Phase I/II Study of the Combination of Quizartinib (AC220) With 5-Azacytidine or Low-Dose Cytarabine for the Treatment of Patients With Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)
Phase: PHASE1
Conditions: FLT3 Gene Mutation Negative, FLT3 Internal Tandem Duplication Positive, Recurrent Acute Myeloid Leukemia, Recurrent Chronic Myelomonocytic Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Chronic Myelomonocytic Leukemia, Refractory Myelodysplastic Syndrome
Sponsor: M.D. Anderson Cancer Center

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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2012-1047 
Protocol Title 
Phase I/II Study of the Combination of Quizartinib (AC220) with 5-
Azacytidine or Low-Dose Cytarabine for the Treatment of Patients with 
Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome 
(MDS) 
Protocol Version 
25 
Version Date 
February 25, 2020 
 
Protocol PI 
Dr. Yesid Alvarado Valero 
Department 
Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
118819 
 
 

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Page 2 of 48 
Phase I/II Study of the Combination of Quizartinib (AC220) with 
5-Azacytidine or Low-Dose Cytarabine for the Treatment of 
Patients with Acute Myeloid Leukemia (AML) and 
Myelodysplastic Syndrome (MDS) 
1.0 
OBJECTIVES ..................................................................................................................... 3 
1.1 
Primary Objectives .......................................................................................................... 3 
1.2 
Secondary Objectives: .................................................................................................... 3 
2.0 
BACKGROUND ................................................................................................................ 3 
2.1 
AC220 ............................................................................................................................. 4 
2.2 
5-azacytidine ................................................................................................................... 6 
3.0 
STUDY DESIGN.............................................................................................................. 11 
4.0 
PATIENT SELECTION ................................................................................................... 11 
4.1 
Inclusion Criteria .......................................................................................................... 12 
5.0 
TREATMENT PLAN ....................................................................................................... 16 
5.1 
General .......................................................................................................................... 16 
5.2 
Schedule ........................................................................................................................ 16 
5.3 
Duration of Therapy ...................................................................................................... 20 
5.4 
Concomitant Medications ............................................................................................. 21 
6.0 
DOSING DELAYS/DOSE MODIFICATIONS............................................................... 22 
6.1 
Toxicity Directly Attributable to Study Drug ............................................................... 22 
6.2 
Toxicity Grading ........................................................................................................... 22 
6.3 
Dose Reductions ........................................................................................................... 22 
6.4 
Myelosuppression ......................................................................................................... 25 
6.5 
Intrapatient Dose Escalation for Patients Treated at Dose Level -1 or Lower ............. 26 
7.0 
AGENT FORMULATION AND PROCUREMENT ...................................................... 25 
7.1 
Dose Preparation and Storage of 5-azacytidine ................................................................  
7.2 
AC220 ........................................................................................................................... 26 
8.0 
CORRELATIVE/SPECIAL STUDIES ............................................................................ 28 
9.0 
PATIENT EVALUATION ............................................................................................... 28 
9.1 
Pre-Treatment Evaluation ............................................................................................. 28 
10.0 
CRITERIA FOR RESPONSE .......................................................................................... 31 
10.1 
Response Criteria for MDS ........................................................................................... 31 
10.2 
Response Criteria for AML .......................................................................................... 32 
11.0 
ADVERSE EVENT REPORTING................................................................................... 33 
12.0 
STATISTICAL CONSIDERATIONS.............................................................................. 37 
12.1 
Overview ....................................................................................................................... 37 
12.2 
Phase I ........................................................................................................................... 32 
12.3 
Phase II.......................................................................................................................... 32 
12.4 
Analysis Plan ................................................................................................................ 33 
13.0 
PROTOCOL ADMINISTRATION .................................................................................. 43 
14.0 
REFERENCES ................................................................................................................. 43 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Phase I: To determine the DLT and MTD of the combination of quizartinib 
(AC220) with either 5-azacitidine (AZA) or low-dose cytarabine (LDAC) 
in patients with acute myeloid leukemia (AML) or high-risk 
myelodysplastic syndrome (MDS). 
 
1.1.2 Phase II: To determine the clinical activity of the combination of 
quizartinib with either AZA or LDAC in patients with AML or MDS. 
 
1.2 
Secondary Objectives:  
 
1.2.1 Phase I: To determine the clinical activity of the combination of quizartinib 
with either AZA or LDAC in patients with AML or MDS. 
 
1.2.2 Phase II: To determine the safety of the combination of quizartinib with 
either AZA or LDAC in patients with AML or MDS. 
 
1.2.3 Both: 
 
1.2.3.1 
To determine the induction of hypomethylation, DNA damage 
and FLT3 signaling during therapy with this combination and its 
correlation with response.   
 
1.2.3.2 
To determine the effect of this combination therapy on plasma 
levels of FLT3-ligand 
 
1.2.3.3 
To determine the pharnacodynamicvs of this combination 
therapy in patients with AML or high-risk MDS. 
 
2.0 
BACKGROUND 
 
Acute myeloid leukemia (AML) is a malignancy of immature granulocytes or monocytes. 
Malignancy is characterized by accumulation of leukemic blastocytes and blockade of 
normal bone marrow production resulting in thrombocytopenia, anemia, and neutropenia. 
In the U.S., approximately 11,930 new cases of AML are expected to be diagnosed in 2006, 
with an estimated 9,040 deaths occurring in the same time period. Almost all newly 
diagnosed cases, as well as deaths, will be in adults.1 Standard treatment for AML includes 
systemic combination chemotherapy to control bone marrow and systemic disease. 
Treatment is generally divided into an induction phase, to attain remission, and a 
maintenance phase. Approximately 60% to 70% of adults with AML can be expected to 
attain complete remission status following appropriate induction therapy. Remission rates 
in adult AML are inversely related to age, with an expected remission rate of >65% for 

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those younger than 60 years. Increased morbidity and mortality during induction appear to 
be directly related to age.2 
 
Signaling via receptor tyrosine kinases (RTKs) is frequently dysregulated in disease. FLT3 
(FMS-like tyrosine kinase III) is a transmembrane tyrosine kinase that belongs to the Class 
III family of RTKs. FLT3 is primarily expressed on immature hematopoietic progenitors 
and also on some mature myeloid and lymphoid cells.3-5 FLT3 is activated following 
binding of FLT3 ligand, which causes receptor dimerization leading to increased kinase 
activity and activation of downstream signaling pathways including Stat5, Ras, and 
PI3’kinase.6-8 FLT3 plays a normal role in the regulation of survival and proliferation of 
hematopoietic progenitor cells, in particular by synergy with other RTKs and cytokine 
receptors.9-11 FLT3 is also expressed in acute myeloid leukemia cells from approximately 
90% of patients and stimulates survival and proliferation of leukemic blasts.12-14 
 
Additionally, FLT3 is mutated in 30% of AML cases.15 The two leading types of mutations 
found in AML include internal tandem duplications in the juxtamembrane domain (ITD, 
17-34%) and mutations in the activation loop (approximately 7%). Patients with mutations 
in FLT3 have a worse prognosis when treated with conventional chemotherapy compared 
to patients with wild-type FLT3.15 Initial studies using small molecule FLT3 inhibitors 
have offered encouragement that when added to the conventional arsenal of AML 
treatments, patients with AML expressing mutated FLT3 may experience significant 
clinical benefit.15 
 
2.1 
AC220 (Quizartinib) 
 
AC220 is a novel second-generation Class III RTK inhibitor with potent and highly 
efficacious FLT3 activity in vitro and in vivo. Activating gene mutations in the 
RTK FLT3 (FLT3 mutant) are present in approximately 30% of patients with AML. 
These patients with FLT3-mutants have a significantly worse prognosis than 
patients with FLT3 wild type (FLT3 WT), suggesting that the activated kinase is a 
driver of AML and a potential target for kinase inhibitor therapy.  
 
Toxicology studies with AC220 in rats, dogs, and monkeys up to 90 days in 
duration have shown that the principle toxicological target organs were the bone 
marrow and lymphoid organs in rat, dog, and monkey. These findings are consistent 
with the presumed FLT-3 and c-KIT kinase inhibition mechanism of action of the 
drug. In addition, toxicological effects were observed in the kidney (all species), 
the liver (dog only) and the ovary, vagina, and testes (rat only). Target-organ 
toxicity appears to be dose-, time-, and species-dependent, but reversible following 
a 28-day reversal period, except for the dog-specific liver toxicity. Bioavailability 
and exposure were good across species, ranging from 16% in monkeys to 40% in 
dogs. Plasma protein binding with AC220 was high (> 99%) in all 5 species 
examined (mouse, rat, dog, monkey, and human) and the compound has been 
shown to penetrate the brain poorly. In vitro CYP450 studies demonstrate that 
AC220 is neither an inhibitor nor inducer of major human CYP isoforms. Evidence 

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from rat toxicokinetic studies indicate that AC220 does not accumulate nor does it 
induce its own metabolism. A major pharmacologically active metabolite, termed 
AC886, has been identified in the plasma of rat, dog, monkey, and humans. 
 
A cardiovascular safety pharmacology study in cynomolgus monkeys demonstrates 
that single oral doses of AC220 result in prolonged QTc interval at ≥10 mg/kg doses 
and biologically significant increased systolic blood pressure at ≥30 mg/kg doses. 
It should be noted that increases in blood pressure were not observed in the Phase 
1 dose-escalation study, Protocol AC220-CP0001; henceforth called Study 
CP0001.16  No QTc interval prolongation was evident in monkeys dosed with 3 
mg/kg AC220. The prolonged QTc interval is presumably not related to inhibition 
of the IKr ion channel as evidenced by negative human ether-a-go-go-related gene 
(hERG) assays conducted for AC220 and the major metabolite, AC886 (11%-15% 
IKr channel inhibition at 10 μM for AC220 and < 10% at 10 μM for AC886). 
There were no apparent electrocardiogram (ECG) abnormalities in the dog (28- and 
90-day) or monkey (28-day) general toxicology studies. In addition, there were no 
apparent toxicologically relevant AC220-related heart microscopic changes in the 
rat, dog, or monkey general toxicology studies. At steady-state, there is 
approximately a 1.5-fold exposure margin of AC220+AC886 between monkeys 
dosed with 30 mg/kg and humans dosed with 200 mg/day. 
 
Interim results from Study CP000116 have shown that AC220 has been well 
tolerated in the 76 patients treated thus far. The majority of adverse events (AEs) 
observed in the study were those associated with the underlying disease. In 
addition, the safety profile was similar between patients receiving continuous 
dosing (28 days continuous dosing as 1 cycle) and those on the intermittent 
schedule (14 days dosing and 14 days rest as 1 cycle). In spite of limitations of the 
Phase 1 design, e.g., limited evaluation of response and the potentially suboptimal 
intermittent dosing schedule, encouraging preliminary evidence of clinical activity 
has been observed in the first 76 patients treated with AC220. The overall response 
(complete remission [CR] + partial remission [PR]) observed in all AC220-treated 
patients was 32% (24/76). Responses were defined per modified Cheson criteria.17  
Ten patients achieved a CR defined as a decrease of < 5% blast in bone marrow: 2 
complete hematological recovery, 4 with incomplete platelet recovery (CRp), and 
4 with incomplete platelet and neutrophil recovery (CRi). One of these patients also 
had complete resolution of leukemia cutis. Fourteen patients had PR, defined as a 
decrease of ≥ 50% blasts to levels of 5% to 25% in the bone marrow but with 
incomplete peripheral recovery of neutrophils and platelets. Most of the patients 
had best bone marrow responses (14/22, 64%) during the first 28 days of treatment 
(defined as Cycle 1). Median duration of response was 14.1 weeks (range, 4 to 61+ 
weeks). Consistent with the proposed mechanism of action, the response in the 
FLT3-ITD mutant population was the highest with an overall response rate of 61% 
(11/18) including 6 PR, 3 CRi, 1 CRp, and 1 CR. 
 

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The dose-limiting toxicity (DLT) as per protocol in Study CP0001 was National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 3 (v3) Grade 3 QTcF (corrected QTc by Fridericia’s correction 
factor) interval prolongation at the 300-mg dose of AC220 administered 
continuously, and considered to be possibly drug related. It should be noted that 
this study did not exclude high risk cardiac patients, including those with abnormal 
baseline QTcF prolongation, nor did it exclude the administration of QT/QTc-
prolonging concomitant medications, and patients were sometimes in a state of 
electrolyte imbalance with low serum potassium and/or magnesium levels. These 
patients with Grade 3 QTcF interval prolongation have been asymptomatic, with 
no evidence of arrhythmias and have had reversal of QTcF prolongation when 
AC220 dosing was interrupted. The ECGs were originally analyzed by the sites, 
however they were subsequently re-read using a centralized digital analysis system 
employed by a central ECG laboratory (EResearch Technology in Philadelphia, 
PA) and a formal analysis was performed. This determined that the ECG data in 
Study CP0001 did not demonstrate any clear signal of any clinically important 
effect on heart rate, PR (atrioventricular conduction), or QRS interval duration 
(depolarization) or morphology. The primary finding in this first-in-human study 
with limited cardiac safety data was that AC220 appears to have a marked effect on 
cardiac repolarization, which is best defined by the Fridericia’s corrected QT data 
(QTcF). The time-averaged mean change from baseline for QTcF duration for the 
intermittent dose groups showed no QTcF effect for the 12- to 60-mg dose groups. 
Starting with the 90-mg dose, however, the QTcF interval change from baseline 
was > 20 ms and tended to increase with dose, up to 30 to 38 ms for the 300- to 
450-mg doses. For the continuous treatment dose groups, the QTcF interval change 
from baseline for 200 mg was 26 ms and for 300 mg was 54 ms. During the first 14 
days of dosing, the intermittent and continuous treatment dose groups at 200 mg 
and 300 mg experienced the same exposure to AC220, and therefore, the data over 
this time period may be considered together. Taken together, the QTcF interval 
change from baseline for the 200-mg dose was 22 ms to 26 ms, and for the 300-mg 
dose was 38 ms to 54 ms, and the incidence of new cases (not seen at baseline) of 
Grade 3 QTcF interval prolongation (> 500 ms) was 9.5% (2/21 patients) at 200 mg 
and 30% (3/10 patients) at 300 mg. This demonstrates a clear dose-related and 
marked QTcF interval change at the ≥200-mg dose level. The QTcB (Bazett’s 
correction factor) results were comparable. The onset of increase to > 500 ms QTcF 
occurred as early as 2 hours after the first dose and by Cycle 1 Day 8 of dosing in 
the cases that were observed. Additional observations were made in women and 
patients of > 62 years, as is usual in these settings. The pharmacokinetic-
pharmacodynamic (PK-PD) relationship for parent and metabolite was also 
indicative that AC220 caused a positive QTc response of a magnitude that was 
observed by the ECG data. 
 
2.2 
5-azacytidine 
 

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5-azacytidine, an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and 
metabolism. Since the early 1970s, 5-azacytidine has been investigated primarily 
in the US for the treatment of acute leukemia. Clinical studies have focused mainly 
on patients with disease refractory to conventional chemotherapy. Results of these 
investigations demonstrated activity of 5-azacytidine in the treatment of AML. 
Clinical studies subsequently evaluated the effects of 5-azacytidine in a variety of 
other 
malignant 
and 
hematologic 
disorders, 
including 
solid 
tumors, 
hemoglobinopathies (eg, thalassemia and sickle cell anemia), and MDS. In 1984, 
the Cancer and Leukemia Group B (CALGB) began a series of clinical studies with 
5-azacytidine in patients with MDS. These studies, in addition to other supportive 
data, led to the approval of Vidaza® (5-azacytidine) in May 2004 for the treatment 
of MDS.  
 
5-azacytidine inhibits the methylation of newly synthesized DNA by inhibiting 
DNA 
methyltransferase 
(DNMT).18-20 
Increased 
methylation 
of 
DNA 
(hypermethylation) may result in the silencing of critical genes responsible for cell 
growth control and differentiation. Hypermethylation of CpG islands spanning the 
promoter regions of tumor suppressor genes is commonly associated with 
cancers.21 It is now widely recognized that hypermethylation of DNA is frequently 
associated with myelodysplastic syndromes and other cancers,22-24 such as renal,25 
melanoma,26 breast,27 colorectal,28 non-small cell lung29 and hematologic 
malignancies.30 5-azacytidine is believed to exert its antineoplastic effects through 
hypomethylation and cytotoxicity on abnormal hematopoietic cells in the bone 
marrow.31-35 Hypomethylation may restore normal function to genes that are critical 
for differentiation and proliferation.21,36,37 The cytotoxic effects of 5-azacytidine 
cause the death of rapidly dividing cells, including cancer cells that are no longer 
responsive to normal growth control mechanisms.31,38-40  
 
The cytotoxicity of 5-azacytidine is proportional to dose and exposure time.31,32 
Although the mechanisms of cytotoxicity are complex and multifaceted, there is 
general agreement that incorporation of 5-azacytidine into DNA and ribonucleic 
acid (RNA), and inhibition of protein synthesis, are critically important.41 
Cytotoxicity is greatest in cells that are proliferating (S phase) and metabolically 
active.31 Cytotoxic effects may also be mediated through induction of the DNA 
damage response pathways.40 Nonproliferating cells are relatively insensitive to 5-
azacytidine.31  
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus 
monkeys.42 Most of the studies were performed during the 1970s and early 1980s 
according to existing guidelines and standards in place during that period. The 
preclinical studies identified the bone marrow, liver, kidneys, and lymphoid tissues 
(spleen, lymph nodes, and thymus) as the main target organs of toxicity for 5-
azacytidine.42  In single-dose studies, the lethal dose of 5-azacytidine after 
intravenous (IV) administration in mice, rats, and dogs was approximately 250 

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mg/m2. Repeated daily dosing appears to increase the toxicity of 5-azacytidine.42 
The genotoxicity of 5-azacytidine is consistent with that of other nucleoside analogs 
that interact with nucleic acids.42 Likewise, similar to other agents with cytostatic 
properties, 5-azacytidine was embryotoxic and reduced the reproductive 
performance in mice and rats.42 
 
Limited 5-azacytidine pharmacokinetic data are currently available. Based on 
human plasma concentrations of total radioactivity (which represents parent drug 
plus circulating metabolites), 5-azacytidine is rapidly absorbed when given 
subcutaneously (SC), with maximum plasma concentrations found 0.5 to 2 hours 
after dosing.42 5-azacytidine and/or its by-products are then rapidly cleared by the 
kidneys. The half-lives and percent radioactivity recovered in urine are similar 
following IV and SC routes of administration. The effects of renal or hepatic 
impairment, gender, age, or race on the pharmacokinetics of 5-azacytidine have not 
been studied.42 A single dose (75 mg/m2) SC versus IV crossover study in 6 MDS 
subjects43 revealed an approximate bioavailability of 89% for the SC dose (range 
52% to 128%) with mean half-lives of 0.69 hour and 0.36 hour after SC and IV 
administration, respectively. These results demonstrated that 5-azacytidine is 
rapidly and nearly completely absorbed after SC administration and that 
elimination is also rapid. The apparent SC clearance (167 L/h or 2791 mL/min) and 
systemic IV clearance (147 L/h) of 5-azacytidine exceeded the glomerular filtration 
rate (approximately 125 mL/min) and total renal blood flow (1200 mL/min) in 
healthy subjects. This indicates that non-renal elimination (eg, metabolism, 
hydrolysis, and/or degradation) plays a role in the elimination of parent 5-
azacytidine. In addition, 5-azacytidine 75 mg/m2 was generally well-tolerated after 
single SC injection or IV infusion over 10 minutes.43  
 
A number of studies have looked at different parenteral doses and schedules of 5-
azacytidine, finding maximum tolerated doses of up to 500 mg/m2 when 
administered weekly.44 
 
During the two decades between the start of the CALGB studies and the approval 
of 5-azacytidine, a new understanding of MDS has developed, such as the World 
Health Organization (WHO) diagnostic criteria, the International Prognostic 
Scoring System (IPSS), and the International Working Group (IWG) response 
criteria. Silverman et al. reevaluated the combined data (N = 309) from 3 of the 
CALGB studies using the WHO classification system for MDS and AML and the 
IWG response criteria.45 Using the IWG response criteria in MDS patients, 
response rates were between 40% and 70% in 5-azacytidine treated patients. Ten to 
17% of patients achieved a complete remission; partial remission was rare; and 23% 
to 36% of patients had a hematologic improvement. In patients with AML (N = 
103), 35% to 48% had hematologic improvement or better responses. The median 
survival time for 27 patients assigned to 5-azacytidine was 19.3 months compared 
with 12.9 months for the 25 patients assigned to observation.45 
 

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A randomized international Phase III trial (Study 5-azacytidine PH GL 2003 CL 
001) for higher-risk MDS patients, classified by FAB as RAEB, RAEB-T, or 
CMML with 0-29% marrow blasts, with an IPSS of Intermediate -2 or High by 
central pathology/cytogenetic review was recently reported.46 Patients were 
randomized to 5-azacytidine (75 mg/m2/day x 7days in 28 day cycles) or 
conventional care regimens (CCR) , where CCR was pre-selected by the 
Investigator as best supportive care (transfusions, antibiotics, and G-CSF for 
neutropenic infection), low-dose cytarabine (20 mg/m2/day x 14 days in 28 day 
cycles); or standard chemotherapy (conventional induction/consolidation). Patients 
were stratified by FAB/IPSS and randomized 1:1 to 5-azacytidine or CCR. This 
trial did not allow erythropoietin. Three-hundred fifty eight patients (70% male) 
were randomized at 79 centers to 5-azacytidine (N=179) or CCR (N=179): best 
supportive care only (N=105, 59%), low-dose cytarabine (N=49, 27%), or standard 
chemotherapy (N=25, 14%). Median age was 69 years (range 38-88 years). The 5-
azacytidine and CCR groups were comparable for baseline patient characteristics. 
At baseline, 95% of patients were higher risk: RAEB (58%), RAEB-T/WHO AML 
(34%), CMML (3%), and other (5%). By IPSS, 87% were higher risk: Intermediate 
-2 (40%), High (47%), and 13% Indeterminate/other. 5-azacytidine was 
administered for a median of 9 cycles; low-dose cytarabine for 4 cycles. Median 
follow-up for the survival analysis was 21.1 months. 5-azacytidine demonstrated 
statistically superior overall survival compared to CCR, with a median overall 
survival of 24.4 months vs. 15 months for CCR (stratified log-rank p=0.0001, 
hazard ration 0.58). Two-year survival approximately doubled in the 5-azacytidine 
arm compared to CCR: 51% vs. 26% (p<0.0001). 5-azacytidine was well tolerated 
with safety data consistent with previous reports.  
 
Further details can be found in the 5-azacytidine Investigator’s Brochure, which 
contains 
comprehensive 
pharmacology, 
toxicology, 
pharmacokinetics, 
pharmacodynamics, metabolism, preclinical, and clinical efficacy and safety data 
information.42   
 
2.3 
Cytarabine 
 
Cytarabine has been the mainstay of AML therapy for nearly 40 years. In young 
patients cytarabine is usually combined with an anthracycline. With this standard 
therapy the CR rates are 60% to 70% and the cure rates are 15% to 35%.  
Prognosis is related to 1) leukemia karyotype, 2) patient age, and 3) performance 
and organ functions.  Patients with t(8;21), inversion 16 or t(15;17) have CR rates 
of 90% and cure rates of 50% to 80%.  Younger patients (age < 50 years) with 
diploid karyotypes have CR rates of 70% to 80% and cure rates of 20% to 25%.  
Older patients and those with adverse karyotypes have CR rates of 35% to 50% 
and cure rates of 10% or less.  Older patients with AML have a poor prognosis. 
This is due in part to the poor tolerance to therapy, and also the higher frequency 
of poor prognostic features, such as high-risk cytogenetic abnormalities and MDR 
expression. The experience at M.D. Anderson from 1996 to 2000 for patients age 

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65 years or older is a clear example of this poor prognosis. We treated 245 
patients in this age group during this period. CR was achieved in 118 (48%) while 
induction mortality (i.e., death within 7 weeks from the start of chemotherapy) 
occurred in 54 (22%). 38 patients (18%) were alive in CR after year, and 16 (8%) 
at 2 years. Low-dose cytarabine is better tolerated and has been shown to improve 
survival compared to supportive care ± hydroxyurea,47 and has become a “de 
facto” standard therapy for older patients not fit for intensive chemotherapy. 
However, the median survival is still only approximately 4 months.47 Thus, there 
is a need to improve the results obtained with standard chemotherapy. 
 
 
Rationale for study:  
We hypothesize that adding AC220 to a hypomethylating agent such as AZA or to 
standard chemotherapy such as cytarabine may improve the response rate expected 
from the use of either agent alone. In the first portion of this study, we propose to 
explore the proper dose for these combinations and will explore this in patients with 
refractory or relapsed AML or MDS. Once the dose finding study is completed we 
will take this approach to a frontline or first salvage setting. Furthermore, in the 
phase 2 study of AC220 as single agent in patients with refractory or relapsed AML 
without FLT3 mutations, a response rate of 30% to 36% was reported in older 
patients receiving first salvage, or patients of any age receiving second salvage. 
This is a very significant response rate achieved with a single agent, well-tolerated 
agent, not regularly achieved with other standard or investigational agents Despite 
a high response rate for this setting with a single-agent oral agent, the use of AC220 
in this subset of patients has not been further explored clinically. We hypothesize 
that the combination of AC220 and azacytidine may result in a higher response rate 
and may offer a valuable salvage strategy to this patient population.  
 
2.4 
Recently, the results of a randomized trial comparing two lower doses of 
quizartinib were reported. In this trial, patients with relapsed or refractory AML 
with FLT3 mutation were randomized to receive quizartinib 30 mg or 60 mg 
orally, daily. A total of 76 patients were enrolled (38 to each arm). The overall 
composite response rate (CRc, which was the primary endpoint) was identical for 
the two arms (47%). The overall response rate was slightly higher with 60 mg 
daily (71%) than with 30 mg daily (61%) because of a higher rate of partial 
responses in the 60mg arm (24%) compared to the 30 mg arm (13%). QTc 
prolongation to >500 msec (the dose limiti98ng toxicity for quizartinib) occurred 
in only 3% with 60 mg and 5% with 30 mg. When comparing these results with a 
prior study exploring higher doses (90 mg, 135 mg, and 200 mg) it is clear that 
the rate of CRc is identical at all dose levels with some increase in PR with 
progressively higher doses. However, QTc prolongation is clearly dose dependent 
and prolongations >60 msec from baseline occur in 40% or more of the patient s 
treated at doses of 90mg or above, exceeding the threshold of acceptable grade 3 
toxicity for the standard definition of MTD. Although these prolongations have 
been asymptomatic and transient, resolving with lower doses, based on this new 
data we have decided not to explore a dose level of 90 mg daily and expand 60 

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mg (i.e., the starting dose level) for the phase 2 portion of the study provided 
MTD is not exceeded as defined in the protocol section 5.2.5. If MTD is exceeded 
at this dose level, 30 mg will be explored.    
 
 
 
2689-CL-2004 
 AC220-002 (Cohort 2) 
30 mg/day 
(N = 38) 
60 
mg/day 
(N = 38) 
 90 mg/day 
(N=57) 
135 mg/day 
(N=67) 
200 mg/day  
(N=12) 
Best Response 
   CRc Rate 
47% 
47% 
 47% 
45% 
42% 
   PR Rate 
13% 
24% 
 25% 
28% 
50% 
Maximum change in QTcF from baseline (msec) 
   ≤ 30  
50% 
44% 
 9% 
9% 
0% 
   > 30 to ≤ 
60 
47% 
36% 
 46% 
51% 
8% 
   > 60 
3% 
19% 
 46% 
39% 
92% 
 
 
3.0 
STUDY DESIGN 
 
• 
This will be a phase I/II, two-arm, open-label study. 
 
• 
Patients will receive therapy with quizartinib orally daily on 28 day cycles.  
 
• 
In addition patients will receive either AZA subcutaneously or intravenously daily 
for the first 7 days of each treatment cycle or LDAC subcutaneously twice daily for 
the first 10 days of each treatment cycle. Cycles will be repeated approximately 
every 28 days, and therapy will be continued until clinically significant disease 
progression or documentation of unacceptable toxicity. 
 
4.0 
PATIENT SELECTION 
 
Patients must have baseline evaluations performed prior to the first dose of study drug and 
must meet all inclusion and exclusion criteria. Results of all baseline evaluations, which 
assure that all inclusion and exclusion criteria have been satisfied, must be reviewed by the 
Principal Investigator or his/her designee prior to enrollment of that patient. In addition, 
the patient must be thoroughly informed about all aspects of the study, including the study 
visit schedule and required evaluations and all regulatory requirements for informed 
consent. The written informed consent must be obtained from the patient prior to initiating 
treatment. The following criteria apply to all patients enrolled onto the study unless 
otherwise specified. 

2012-1047 
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Page 12 of 48 
Page 12 of 48 
 
4.1 
Inclusion Criteria 
 
4.1.1 Patients with MDS, CMML or AML 
 
4.1.2 For Phase I only 
 
4.1.2.1 
Refractory or relapsed disease defined as follows: 
 
4.1.2.1.1 Patients with MDS or CMML should have failed 
prior therapy (e.g., with a hypomethylating agent, 
clofarabine, and/or with lenalidomide).  
 
4.1.2.1.2 Patients with AML should have failed any prior 
induction therapy or have relapsed after prior 
therapy. 
 
4.1.2.1.3 Patients (any age) with MDS or CMML who 
received therapy with a hypomethylating agent and 
progress to AML are eligible at the time of diagnosis 
of AML regardless any prior therapy for AML.  The 
WHO classification will be used for AML. 
 
4.1.2.1.4 Patients with any of the eligible diagnoses who have 
received no prior therapy are eligible if not 
candidates to receive standard intensive therapy (ie, 
high-dose cytarabine-based chemotherapy). 
 
4.1.2.2 
Patients are eligible regardless of their FLT3 mutation status 
 
4.1.2.3 
Age ≥18 years 
 
4.1.3 For Phase II only: two cohorts will be enrolled: 
 
4.1.3.1 Cohort 2A – FLT3-ITD: 
 
4.1.3.1.1 Patients with MDS, CMML or AML who are either: 
 
4.1.3.1.1.1 Age 60 years or older and newly diagnosed, 
previously 
untreated. 
Prior 
therapy 
with 
hydroxyurea or single agent ara-C for the 
purpose of control of WBC is acceptable. 
 
4.1.3.1.1.2 Age 18 years or older and with refractory or 
relapse disease who have received no more than 

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February 25, 2020 
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one prior treatment regimen and will be receiving 
first salvage. For this purposes, a second 
induction cycle with the same drugs used during 
the first cycle, consolidation chemotherapy or 
stem cell transplant in CR (or CRp or CRi) will 
be considered part of the prior regimen. Prior 
therapy for MDS (or other malignancies) is not 
considered a prior regimen for AML in patients 
who progress from MDS (or other malignancies). 
 
4.1.3.1.2 Patients (any age) with MDS or CMML who received 
therapy with a hypomethylating agent and progress to 
AML are eligible regardless of any prior therapy for 
AML.  The WHO classification will be used for AML. 
 
4.1.3.1.3 Patients must have evidence of FLT3 ITD in their most 
recent assessment.  
 
4.1.3.2 Cohort 2B – FLT3-WT: 
 
4.1.3.2.1 Patients with MDS, CMML or AML who are either: 
 
4.1.3.2.1.1 Age 60 years or older and newly diagnosed, 
previously 
untreated. 
Prior 
therapy 
with 
hydroxyurea or single agent ara-C for the 
purpose of control of WBC is acceptable. 
 
4.1.3.2.1.2 Age 18 years or older and with refractory or 
relapse disease who have received no more than 
two prior treatment regimens and will be 
receiving second salvage, or who have received 
a prior SCT and will be receiving their first 
salvage. For this purposes, a second induction 
cycle with the same drugs used during the first 
cycle, consolidation chemotherapy or stem cell 
transplant in CR (or CRp or CRi) will be 
considered part of the prior regimen. Prior 
therapy for MDS (or other malignancies) is not 
considered a prior regimen for AML in patients 
who progress from MDS (or other malignancies). 
 
4.1.3.2.2 Patients (any age) with MDS or CMML who received 
therapy with a hypomethylating agent and progress to 
AML are eligible at the time of diagnosis of AML 
regardless any prior therapy for AML.  The WHO 

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Page 14 of 48 
classification will be used for AML. 
 
4.1.3.2.3 Patients must have no evidence of FLT3 mutations in 
their most recent assessment. 
 
4.1.4 For Phase I and II 
4.1.4.1 ECOG Performance Status ≤2  
 
4.1.4.2 Adequate liver (bilirubin ≤2x ULN, ALT ≤2.5x ULN) and renal 
(creatinine ≤2x ULN) function.  For patients with suspected liver 
infiltration from leukemia, ALT should be </= 5 x ULN. 
 
4.1.4.3 Serum potassium, magnesium, and calcium (normalized for 
albumin) levels should be at least within institutional normal limits.  
 
4.1.4.4 Patients must provide written informed consent. 
 
4.1.4.5 Patients must have been off chemotherapy for 2 weeks prior to 
entering this study, unless there is evidence of rapidly progressive 
disease, and must have recovered from the toxic effects of that 
therapy to at least grade 1. Use of hydroxyurea for patients with 
rapidly proliferative disease is allowed before the start of study 
therapy and for the first four weeks on therapy. The additional days 
of Hydrea after 28 is permitted as clinically indicated, on case by 
case basis and after discussion with the PI.  Other agents given 
transiently with the intention to control rapid proliferation such as 
1-2 doses of single agent ara-C or few doses of sorafenib are also 
allowed. 
 
4.1.4.6 Women of childbearing potential must practice contraception. 
Women considered not of childbearing potential include any of the 
following: no menses for at least 2 years or menses within 2 years 
but amenorrheic for at least 2 months and luteinizing hormone (LH) 
and follicular stimulating hormone (FSH) values within normal 
range (according to definition of postmenopausal for laboratory 
used) or bilateral oophorectomy or radiation castration and 
amenorrheic for at least 3 months.  Females of childbearing potential 
should practice effective methods of contraception Effective 
methods of contraception include barrier methods (e.g., condoms, 
diaphragm), spermicidal jelly or foam, oral, depo provera, or 
injectable contraceptives, intrauterine devices, tubal ligation, and 
abstinence. Male patients with female partners who are of 
childbearing potential should also practice contraception. 
 
4.1.5 Negative urine or serum pregnancy test. 

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Page 15 of 48 
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4.2 
Exclusion Criteria 
 
4.2.1 Patients with known allergy or hypersensitivity to quizartinib, mannitol, 
AZA, cytarabine or any of their components. 
 
4.2.2 Patients with electrolyte abnormalities at study entry defined as follows: 
 
4.2.2.1 
Serum potassium < 3.5 mEq/L despite supplementation, or > 5.5 
mEq/L. 
4.2.2.2 
Serum magnesium above or below the institutional normal limit 
despite adequate management. 
4.2.2.3 
Serum calcium (corrected for albumin levels) above or below 
institutional normal limit despite adequate management. 
 
4.2.3 Patients with known significant impairment of gastrointestinal (GI) function 
or GI disease that may significantly alter the absorption of quizartinib. 
 
4.2.4 Patients with any other known disease concurrent severe and/or 
uncontrolled medical condition (e.g. uncontrolled diabetes, cardiovascular 
disease including congestive heart failure, myocardial infarction within 6 
months and poorly controlled hypertension, chronic renal disease, or active 
uncontrolled infection) which could compromise participation in the study.  
Patients with current active malignancies or any remission for < 6 months, 
except patients with carcinoma in situ or with non-melanoma skin cancer 
who may have active disease or be in remission for less than 6 months. 
 
4.2.5 Patients with a known confirmed diagnosis of HIV infection or active viral 
hepatitis. 
 
4.2.6 Patients who have had any major surgical procedure within 14 days of Day 
1. 
 
4.2.7 Patients with known malignant disease of the central nervous system. 
 
4.2.8 Impaired cardiac function including any of the following 
 
4.2.8.1 
Screening ECG with a QTc >450 msec.  The QTc interval will 
be calculated by Fridericia’s correction factor (QTcF) at 
Screening and on Day 5 prior to the first dose of AC220. The 
QTcF will be derived from the average QTcF in triplicate.  If 
QTcF >450 msec on Day 5, AC220 will not be given. 
 
4.2.8.2 
Patients with congenital long QT syndrome 
 

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February 25, 2020 
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Page 16 of 48 
4.2.8.3 
History or presence of sustained ventricular tachycardia 
requiring medical intervention 
 
4.2.8.4 
Any history of clinically significant ventricular fibrillation or 
torsades de pointes 
 
4.2.8.5 
Known history of second or third degree heart block (may be 
eligible if the patient currently has a pacemaker) 
 
4.2.8.6 
Sustained heart rate of  <50/minute on pre-entry ECG 
 
4.2.8.7 
Right bundle branch block + left anterior hemiblock 
(bifascicular block) 
 
4.2.8.8 
Patients with myocardial infarction or unstable angina within 6 
months prior to starting study drug 
 
4.2.8.9 
CHF NY Heart Association class III or IV 
 
4.2.8.10 
Atrial fibrillation documented within 2 weeks prior to first dose 
of study drug. 
 
4.2.8.11 
Patients who require treatment with concomitant drugs that 
prolong QT/QTc interval or strong CYP3A4 inhibitors or 
inducers with the exception of antibiotics, antifungals, and 
antivirals that are used as standard of care to prevent or treat 
infections and other such drugs that are considered absolutely 
essential for the care of the subject. 
 
4.2.9 Known family history of congenital long QT syndrome 
 
5.0 
TREATMENT PLAN 
 
5.1 
General 
 
All patients will be registered through CORe. The objective will be to administer 
AZA or LDAC, and quizartinib at dose level 0 as defined in the Table below. We 
will first treat 6 patients at dose level -1. If no DLT is identified in >1 patient, this 
level is defined as MTD and up to 20 patients will be treated at this level with each 
treatment combination (AC220+ AZA or AC220 + LDAC) for the phase II portion. 
Other dose levels will be used for dose adjustments for toxicity during therapy. 
 
Approximately 200 patients will be enrolled on this study. 
 
5.2 
Schedule 

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Page 17 of 48 
 
 
5.2.1 Patients will be treated according to the following schedule: 
 
• AZA will be administered subcutaneously (SQ) or intravenously (IV) 
for 7 days of every cycle (Days 1-7) as determined by the treating 
physician.  Both SQ and IV forms of administration are FDA approved 
and considered interchangeable. Patients may start receiving AZA IV 
and changed to SQ at any time (and vice versa) as needed based on 
patient and physician preference.  AZA is administered in the clinic or 
chemotherapy administration area.  
 
• Cytarabine will be administered SQ twice daily for 10 days of every 
cycle (Days 1-10) as determined by the treating physician.  Cytarabine 
can be self-administered by the patient. 
 
• Quizartinib will be administered orally daily for 28 days of every cycle. 
For the first cycle only, quizartinib will be administered starting on day 
5 of the cycle. All subsequent cycles quizartinib will start concomitantly 
with AZA or cytarabine.   
 
5.2.1.1 
The starting and target dose is dose level 1. 
 
 
Table 1(a):  Dose reduction and escalation for Cytarabine + AC220 treatment 
arm 
Dose Level 
Cytarabine (mg BID x 
10 days) 
AC220 (mg/d, 
uninterrupted) 
-3 
10 
30 
-2 
15 
30 
-1 
20 
30 
1 (Starting and target 
dose) 
20 
60 
2  
20 
90 
 
 
 
 
Table 1(b):  Dose reduction and escalation for AZA+ AC220 treatment arm 
Dose Level 
AZA (mg/m2/d x 7 
days) 
AC220 (mg/d, 
uninterrupted) 
-3 
25 
30 
-2 
50 
30 
-1 
75 
30 
1 (Starting and target 
dose) 
75 
60 
2  
75 
90 
 

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February 25, 2020 
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Page 18 of 48 
5.2.1.2 
Dose reductions beyond those mentioned in this table or 
different to the doses specified should be discussed with the PI 
and documentation of the justification recorded in the chart. 
 
5.2.2 Patients will be assigned to treatment arm by physician’s choice and 
according to the availability of slots. 
5.2.2.1 Treatment arm is defined by the use of each of the possible 
chemotherapy agents (i.e., AZA + AC220 is one treatment arm and 
Cytarabine + AC220 is another treatment arm). 
5.2.2.2 Patients in Cohort 2B (FLT3 WT) will only be treated with AZA + 
AC220. The combination with cytarabine will not be explored in 
this subset of patients in this study.   
 
5.2.3 The first 6 patients on each cohort will receive dose level 1.  At least 3 of 
the patients will be females.   
5.2.3.1 A cohort is defined by each dose level. 
 
5.2.4 Prior to advancing/changing cohorts a cohort summary will be completed 
and submitted to the Medical Monitor in the IND Office. 
 
5.2.5 DLT is defined as any clinically significant non-hematologic adverse 
event or abnormal laboratory value occurring during the first cycle on 
study unless the event or laboratory value can clearly be determined to be 
unrelated to AC220 with the following exceptions:  
• 
CTCAE Grade 3 or 4 AST (SGOT) or ALT (SGPT) that resolves to ≤ grade 
2 in 14 days 
• 
Grade 3 nausea, vomiting, or diarrhea that can be managed to ≤  grade 2 
with standard antiemetic or antidiarrheal medications used at prescribed 
dose within 7 days of onset.  
• 
Grade 4 vomiting, or diarrhea that can be managed to  ≤  grade 3 with 
standard antiemetic or antidiarrheal medications used at prescribed dose 
within 48 hours of onset.  
• 
Grade 3 or 4 electrolyte abnormalities will only be considered DLT if 
possibly related to study drug and not corrected by optimal replacement 
therapy within 48 hours. 
• 
Grade 3 biochemical abnormalities of amylase or lipase without evidence 
of clinical pancreatitis.  
• 
Grade 3 anorexia or fatigue. 
• 
Grade 3 or 4 QTc prolongation will constitute DLT as follows:  The QTc 
interval will be calculated by Fridericia’s correction factor (QTcF). If the 
QTc is > 500 msec the EKG must be evaluated within 2 hours in triplicate 
and if ≥ grade 3 QTc prolongation is confirmed this will be considered a 
DLT. 

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Page 19 of 48 
Hematologic DLT is defined as grade ≥3 neutropenia and/or 
thrombocytopenia with a hypocellular bone marrow lasting for 6 weeks or 
more after the start of a course in the absence of residual leukemia (i.e., with 
less than 5% blasts). Anemia will not be considered for the definition of 
DLT.  
 
5.2.5.1 
If DLT occurs in ≥2/6 patients, this dose level would exceed the 
MTD, and an additional 6 patients will be treated at the next 
lower dose level. The dose level at which 0-1/6 patients 
experience DLT (but not higher than 60 mg/day) will be used to 
treat a maximum of 20 patients in each cohort in the phase II 
portion of the study. If ≥2/6 patients experience DLT at dose 
level -1 in any arm, dose level -2 may be explored for that 
arm(s). 
 
5.2.5.2 
If DLT is observed in 0 or 1/6 in dose level 1, this cohort will be 
expanded to treat up to 20 patients in the phase II portion of the 
study.  If ≥ 2/6 patients experience DLT at dose level 1 for any 
arm of the study, the dose level at which </=1/6 patients have 
experienced DLT will be used for the phase II portion of the 
study for that arm. 
 
5.2.5.3 
If DLT is observed in 2/6 patients treated at dose level 1 in any 
arm, the study will continue at the quizartinib dose of 30 mg PO 
(dose level -1) for that arm to treat an additional 26 patients at 
this dose level in the phase II portion of the study. 
 
5.2.5.4 
Patients that are removed from study before day 28 for any 
reason other than toxicity and have not experienced DLT will be 
replaced.  
 
5.2.5.5 
DLT and MTD will be defined independently for each treatment 
arm (i.e., AC220 + AZA and AC220 + cytarabine). 
 
5.2.6 One cycle of therapy is defined 7 days of AZA or 10 days of LDAC, and 28 
days of quizartinib. Patients will receive one cycle of therapy every 4 weeks.  
 
5.2.6.1 
Cycles may be started early (but not earlier than day 21) for 
patients with active disease if judged in the best interest of the 
patient.  
 
5.2.6.2 
Subsequent cycles may be delayed for recovery of toxicity. 
Delays in start of subsequent cycles greater than 8 weeks should 
be discussed with the principal investigator. 
 

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5.2.6.3 
Quizartinib therapy may continue if there is a delay in the start 
of the next cycle of AZA provided the delay is not due to toxicity 
possibly related to quizartinib. 
 
5.2.6.4 
Subsequent courses may be administered regardless of 
peripheral blood counts during the first 4 cycles and/or in the 
presence of residual leukemia. If prolonged myelosuppression 
(more than 60 days) with evidence of a hypocellular marrow 
(marrow cellularity less than 5% without evidence of leukemia) 
is observed subsequent courses of AZA may be given at the next 
lower dose. If the peripheral counts do not recover (ANC <1 
x109/L and/or platelets <30 x109/L) but there is evidence of 
residual leukemia in the bone marrow, subsequent cycles can be 
administered at the discretion of the treating physician not 
earlier than 3 weeks after the prior cycle.  
 
 
5.2.7 Quizartinib Administration 
 
Quizartinib will be administered orally at a starting dose of 60 mg daily for 
the scheduled 28 days in each cycle.  
 
5.2.7.1 
If a dose is missed or vomited, the next dose should not be 
increased to account for missing a dose. The subject should take 
the next regular dose at the regularly scheduled time. 
 
5.2.7.2 
Treatment may be prolonged beyond the planned 28 days of 
each cycle if the start of the next cycle of AZA or LDAC is 
delayed. However, if there are adverse events that mandate 
treatment interruption or it is considered in the best interest of 
the patient for safety reasons to interrupt therapy, quizartinib 
administration can be transiently discontinued and re-started as 
per guidelines in section 6.0.  
 
 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 
 
1. 
Clinically significant progressive disease 
 
2. 
Grade 4 QTc prolongation.  
 
3. 
Intercurrent illness that prevents further administration of treatment 

2012-1047 
February 25, 2020 
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Page 21 of 48 
 
4. 
Patient request 
 
5. 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
6. 
Unacceptable toxicity that in the opinion of the investigator makes it unsafe 
to continue therapy.  This includes patients with grade 4 non-hematological 
toxicity unless it reverses to grade ≤ 1 on or before 14 days of interrupting 
AC220. 
 
5.3.1 It is planned that up to a total of 12 cycles of therapy will be administered 
for patients deriving benefit from this regimen. Continuation of therapy for 
patients completing 12 cycles of therapy may be considered on a case by 
case basis after discussion with the principal investigator.  
 
5.3.2 A minimum of 1 full course (defined as the administration of AZA for 7 
days or LDAC for 10 days, and quizartinib for 24 days for cycle one, i.e. 
days 5-28) will be required for a patient to be considered as having received 
an adequate trial to evaluate efficacy.  All patients receiving at least one 
dose of any of the two drugs will be considered evaluable for toxicity.   
 
5.4 
Concomitant Medications 
 
5.4.1 The use of any concomitant medication/therapies deemed necessary for 
patient supportive care and safety are permitted. Other anticancer agents 
including systemic chemotherapy, radiation therapy, or biologic response 
modifiers are not permitted during the study.  No other investigational drug 
is allowed during the study. Patients must be off growth factors for five days 
in order to declare a neutrophil response. Antiemetics may be used for the 
prevention or treatment of nausea and vomiting.  
 
5.4.2 The administration of drugs known to prolong QTc interval or strong 
CYP3A4 inhibitors should be administered with caution. Any drug known 
to inhibit or induce CYP3A4 will likely interact with quizartinib.     
 
The list of drugs that can be associated with Torsades de Pointes or 
prolonged QT interval can be found online at:   
http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm. 
 
The list of drugs that interact with CYP3A4 can be found online at: 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx 
 
5.4.3 Administration of other antineoplastic agents is prohibited for patients 
while on this study with the following exceptions: 1) Hydroxyurea may be 

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used for the first 28 days of therapy. The additional days of Hydrea after 28 
days is permitted as clinically indicated, on case by case basis and after 
discussion with the PI .  2) Administration of intrathecal chemotherapy is 
allowed when clinically indicated. 
 
6.0 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Toxicity Directly Attributable to Study Drug 
 
Patients experiencing unacceptable toxicity directly attributable to the study drugs 
should temporarily stop treatment according to the guidelines in the dose 
adjustment schema. 
 
6.2 
Toxicity Grading 
 
Toxicity grading will be according to the NCI CTCAE, v4.  To prevent unnecessary 
morbidity, the following guidelines for dose adjustment for drug-related toxicities 
are recommended.  
 
6.3 
Dose Reductions 
 
Table 2(a):  Dose reduction and escalation for Cytarabine + AC220 treatment arm 
 
Dose Level 
Cytarabine (mg BID x 
10 days) 
AC220 (mg/d, 
uninterrupted) 
-3 
10 
30 
-2 
15 
30 
-1 
20 
30 
1 (Starting and target 
dose) 
20 
60 
2  
20 
90 
 
 
 
Table 2(b):  Dose reduction and escalation for AZA+ AC220 treatment arm 
Dose Level 
AZA (mg/m2/d x 7 
days) 
AC220 (mg/d, 
uninterrupted) 
-3 
25 
30 
-2 
50 
30 
-1 
75 
30 
1 (Starting and target 
dose) 
75 
60 
2  
75 
90 
 
Dose reductions for non-hematologic toxicity possibly related to study drugs 
should be performed according to the following table: 
 

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Page 23 of 48 
Toxicity 
Grade 
Actions 
Non-hematological 
(excludes myalgia/ 
arthralgia responding to 
treatment, inadequately 
treated nausea, 
vomiting and diarrhea, 
or electrolyte 
abnormalities unless 
not responding to 
optimal 
supplementation) 
3 
Hold therapy until recovery to 
Grade ≤ 1, then re-start and 
reduce to the next lower dose 
level. If toxicity recurs again, 
hold therapy until recovery to 
grade ≤1, then re-start and 
reduce one additional dose 
level.  Dose reductions below 
dose level -3 will be 
considered on an individual 
basis after discussion with the 
principal investigator.  
Non-hematological, 
study-drug related 
4 
Remove from study.  An 
exception can be made if grade 
4 toxicity reverses to Grade ≤ 
1 on or before 14 days of 
interrupting study drug and re-
dosing with AC220 is 
considered safe and in the best 
interest of the patient.  In those 
instances treatment may be 
resumed with a 1 dose-level 
reduction after discussion with 
PI and Sponsor. 
Non-hematological 
(excludes myalgia/ 
arthralgia responding to 
treatment, inadequately 
treated vomiting and 
diarrhea, or electrolyte 
abnormalities unless 
not responding to 
optimal 
supplementation)  
Persistent 2 considered 
clinically significant or 
upon patient’s request  
Hold therapy until recovery to 
Grade ≤ 1, then re-start and 
reduce to the next lower dose 
level. If toxicity recurs again, 
hold therapy until recovery to 
grade ≤1, then re-start and 
reduce one additional dose 
level.  Dose reductions below 
dose level  -3 will be 
considered on an individual 
basis after discussion with the 
principal investigator. 
Cardiac Toxicity 
QTc > 450 and ≤ 480 
msec 
Check magnesium and 
potassium levels and correct 
any abnormalities. If possible, 
stop any medications that may 
prolong the QTc interval. 
Continue quizartinib at the 
same dose. 

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Page 24 of 48 
Cardiac Toxicity 
QTc > 480 and ≤ 500 
msec 
Check magnesium and 
potassium levels and correct 
any abnormalities. If possible, 
stop any medications that may 
prolong the QTc interval. 
Decrease AC220 to next 
lowest dose level until QTc 
interval improves to ≤480 
msec. AC220 dose may then 
be escalated to the previous 
dose if other external factors 
have been corrected and QTc 
has remained below 480 msec 
in at least 3 consecutive ECG 
separated for at least 2 weeks. 
Cardiac Toxicity 
QTc interval >500 
msec 
Check magnesium and 
potassium levels and correct 
any abnormalities. Interrupt 
AC220 and if possible any 
medications that may prolong 
the QTc interval.  If QTc 
interval resolves to within 30 
msec of baseline value within 
7 days resume AC220 at the 
next lower dose level.   If not 
resolved within 7 days, 
discontinue therapy 
permanently.   
Cardiac Toxicity 
QTc interval >500 or 
>60 ms change from 
baseline, and Torsade 
de pointes or 
polymorphic 
ventricular tachycardia 
or signs/symptoms of 
serious arrhythmia (i.e., 
grade 4) 
Discontinue therapy 
 
6.3.1 Patients in whom the toxicity occurs or persists beyond the planned 
completion of drug administration for the cycle will have the dose 
reductions implemented in subsequent cycles provided the toxicity has 
resolved as specified in the table above.  
 
6.3.2 If adverse events are clearly associated with one of the drugs, dose 
adjustments to only that agent may be performed. 

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Page 25 of 48 
 
6.3.3 Dose modifications different than those described above (e.g., dose 
reductions by 2 dose levels, decreased number of days of administration of 
either drug continuation of only quizartinib) may be implemented if judged 
in the best interest of the patient after discussion with the PI and 
documentation of the rationale for this action. 
 
6.3.4 Dose adjustments for only of the drugs may be considered when the adverse 
event may be clearly associated with only one drug (e.g., QTc prolongation 
with quizartinib).  
 
6.3.5 Patients in whom therapy is held for > 8 weeks due to toxicity will be 
removed from the trial. 
 
6.4 
Myelosuppression 
 
Patients with leukemias and MDS usually present with abnormal peripheral blood 
counts at the time therapy is started and myelosuppression is an expected event 
during the course of therapy for acute leukemias and myelodysplastic syndromes. 
Thus, no dose adjustments or treatment interruptions for myelosuppression will be 
planned for the first 4 weeks of therapy. After this time, treatment interruptions and 
dose adjustments may be considered on an individual basis. The following 
guidelines can be used to consider treatment: 
 
6.4.1 Patients with neutropenia or thrombocytopenia as a consequence of the 
disease do not require treatment interruptions for myelosuppression. Dose-
reductions in these patients should be considered in an individual case and 
discussed with the PI. The following guidelines can be used for these 
patients:  
 
6.4.1.1 
Patients with a response and pre-cycle counts of neutrophils 
>1x109/L and platelets >50 x109/L who have sustained low 
counts of neutrophils <0.5 x109/L or a platelet count <20 x 
x109/L for more than 2 consecutive weeks in the current cycle, 
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. 
 
6.4.1.2 
If there are persistent peripheral blood blasts, or the bone 
marrow shows >5% blasts, may continue treatment regardless of 
neutrophil and platelet count and give supportive care as needed.  
 
6.4.1.3 
If no marrow evidence of leukemia, may hold therapy until 
recovery of granulocytes to ≥1 x109/L and platelets ≥ 60 x109/L, 

2012-1047 
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then resume at same or 1 lower dose level according to 
guidelines mentioned above. 
 
6.5 
Intrapatient Dose Escalation for Patients Treated at Dose Level -1 or Lower 
 
Intrapatient dose escalation will be permitted for these patients provided: 
 
6.5.1 Patient has completed ≥1 cycle at dose level -1 or lower, and 
 
6.5.2 Patient has not experienced any grade 3 or higher non-hematologic toxicity, 
and 
 
6.5.3 Patient has not experienced hematologic DLT, and 
 
6.5.4 At least 3 patients have been treated at the next higher dose level and 
followed for at least 28 days without experiencing DLT. 
 
6.5.5 Patients who have experienced no QTc prolongation above 480 msec in 
whom optimal anti-leukemia effect has not been reached may have the dose 
of quizartinib increased to by one dose level. Patients who have such dose 
escalation will have an EKG done 24 hours and 7 days after dose escalation. 
No dose escalation above 90 mg/day will be allowed. 
 
6.5.6 Because of the increased risk of QTc prolongation in women treated at 
doses > 90 mg/day in prior studies with AC220, dose escalation above 90 
mg/day is not allowed in women. 
 
 
 
 
7.0 AGENT FORMULATION AND PROCUREMENT 
 
7.1 
Quizartinib (AC220) 
 
7.1.1 Description 
 
The chemical name of the investigational product, quizartinib, is N-(5-tert-
Butyl-isoxazol-3-yl)-N′-[4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-
b][1,3]benzothiazol-2-yl]phenyl] urea dihydrochloride salt.  
 
AC220 is supplied as tablets each containing 30 mg AC220 (26.5 mg free 
base) and 300 mg HPβCD. The tablets also contain microcrystalline 
cellulose, magnesium stearate, and Opadry® II 85F18422 white film 
coating. They are packaged in high density polyethylene bottles, each 
containing 30 tablets, with child-resistant caps. 
 

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7.1.2 Clinical Pharmacology 
 
Analysis of human plasma samples demonstrate that AC220 is orally 
bioavailable with a long effective half-life, estimated to be about 1.5 days. 
In addition, AC220 exhibits minimal peak and trough variation of plasma 
levels with once daily dosing. In addition, a pharmacologically active 
metabolite, AC886, has been identified in plasma and urine samples, which 
has a slightly longer half-life of about 2 days. Since food has been shown to 
affect absorption in animals, AC220 should be taken in the morning on an 
empty stomach. 
 
7.1.3 Potential Indications and Usage 
 
AC220 is currently being evaluated as a treatment for patients with AML 
who are not candidates for standard therapy (Phase 1 study), or whose 
disease is refractory to, or has relapsed, following standard therapy in a 
multiple cohorts of patients (Phase 2 study) irrespective of age. Patients 
with and without FLT3 mutations are being investigated. It is planned to 
assess the safety and efficacy of AC220 as monotherapy and/or in 
combination with other agents for the treatment of AML and also in other 
oncology and disease indications. 
 
7.1.4 Dosing 
 
Each patient will receive or be instructed to take AC220 oral tablets at the 
assigned dose once a day on an empty stomach at least 1 hour before or 2 
hours after a meal in the morning for 28 consecutive days as 1 cycle of 
treatment. 
 
7.1.5 Selection and Timing of Dose 
 
Each treatment cycle consists of 28 consecutive days. AC220 will be taken 
orally once a day on an empty stomach (i.e., 1 hour before or 2 hours after 
a meal) in the morning. The starting dose in the Phase 2 monotherapy study 
was 200 mg/day.  Due to a higher than anticipated rate of QT prolongation, 
lower doses of 90mg/day in females and 135mg/day in males was pursued 
after the initial 17 subjects were enrolled out of a total of 333 subjects in the 
Phase 2 study.  
 
7.1.6 Packaging and Labeling 
 
Please refer to the Pharmacy Manual for packaging and labeling 
information. 
 
7.1.7 Study Drug Preparation 

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Please refer to the Pharmacy Manual for packaging and labeling 
information. 
 
7.2 
AZA and cytarabine: these drugs are commercially available and will be 
handled as per the packet insert and standards in the MDACC investigational 
pharmacy.  
 
7.3 
Disposition of unused drug:  all unused drug will be disposed of per institutional 
guidelines and procedures. 
 
8.0 
CORRELATIVE/SPECIAL STUDIES (Optional) 
 
In patients treated with FLT3 inhibitors, the degree of FLT3 inhibition in vivo has been 
shown to be an important parameter in determining clinical response (Levis et al 2011 
Blood 117:3294).  In addition, the plasma levels of FLT3 ligand (FL) may influence the 
degree of in vivio inhibition (Sato et al 2011 Blood 117:3286).  In patients treated with 
quizartinib and 5-azacitidine or low-dose AraC (LDAC), it is hypothesized that in vivo 
FLT3 inhibition, which may be impacted by FL levels, will influence clinical responses.  
Therefore, we propose to measure in vivo FLT3 inhibition and FL levels in patients 
enrolled on this trial.  We will collect whole blood into a 10 cc heparinized (green top) 
vacutainer tube pre-treatment and on Days 1, 8, and 15 of each cycle up to the first 4 cycles 
(all ±2 days) ;   (therefore 12 samples maximum per patient).  For each time point, therefore, 
approximately 8 cc whole blood will be collected.  The blood will be centrifuged to separate 
the cellular fraction, and the plasma (3-5 cc per sample) will be transferred into a separate 
tube for frozen storage.  Samples will be shipped in batches every month to the laboratory 
of Dr. Mark Levis: 
 
Mark Levis MD PhD 
Cancer Research Building 1, Room 230 
1650 Orleans Street 
Baltimore, MD 21231 
 
For analysis, frozen plasma will be thawed rapidly, then stored on ice.  For FL levels, 200 
microliters will be used in an ELISA-based assay system (R&D).  For determination of in 
vivo FLT3 inhibition, the remaining plasma will be assayed using a Plasma Inhibitory 
Activity assay for FLT3 by incubating 1 cc plasma with the FLT3/ITD-expressing Molm14 
cell line, then performing immunoblotting for phospho-FLT3 as described (Levis et al 2006 
Blood 108:3477).  The degree of in vivo FLT3 inhibition will be calculated as a percent of 
the baseline (from the baseline sample collected pre-treatment).  Results will be entered 
into a spreadsheet and returned to the study PI when all samples have been analyzed. 
 
9.0 
PATIENT EVALUATION (See Appendix AA) 
 
9.1 
Pre-Treatment Evaluation 

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All pretreatment studies should be obtained within 14 days of entry into the trial, 
unless otherwise stated. 
 
9.1.1 A complete history and physical, documentation of all measurable disease, 
concomitant medications and performance status. 
 
9.1.2 CBC, platelet count, differential (differential can be omitted if WBC is ≤0.5 
x109/L). 
 
9.1.3 Creatinine, total bilirubin, ALT, potassium, magnesium,  calcium, sodium, 
chloride, CO2, uric acid, phosphorus, and BUN.    
 
9.1.4 Pregnancy test (urine or plasma) in females of childbearing potential, 
should be performed 48 hours before initiation of study. 
 
9.1.5 Bone marrow aspirate during the last 21 days preceding study initiation. 
Cytogenetics will be obtained prior to therapy (results from prior analysis 
can be used for this purpose). 
 
9.1.6 Evaluation of FLT3 if not done within 90 days, provided there has been no 
intervening therapy other than hydroxyurea or isolated single-agent doses 
of cytarabine. 
 
9.1.7 EKG and ECHO and/or MUGA will be performed before initiating study 
treatment if not done within 28 days. 
 
9.1.8 Pretreatment optional correlative studies (see Section 8.0) 
 
9.2 
Evaluation During Treatment 
 
9.2.1 Physical exam at the start of each cycle (± 5 days) for the first 2 cycles, then 
every 2-3 cycles and documentation of all concomitant medications. 
9.2.1.1 Patients will keep a diary for drug administration of self-
administered drugs (cytarabine and AC220) 
 
9.2.2 CBC, platelet count, differential once weekly for the first 3 cycles, then 
every 2-4 weeks (all ±2 days)  (differential can be omitted if WBC is ≤0.5 
x109/L) 
 
9.2.3 Creatinine, total bilirubin, ALT, K, Mg, Ca, sodium, chloride, and CO2 on 
day 5 prior to start of AC220, then weekly for the first 3 cycles, then every 
2-4 weeks(all ±2 days)  . 
 
9.2.4 Bone marrow aspiration on day 28 (+/- 7 days) of cycle 1, then every 1-3 

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cycles. 
 
9.2.5 EKG will be performed on day 1, day 5, day 8, and day 12  of the first cycle 
(all ±2 days) Day 1 and day 8 ECG are collected pre-dose; day 5 are 
collected pre-dose and 4 hrs (+/- 2 hrs) post-dose; day 12 are collected 4 hrs 
(+/- 2 hrs) post-dose. Then ECG to be done on day 1 of each cycle for cycles 
2 and 3 before initiation of quizartinib and 4 hr (+/-2 hrs) post dose, then 
pre-dose every 2-3 cycles.   EKG may be omitted if patient has not received 
study drug (AC220) in the 48 hrs preceeding the time when EKG is done.  
EKG for the first 3 cycles will be done in triplicate.  Day 5 pre AC-220 will 
be used as baseline. 
 
9.2.5.1 
On patients in whom quizartinib is escalated to 90 mg daily as 
described in section 6.5.5 or who start therapy with a drug that 
may prolong QT/QTc or that is a strong CYP3A4 inhibitor or 
inducer , an EKG will be required 24 hrs (±6 hrs), 7 days (±2 
days) and 14 days (±2 days) after the dose increase or after the 
start of such drug.  
 
9.2.5.2 
Patients who had their dose reduced because of QTc 
prolongation and have their dose re-escalated as described in 
section 6.3 will have an EKG repeated 24 hrs (±6 hrs) and 7 days 
(± 2 days) after re-escalation. 
 
9.2.5.3 
The QTc interval will be calculated by Fridericia’s correction 
factor (QTcF). The 12–lead EKG evaluation will consist of 3 
separate EKGs obtained at least 5 minutes apart. 
 
9.2.6 Correlative studies on days 1, 8 and 15 of each cycle up to the first 4 cycles 
(all ±2 days).     (Optional – See Section 8.0). 
 
9.2.7 For patients that remain on study with no significant toxicity for more than 
6 months, subsequent evaluations during study may be modified after 
discussion with the principal investigator.  These include a decrease in 
frequency of standard laboratory tests to once every cycle, bone marrow 
aspirations to every 6-12 months (or as clinically indicated). 
 
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 E) 

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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 approximately every month. 
 
 
10.0 CRITERIA FOR RESPONSE 
 
Criteria for response will be as per the international working group for MDS and AML. 
 
10.1 
Response Criteria for MDS 
 
Response criteria will be according to the International Working Group (Blood 
2006; 108: 419-425). Responders are patients who obtain a CR, CRi, or PR, with 
or without cytogenetic response, hematologic improvements, and morphologic 
leukemia-free state. Briefly, criteria are as follows: 
 
10.1.1 
Morphologic Complete Response (CR) 
 
 
♦ 
Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count ≥1.0 x109/L  
 
Platelet count ≥100 x109/L 
 
♦ 
Bone marrow aspirate and biopsy: 
 
< 5% blasts 
 
No extramedullary leukemia 
 
10.1.2 Partial Response (PR) 
♦ 
All CR criteria if abnormal before treatment  except: 
♦ 
≥50 % reduction in bone marrow blast but still >5% 
 
10.1.3 Marrow CR 
♦ 
Bone marrow: 
5% myeloblasts and decrease by 50% over 
pretreatment 

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♦ 
Peripheral blood: if HI responses, they will be noted in addition to 
marrow CR 
 
10.1.4 
Hematologic Improvement (HI): Hematologic response must be 
described by the number of positively affected cell lines. 
 
♦ 
Erythroid response (E) (pretreatment Hgb <11 g/dL) 
 
Hgb increase by 1.5 g/dL 
 
♦ 
Platelet response (P) (pretreatment platelets <100 x109/L) 
 
Absolute increase of 30 x 109/L for patients starting with > 20 x 
109/L platelets 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
 
♦ 
Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
 
At least 100% increase and an absolute increase > 0.5 x 109/L 
 
10.2 
Response Criteria for AML 
 
Response criteria will be modified from the International Working Group for AML 
(JCO 2003; 21: 4642-9). Responders are patients who obtain a CR, CRi, or PR, 
with or without cytogenetic response, hematologic improvements, and morphologic 
leukemia-free state. Briefly, criteria are as follows: 
 
10.2.1 
Complete remission (CR):  
 
♦ 
Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count ≥1.0 x109/L  
 
Platelet count ≥100 x109/L 
 
♦ 
Bone marrow aspirate and biopsy: 
 
≤5% blasts 
 
No Auer rods 
 
No extramedullary leukemia 
 
10.2.2  Complete remission with incomplete blood count recovery (CRi): 
 
♦ 
Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count <1.0 x109/L, and/or 
 
Platelet count <100 x109/L 
 
♦ 
Bone marrow aspirate and biopsy: 
 
≤ 5% blasts 

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Page 33 of 48 
 
No Auer rods 
 
No extramedullary leukemia 
 
10.2.3 
Partial remission:  
♦ 
All CR criteria if abnormal before treatment  except: 
♦ 
≥50 % reduction in bone marrow blast but still >5% 
 
10.2.4 
Morphologic leukemia-free state:  
♦ 
Bone marrow: ≤5% myeloblasts   
 
10.2.5 
Hematologic Improvement (HI): Hematologic response must be 
described by the number of positively affected cell lines. 
 
♦ 
Erythroid response (E) (pretreatment Hgb <11 g/dL) 
 
Hgb increase by 1.5 g/dL 
 
♦ 
Platelet response (P) (pretreatment platelets <100 x109/L) 
 
Absolute increase of 30 x 109/L for patients starting with > 20 x 
109/L platelets 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
 
♦ 
Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
 
At least 100% increase and an absolute increase > 0.5 x 109/L 
 
♦ 
Blast response (Bl) a ≥50% reduction in blast percentage in bone 
marrow and/or ≥50% reduction in peripheral blood total blast count. 
 
11.0 
ADVERSE EVENT REPORTING 
 
11.1 
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 
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. 
 

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The Investigator or physician designee is responsible for verifying and 
providing source documentation for all adverse events and assigning the 
attribution for each event for all subjects enrolled on the trial. 
 
11.2 
PDMS/CORe will be used as the electronic case report form for this 
protocol.  Adverse events will be documented in the medical record and 
entered into PDMS/CORe. 
 
11.3 
Adverse Events (AEs) will be evaluated according to the latest CTC 
version and documented in medical record.  All suspected adverse drug 
reactions (SADR) will be recorded in the Case Report Form (CRF).  
Expected events during leukemia therapy are: 
 
11.3.1 
Myelosuppression related events (due to disease or 
leukemia therapy) 
 
11.3.1.1 febrile or infection episodes not requiring management 
in the intensive care unit 
 
11.3.1.2 
epistaxis or bleeding except for catastrophic CNS or 
pulmonary hemorrhage 
 
11.3.1.3 
anemia, neutropenia, lymphopenia, 
thrombocytopenia, leukopenia 
 
11.3.2 Disease related events 
 
11.3.2.1 
symptoms associated with anemia 
 
11.3.2.1.1 fatigue 
 
11.3.2.1.2 weakness 
 
11.3.2.1.3 shortness of breath 
 
11.3.2.2 electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, 
magnesium) 
 
11.3.2.3 chemistry abnormalities (LDH, phosphorus, calcium, BUN, 
protein, albumin, uric acid, alkaline phosphatase, glucose) 
 
11.3.2.4 coagulation abnormalities 
 
11.3.2.5 disease specific therapy (induction, maintenance, salvage, or 
stem cell therapy) 

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Page 35 of 48 
 
11.3.2.6 alopecia 
 
11.3.2.7 bone,  joint, or muscle pain 
 
11.3.2.8 liver function test abnormalities associated with infection or 
disease progression 
 
11.3.2.9 disease progression 
 
11.3.2.10abnormal hematologic values  
 
11.3.3 
General therapy related events 
 
11.3.3.1 catheter related events 
 
11.3.3.2 renal failure related to tumor lysis syndrome or antibiotic/ 
antifungal therapy 
 
11.3.3.3 rash related to antibiotic use 
 
11.3.4 
Hospitalization for the management of any of the above expected events 
 
11.4 
Abnormal hematologic values will not be recorded on the case report form.  
For abnormal chemical values, the apogee or nadir (whichever is appropriate) will be 
reported per course on the case report form. 
 
11.5 
Serious Adverse Event Reporting (SAE) 
 
SAE reports should be addressed to DSI Clinical Safety and Pharmacovigilance 
(CSPV) via email (CSPV-Clinical@dsi.com) or facsimile (732-906-9621).  The PI 
will use Institution’s standard forms for reporting SAEs (Serious Adverse Event 
Reporting (SAVER) form) and pregnancies (Exposure In Utero (EIU) form) in 
accordance with ICH guidance. DSI’s awareness date is the date a SAE is received 
from the PI. The PI will provide DSI CSPV with final CIOMS report by email 
(CSPVClinical@dsi.com) or facsimile (732-906-9621) in accordance with the 
following timeframe: (a) Fatal or life-threatening and related SAEs shall be 
reported within seven (7) calendar days of the date of awareness (b) All other SAEs 
shall be reported within fifteen (15) calendar days of the date of awareness.  SAE 
submissions to Celgene within 24 hours of becoming aware of the event will be 
reported by fax to Celgene Drug Safety (908-673-9115).  The reporting period ends 
thirty (30) days after discontinuation of drug, or Completion of subject’s 
participation.  In addition, PI must notify Celgene of any SAE that may occur after 
this time period which the PI believes to be certainly, probably or possibly related 
to Study Drug. Information not available at the time of the initial report (e.g., an 

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Page 36 of 48 
end date for the adverse event or laboratory values received after the report) must 
be documented on a follow-up report.  A final report to document resolution of the 
SAE is required.   
 
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 INDIND 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 and those that constitute a clinically important increase in the rate of serious adverse 
reactions over those listed in the protocol or Investigator Brochure, must have a written 
report submitted within 24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office.   
 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  Serious adverse 
events will be captured from the time of the first protocol-specific intervention, until 
30 days after the last dose of drug, unless the participant withdraws consent. 
Serious adverse events must be followed until clinical recovery is complete and 

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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. 
 
MDACC Reporting Requirements  
 
All SAEs will be reported to the IRB according to MDACC guidelines.  Serious 
Adverse Events will be submitted electronically via the eSAE system to the IND 
Office and will be submitted to the FDA by the Safety Coordinator according to 
21 CFR 312.32.  
 
 
Investigator Communication with Supporting Companies: 
 
Any serious suspected unexpected adverse reaction (where SAE is not reported in 
the Investigator Brochure and is considered to be related to study drug) will be 
reported to DSI Clinical Safety and Pharmacovigilance (CSPV) via email (CSPV-
Clinical@dsi.com) or facsimile (732-906-9621) and by fax to Celgene Drug Safety 
(908-673-9115) only if related to Vidaza.  Information not available at the time of 
the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final report 
to document resolution of the SAE is required.   
 
 
12.0 
STATISTICAL CONSIDERATIONS48 
 
12.1 
Overview 
 
This is a phase I/II study of two combination therapies in patients with AML or 
MDS: AC220 + 5-azacytidine, and AC220 + low-dose cytarabine. Patients will be 
assigned to the two treatments based on physicians’ choice. The two treatments will 
be evaluated separately. 
 
12.2 
Phase I 

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The primary objective of the phase I portion of the study is to determine the MTD 
of each combination therapy. The dose schedule is listed in table 1 of section 5.2.1. 
Up to 2 dose levels of AC220 will be tested in each combination with a fixed dose 
of the other drug. Initially, 6 patients will be treated at dose level1, if ≤1 patients 
experience DLT at dose level1, then 6 subsequent patients will be treated at the next 
higher dose level, dose level2.  If ≤1 patients experience DLTs in dose level2, this 
level will be defined as the MTD and will be used in the phase II portion of the 
study. If >1 patients experience DLTs at dose level1, then the 6 subsequent patients 
will be treated at the next lower dose level, level   -1. The MTD is defined as the 
highest dose at which no more than 1 patient experiences DLTs. For each 
combination therapy, 12 patients will be evaluated. The total sample size for the 
phase I portion will be 24. 
 
12.3 
Phase II 
 
A: Cohort 2A – FLT3-ITD 
 
The primary endpoint of the phase II portion of the study is overall response 
(CR+Cri+PR+HI) (first 2 treatment courses).  It would be encouraging if the overall 
response rate reaches 50%.   
 
Treatment with AC220 + low-dose cytarabine (Cohort 2A-FLT3-ITD) 
 
Patients enrolled in the treatment of AC220 + low-dose cytarabine could be newly 
diagnosed or previously treated. A total of 26 patients (including 6 patients treated 
at MTD in Phase I) will be treated with this treatment combination. The toxicity 
and efficacy (CR+Cri+PR+HI) will be monitored during the study, and all the data 
will be used to update the prior distributions for toxicity and efficacy parameters. 
The study will be stopped for toxicity and futility based on the following stopping 
rules. If the trial for this treatment continues until 26 patients are evaluated, and 
assuming the overall response rate is 50%, then the 95% credible interval for overall 
response rate would be (0.32, 0.68). 
 
12.3.1 
Overall response 
Response will be monitored closely in patients using the method of Thall 
et al (1995).  Denote the probability of overall response by PE.  We assume 
PE ~ beta (1, 1).  We will stop the trial of this treatment if at any point Pr 
(PE < 0.5 | data) > 0.98. That is, we will stop the treatment of this 
combination if, at any time during the study, we determine that there is 
more than 98% chance that the response rate is less than 50%. The trial 
will be stopped if (the number of response observed / among number of 
patients) ≤ 1/10, 2/12, 3/15, 4/18, 5/21, and 6/24. 
 
 

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12.3.2 
Toxicity 
 
Toxicity will be monitored closely using the method of Thall et al (1995). 
Denote the probability of toxicity by θE, where toxicity is defined as 
DLTs.  We assume θE ~ beta (0.6, 1.4).  We will stop the trail if at any 
point Pr(θE > 0.30 | data)  >0.9. That is, we will stop the trial of this 
combination therapy 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 trial will be stopped if (the number of toxicity observed / among 
number of patients) ≥ 6/11, 7/14, 8/16, 9/19, 10/22 and 11/24. 
Table 1 presents operating characteristics for the study design. 
 
Table 1: Operating characteristics 
Response rate 
Toxicity rate 
Probability of 
early stopping 
Average number 
of patients 
0.2 
0.1 
0.862 
15.01 
0.2 
0.864 
14.94 
0.3 
0.884 
14.48 
0.4 
0.929 
13.37 
0.5 
0.974 
11.95 
0.3 
0.1 
0.497 
20.31 
0.2 
0.508 
20.14 
0.3 
0.579 
19.11 
0.4 
0.743 
16.64 
0.5 
0.907 
13.62 
0.4 
0.1 
0.175 
24.02 
0.2 
0.192 
23.79 
0.3 
0.309 
23.33 
0.4 
0.577 
18.88 
0.5 
0.847 
14.72 
0.5 
0.1 
0.038 
25.54 
0.2 
0.058 
25.29 
0.3 
0.194 
23.65 
0.4 
0.507 
19.79 
0.5 
0.822 
15.16 
0.6 
0.1 
0.005 
25.93 
0.2 
0.026 
25.67 
0.3 
0.167 
23.99 
0.4 
0.49 
20.02 
0.5 
0.816 
15.27 

2012-1047 
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Page 40 of 48 
Page 40 of 48 
 
MultcLean V1.2 developed in the Department of Biostatistics MDACC was used 
to calculate the stopping boundaries for futility and toxicity monitoring rules. 
 
Treatment with AC220 + 5-azacytidine (Cohort 2A-FLT3-ITD) 
 
Up to 50 newly diagnosed patients (including patients treated at the same dose in 
phase I) and up to 50 previously treated patients (including patients treated at the 
same dose in phase I) will be treated with AC220 + 5-azacytidine. The analysis 
for the two groups of patients will be completed separately.  
 
The study will monitor futility and safety for each patient group and the 
monitoring will begin when 15 patients have been enrolled in that group, and 
thereafter by a cohort of 5 patients. The trial in one group will be stopped early if 
at any time point the data in that group suggest  
Pr (PE < 0.5 | data) > 0.98 or 
Pr(θE > 0.30 | data)  >0.9 
 
Where PE denote the response rate for experimental treatment, and θE denotes the 
toxicity rate for the experimental treatment combination. Assume PE ~ prior beta 
(1,1) and θE ~ prior beta(0.6, 1.4). 
 
That is, the trial in one group will be stopped early for futility if the data for that 
group indicate that there is more than 98% probability that the response rate is 
less than 50% or the trial for one group will be stopped early for toxicity if the 
data that group indicate that there is more than 90% probability that the toxicity 
rate (i.e. DLT rate) is more than 30%.  
 
The corresponding stopping boundaries for futility is: the trial in one group will 
be stopped early if (the number of response observed / among number of patients) 
in that group ≤ 3/15, 5/20, 7/25, 9/30, 11/35, 13/40 and 15/45.  
 
The corresponding stopping boundaries for toxicity is: The trial will be stopped 
early in one group if (the number of patients experienced DLTs / among number 
of patients) in that group ≥ 8/15, 9/20, 11/25, 13/30, 15/35, 16/40 and 18/45. 
 
Table 2 presents the operating characteristics for the above design. 
 
Table 2: OCs for the design for cohort 2A with AC220 + 5-AZA 
Response rate 
Toxicity rate 
Probability of 
early stopping 
Average number of 
patients 
0.2 
0.1 
0.993 
18.6 
0.2 
0.993 
18.6 

2012-1047 
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Page 41 of 48 
Page 41 of 48 
0.3 
0.994 
18.2 
0.4 
0.998 
17.4 
0.5 
1 
16.2 
0.35 
0.1 
0.584 
35.8 
0.2 
0.59 
35.5 
0.3 
0.669 
32.9 
0.4 
0.865 
26 
0.5 
0.983 
19.4 
0.5 
0.1 
0.055 
48.6 
0.2 
0.069 
48.2 
0.3 
0.247 
43.7 
0.4 
0.694 
31.7 
0.5 
0.96 
21 
0.65 
0.1 
0.009 
50 
0.2 
0.016 
49.6 
0.3 
0.204 
44.8 
0.4 
0.676 
32.4 
0.5 
0.958 
21.2 
 
If the trial in one group continues until 50 patients are evaluated, and assuming the 
overall response rate is 50%, then the 95% credible interval for overall response 
rate would be (0.36, 0.64). 
 
 
B: Cohort 2B – FLT3-WT 
 
Up to 50 patients FLT3-WT will be treated AC220 + 5-azacytidine. The primary 
objective is to determine the over response. In a recent phase 2 study, we 
observed a single agent AC220 response of 30% in a salvage setting. We would 
like to have a 15% improvement (i.e. response rate of 45%) under the 
combination treatment in this study.  
 
The study will also monitor futility and safety for this cohort.  Monitoring will 
begin when 15 patients have been enrolled in that group, and thereafter by a 
cohort of 5 patients. The trial in this cohort will be stopped early if at any time 
point the data in that group suggest  
 
Pr (PE < 0.15 + PS  | data) > 0.98 or 
Pr(θE > 0.30 | data)  >0.9 
 

2012-1047 
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Page 42 of 48 
Where PE and PS  denote the response rate for experimental and standard 
treatment, respectively, and θE denotes the toxicity rate for the experimental 
treatment combination. Assume PE ~ prior beta(0.6, 1.4) and θE ~ prior beta(0.6, 
1.4). 
 
That is, the trial in this cohort will be stopped early for futility if the data indicate 
that there is more than 98% probability that the response rate is not improved by 
15% or the trial will be stopped early for toxicity if the data indicate that there is 
more than 90% probability that the toxicity rate (i.e. DLT rate) is more than 30%.  
The corresponding stopping boundaries for futility is: the trial in this cohort will 
be stopped early if (the number of response observed / among number of patients) 
in this cohort  ≤ 3/15, 4/20, 6/25, 8/30, 10/35, 11/40 and 13/45.  
 
The corresponding stopping boundaries for toxicity is: The trial will be stopped 
early in this cohort if (the number of patients experienced DLTs / among number 
of patients) in this cohort ≥ 8/15, 9/20, 11/25, 13/30, 15/35, 16/40 and 18/45. 
 
Table 3 presents the operating characteristics for the above design. 
 
Table 3: OCs for the design for cohort 2B 
Response 
rate 
Toxicity rate 
Probability of early 
stopping 
Average number of 
patients 
0.3 
0.1 
0.64 
33 
0.3 
0.3 
0.72 
30.6 
0.3 
0.5 
0.99 
18.8 
0.45 
0.1 
0.08 
47.8 
0.45 
0.3 
0.27 
43 
0.45 
0.5 
0.96 
20.9 
0.6 
0.1 
0.002 
49.9 
0.6 
0.3 
0.21 
44.8 
0.6 
0.5 
0.96 
21.2 
 
If the trial in one group continues until 50 patients are evaluated, and assuming the 
overall response rate is 45%, then the 95% credible interval for overall response 
rate would be (0.31, 0.58). 
 
 
12.4 
Analysis Plan: 
 
For discrete or categorical data, descriptive statistics will include tabulations of 
frequencies.  For continuous data, summary statistics including n, mean, standard 
deviation, median, minimum and maximum will be computed.  The posterior 
response rate and its 95% credible intervals will be estimated. 
 

2012-1047 
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Page 43 of 48 
Page 43 of 48 
13.0 
PROTOCOL ADMINISTRATION 
 
Protocol amendments 
 
Changes to the protocol will be made only when protocol amendments have been signed 
by the principal investigator and approved by the sponsor and the IRB of the study center. 
 
Archival of data 
 
All patient data (including source data) generated in connection with this study will be kept 
in the archives of the MDACC for at least 15 years after the study has been completed. All 
data will be available for inspection by company representatives of the Medical 
Department and by regulatory authorities. 
 
14.0 
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40. Ueno M, Katayama K, Yasoshima A, Nakayama H, Doi K. 5-Azacytidine (5AzC)-
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42. Pharmion Corporation. Azacitidine Investigator's Brochure, Edition 5. Boulder, CO; 
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43. Marcucci G, Silverman L, Eller M, Lintz L, Beach CL. Bioavailability of azacitidine 
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44. Von Hoff DD, Slavik M, Muggia FM. 5-Azacytidine. A new anticancer drug with 
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45. Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with 
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46. Fenaux P, Mufti G, Santini V, et al. Azacitidine (AZA) treatment prolongs overall 
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48. Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-
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Appendix AA – Schedule of Events* 
 
Assessment 
Pre-Treatment 
Evaluation (procedures  
to be performed within 
14 days prior to study 
drug administration 
except where indicated) 
Cycle 1 and 2 - 
Day 1 (+/- 5 days), 
then every 2-3 
cycles until end of 
Month 6 
Once weekly 
during Cycles 1-3, 
then every 2-4 
weeks until end of 
Month 6 (all ±2 
days)   
Cycle 1 Day 28 
(+/- 7 days), then 
every 1-3 cycles 
until end of 
Month 6 
Cycle 1-4, 
Days 1, 8, 
and 15 (all 
±2 days)   
Complete 
Historya 
X 
 
 
 
 
Physical 
Examination 
X 
X 
 
 
 
Concomitant 
Medications 
X 
X 
 
 
 
Performance 
Status 
X 
 
 
 
 
CBC, Platelet 
Count, 
Differentialb 
X 
 
 
X 
 
 
Serum 
Chemistry 
XC 
 
Xj 
 
 
Urine or Serum 
Pregnancy Test 
(WCBP)d 
X 
 
 
 
 
Bone Marrow 
Aspiration 
Xe 
 
 
X 
 
FLT3 
Evaluationf 
X 
 
 
 
 
EKG, ECHO, 
and/or MUGAg 
X 
 
 
 
 
Correlative 
Studiesh 
X 
 
 
 
X 
Drug 
Administration 
Diary 
 
Xi 
 
 
 
EKG 
 
Xk 
 
 
 
 
* For patients that remain on study with no significant toxicity for more than 6 months, subsequent evaluations during study may be modified 
after discussion with the principal investigator.  These include a decrease in frequency of standard laboratory tests to once every cycle, bone 
marrow aspirations to every 6-12 months (or as clinically indicated). 
 
a documentation of all measureable disease  
b differential can be omitted if WBC is ≤ 0.5x109/L 
c creatinine, total bilirubin, ALT, potassium, magnesium, calcium, sodium, chloride, CO2, uric acid, phosphorus, BUN 
d 48 hours before initiation of study 
e during the last 14 21 days preceding study initiation. Cytogenetics will be obtained prior to therapy (results from prior analysis can be used for 
this purpose) 
f if not done within 90 days, provided there has been no intervening therapy other than hydroxyurea or isolated single-agent doses of cytarabine. 
g before initiating study treatment if not done within 28 days 
h see Protocol Section 8.0 

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i drug administration of self-administered drugs (cytarabine and AC220) 
j creatinine, total bilirubin, ALT, K, Mg, Ca, sodium, chloride, and CO2; on day 5 prior to start of AC220 and on day 6 as clinically indicated 
k EKG will be performed on day 1, day 5, day 8, and day 12  of the first cycle (all ±2 days) Day 1 and day 8 ECG are collected pre-dose; day 5 
are collected pre-dose and 4 hrs (+/- 2 hrs) post-dose; day 12 are collected 4 hrs (+/- 2 hrs) post-dose. Then ECG to be done on day 1 of each 
cycle for cycles 2 and 3 before initiation of quizartinib and 4 hr (+/-2 hrs) post dose, then pre-dose every 2-3 cycles.   EKG may be omitted if 
patient has not received study drug (AC220) in the 48 hrs preceeding the time when EKG is done.  EKG for the first 3 cycles will be done in 
triplicate.  Day 5 pre AC-220 will be used as baseline.