combination dose levels are defined. A 3+3 design will be used to for dose 
escalation. Detailed dose escalation rules are described in the section 2.1 of the 
protocol. A maximum of 24 patients will enroll in the phase I study. 
 
Phase II 
The phase II portion of the study will include only newly diagnostic AML patients, and the 
primary objective is to compare the event-free survival (EFS) between treatment CIA and 
FLAI, where event is defined as be resistance to treatment, relapse (after response) or 
death, whichever occurred first.   
 
A maximum of 200 front-line patients will be enrolled in the study. To enroll 200 front 
line patients, the total sample size (front-line and salvage patients combined) is 280.  
This section will focus on front-line patients only. An adaptive randomization algorithm 
will be used to assign the patients to the two treatment arms. Initially 40 patients will be 
randomized equally to the two treatment arms. After the completion of the equal 
randomization, the adaptive randomization algorithm will be employed to unbalance the 

 
 
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randomization probabilities in favor of the treatment arm with a better event free 
survival.  The expected accrual rate is about 5 patients per month, and the additional 
follow-up time is 12 months after all patients have been enrolled to the study. 
 
The historical data suggested the median event free survival time for FLAI treatment 
was 5 months.  Let 1 and 2 denote the median event free survival time for  treatment 
arm CIA and FLAI respectively, we assume the prior for the median event free survival 
time follows Inverse Gamma (IG) distribution:  1 ~ IG(3, 10), and 2 ~ IG(3, 10). Each 
time a new patient enters the trial, be the posterior probabilities i = Pr(i > j | data)  will 
be calculated (i, j = 1,2). The randomization probability to treatment arm CIA and FLAI 
will be the posterior probabilities i = 
 . 
 
The trial will be stopped early for both efficacy and futility based on the follow stopping 
rules. Table 1 presents the operating characteristics of simulations based on the 
described design.  
1. Early loser selection: Suspend accrual to an arm I if Pr (I < j≠ I | Data) < 0.025 
2. Early winner selection: Stop the trial and select an arm i as superior if Pr (i > j≠ i | 
Data) > 0.975 
3 Final winner selection: At the final analysis after all patients have been evaluated, 
select arm i as superior if Pr(i > j≠ i | Data ) > 0.975 
Table 1: Operating characteristics from simulations 
 

 
 
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Arm 
True Median 
Survival (M) 
Pr(Selected) 
Pr(Selected 
Early) 
Pr(Stopped 
Early) 
# Patients (2.5%, 97.5%) 
Scenario 1 
Arm1 
5 
0.12 
0.116 
0.111 
88.2 (20, 137) 
Arm2 
5 
0.111 
0.106 
0.12 
87.1 (20, 135) 
  
  
  
  
  
  
  
Scenario 2 
Arm1 
2 
0 
0 
1 
22.5 (20, 35) 
Arm2 
5 
1 
1 
0 
27.7 (20, 64) 
  
  
  
  
  
  
  
Scenario 3 
Arm1 
7 
0.757 
0.718 
0.014 
74.8 (20, 140) 
Arm2 
5 
0.014 
0.014 
0.757 
50.6 (20, 110) 
  
  
  
  
  
  
  
Scenario 4 
Arm1 
8 
0.937 
0.909 
0.001 
62.3 (20, 134) 
Arm2 
5 
0.001 
0.001 
0.937 
40 (20, 90) 
  
  
  
  
  
  
  
Scenario 5 
Arm1 
10 
0.995 
0.992 
0.001 
43.7 (20, 109) 
Arm2 
5 
0.001 
0.001 
0.995 
30.5 (20, 66) 
 
 
 
 
Toxicity monitoring  
Toxicity will be monitored closely for each treatment arm using the method of Thall et al 
(1995). Denote the probability of toxicity by PE, where toxicity is defined as any 
treatment-related grade 3 or greater non-hematological toxicities.  We assume PE ~ 
beta (0.6, 1.4).  We will stop the trial if at any point Pr (PE > 0.30 | data) >0.95. That is, 
we will stop the trial if, at any time during the study, we determine that there is more 
than 95% chance that the toxicity rate is more than 30%. The trial will be stopped if (the 
number of toxicity observed / among number of patients) ≥ 6/10, 11/20, 15/30, 19/40, 
22/50, 26/60, 30/70, 34/80, 38/90, 42/100, 46/110, 49/120, 53/130.    The operating 
characteristics are listed in table 2. 

 
 
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Table 2: The operating characteristics for toxicity monitoring are summarized in the 
following table 
 
True toxicity 
probability  
Probability 
of early 
stop 
Sample size 
percentiles (10, 25, 
50, 75, 90) 
0.1 
0.0002 
 140 140 140 140 
140 
0.2 
0.008 
140 140 140 140 
140 
0.3 
0.095 
140 140 140 140 
140  
0.4 
0.666 
10 30 70 140 140 
0.5 
0.995 
       10 10 20 40 60 
 
AdaptiveRandomization 4.1.1 software and Multic99 were used for the trial design. 
 
 
Analysis method 
Data analysis will be performed using SAS or S-plus, as appropriate. The median EFS 
time will be estimated by Bayesian posterior estimates, along with the 95% credible 
intervals for both treatment arms. The posterior probability that one arm has a better 
EFS than the other arm will be also calculated. 

 
 
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 Demographic and baseline laboratory results will be summarized using descriptive 
statistics, including means with standard deviations, or medians with ranges, histograms 
and box-plot. Fisher’s exact test and Wilcoxon rank test will be used in the data 
analyses of categorical and continuous variables, respectively. Survival or times to 
failure and time to progression functions will be estimated using the Kaplan-Meier 
method. The two-sided log-rank test will be used to assess the differences of time to 
events between groups, and Cox proportional hazards model will also be fitted to 
compare the time-to-event outcomes between the two treatment arms adjusting for the 
effects of covariates. Toxicity will be reported by type, frequency and severity. Highest 
toxicity grades per patient per course will be tabulated for selected adverse events and 
laboratory measurements. 
 
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(3) Gandhi V, Estey E, Keating MJ, Plunkett W. Fludarabine potentiates metabolism of 
cytarabine in patients with acute myelogenous leukemia during therapy. JCO. 
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