Clinical trial NCT01876953
Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia
Sponsor: City of Hope Medical Center
Start date: 2013-09-13; Completion date: 2018-04-25
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase I/II trial studies the side effects and best dose of dasatinib when given together with cytarabine and idarubicin hydrochloride and to see how well they work in treating patients with acute myeloid leukemia that is likely to come back or spread. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and idarubicin hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving dasatinib together with cytarabine and idarubicin hydrochloride may be a better treatment for acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. Of the dose levels studied, to determine the maximum tolerated dose of dasatinib when given in combination with cytarabine and idarubicin for treatment of high risk acute myeloid leukemia (AML). (Phase I)

II. To determine the anti-tumor activity of dasatinib when given in combination with cytarabine and idarubicin, as assessed by complete remission rate (CR) and remission duration. (Phase II)

SECONDARY OBJECTIVES:

I. To document CR and survival outcomes (overall, event-free). (Phase I)

II. To estimate the survival probabilities (overall and event-free) and cumulative incidence of relapse/progression. (Phase II)

III. To describe and summarize all toxicities by organ and severity. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of dasatinib, followed by a phase II study.

Patients receive cytarabine intravenously (IV) continuously over 168 hours on days 1-7, dasatinib orally (PO) once daily (QD) on days 1-7, and idarubicin hydrochloride IV on days 1-3. Patients with non-responsive disease on day 30 may receive a second course of therapy (re-induction therapy) within 1 week in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 2 months for up to 2 years.

Arms: arm 1: Patients receive cytarabine IV continuously over 168 hours on days 1-7, dasatinib PO QD on days 1-7, and idarubicin hydrochloride IV on days 1-3. Patients with non-responsive disease on day 30 may receive a second course of therapy (re-induction therapy) within 1 week in the absence of unacceptable toxicity. arm 2: Patients receive cytarabine IV continuously over 168 hours on days 1-7, dasatinib PO QD on days 1-7, and idarubicin hydrochloride IV on days 1-3. Patients with non-responsive disease on day 30 may receive a second course of therapy (re-induction therapy) within 1 week in the absence of unacceptable toxicity.
Interventions: intervention 1: cytarabine intervention 2: idarubicin intervention 3: dasatinib intervention 4: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB Protocol No. 12393 
 
Version Date 01/22/2016 
Version: 4 
CITY OF HOPE MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HCT                                                                 
 
TITLE: Phase I/II study of the combination of Dasatinib with chemotherapy for high risk acute myeloid 
leukemia (AML) patients 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 12393  
 
VERSION: 4.0  
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
COH Initial (dated 07/17/2013) 
Version: 0.0 
COH Amendment v 1.0 (dated 10/04/2013) 
Version: 1.0    
COH Amendment v 2.0 (dated 03/20/2014) 
 Version: 2.0    
COH Amendment v 3.0 (dated 07/07//2014) 
Version: 3.0 
COH Amendment v 4.0 (dated 01/22/2016) 
 Version: 4.0 
 
 
 
DISEASE SITE: 
Bone Marrow/Blood 
 
 
 
 
 
STAGE (If applicable): 
 
 
 
AML   
 
 
 
MODALITY:  
 
 
 
 
Chemotherapy 
 
 
 
 
TYPE:  
 
 
 
 
 
Phase I/II 
 
PRINCIPAL INVESTIGATOR: 
 
 
Ahmed Aribi, M.D 
 
 
COLLABORATING INVESTIGATOR(S): 
 
Anthony Stein, M.D. 
 
 
PARTICIPATING CLINICIANS: 
 
 
Monzr Al Malki, M.D., Ibrahim Aldoss, M.D., Haris Ali, M.D., 
Elizabeth Budde, M.D., Ji-Lian Cai, M.D., PhD, Thai Cao, 
M.D., Robert Chen, M.D., Len Farol, M.D., Stephen Forman, 
M.D., Alex Herrera, M.D., Myo Htut, M.D.,  Chatchada 
Karanes, M.D., Samer Khaled, M.D., Amrita Krishnan, M.D., 
Guido Marcucci, M.D., Matthew Mei, M.D., Auayporn 
Nademanee, M.D., Ryotaro Nakamura, M.D., Nitya Nathwani, 
M.D., Margaret O’Donnell, M.D., Pablo Parker, M.D., Leslie 
Popplewell, M.D.,  Vinod Pullarkat, M.D., Michael 
Rosenzweig, M.D., Firoozeh Sahebi, M.D., Amandeep 
Salhotra, M.D., Tanya Siddiqi, M.D., Eileen Smith, M.D., 
David Snyder, M.D., Ricardo Spielberger, M.D., Jasmine 
Zain, M.D. 
 
STUDY STATISTICIAN: 
                                  Joycelynne M. Palmer, PhD 
 
 
 
 
 
 
 
 
PARTICIPATING SITES:                                         City of Hope 


Page 2 of 45 
IRB Protocol No. 12393 
 
Version Date:  07/07/2014 
Version:  3.0 
Investigators 
 
PRINCIPAL INVESTIGATOR: 
Ahmed Aribi, MD 
 
City of Hope National Medical Center 
 
1500 E. Duarte Road 
Duarte, CA 91010 
 
Phone: (626) 256-4673 x 62405 
 
Fax: 
(626) 301-8116 
 
e-mail: aaribi@coh.org 
 
 
STUDY STATISTICIAN: 
Joycelynne M. Palmer, PhD   
 
City of Hope National Medical Center  
 
1500 E. Duarte Road, Bldg 171, Office 1006 
Duarte, CA 91010 
 
Phone: (626) 256-4673 x 65266 
 
Fax: 
(626) 471-7106 
 
e-mail: jmpalmer@coh.org 
 
 
 
 
COLLABORATING  INVESTIGATORS: 
 
Ravi Bhatia, M.D. 
City of Hope National Medical Center 
Anthony Stein, M.D. 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
1500 E. Duarte Road 
Duarte, CA 91010 
Phone: (626) 256-4673 x62705 
Phone: (626) 256-4673 x62705 
Fax: 
(626) 301-8973 
Fax: 
(626) 301-8973 
e-mail: rbhatia@coh.org 
e-mail: astein@coh.org 
 
 
 
 
 
 
 
 
 
AGENT NSC# AND IND#: 
 
N/A 
 
COORDINATING CENTER: 
City of Hope National Medical Center  
 
 


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IRB Protocol No. 12393 
 
Version Date:  07/07/2014 
Version:  3.0 
Experimental Design Schema 
Induction Phase 
 
Screening 
Study Treatment Phase 
Post Study 
Treatment 
Phase  
Follow Up  
Day of Cycle 
Day -14 to Day 0 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 to D28 
Up two years 
Treatment with 
Cytarabine 
200mg/m2 /day 
  
X 
X 
X 
X 
X 
X 
X 
  
  
Treatment with 
Idarubicin  
12mg/m2 /day 
  
X 
X 
X 
  
  
  
  
  
  
Treatment with 
Dasatinib* 
  
X 
X 
X 
X 
X 
X 
X 
  
  
*Dasatinib dose pending to cohort assigment  
Re-Induction Phase# 
  
Study treatment Phase 
Post Study 
Treatment Phase  
Follow Up  
Day of Cycle 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 to D28 
Up two years 
Treatment with 
Cytarabine  
200mg/m2 /day 
X 
X 
X 
X 
X 
X 
X 
  
  
Treatment with 
Idarubicin 
12mg/m2 /day  
X 
X 
X 
  
  
  
  
  
  
Treatment with 
Dasatinib* 
X 
X 
X 
X 
X 
X 
X 
  
  
*Dasatinib dose pending to cohort assigment  
# Re-induction therapy will start within one week after day 30 bone marrow. 
 
 


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IRB Protocol No. 12393 
 
Version Date:  07/07/2014 
Version:  3.0 
Protocol Synopsis 
Protocol Title: 
PHASE I/II STUDY OF THE COMBINATION OF DASATINIB WITH CHEMOTHERAPY 
FOR HIGH RISK ACUTE MYELOID LEUKEMIA (AML) PATIENTS 
Brief Protocol Title for the Lay Public (if applicable): 
COMBINATION OF DASATINIB WITH CHEMOTHERAPY FOR HIGH RISK ACUTE 
MYELOID LEUKEMIA 
Study Phase: 
I/II 
Participating Sites: 
City of Hope 
Rationale for this Study: 
AML is the most common acute leukemia in adults and accounts for approximately 80% 
of cases, with a median age at diagnosis of approximately 65 years. While standard 
induction chemotherapy (anthracycline plus cytarabine) produces a 50-75% complete 
remission rate, only a small percentage of younger patients (<60y) achieve a durable 
remission; the majority of AML patients eventually relapse and die from recurrent 
disease. AML patients with poor risk cytogenetics, elderly patients with AML, AML 
secondary to myelodysplasia or myeloproliferative disorder, and therapy-related AML, 
have an even worse prognosis, with even lower complete remission rates and long-term 
survival despite aggressive chemotherapy. Clearly there is a need to improve the outcome 
of poor risk AML patients. 
Tyrosine kinases play an important role in AML pathogenesis. Pre-clinical studies 
performed at our center have shown that Src family tyrosine kinases (SFKs) including 
Lyn, Hck and Fgr are abnormally activated in AML compared to normal hematopoietic 
stem and progenitor cells. Other studies show that the c-Kit receptor tyrosine kinase is 
often overactivated in AML and contributes to abnormal growth. The small molecule 
SFK and c-Kit inhibitor Dasatinib reduces proliferation and survival of AML stem and 
progenitor cells. Importantly, Dasatinib treatment enhances sensitivity of AML 
stem/progenitor cells to chemotherapeutic agents, through inhibition of Akt signaling and 
activation of p53. These results provide a strong rationale to conduct a clinical study to 
determine the safety and tolerability of combination of Dasatinib with AML standard 
chemotherapy and its effect on complete remission (CR) rate, overall survival (OS) and 
event free survival (EFS). 
Objectives: 
1. Phase I Objectives:  
1.1. Primary: Of the dose levels studied, to determine the maximum tolerated dose 
of dasatinib when given in combination with cytarabine and idarubicin for 
treatment of high risk AML. The selected dose will be used in the phase II study. 
To describe the safety, tolerability, and toxicity profile of Dasatinib, given in 
combination with cytarabine and idarubicin.  
1.2. Secondary: To document complete remission rate (CR) and survival outcomes 


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IRB Protocol No. 12393 
 
Version Date:  07/07/2014 
Version:  3.0 
(overall, event-free).  
 
2. Phase II Objectives:  
2.1. Primary: To determine the anti-tumor activity of Dasatinib given in combination 
with cytarabine and idarubicin, as assessed by complete remission rate (CR) and 
remission duration.  
2.2. Secondary: i) To estimate the survival probabilities (overall and event-free) and 
cumulative incidence of relapse/progression incidence. ii) To describe, 
summarize all toxicities by organ and severity.  
Study Design: 
 Phase I  
The study design is based on a standard 3 + 3 dose escalation design.  
 
Dose level 1 will be the first dose level tested. Initially three subjects will be treated, if 
0/3 experiences a dose limiting toxicity (DLT), enter 3 subjects at dose level 2. If 1/3 of 
the first 3 subjects has DLT, enter 3 more subjects at dose level 1. If none of these 3 
additional subjects has DLT, then proceed to dose level 2. If one or more of these 3 
additional subjects has DLT, then a dose reduction (to dose level -1) will be applied.  
 
Among the patients treated at dose level 2, if 0/3 or 1/3 of the first 3 subjects experiences 
DLT, enter 3 more subjects at dose level 2. If ≤ 1/6 subjects on dose level 2 have DLT, 
dose  level 2 will be declared the phase II dose (P2D). If ≥ 2/6 subjects have DLT at dose 
level 2, dose level 1 will be declared the P2D, assuming at least six patients have been 
treated at dose level 1 and ≤ 1/6 subjects has DLT.  
 
Assuming a dose reduction is necessary, among the patients treated at dose level -1, if 0/3 
or 1/3 on the first 3 subjects has DLT, enter 3 more subjects at dose level -1. If ≤ 1/6 
subjects treated on dose level -1 has DLT, dose level -1 will be declared the P2D. If ≥ 2/6 
subjects have DLT on dose level -1, then the study will be terminated.  
  
Dose Level 
Cytarabine* 
Idarubicin# 
Dasatinib^ 
-1 
200mg/m2 
12mg/m2 
70mg/day 
1 
200mg/m2 
12mg/m2 
100mg/day 
2 
200mg/m2 
12mg/m2 
140mg/day 
*: IV QD, days 1-7 
#: IV QD, days 1-3 
^: PO QD, days 1-7 
The phase I study is expected to enroll 9-18 evaluable (a maximum of 18) patients. 
Toxicities will be monitored, graded, and recorded according to the NCI-Common 
Terminology Criteria for Adverse Events version 4.0.   
Dose limiting toxicity is defined as any of the toxicities listed below that occur from the 
first dose of dasatinib through the DLT observation period discussed below. Patients 
must not have persistent leukemia after induction to be considered evaluable for DLTs 
associated with hematologic toxicity. Patients who have persistent leukemia are still 
potentially evaluable patients for safety and cohort advancement based on the non-


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IRB Protocol No. 12393 
 
Version Date:  07/07/2014 
Version:  3.0 
hematologic DLT criteria below.  
Hematologic Toxicities:  
For patients without persistent leukemia following induction:  
Grade 4 hematological toxicity persisting >42 days following the last dose of dasatinib 
(i.e., Day 49) not attributable to persistent leukemia with exclusion of chronic cytopenia 
attributed to preexistent condition such as MDS, MPN, and MF.  
Non-Hematologic Toxicities:  
For all patients, within the first 28 days: 
Any grade 3 or higher non-hematologic toxicity, excluding:  
 Anorexia, fatigue, uric acid, fever with or without neutropenia, or bleeding during a 
period of Grade 4 thrombocytopenia   
 Diarrhea, nausea, abdominal bloating, vomiting or mucositis that resolves to ≤ Grade 
1 or to baseline within 7 days of onset with optimal medical management  
 Elevated AST, ALT, alkaline phosphatase, or bilirubin that returns to ≤ Grade 2 or to 
baseline within 14 days of onset  
 Rash or elevated amylase or lipase that returns to ≤ Grade 2 or to baseline within 7 
days of onset  
 Infections or complications of infections due to neutropenia  
 Electrolyte disturbance that can be corrected with supplementation within 10 days.  
Any grade 5 toxicity not due to disease, will be considered a DLT. 
 
As of 7/7/14, nine patients have been treated and are evaluable for toxicity evaluation 
(six treated at dose level 1 and three treated at dose level 2). Under the revised DLT 
definition, to ensure safety, three additional patients will be treated on dose level 1, for a 
total of nine.  
Patients must complete all 7 days of dasatinib or experience a DLT to be evaluable for 
toxicity. Phase I patients treated at the P2D will count toward the phase II trial accrual 
goal. 
 
Observed toxicities will be summarized in terms of type (organ affected or laboratory 
determination such as absolute neutrophil count) severity (by NCI CTCAE v4.0, date of 
onset, duration, reversibility, and attribution. Tables will be created to summarize these 
toxicities and side effects. Baseline information (e.g. cytogenetic risk) and demographic 
information will be presented for all study patients. While not the primary objective of 
the phase I study, a preliminary estimate of complete remission rate (CR) and remission 
duration will be reported. Survival probabilities, overall survival (OS) and event-free 
(EFS) will be estimated. 
 
Phase II  
This is a single center phase II trial to determine the anti-tumor activity of Dasatinib 
given in combination with cytarabine and idarubicin as assessed by complete remission 
rate (CR) (Cheson et al. 2003), the primary endpoint; secondary endpoints are remission 


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IRB Protocol No. 12393 
 
Version Date:  07/07/2014 
Version:  3.0 
duration, survival (overall and event-free) and toxicities. Patients with high-risk AML 
will be eligible. This study will implement a single arm SWOG Phase II two-stage design 
to study the activity of Dasatinib plus cytarabine and idarubicin (Green SJ, Benedetti J, 
and Crowely J, 1997).  
 
The phase II portion of the trial is expected to enroll a minimum of 20 and a maximum of 
40 patients. The sample size is based on the desire to discriminate a promising remission 
rate from a disappointing rate (assuming a 20% difference in the two rates) using a type I 
error rate of 0.05 and power of approximately 80%.  
 
At stage 1, 20 patients will be entered on the study (including the 6 patients treated at the 
MTD from Phase I). A 2% false-negative rate ruling out the promising CR rate will result 
in termination of the study, using the Green-Dahlberg rule. At stage 2, 20 additional 
patients will be entered. At the end of stage 2,  the CR rate must rule out the discouraging 
CR rate with a type I error of 5% to be declared a success. This design incorporates the 
Green-Dahlberg rule of 2% false – negative error rate in the first stage (Green SJ and 
Dahlberg S,1992). Accrual is expected to be complete within 18-24 months. 
Remission rates will be calculated as the percent of evaluable patients that have a 
confirmed CR, and exact 95% confidence intervals will be calculated for these estimates. 
Time to confirmed complete remission, duration of remission, and survival will be 
estimated using the product-limit method of Kaplan and Meier. Toxicity will be 
monitored on an ongoing basis. If the percentage of unacceptable toxicities exceeds 25% 
with 6 or more patients accrued, patient accrual will be halted and a full review of the 
data by the Data Safety Monitoring Committee will be mandated. Patient accrual will not 
resume until approved by the Data Safety Monitoring Committee to do so. 
Endpoints: 
Phase I: Toxicity 
Phase II: Primary-complete response rate (CR); Secondary-response duration, survival 
(overall and event-free) and toxicities. 
Sample Size: 
Phase I, Expected: 9, maximum 18 
Phase II, Expected: 40 (6 patients brought forward from Phase I trial + 34 additional) 
At stage 1, 20 patients will be entered on the study (14 newly enrolled combined with the 
6 patients treated at the MTD from Phase I for a total of 20).  
At stage 2, 20 additional patients would be entered on the study. 
Estimated Duration of the Study 
Accrual is expected to be complete within 18-24 months. Combination treatment will be 
last 1-3 months for each patient. 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
1. Patients diagnosed with AML meeting one of following criteria: 
1.1. Newly diagnosed, age 60 and older 
1.2. High risk cytogenetics and molecular abnormalities (NCCN criteria) 
1.3. Relapsed or refractory to prior chemotherapy 


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IRB Protocol No. 12393 
 
Version Date:  07/07/2014 
Version:  3.0 
1.4. Secondary AML 
2. Any prior chemo therapy must have been completed ≥2 weeks prior to day 1 of study 
treatment and the participant must have recovered to eligibility levels from prior 
toxicity.  
2.1. Only one prior regimen is allowed for relapsed AML Patients.  
2.2. Hydroxyurea is allowed prior to day 1 of study treatment to keep WBC below 20 
K.  
3. Age ≥18 years.   
4. Karnofsky performance status ≥60%.  
5. Patients must have normal organ function as defined below: 
5.1. Total bilirubin <1.5 X institutional upper limit of normal 
5.2. AST(SGOT)/ALT(SGPT)   ≤2.5 X institutional upper limit of normal 
5.3. Creatinine <1.5 X institutional upper limit of  normal  
5.4. OR Creatinine clearance ≥60 mL/min for patients with creatinine levels above 
1.5 X institutional upper limit of normal,  
5.5. EF ≥45%. 
6. Ability to understand and sign a written informed consent document. 
7. Patients should not be receiving any other investigational agents.  
Exclusion Criteria:  
1. Patients with clinically significant illnesses which would compromise participation in 
the study, including, but not limited to: active or uncontrolled infection, immune 
deficiencies or confirmed diagnosis of HIV infection, active Hepatitis B, active 
Hepatitis C, or uncontrolled diabetes, uncontrolled hypertension, symptomatic 
congestive heart failure, unstable angina pectoris, myocardial infarction within the 
past 6 months, uncontrolled cardiac arrhythmia; or psychiatric illness/social situations 
that would limit compliance with study requirements. 
2. Patients with additional (other than AML) currently active primary malignancy other 
than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the 
skin. Patients are not considered to have a "currently active" malignancy if they have 
completed therapy for a prior malignancy and disease free from prior malignancies 
for >2 years   
 
3. Patients with active central nervous system (CNS) disease.    
4. Patients with Chronic Myelogenous Leukemia (CML) in Myeloid blasts crisis. 
5. Active infections, including opportunistic infections 
6. Women of childbearing potential (WOCBP) who have a positive serum pregnancy 
test within 14 days of the first administration of oral Dasatinib.  
Investigational Product Dosage and Administration: 
Induction Chemo Therapy 
Patients will receive cytarabine 200mg/m2 /day IV continuously over 168 hours on days 


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IRB Protocol No. 12393 
 
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1-7 with idarubicin 12mg/m2  /day IV slow push days 1-3, and oral Dasatinib   (depending 
on the dose level the patient is assigned to) once daily on days 1 to 7.  
Patients who are in CR (Complete Remission) on day 30 BM undergo consolidation 
therapy, and patients with non-responsive disease on day 30 (bone marrow cellularity ≥ 
20 % and leukemia blasts ≥ 5%) receive a re-induction therapy.  
After completion of study therapy, patients will be followed every 2 months for 2 years.  
Clinical Observations and Tests to be Performed: 
Standard induction chemo-therapy tests and procedure will be used for this study  
Statistical Considerations: 
See Study Design Section 
Sponsor/Licensee: 
City of Hope National Medical Center  
Case Report Forms 
All data will be collected and submitted using electronic case report forms in Medidata Rave 
EDC. 


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IRB Protocol No. 12393 
 
Version Date:  07/07/2014 
Version:  3.0 
Table of Contents 
SECTION 
PAGE 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) ................................................................ 13 
1.1 
PHASE I OBJECTIVES: .................................................................................................................. 13 
1.1.1 Primary: .................................................................................................................................. 13 
1.1.2 Secondary: .............................................................................................................................. 13 
1.2 
PHASE II OBJECTIVES: ................................................................................................................. 13 
1.2.1 Primary Endpoints .................................................................................................................. 13 
1.2.2 Secondary Endpoints: ............................................................................................................. 13 
2.0 
BACKGROUND ........................................................................................................................... 13 
2.1 
INTRODUCTION/RATIONALE FOR DEVELOPMENT ....................................................................... 13 
2.2 
OVERVIEW OF PROPOSED STUDY ................................................................................................ 14 
2.2.1 Phase I .................................................................................................................................... 14 
2.2.2 Phase II ................................................................................................................................... 14 
2.3 
PRECLINICAL STUDIES ................................................................................................................ 15 
2.3.1 2.3.1 Dasatinib ........................................................................................................................ 15 
2.4 
HUMAN STUDIES ......................................................................................................................... 16 
2.4.1 Dasatinib ................................................................................................................................. 16 
2.4.2 Cytarabine ............................................................................................................................... 18 
2.4.3 Idarubicin ................................................................................................................................ 20 
3.0 
PATIENT ELIGIBILITY ............................................................................................................ 22 
3.1 
INCLUSION CRITERIA .................................................................................................................. 22 
3.2 
EXCLUSION CRITERIA ................................................................................................................. 22 
3.2 
INCLUSION OF WOMEN AND MINORITIES ................................................................................... 23 
4.0 
SCREENING AND REGISTRATION PROCEDURES ........................................................... 23 
4.1 
SCREENING PROCEDURES ........................................................................................................... 23 
4.2 
INFORMED CONSENT ................................................................................................................... 23 
4.3 
REGISTRATION REQUIREMENTS/PROCESS .................................................................................. 23 
4.4 
RANDOMIZATION AND/OR DOSE LEVEL ASSIGNMENT ............................................................... 23 
5.0 
TREATMENT PROGRAM ......................................................................................................... 23 
5.1 
TREATMENT OVERVIEW .............................................................................................................. 23 
5.1.1 Schedule .................................................................................................................................. 24 
5.2 
PLANNED DURATION OF THERAPY ............................................................................................. 24 
5.3 
CRITERIA FOR REMOVAL FROM TREATMENT ............................................................................. 24 
5.4 
SUBJECT FOLLOW-UP ................................................................................................................. 24 
5.5 
SUPPORTIVE CARE ...................................................................................................................... 24 
5.5.1 Supportive Care ...................................................................................................................... 24 
5.5.2 Other Concomitant Therapy ................................................................................................... 24 
5.5.3 Prohibited Medications ........................................................................................................... 26 
5.6 
ADDITIONAL LABORATORY STUDIES.......................................................................................... 27 
5.7 
DEFINITION OF DOSE-LIMITING TOXICITY (DLT) ...................................................................... 27 
6.0 
DOSE DELAYS/MODIFICATIONS FOR ADVERSE EVENTS............................................ 27 
6.1 
DOSE MODIFICATION FOR DASATINIB ......................................................................................... 27 


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6.2 
DOSE MODIFICATION FOR STANDARD CHEMO THERAPY ........................................................... 28 
7.0 
DATA AND SAFETY MONITORING ...................................................................................... 28 
7.1 
DEFINITION OF RISK LEVEL ........................................................................................................ 28 
7.2 
MONITORING AND PERSONNEL RESPONSIBLE FOR MONITORING ....... ERROR! BOOKMARK NOT 
DEFINED. 
 
7.3 DEFINITIONS ....................................................................... ERROR! BOOKMARK NOT DEFINED. 
7.3 ........................................................................................................................................................... 33 
 
REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS ...... ERROR! BOOKMARK NOT 
DEFINED. 
7.4 ........................................................................................................................................................... 33 
8.0 
STUDY AGENT INFORMATION AND RISKS....................................................................... 33 
8.1 
DASATINIB .................................................................................................................................. 33 
 
CYTARABINE ................................................................................................................................... 33 
8.2 ........................................................................................................................................................... 33 
8.3 
IDARUBICIN ................................................................................................................................. 33 
9.0 
CORRELATIVE/SPECIAL STUDIES ...................................................................................... 33 
10.0 
STUDY CALENDAR ................................................................................................................... 34 
11.0 
ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT .......................... 36 
12.0 
DATA REPORTING/PROTOCOL DEVIATIONS .................................................................. 37 
12.1 
DATA REPORTING ....................................................................................................................... 37 
12.1.1 
Confidentiality and Storage of Records .............................................................................. 37 
12.1.2 
Subject Consent Form ......................................................................................................... 37 
12.1.3 
Data Collection Forms and Submission Schedule .............................................................. 37 
12.2 
PROTOCOL DEVIATIONS .............................................................................................................. 37 
12.2.1 
Deviation Policy .................................................................................................................. 37 
12.2.2 
Reporting of Deviations ...................................................................................................... 38 
12.2.3 
Resolving Disputes .............................................................................................................. 38 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 38 
13.1 
STUDY DESIGN ............................................................................................................................ 38 
13.1.1 
Phase I ................................................................................................................................ 38 
13.1.2 
Phase II ............................................................................................................................... 39 
13.2 
SAMPLE SIZE ACCRUAL RATE .................................................................................................... 40 
13.3 
STATISTICAL ANALYSIS PLAN .................................................................................................... 40 
14.0 
HUMAN SUBJECT ISSUES ....................................................................................................... 41 
14.1 
INSTITUTIONAL REVIEW BOARD ................................................................................................. 41 
14.2 
RECRUITMENT OF SUBJECTS ....................................................................................................... 41 
14.3 
ADVERTISEMENTS ....................................................................................................................... 42 
14.4 
STUDY LOCATION AND PERFORMANCE SITES ............................................................................. 42 
14.5 
CONFIDENTIALITY ....................................................................................................................... 42 
14.6 
FINANCIAL OBLIGATIONS AND COMPENSATION......................................................................... 42 
14.7 
INFORMED CONSENT PROCESSES ................................................................................................ 42 
15.0 
REFERENCES .............................................................................................................................. 44 
 


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Abbreviations 
Abbreviation 
Meaning 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDS 
Investigational Drug Services 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
 


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1.0 
Goals and Objectives (Scientific Aims) 
1.1 Phase I Objectives:  
1.1.1 
Primary:  
Of the dose levels studied, to determine the maximum tolerated dose of Dasatinib when given in 
combination with Cytarabine and Idarubicin for treatment of high risk AML patients. The selected dose 
will be used in the Phase II study.  
1.1.2 
Secondary:  
To document complete remission rate (CR) and survival outcomes (overall, event-free).  
 
1.2 Phase II Objectives:  
1.2.1 
Primary Endpoints 
To determine the anti-tumor activity of Dasatinib when given in combination with Cytarabine and 
Idarubicin, as assessed by complete remission rate (CR) and remission duration.  
1.2.2 
Secondary Endpoints: 
To estimate the survival probabilities (overall and event-free) and cumulative incidence of relapse/ 
progression.  
To describe and summarize all toxicities by organ and severity.  
2.0 Background 
2.1 Introduction/Rationale for Development 
AML is the most common acute leukemia in adults and accounts for approximately 80% of cases, with a 
median age at diagnosis is approximately 65 years. While standard induction chemotherapy 
(anthracycline plus cytarabine) leads to a complete remission rate of roughly 50-75%, only a small 
percentage of younger patients (<60y) enjoy a durable remission. The majority of AML patients 
eventually relapse and die from recurrent disease. Newly diagnosed  elderly AML patients (>60),  poor 
risk cytogenetics, , as well as AML secondary to myelodysplasia and myeloproliferative disorders, and 
therapy-related AML, have an even worse prognosis, with even lower complete remission rates and long-
term survival despite aggressive chemotherapy. CR rates for these patient subgroups are as follows: high 
risk cytogenetics <60y, CR rate 50% Mrozek (2012); high risk cytogenetics ≥60y, CR rate 39% Mrozek 
(2012); newly diagnosed patients, aged 60 and older, CR rate 48% (41-55%) van der Holt (2005); 
secondary AML, CR rate 24% Leith (1997); relapsed/refractory CR rate 30%.Clearly there is a need to 
improve the outcome of poor risk AML patients 
Tyrosine kinases play an important role in AML pathogenesis. Pre-clinical studies performed at our 
center have shown that Src family tyrosine kinases (SFKs) including Lyn, Hck and Fgr are abnormally 
activated in Acute Myeloid Leukemia (AML) compared to normal hematopoietic stem and progenitor 
cells. Other studies show the the c-Kit receptor tyrosine kinase is often overactivated in AML and 
contributes to abnormal growth. The small molecule SFK and c-Kit inhibitor Dasatinib reduces 
proliferation and survival of AML stem and progenitor cells. Importantly, Dasatinib treatment enhances 
sensitivity of AML stem/progenitor cells to chemotherapeutic agents, through inhibition of Akt signaling 
and activation of p53. These results provide a strong rationale to conduct a clinical study to determine the 
safety and tolerability of combination of Dasatinib with AML standard chemotherapy and its effect on 
complete remission (CR) rate, overall survival (OS) and event free survival (EFS).  


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2.2 Overview of Proposed Study 
This is an open label, Phase I/II study. 
2.2.1 
 Phase I  
The study design is based on a standard 3 + 3 dose escalation design.  
 
Dose level 1 will be the first dose level tested. Initially three subjects will be treated, if 0/3 experiences a 
dose limiting toxicity (DLT), enter 3 subjects at dose level 2. If 1/3 of the first 3 subjects has DLT, enter 3 
more subjects at dose level 1. If none of these 3 additional subjects has DLT, then proceed to dose level 2. 
If one or more of these 3 additional subjects has DLT, then a dose reduction (to dose level -1) will be 
applied.  
 
Among the patients treated at dose level 2, if 0/3 or 1/3 of the first 3 subjects experiences DLT, enter 3 
more subjects at dose level 2. If ≤ 1/6 subjects on dose level 2 have DLT, dose  level 2 will be declared 
the phase II dose (P2D). If ≥ 2/6 subjects have DLT at dose level 2, dose level 1 will be declared the P2D, 
assuming at least six patients have been treated at dose level 1 and ≤ 1/6 subjects has DLT.  
 
Assuming a dose reduction is necessary, among the patients treated at dose level -1, if 0/3 or 1/3 on the 
first 3 subjects has DLT, enter 3 more subjects at dose level -1. If ≤ 1/6 subjects treated on dose level -1 
has DLT, dose level -1 will be declared the P2D. If ≥ 2/6 subjects have DLT on dose level -1, then the 
study will be terminated.  
 
Dose Level 
Cytarabine* 
Idarubicin# 
Dasatinib^ 
-1 
200mg/m2 
12mg/m2 
70mg/day 
1 
200mg/m2 
12mg/m2 
100mg/day 
2 
200mg/m2 
12mg/m2 
140mg/day 
*: IV QD, days 1-7 
#: IV QD, days 1-3 
^: PO QD, days 1-7 
The phase I study is expected to enroll 9-18 evaluable patients.  Toxicities will be monitored, graded, and 
recorded according to the NCI-Common Terminology Criteria for Adverse Events version 4.0.  Patients 
must complete all 7 days of dasatinib or experience a dose limiting toxicity (DLT) to be evaluable for 
toxicity. Patients treated during the phase I portion of the trial at the dose selected for the phase II trial 
will be counted in the phase II trial. 
Observed toxicities will be summarized in terms of type (organ affected or laboratory determination such 
as absolute neutrophil count) severity (by NCI CTCAE v4.0), date of onset, duration, reversibility, and 
attribution. Tables will be created to summarize these toxicities and side effects. Baseline information 
(e.g. cytogenetic risk) and demographic information will be presented for all study patients. While not the 
primary objective of the phase I study, a preliminary estimate of complete remission rate (CR) will be 
reported. Survival outcomes overall survival (OS), event-free (EFS)) and remission duration will be 
estimated/summarized to describe the outcome of treated patients.  
2.2.2 
Phase II 
This is a single center phase II trial to determine the anti-tumor activity of Dasatinib when given in 
combination with cytarabine and idarubicin as assessed by complete remission rate (CR), the primary 
endpoint; secondary endpoints are response duration, survival (overall and event-free) and toxicities. CR 
is noted as the objective status on 2 consecutive evaluations at least 7 days apart; the first evaluation to 
occur on day 14. Patients with high-risk AML will be eligible. This study will implement a single arm 


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SWOG Phase II two-stage design to study the activity of Dasatinib plus cytarabine and idarubicin (Green 
SJ, Benedetti J, and Crowely J, 1997). The phase II portion of the trial is expected to enroll a minimum of 
20 and a maximum of 40 patients. Accrual is expected to be complete within 18-24 months. 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the 
applicable regulatory requirements. 
2.3 Preclinical Studies 
2.3.1 
2.3.1 Dasatinib 
Current treatments for AML can induce clinical remissions, but are associated with a high likelihood of 
relapse due to persistence of leukemia stem cells (LSC). There is a pressing need for new approaches to 
eliminate LSC to improve outcomes for AML patients.  
Preliminary studies from Dr. Ravi Bhatia’s 
laboratory have shown that AML stem and 
progenitor cells display higher constitutive SRC-
family kinase (SFK) phosphorylation compared to 
their normal counterparts (Fig 1). No difference in 
SFK phosphorylation was observed between 
good, intermediate and poor cytogenetic risk 
groups, suggesting that SFKs are activated in 
AML independently of underlying cytogenetic 
abnormality.  
Dasatinib, a dual ABL-SRC inhibitor approved 
for the treatment of CML, inhibited SFK 
phosphorylation in AML stem/progenitor cells, 
and induced significant dose dependent inhibition 
of AML compared to normal CFC; within the 
range of plasma drug concentration achieved in 
patients (Fig 2). Treatment with Dasatinib 
(200nM) also resulted in reduced growth of AML 
stem cells in long-term culture-initiating cells 
(LTC-IC) assays, and a significantly greater 
increase in apoptosis and significantly greater 
proliferation inhibition in AML compared to 
normal progenitor cells.  
Figure 1. Increased SFK activity in AML LSC. A. 
Representative FACS plots for p-SFK expression. B. Increased 
p-SFK levels in AML CD34+CD38- cells. C. Similar levels of p-
SFK in good, intermediate and high risk AML cells. 
NL Lin- CD34-CD38-
SFK
control
p-Src  (Y416)
AML Lin- CD34-CD38-
SFK
contro
l
p-Src  (Y416)
Lin- CD34+ CD38-
AML Lin- CD34+CD38-
A
B
C
NL Lin- CD34-CD38-
SFK
control
p-Src  (Y416)
SFK
SFK
control
control
p-Src  (Y416)
AML Lin- CD34-CD38-
SFK
contro
l
p-Src  (Y416)
SFK
SFK
contro
l
contro
l
p-Src  (Y416)
Lin- CD34+ CD38-
AML Lin- CD34+CD38-
A
B
C
 
Figure2. Dasatinib treatment inhibits AML progenitor 
growth in vitro. Treatment with Dasatinib results in increased 
apoptosis (A), reduced colony growth (B), and reduced LTCIC 
growth (C) of AML compared to normal CD34+ cells.  


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The combination of Dasatinib (200nM) with Daunorubicin (DNR) or cytarabine (Ara-C), 
chemotherapeutic agents commonly used for 
treatment of AML, resulted in significantly greater 
inhibition of AML CD34+ cell proliferation, survival, 
and colony growth compared to chemotherapy alone 
(Fig. 3). This synergistic effect was specific to AML 
samples and was not observed for normal CD34+ 
cells. Treatment of AML CD34+ cells with Dasatinib 
plus chemotherapy resulted in significantly reduced 
long-term (12 weeks) engraftment of human AML 
cells following transplantation into immunodeficient 
mice, indicating significantly enhanced inhibition of 
AML LSC. In addition, in vivo administration of 
Dasatinib in combination with chemotherapeutic 
agents in a genetic AML mouse model enhanced 
elimination of primary AML cells, including AML 
LSC capable of regenerating leukemia in secondary 
recipients. The combination of Dasatinib with DNR 
or Ara-C did not inhibit long term engraftment of 
normal HSC compared to DNR and Ara-C alone. 
Studies of underlying mechanisms show that the 
combination of Dasatinib with DNR enhances p53 
activity in AML cells by inhibiting AKT mediated 
MDM2 phosphorylation. These results indicate that 
c-Kit and SFK inhibition with Dasatinib significantly 
enhances the killing of AML LSC by 
chemotherapeutic agents, while sparing normal stem/ 
progenitor cells and provide a strong rationale for the 
proposed clinical trial of Dasatinib in combination 
with chemotherapy in high-risk AML patients. 
 
 
2.4 Human Studies 
2.4.1 
 Dasatinib 
Dasatinib (BMS-354825, Sprycel®; Bristol Myers Squibb, New York, NY, USA) is a potent, second-
generation, small-molecule, multi-target kinase inhibitor of BCR-ABL. This agent exerts greater in vitro 
activity against non-mutated ABL kinase than imatinib. Dasatinib was initially developed as an inhibitor 
of the Src family of kinases such as Fyn, Yes, Src, and Lyk, but it also inhibits BCR-ABL, EphA2, 
platelet-derived growth factor receptor, and c-Kit. \Dasatinib can inhibit the proliferation and kinase 
activity of wild-type and BCR-ABL mutant cell lines that are resistant to imatinib, except those carrying 
the T315I mutation. In vivo studies have shown that Dasatinib is 325-fold more potent than imatinib and 
16-fold more potent than nilotinib, another BCR-ABL kinase inhibitor, against non-mutated BCR-ABL. 
In murine models Dasatinib was shown to inhibit leukemic cell growth and to prolong the survival of 
mice harboring wild-type BCR-ABL and M351T, but not the T315I mutant. Dasatinib is a dual-specific 
Src and Abl inhibitor that can inhibit both the active and inactive conformations of ABL. In June 2006, 
the Food and Drug Administration approved Dasatinib for the treatment of chronic phase, accelerated 
phase, or blastic phase CML, resistant or intolerant to imatinib, and for Ph chromosome-positive acute 
lymphoid leukemia that was resistant or intolerant to prior therapy.  
 
 
Figure 
3. 
Dasatinib 
treatment 
enhances 
targeting of AML stem/progenitor cells by 
chemotherapy. Treatment of AML CD34+ cells 
with a combination of Dasatinib with DNR and Ara-
C results in (A) reduced proliferation, (B) increased 
apoptosis, (C) reduced colony growth, and (D) 
reduced engraftment in immunodeficient NSG 
mice, compared to chemotherapy or Dasatinib 
alone. 


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2.4.1.1 Mechanism of action 
Dasatinib binds to the ATP-binding site of ABL, but extends in the opposite direction from imatinib. 
Dasatinib binds the inactive and active conformation of the ABL kinase domain, requires fewer contact 
points with ABL, and has a greater affinity to the ABL kinase domain compared to imatinib. In vitro, 
Dasatinib has demonstrated greater than 325-fold activity against BCR-ABL wild-type, and the kinase 
activity of 14 of 15 BCR-ABL imatinib-resistant isoforms has been successfully inhibited at nanomolar 
concentrations of Dasatinib. The activity of Dasatinib against several ABL kinase mutations is explained 
by the fact that it does not require interaction with some of the residues involved in those mutations. 
Dasatinib’s inhibiting potential against Src family kinase members is greater (IC50 0.5 nmol/L) than its 
inhibitory activity against ABL (1 nmol/L). At nanomolar concentrations, Dasatinib also inhibits c-KIT, 
platelet-derived growth factor receptor and EphA2. Dasatinib was also shown to significantly suppress 
CML colony-forming cells and long-term culture-initiating cells, but it did not significantly alter the level 
of apoptosis-regulating proteins in CML CD34 + cells. Therefore, Dasatinib suppresses progenitor growth 
through inhibition of proliferation and a modest increase in apoptosis in dividing progenitors.  In addition, 
Dasatinib did not enhance suppression and targeting of CML primitive and committed progenitors.  
2.4.1.2 Pharmacokinetics 
Dasatinib is administered orally and peaks from 0.5 to 6 hours after oral dosing. Its half-life is 3 to 5 
hours and the absorption is not affected by food intake. Dasatinib is metabolized by the cytochrome P450 
(CYP) 3A4 isozyme into active and inactive metabolites. Therefore, concomitant use of Dasatinib with 
inducers of CYP3A4 can decrease Dasatinib exposure, whereas inhibitors of the 3A4 enzyme, such as 
antiretrovirals, azole antifungals and macrolides, can increase the toxicity of Dasatinib. Recent data 
suggest that Dasatinib given orally crosses the blood–brain barrier. The concentrations of Dasatinib found 
in the cerebrospinal fluid of patients ranged from 1.4 to 20.1 nM, and were consistent with the observed 
antitumor activity in the central nervous system. The elimination of Dasatinib is primarily via the feces. 
The concomitant use of H2 blockers and proton pump inhibitors is not recommended since the solubility 
of Dasatinib depends on intestinal pH, and therefore, anti-acid agents reduce the concentration of 
Dasatinib by approximately 60%. No clinically relevant data are available for dose modifications based 
on age, gender or ethnicity, although patients greater than 65 years showed increased fluid retention over 
younger patients. More importantly, the efficacy of Dasatinib appears to be independent of patient age. 
2.4.1.3 Toxicity 
Dasatinib is generally well tolerated. The most common non-hematologic adverse events in clinical trials 
with Dasatinib included gastrointestinal symptoms, such as diarrhea, nausea, vomiting, anorexia, 
abdominal pain and anorexia; headache; peripheral edema; and pleural effusion. Fewer than 10% of 
patients reported mucositis, stomatitis, abdominal distention, constipation, colitis, dysphagia, anal fissure, 
upper gastrointestinal ulcers, pancreatitis and esophagitis. Pleural and pericardial effusion, severe 
pulmonary edema, pulmonary hypertension, and ascites were less common. Ascites and pleural effusion 
are usually reversible with temporary dose interruption, diuretics and steroids. 
Myelosuppression is common and it is reversible by interruption, reduction or discontinuation of the 
myelosuppression-inducing Dasatinib dose. Grade 3–4 myelo-suppression is more frequent in patients 
with accelerated or blastic phase CML and constitutes the most common reason for drug interruption. 
Thrombocytopenia is more significant than neutropenia and its associated rates of gastrointestinal 
bleeding and central nervous system hemorrhage are <4% and <1%, respectively, whereas the rate of 
other severe hemorrhages is approximately 2%. Dasatinib-induced thrombocytopenia associated with 
hemorrhagic complications suggests that patients receiving anticoagulation or antiplatelet agents should 
be treated with caution. 
Cardiac adverse events are infrequent and include left ventricular dysfunction, cardiac failure, 
cardiomyopathy, ventricular failure, diastolic dysfunction, and QT-interval prolongation. Skin sequelae 


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include erythema, erythema multiforme, pustular rash, pruritic rash, skin exfoliation, skin irritation, 
systemic lupus erythematous, vesicular rash, and maculopapular rash. Fewer than 10% of patients develop 
acne, alopecia, skin ulcer, pigmentation disorder, panniculitis, photosensitivity, nail disorders, and palmar 
plantar erythrodysesthesia. 
The use of Dasatinib is also associated with hypocalcemia, hypophosphatemia, transaminitis and 
creatinine elevation. Symptoms from the central nervous system are noted in <10% of patients and 
include neuropathy, dizziness, dysgeusia, somnolence, tremor, syncope, transient ischemic attack, 
cerebrovascular disease and seizures. Other toxicities include hypersensitivity, gynecomastia, irregular 
menses, vertigo, appetite disturbances, increased triglycerides, cholesterol, pyrexia and fatigue. 
2.4.1.4 Dasatinib and Chemotherapy Combinations 
Ravandi and colleagues examined the efficacy and safety of combining chemotherapy with 
Dasatinib for patients with newly diagnosed Ph+ ALL. Patients received Dasatinib 100 mg 
daily for the first 14 days of each cycle of alternating hyper-CVAD, and high-dose cytarabine 
and methotrexate, for 8 cycles, and patients achieving CR received maintenance Dasatinib, 
vincristine and prednisone for 2 years, followed by Dasatinib indefinitely. Of 35 patients 
(median age of 53 years, range, 21-79 years) treated, 33 patients (94%) achieved complete 
CR. Grade 3 and 4 adverse events included hemorrhage and pleural and pericardial effusions. 
The estimated 2-year survival was 64%. These results indicate that the combination of 
chemotherapy with Dasatinib is safe and potentially effective in patients with newly 
diagnosed Ph+ ALL. 
2.4.2 
Cytarabine 
Cytarabine for Injection USP, commonly known as ara-C, an antineoplastic for intravenous, 
intrathecal, or subcutaneous administration, contains sterile lyophilized cytarabine (1-ß-D-
Arabinofuranosylcytosine). Cytarabine is an odorless, white to off-white, crystalline powder 
which is freely soluble in water and slightly soluble in alcohol and in chloroform. Cytarabine 
is a synthetic nucleoside which differs from the normal nucleosides cytidine and 
deoxycytidine in that the sugar moiety is arabinose rather than ribose or deoxyribose. 
 
2.4.2.1 Cell Culture Studies 
 
Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase 
specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions 
blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is 
not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A 
limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported.  
Extensive chromosomal damage, including chromatoid breaks, has been produced by cytarabine, 
and malignant transformation of rodent cells in culture has been reported. Deoxycytidine 
prevents or delays (but does not reverse) the cytotoxic activity. 
2.4.2.2 Cellular Resistance and Sensitivity 
Cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to the nucleotide 
triphosphate, an effective inhibitor of DNA polymerase; it is inactivated by a pyrimidine nucleoside 
deaminase, which converts it to the nontoxic uracil derivative. It appears that the balance of kinase and 


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deaminase levels may be an important factor in determining sensitivity or resistance of the cell to 
cytarabine. 
2.4.2.3 Human Pharmacology 
Cytarabine is rapidly metabolized and is not effective when taken orally; less than 20% of the orally 
administered dose is absorbed from the gastrointestinal tract. 
Following rapid intravenous injection of cytarabine labeled with tritium, the disappearance from 
plasma is biphasic. There is an initial distributive phase with a half-life of about 10 minutes, 
followed by a second elimination phase with a half-life of about 1 to 3 hours. After the 
distributive phase, more than 80% of plasma radioactivity can be accounted for by the inactive 
metabolite 1-ß-D-Arabinofuranosyluracil (ara-U). Within 24 hours, about 80% of the 
administered radioactivity can be recovered in the urine, approximately 90% of which is excreted 
as ara-U. 
Relatively constant plasma levels can be achieved by continuous intravenous infusion. 
After subcutaneous or intramuscular administration of cytarabine labeled with tritium, peak 
plasma levels of radioactivity are achieved about 20 to 60 minutes after injection and are 
considerably lower than those after intravenous administration. 
Cerebrospinal fluid levels of cytarabine are low in comparison to plasma levels after single 
intravenous injection. However, in one patient in whom cerebrospinal levels were examined after 
2 hours of constant intravenous infusion, levels approached 40% of the steady-state plasma level. 
With intrathecal administration, levels of cytarabine in the cerebrospinal fluid declined with a 
first-order half-life of about 2 hours. Because cerebrospinal fluid levels of deaminase are low, 
little conversion to ara-U was observed. 
2.4.2.4 Adverse Reactions 
2.4.2.4.1 
Expected Reactions 
Because cytarabine is a bone marrow suppressant, anemia, leukopenia, thrombocytopenia, 
megaloblastosis, and reduced reticulocytes can be expected as a result of administration of cytarabine. 
The severities of these reactions are dose and schedule dependent. Cellular changes in the morphology of 
bone marrow and peripheral smears can be expected. 
Following 5-day constant infusions or acute injections of 50 to 600 mg/m2, white cell depression 
follows a biphasic course. Regardless of initial count, dosage level, or schedule, there is an initial 
fall starting the first 24 hours with a nadir at days 7 to 9. This is followed by a brief rise which 
peaks around day 12. A second and deeper fall reaches nadir at days 15 to 24. Then there is a 
rapid rise to above baseline in the next 10 days. Platelet depression is noticeable at day 5 with a 
peak depression occurring between days 12 to 15. Thereupon, a rapid rise to above baseline 
occurs in the next 10 days. 
2.4.2.4.2 
Infectious Complications 
Infection - Viral, bacterial, fungal, parasitic, or saprophytic infections, in any location in the body may be 
associated with the use of cytarabine alone or in combination with other immunosuppressive agents 
following immunosuppressant doses that affect cellular or humoral immunity. These infections may be 
mild, but can be severe and at times fatal. 


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2.4.2.4.3 
The Cytarabine (Ara-C) Symdrome 
A cytarabine syndrome has been described by Castleberry. It is characterized by fever, myalgia, bone 
pain, occasionally chest pain, maculopapular rash, conjunctivitis, and malaise. It usually occurs 6 to 12 
hours following drug administration. Corticosteroids have been shown to be beneficial in treating or 
preventing this syndrome. If the symptoms of the syndrome are deemed treatable, corticosteroids should 
be contemplated, as well as continuation of therapy with cytarabine. 
2.4.2.4.4 
Most Frequent Adverse Reactions 
anorexia 
hepatic dysfunction 
nausea 
fever 
vomiting 
rash 
diarrhea 
thrombophlebitis 
oral and anal inflammation 
or ulceration 
bleeding (all sites) 
Nausea and vomiting are most frequent following rapid intravenous injection. 
2.4.3 
Idarubicin 
IDAMYCIN® (idarubicin hydrochloride for injection, USP) is a sterile, semi-synthetic antineoplastic 
anthracycline for intravenous use. Chemically, idarubicin hydrochloride is 5,12-Naphthacenedione, 9-
acetyl-7-[(3-amino-2,3,6 trideoxy-α-L-lyxohexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,9,11-
trihydroxyhydrochloride, (7S-cis). 
2.4.3.1 Mechanism of Action 
Idarubicin hydrochloride is a DNA-intercalating analog of daunorubicin which has an inhibitory effect on 
nucleic acid synthesis and interacts with the enzyme topoisomerase II. The absence of a methoxy group at 
position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an 
increased rate of cellular uptake compared with other anthracyclines. 
2.4.3.2 Pharmacokinetics 
Pharmacokinetic studies have been performed in adult leukemia patients with normal renal and hepatic 
function following intravenous administration of 10 to 12 mg/m2 of idarubicin daily for 3 to 4 days as a 
single agent or combined with cytarabine. The plasma concentrations of idarubicin are best described by a 
two or three compartment open model. The elimination rate of idarubicin from plasma is slow with an 
estimated mean terminal half-life of 22 hours (range, 4 to 48 hours) when used as a single agent and 20 
hours (range, 7 to 38 hours) when used in combination with cytarabine. The elimination of the primary 
active metabolite, idarubicinol, is considerably slower than that of the parent drug with an estimated mean 
terminal half-life that exceeds 45 hours; hence, its plasma levels are sustained for a period greater than 8 
days. 
2.4.3.3 Adverse Reactions 
Approximately 550 patients with AML have received IDAMYCIN (idarubicin 
hydrochloride for injection, USP) in combination with cytarabine in controlled clinical trials worldwide. 
In addition, over 550 patients with acute leukemia have been treated in uncontrolled trials utilizing 
IDAMYCIN as a single agent or in combination. The table below lists the adverse experiences reported in 
U.S. Study 2 (see CLINICAL STUDIES) and is representative of the experiences in other studies. These 


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adverse experiences constitute all reported or observed experiences, including those not considered to be 
drug related. Patients undergoing induction therapy for AML are seriously ill due to their disease, are 
receiving multiple transfusions, and concomitant medications including potentially toxic antibiotics and 
antifungal agents. The contribution of the study drug to the adverse experience profile is difficult to 
establish. 
The following information reflects experience based on U.S. controlled clinical trials. 
2.4.3.3.1 Myelosuppression 
Severe myelosuppression is the major toxicity associated with IDAMYCIN therapy, but this effect of the 
drug is required in order to eradicate the leukemic clone. During the period of myelosuppression, patients 
are at risk of developing infection and bleeding which may be life-threatening or fatal. 
2.4.3.3.2 
Gastrointestinal 
Nausea and/or vomiting, mucositis, abdominal pain and diarrhea were reported frequently, but were 
severe (equivalent to WHO Grade 4) in less than 5% of patients. Severe enterocolitis with perforation has 
been reported rarely. The risk of perforation may be increased by instrumental intervention. The 
possibility of perforation should be considered in patients who develop severe abdominal pain and 
appropriate steps for diagnosis and management should be taken. 
2.4.3.3.3 
Dermatologic 
Alopecia was reported frequently and dermatologic reactions including generalized rash, urticaria and a 
bullous erythrodermatous rash of the palms and soles have occurred. The dermatologic reactions were 
usually attributed to concomitant antibiotic therapy. Local reactions including hives at the injection site 
have been reported. Recall of skin reaction due to prior radiotherapy has occurred with IDAMYCIN 
administration. 
2.4.3.3.4 
Hepatic and Renal 
Changes in hepatic and renal function tests have been observed. These changes were usually transient and 
occurred in the setting of sepsis and while patients were receiving potentially hepatotoxic and nephrotoxic 
antibiotics and antifungal agents. Severe changes in renal function (equivalent to WHO Grade 4) occurred 
in no more than 1% of patients, while severe changes in hepatic function (equivalent to WHO Grade 4) 
occurred in less than 5% of patients. 
2.4.3.3.5 
Cardiac 
Congestive heart failure (frequently attributed to fluid overload), serious arrhythmias including atrial 
fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF have been reported in 
patients undergoing induction therapy for AML. Myocardial insufficiency and arrhythmias were usually 
reversible and occurred in the setting of sepsis, anemia and aggressive intravenous fluid administration. 
The events were reported more frequently in patients over age 60 years and in those with pre-existing 
cardiac disease. 
2.4.3.3.6 
Pregnancy Category D 
Idarubicin was embryotoxic and teratogenic in the rat at a dose of 1.2 mg/m2/day or one tenth the human 
dose, which was nontoxic to dams. Idarubicin was embryotoxic but not teratogenic in the rabbit even at a 
dose of 2.4 mg/m2/day or two tenths the human dose, which was toxic to dams. There is no conclusive 
information about idarubicin adversely affecting human fertility or causing teratogenesis. There has been 
one report of a fetal fatality after maternal exposure to idarubicin during the second trimester. There are 
no adequate and well-controlled studies in pregnant women. If IDAMYCIN is to be used during 
pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the 
potential hazard to the fetus. Women of childbearing potential should be advised to avoid pregnancy. 


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3.0 Patient Eligibility 
3.1 Inclusion Criteria  
– Patients diagnosed with AML meeting one of following criteria: 
 
Newly diagnosed, age 60 and older 
 
High risk cytogenetics and molecular abnormalities (NCCN criteria) 
 
Relapsed or refractory to prior chemotherapy 
 
Secondary AML  
– Any prior chemo therapy must have been completed ≥2 weeks prior to day 1 of study 
treatment and the participant must have recovered to eligibility levels from prior toxicity.  
 
Only one prior regimen is allowed for Relapsed AML patients  
Note one prior regimen is defined as follows: 
 
Induction chemotherapy followed by consolidation is considered one regimen 
 
Induction chemotherapy followed by re-induction in case of persistent disease followed by 
consolidation is considered one regimen 
 
Hydroxyurea is allowed prior to day 1 of study treatment to keep WBC below 20 K.  
– Age ≥18 years.   
– Karnofsky performance status ≥60%.  
– Patients must have normal organ function as defined below: 
 
Total bilirubin <1.5 X institutional upper limit of normal 
 
AST(SGOT)/ALT(SGPT)   ≤2.5 X institutional upper limit of normal 
 
Creatinine <1.5 X institutional upper limit of  normal  
 
OR Creatinine clearance ≥60 mL/min for patients with creatinine levels above 1.5 X 
institutional upper limit of normal,  
 
EF ≥45%. 
– Ability to understand and sign a written informed consent document. 
– Patients should not be receiving any other investigational agents.  
3.2 Exclusion Criteria 
– Patients with clinically significant illnesses which would compromise participation in the 
study, including, but not limited to: active or uncontrolled infection, immune deficiencies 
or confirmed diagnosis of HIV infection, active Hepatitis B, active Hepatitis C, or 
uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, 
unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled 
cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance 
with study requirements. 
– Patients with additional (other than AML) currently active primary malignancy other than 
curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin. 
Patients are not considered to have a "currently active" malignancy if they have 
completed therapy for a prior malignancy and disease free from prior malignancies for >2 
years 
– Patients with active central nervous system (CNS) disease.    
– Patients with Chronic Myelogenous Leukemia (CML) in Myeloid blasts crisis.  
– Active infections, including opportunistic infections 


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Women of childbearing potential (WOCBP) who have a positive serum pregnancy test 
within 14 days of the first administration of oral Dasatinib.  
3.2 Inclusion of Women and Minorities 
The study is open anyone regardless of gender or ethnicity.  Efforts will be made to extend the accrual to 
a representative population, but in a trial which will accrue approximately 43 subjects (Phase I trial 
expected number: 9; Phase II trial expected number: 40 (6 patients brought forward from Phase I trial + 
34 additional), a balance must be struck between subject safety considerations and limitations on the 
number of individuals exposed to potentially toxic or ineffective treatments on the one hand and the need 
to explore gender, racial, and ethnic aspects of clinical research on the other.  If differences in outcome 
that correlate to gender, racial, or ethnic identity are noted, accrual may be expanded or additional studies 
may be performed to investigate those differences more fully. 
4.0 Screening and Registration Procedures 
4.1 Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Studies or procedures that were for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values, even if the studies or 
procedures were done before informed consent was obtained.  Reference is made to Section 10.0 – Study 
Calendar. 
4.2  Informed Consent  
The investigational nature and objectives of the trial, the procedures and treatments involved and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the 
subject and a signed informed consent will be obtained.  Documentation of informed consent for 
screening will be maintained in the subject’s research chart and medical record.   
At the time of registration, the original signed and dated patient’s Informed Consent with the 
Experimental Subject’s Bill of Rights (for the medical record) and three copies (for the patient, the 
research record, and the Coordinating Center) must be available. All Institutional, NCI, Federal, and State 
of California regulations concerning the Informed Consent form will be fulfilled.  
4.3  Registration Requirements/Process 
– Pre-study laboratory tests, bone marrow biopsy, x-ray, ECHO and other required tests must be 
completed prior to registration, within the time frame specified in the protocol. Patients must sign 
an informed consent prior to the study screening.  
– A patient failing to meet all protocol requirements may not be registered. 
– Once all the pre-study requirements have been fulfilled, and informed consent has been obtained, 
and the eligibility checklist has been completed. The study coordinator can register the eligible 
patient into MIDAS.  
– Patients must begin protocol therapy within 1 week of registration. 
4.4 Randomization and/or Dose Level Assignment  
Patients will be assigned to the dose level that is currently open after their eligibility has been confirmed. 
5.0 Treatment Program 
5.1 Treatment Overview 
This combination induction chemotherapy will be used for in-patients only. 


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5.1.1 
Schedule 
For a tabular view of the treatment, monitoring, and follow-up schedule, see study calendar in Section 10. 
5.2 Planned Duration of Therapy 
Induction therapy: Patients will receive cytarabine 200mg/m2 /day IV continuously over 168 hours on 
days 1-7, Idarubicin 12mg/m2  / day IV slow push on days 1-3, and oral Dasatinib (depending on the dose 
level the patient is assigned to) once daily on days 1 to 7. Patients are in CR (Complete Remission) on 
day 30 BM will undergo consolidation therapy, and patients with non-responsive disease (bone marrow 
cellularity ≥ 20 % and leukemia blasts ≥ 5%) will receive a second course of induction therapy. The re-
induction therapy will be the same as the first induction therapy and will start within one week after the 
day 30 bone marrow. 
Dose Level 
Cytarabine* 
Idarubicin# 
Dasatinib^ 
-1 
200mg/m2 
12mg/m2 
70mg/day 
1 
200mg/m2 
12mg/m2 
100mg/day 
2 
200mg/m2 
12mg/m2 
140mg/day 
*: IV QD, days 1-7 
#: IV QD, days 1-3 
^: PO QD, days 1-7 
Dasatinib dose should be given once daily prior to idarubicin dosing to avoid vomiting caused by 
chemotherapy.  Anti-emetics will be used according to standard practices. 
Dasatinib can start and does not need to be held for asymptotic, non-clinical significant grade 3 or 4 non-
hematologic laboratory electrolyte abnormalities. Continuation of combination treatment is permitted 
during the electrolyte supplementation.  
5.3 Criteria for Removal from Treatment 
Reasons that a patient may discontinue treatment: 
– Subject’s condition no longer requires study treatment   
– Intolerable Adverse event(s)  
– Protocol violation  
– Subject withdrew consent  
– Administrative problems 
– New cancer therapy 
– Death  
5.4 Subject Follow-Up 
After completion of study therapy, patients will be followed for AEs up to 30 days of last dose of study 
drugs. Disease status and Survival information will be obtained for every 2 months up to 2 years after the 
study completion. 
5.5 Supportive Care, Other Concomitant Therapy, Prohibited Medications 
5.5.1 
Supportive Care   
All patients will be provided with the best available supportive care. 
5.5.2 
Other Concomitant Therapy 
5.5.2.1 Nausea/Vomiting  


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Nausea and vomiting will be considered refractory if it does not resolve to ≤ Grade 1 with treatment with 
a combination of at least 2 antiemetics. 
5.5.2.2 Diarrhea  
Subjects will not be given anti-diarrhea medication prophylactically.  However, if a subject develops 
diarrhea felt to be related to study medication, anti-diarrhea medication may be instituted for treatment of 
this side effect, such as diphenoxylate with atropine or loperamide.  If diarrhea without blood develops, 
and does not have an identifiable cause other than agent administration, loperamide 4 mg po after the first 
unformed stool with 2 mg po with every subsequent unformed stool may be administered.  This regimen 
can be repeated for each diarrheal episode.  The occurrence of liquid stools after a 24 hour diarrhea-free 
period will be considered a new episode.  If subject develops blood or mucus in the stool, dehydration or 
hemodynamic instability, loperamide will be discontinued and the subject will be treated with IV fluids 
and antibiotics as clinically indicated.  Other potentially helpful treatments may also be administered, 
such as somatostatin analogues, probanthine, etc.  
5.5.2.3 Electrolyte Abnormalities  
If hypokalemia, hypophosphatemia, or hypomagnesemia occur, the patient may receive oral or IV 
supplementation to correct the abnormality.  If hyponatremia occurs, the patient may receive 
0.9% Sodium Chloride intravenously to correct the abnormality. 
5.5.2.4 Neutropenia  
If clinically indicated, granulocyte growth factors can be administered per physician discretion. Febrile 
neutropenia is a life-threatening complication requiring hospitalization and urgent broad-spectrum 
antibiotics, as well as an aggressive search for the source and microbial cause of the episode. 
In the presence of residual leukemia, neutropenia (including febrile neutropenia) is presumed to be due to 
the underlying disease.  Study medications should be re-initiated as soon as the febrile neutropenia is 
evaluated and appropriate antibiotic therapy is started.  Resolved episode of Febrile neutropenia is not in 
itself a reason to delay treatment. 
5.5.2.5 Anemia  
Symptomatic anemia should be treated with red blood cell infusion and is recommended if the 
hemoglobin falls below 8.5G/dL.  Use of red blood cell growth factors is allowed per physician 
discretion.  
5.5.2.6 Thrombocytopenia  
Thrombocytopenia will be treated as per standard practice.  In the absence of bleeding, fever, or a 
necessary invasive procedure, platelet transfusions should be given for a platelet count ≤10K/uL.  In case 
patient is febrile or has other evidence of infection, platelet transfusions should be given for a platelet 
count ≤20K/uL.  If invasive procedure(s) are planned or the subject develops bleeding, platelet 
transfusions should be administered in accordance with standard of practice, usually maintaining a 
platelet count above 50K/uL.  
5.5.2.7 Antiobiotic Prophylaxis  
Patients may receive prophylaxis directed against gram-negative gastrointestinal infections, fungal 
infection, and/or herpes simplex virus, according to the treating physician’s discretion or individual 
institutional practices. 
5.5.2.8 Antiemetics  
Antiemetics will be used according to standard practices. 
5.5.2.9 Prevention of Tumor Lysis Complications  


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To prevent occurrence and complications of tumor-lysis-induced hyperuricemia, all patients without 
known allergy will receive allopurinol 300 mg qd orally prior to beginningof therapy and continuing 
through the period of maximal tumor lysis (As needed and up to the treating physician’s description. 
Suggested to the time point that WBC≤1,000/uL). For individuals at risk for tumor lysis-induced 
hyperphosphatemia (e.g. AML subtype M5), it is suggested that amphogel 30 cc q 4 - 6 hours orally can 
be instituted on admission and continued through the period of maximal tumor lysis (As needed and up to 
the treating physician’s description. Suggested to the time point that WBC≤1,000/uL). 
5.5.3 
Prohibited Medications 
 
Dasatinib is a CYP3A4 substrate. Systemic administration of a potent CYP3A4 inhibitor is prohibited 
during the Dasatinib treatment period. If cannot be avoided, alternative agents with less enzyme inhibition 
potential should be considered, close monitoring for toxicity and a Dasatinib dose reduction should be 
considered.  
Drugs that are CYP3A4 Inducers may decrease Dasatinib plasma concentrations. Systemic administration 
of a potent CYP3A4 inducer should be avoided during the Dasatinib treatment period. If Dsatinib must be 
administered with a CYP3A4 inducer, alternative agents with less enzyme induction potential should be 
considered and used with caution.   
Please see Appendix A for the list of CYP3A4 inhibitors and inducers 
Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. Simultaneous 
administration of Dasatinib with antacids should be avoided. If antacid therapy is needed, the antacid dose 
should be administered at least 2 hours prior to or 2 hours after the dose of Dasatinib. 
Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, 
famotidine and omeprazole) is likely to reduce dasatinib exposure. The concomitant use of H2 antagonists 
or proton pump inhibitors with Dasatinib is not recommended. The use of antacids (at least 2 hours prior 
to or 2 hours after the dose of Dasatinib) should be considered in place of H2 antagonists or proton pump 
inhibitors in patients receiving Dasatinib therapy. 
 
In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular re-polarization 
(QT interval). Administer Dasatinib with caution to patients who have or may develop prolongation of 
QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT 
syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT 
prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia 
prior to Dasatinib administration. 
 
Patients must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator. All medications taken within 28 
days of screening should be recorded. If concomitant therapy must be added or changed, the reason and 
name of the drug/therapy should be recorded. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient are allowed, including drugs given prophylactically (e.g. antiemetics) with the following 
exceptions: 
– Hydroxyurea is allowed prior to day 1 of study treatment to keep WBC below 20 K.  
– Leukopheresis is allowed prior to day 1 of study treatment to keep WBC below 100K/ul 
– No other investigational therapy should be given to patients 
– No anticancer agents other than the study medications administered as part of this study 
protocol should be given to patients. If such agents are required for a patient then the 
patient must first be withdrawn from the study. 


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5.6 Additional Laboratory Studies 
Blood samples will be obtained pre-treatment and after 1 and 3 days of treatment to assess for P-SRC, P-
AKT, P-MAPK and P53 expression in leukemia cells using flow cytometry and for expression of p53 
target genes (CDKN1A, Necdin, Bax, Puma, Noxa, DR5) by Q-PCR. 40ml peripheral blood sample will 
be collected into green top tubes (Sodium Heparin) at each time point and send to Dr. Ravi Bhatia 
laboratory for correlative studies. 
BM cells will be obtained at recovery and residual leukemia stem/progenitor cells will be evaluated by 
isolating  CD34+ cells (and where possible CD34+CD38- cells) will be isolated and analysis of selected 
populations for  mutations identified pre-treatment by FISH, PCR or sequencing analysis as appropriate. 
20ml bone marrow aspirate sample will be collected into green top tubes (Sodium Heparin) at baseline, 
and each of disease assessment time point and send to Dr. Ravi Bhatia laboratory for correlative studies.  
5.7 Definition of Dose-Limiting Toxicity (DLT) 
Dose limiting toxicity is defined as any of the toxicities listed below that occur from the first dose of 
dasatinib through the DLT observation period discussed below. The list of hematologic and non-
hematologic toxicities was constructed after reviewing published toxicity data (including type, frequency 
and duration) for the Cytarabine/Idarubicin drug combination/regimen and for Dasatinib given as a single 
agent. Patients must not have persistent leukemia after induction to be considered evaluable for DLTs 
associated with hematologic toxicity. Patients who have persistent leukemia are still potentially evaluable 
patients for safety and cohort advancement based on the non-hematologic DLT criteria below.  
Hematologic Toxicities:  
For patients without persistent leukemia following induction:  
Grade 4 hematological toxicity persisting >42 days following the last dose of dasatinib (i.e., Day 49) not 
attributable to persistent leukemia with exclusion of chronic cytopenia attributed to preexistent condition 
such as MDS, MPN, and MF.  
Non-Hematologic Toxicities:  
For all patients, within the first 28 days: 
Any grade 3 or higher non-hematologic toxicity, excluding:  
 
Anorexia, fatigue, uric acid, fever with or without neutropenia, or bleeding during a period of Grade 4 
thrombocytopenia   
 
Diarrhea, nausea, abdominal bloating, vomiting or mucositis that resolves to ≤ Grade 1 or to baseline 
within 7 days of onset with optimal medical management  
 
Elevated AST, ALT, alkaline phosphatase, or bilirubin that returns to ≤ Grade 2 or to baseline within 
14 days of onset  
 
Rash or elevated amylase or lipase that returns to ≤ Grade 2 or to baseline within 7 days of onset  
 
Infections or complications of infections due to neutropenia 
 
Electrolyte disturbance that can be corrected wit supplementation within 10 days. 
Any grade 5 toxicity, not due to disease, will be considered a DLT. 
 
Patients must complete all 7 days of dasatinib or experience a dose limiting toxicity (DLT) to be 
evaluable for toxicity.  
6.0 Dose Delays/Modifications for Adverse Events 
6.1 Dose modification for Dasatinib 
No dose adjustment needed for hematological toxicity 


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For Grade 3-4 non-hematological toxicity, Dasatinib dose must be held until Grade < or = 1, then resume 
to next lower dose level.  
If the patient is at the reduced dose level -1, the same Grade 3-4 non-hematological toxicity recurs, patient 
needs to be discontinued from the study. 
Dasatinib does not need to be held for the following grade 3 or 4 toxicities: 
 Asymptomatic, non-clinically significant Grade 3 or 4 non-hematologic laboratory 
electrolyte abnormalities 
 Grade 3 or 4 non-hematological toxicities that are unrelated to study drug , had a prior 
history of medical conditions before the initiation the study treatment,   
 Grade 3 nausea, vomiting and diarrhea.   
6.2 Dose Modification for Idarubicin 
Idarubicin will be given at 12mg/m2 from days 1-3 
– Total bilirubin < 2.5mg/dL   no dose reduction 
– Total bilirubin ≥2.5mg/dL but < 5mg/dL   50% dose reduction 
– Total bilirubin ≥5mg/dL  do not administer 
6.3 Dose Modification for Cytarabine 
Cytarabine will be given at 200mg/m2 days 1-7. Dose adjustment is not allowed while on the study. 
7.0 Data and Safety Monitoring  
7.1 Definition of Risk Level 
This is a Risk Level 3 study, as defined in the ―City of Hope Data and 
Safety Monitoring Plan‖, http://www.coh.org/dsmc/Pages/forms-and-
procedures.aspx because it is a Phase I/II clinical trial where the risks are at 
least balanced by the potential benefit to subjects and the importance of the 
knowledge that may result. 
 
7.2 Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, CRA, protocol nurse, and statistician is responsible for 
monitoring the data and safety of this study, including implementation of 
any stopping rules for safety and efficacy. 
 
This study will utilize the Phase I tracking log to monitor data and safety 
for dose escalation, recording doses administered, and resultant adverse 
events.  The tracking log will contain dose levels administered, DLT-
defining adverse events, and documentation that the data from a dose level 
is complete before dose escalation.  Those data and safety elements will be 
reported to the COH DSMC as applicable within the PMT report, which 
will be submitted quarterly or semi-annually from the anniversary date of 
activation, as noted in Table 1 below. Protocol specific data collection will 


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include the following items: Patient ID, Dose level, Treatment Courses, 
and AE summary. 
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
7.3 Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it is not 
listed in the investigator’s brochure and/or package insert; is not listed at the specificity or 
severity that has been observed; is not consistent with the risk information described in the 
protocol and/or consent; is not an expected natural progression of any underlying disease, 
disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event 
OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event 
 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or unexpected 
adverse event that results in any of the following outcomes: 
 
Death 


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Is life-threatening experience (places the subject at immediate risk of death from the 
event as it occurred) 
 
Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization 
 
A persistent or significant disability/incapacity 
 
A congenital anomaly/birth defect 
 
Secondary Malignancy 
 
Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the outcomes listed above (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, blood 
dyscrasisas of convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse). 
 
Unanticipated problem (UP) – Any incident, experience, or outcome that meets all three of 
the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the 
characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by 
the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
 
7.4 Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems: Most unanticipated problems must be reported to the COH DSMC 
and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that occurs 
during the study conduct will be reported to the DSMC and IRB by submitting electronically in 
iRIS (http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by the 
physician, nurse, or reported by the patient, will be reported according to definitions and 
guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and Table 2 below.  Those 
SAEs that require expedited reporting will be submitted electronically in iRIS 
(http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that do not 
meet the criteria of serious OR are not unanticipated problems will be reported only in the 
protocol continuation reports and PMT report (see Table 2 below). 
 
 


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Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines 
for the DSMC and IRB 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
 
 


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Externally Sponsored Studies 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations Director. 
The DSMC will review the case and make a determination as to whether the study will be 
suspended, terminated, amended, or allowed to continue without amendment. 
 
 
 
 
 
 
 
 


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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
 
8.0 Study Agent Information and Risks 
8.1 Dasatinib 
Please see section 2.4.1 
8.2 Cytarabine  
Please see section 2.4.2 
8.3 Idarubicin  
Please see 2.4.3 
9.0   Correlative/Special Studies 
Blood samples will be obtained pre-treatment and after 1 and 3 days of treatment to assess for P-SRC, P-
AKT, P-MAPK and P53 expression in leukemia cells using flow cytometry and for expression of p53 
target genes (CDKN1A, Necdin, Bax, Puma, Noxa, DR5) by Q-PCR. 40ml peripheral blood sample will 
be collected into green top tubes (Sodium Heparin) at each time point and send to Dr. Ravi Bhatia 
laboratory for correlative studies. 
BM cells will be obtained at recovery and residual leukemia stem/progenitor cells will be evaluated by 
isolating  CD34+ cells (and where possible CD34+CD38- cells) will be isolated and analysis of selected 
populations for  mutations identified pre-treatment by FISH, PCR or sequencing analysis as appropriate. 
20ml bone marrow aspirate sample will be collected into green top tubes (Sodium Heparin) at baseline, 
and each of disease assessment time point and send to Dr. Ravi Bhatia laboratory for correlative studie


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10.0 Study Calendar 
Study Visit Schedule * 
  
Screening 1 
Study Treatment Phase 
Post Study 
Treatment 
Phase 10 
End of 
Study 11 
Follow Up 
12 
Day of Cycle 
  
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 to D28 
  
  
Informed consent 
X2 
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
  
Treatment with 
Cytarabine3 
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
Treatment with 
Idarubicin3 
  
X 
X 
X 
  
  
  
  
  
  
  
Treatment with 
Dasatinib 
  
X 
X 
X 
X 
X 
X 
X 
  
  
  
Height, Weight, and 
BSA 4 
X 
  
  
  
  
  
  
  
  
  
  
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
Weekly 
X 
  
Medical 
History/Physical 
Examination/ 
Karnofsky 
Performance Status15 
X 
X 
X 
X 
X 
X 
X 
X 
Weekly 
X 
X 
12 Lead ECG 
X 
  
  
  
  
  
  
  
  
  
  
Chest X-Ray  
X 
  
  
  
  
  
  
  
  
  
  
Hematology14  
X 
X 
X 
X 
X 
X 
X 
X 
2X /Weekly 
X 
X 
Biochemistry13  
X 
X 
X 
X 
X 
X 
X 
X 
2X /Weekly 
X 
  
Urinalysis  
X 
  
  
  
  
  
  
  
  
  
  
Serum Pregnancy 
Test 5 
X 
  
  
  
  
  
  
  
  
  
  
Echocardiogram6 
X 
  
  
  
  
  
  
  
  
  
  
AML Genetic 
/Molecular 
Assessments7 
X 
  
  
  
  
  
  
  
  
  
  
Bone marrow 
aspirate/ Biopsy8  
X 
  
  
  
  
  
  
  
D14 and 
D30(+/- 3 days) 
X 
X 
Peripheral Blood 
Sample for 
Correlative Studies9 
X 
X 
  
 X 
  
  
  
  
  
  
  
Adverse events  
  
 X 
X 
X 
X 
X 
X 
X 
 X 
 X 
  
Disease Recurrence 
and Survival Status 
  
  
  
  
  
  
  
  
  
  
X 
* Please note that for all study assessments, more frequent examinations may be performed at physican's discretion, if medically 
indicated. 


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1.Screening evaluations must be performed ≤ 14 days prior to D1, administration of Dasatinib, Any screening tests that are 
performed within 3 days of first dose of Dasatinib do not need have to be repeated on the date of first dose of Dasatinib. Tests 
done within the appropriate window but prior to informed consent will be accepted if done as standard of care. 
2. Informed consent must be obtained ≤ 14 days prior to day 1 of study treatment, administration of Dasatinib 
3. 7+3 (Cytarabine+Idarubicin) treatment order will be used City of Hope standard research order. 
4. Height, Weight and BSA should be performed as per City of Hope Chemotherapy SOP.   
5. Serum Pregnancy test should be performed at the screening for women of childbearing potential.   
6. May be used for screening if done within 30 days of study treatment as part of standard of care. 
7. Molecular assessments for FLT3, NPM1 and c-Kit should be performed at screening. These tests do not have to be repeated 
and the result can be used for baseline if done within 30 days of first dose of Dasatinib. 
8. Bone marrow aspirate/biopsy should be performed at the screening, Day 14(+/-3 days), then again at Day 30(+/-3days) or at 
the counts recovery. Cytogenetic and FISH analysis, molecular assessments of chromosomal breakpoints or other genetic 
abnormalities should be performed based on disease characteristics, institutional practice standards. The bone marrow may be 
performed ≤ 30 days prior to the first administration of Dasatinib. At each time point, additional 20ml bone marrow aspirate 
sample are required to be sent to Dr. Bhatia's laboratory for correlative studies. 
9. 40ml peripheral blood sample for correlative studies need to be sent to Dr. Bhatia's laboratory at screening and on Day 1 and 
Day 3 after first dose of Dasatinib. 
10. Assessments should be performed weekly at least, defined as every 7 days from Day7 (+/-3 days). 
11. EOT assessments should be performed prior to another anti-cancer treatment, unless patient has been withdrawn from study. 
12. Patients who achieve a CR and patients who proceed to HSCT (regardless of remission status) should be followed every 2 
months (+/- 1 week) thereafter up to 2 years of study treatment completion. 
13. Biochemistry tests for Sodium, Potassium, Chloride, Carbon Dioxide, Creatinine, Urea Nitrogen, Calcium, Glucose, 
Albumin, Bilirubin Total, Phosphatase, Alkaline, Protein Total, ALT/SGPT and AST/SGOT), Magnesium, Uric Acid and other 
tests that are necessary per patient’s medical condition should be performed on the screening, daily for days 1-7. Starting on day 
8, biochemistry tests for Sodium, Potassium, Chloride, Carbon Dioxide, Creatinine, Urea Nitrogen, Calcium, Glucose, Bilirubin 
Total, Uric Acid, Magnesium and other tests that are necessary per patient’s medical condition should be performed.  
14. Hematology CBC, Platelets and Differential should be performed at screening and on Day 1. CBC and Platelets should be 
performed daily to counts recover. Differential should be performed every other day until count recover.  
15. Karnofsky Performance Status (KPS) is required on the study screening only. 
 
 
 


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11.0 Endpoint Evaluation Criteria/Measurement of Effect 
Toxicities/Adverse Events:  
From day 1 to day 30, the highest grade of non-hematologic toxicities will be collected,   included start 
and stop dates. 
For hematologic adverse events, from day 1 to day 30, collect every grade change (including start and 
stop dates) for hematologic toxicities grade 3 and above.  
Long-Term AE Monitoring/Data Collection: After the completion of treatment (either one or two cycles 
of therapy), use the late AE form and report only the worst grade of each AE and ONLY report AE’s that 
are possibly, probably, or definitely related to Dasatinib.  
Note: If the patient goes on to receive a second cycle of Dasatinib, report the worst grade of every AE 
until 30 days post the start date of cycle two. 
Overall Survival (OS): Patients are considered a failure for this endpoint if they die, regardless of cause. 
Endpoint measured as time from start of study therapy until death, or last contact, whichever comes first. 
Patients will be followed for up 2 years after completion of study treatment. 
Event Free Survival (EFS): Patients are considered a failure for this endpoint if they die or if they 
relapse/progress or receive other anti-leukemia therapy. Endpoint measured as time from start of study 
therapy until death, relapse/progression, receipt of anti-leukemia therapy, or last contact, whichever 
comes first. Patients will be followed for up 2 years after completion of study treatment. 
Complete remission (CR): Bone marrow blasts ≤5 percent; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count ≥1.0 x 109/L (1000/µL); platelet count ≥100 x 109/L 
(100,000/µL); independence of red cell transfusions 
CR with incomplete recovery (CRi): All CR criteria except for residual neutropenia (<1.0 x 109/L 
(1000/µL)) or thrombocytopenia (<100 x 109/L (100,000/µL)) 
Morphologic leukemia-free state: Bone marrow blasts ≤5 percent; absence of blasts with Auer rods; 
absence of extramedullary disease; no hematologic recovery required 
Partial remission (PR): Relevant in the setting of phase I and II clinical trials only; all hematologic 
criteria of CR; decrease of bone marrow blast percentage to 5 to 25 percent; and decrease of pretreatment 
bone marrow blast percentage by at least 50 percent 
Cytogenetic CR (CRc): Reversion to a normal karyotype at the time of morphologic CR (or CRi) in 
cases with an abnormal karyotype at the time of diagnosis; based on the evaluation of 20 metaphase cells 
from bone marrow 
Relapse: Bone marrow blasts ≥5 percent; or reappearance of blasts in the blood; or development of 
extramedullary disease 
Resistant disease (RD): Failure to achieve CR or CRi (general practice; phase II/III trials), or failure to 
achieve CR, CRi or PR (phase I trials); only includes patients surviving ≥7 days following completion of 
initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination 
Death in aplasia: Deaths occurring ≥7 days following completion of initial treatment while cytopenic; 
with an aplastic or hypoplastic bone marrow obtained within 7 days of death, without evidence of 
persistent leukemia 


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Death from indeterminate cause: Deaths occurring before completion of therapy, or <7 days following 
its completion; or deaths occurring ≥7 days following completion of initial therapy with no blasts in the 
blood, but no bone marrow examination available 
12.0 Data Reporting/Protocol Deviations 
12.1 Data Reporting 
12.1.1 Confidentiality and Storage of Records 
The original data collection forms will be submitted into Medidata Rave Electronic Data Collection 
(EDC).  Data will be stored in encrypted, password protected, secure computers that meet all HIPAA 
requirements.  When results of this study are reported in medical journals or at meetings, identification of 
those taking part will not be disclosed.  Medical records of subjects will be securely maintained in the 
strictest confidence, according to current legal requirements.  They will be made available for review, as 
required by the FDA, HHS, or other authorized users such as the NCI, under the guidelines established by 
the Federal Privacy Act and rules for the protection of human subjects. 
12.1.2 Subject Consent Form 
At the time of registration, the original signed and dated Informed Consent form, HIPAA research 
authorization form, and the California Experimental Subject’s Bill of Rights (for the medical record) and 
three copies (for the subject, the research record, and the Coordinating Center) must be available.  All 
Institutional, NCI, Federal, and State of California requirements will be fulfilled. 
12.1.3 Data Collection Forms and Submission Schedule  
All data will be collected and submitted using electronic case report forms in Medidata Rave EDC. Data 
will be submitted per data collection and submission schedule in Medidata Rave EDC.   
 
12.2 Protocol Deviations 
12.2.1 Deviation Policy 
This protocol will be conducted in accordance with COH’s ―Clinical Research Protocol Deviation Policy‖ 
located at http://www.coh.org/dsmc/Documents/Institutional%20Deviation%20Policy.pdf. 
Deviations from the written protocol that could increase patient risk or alter protocol integrity require 
prior IRB approval of a single subject exception (SSE) request.  In addition, if contractually obligated, the 
sponsor must also approve the deviation.  IRB pre-approved SSE protocol modifications are considered 
an amendment to the protocol and not a deviation.  The submission of a deviation report is not required. 
Brief interruptions and delays may occasionally be required due to travel delays, airport closure, 
inclement weather, family responsibilities, security alerts, government holidays, etc.  This can also extend 
to complications of disease or unrelated medical illnesses not related to disease progression.  The PI has 
the discretion to deviate from the protocol when necessary so long as such deviation does not threaten 
patient safety or protocol scientific integrity.  Examples include, but are not limited to:  a) dose 
adjustments based on excessive patient weight; b) alteration in treatment schedule due to non-availability 
of the research participant for treatment; c) laboratory test results which are slightly outside the protocol 
requirements but at levels that do not affect participant safety.  These instances are considered to be 
deviations from the protocol.  A deviation report will be submitted to the DSMC/IRB within five days. 


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12.2.2 Reporting of Deviations 
All deviations will be reported to the COH DSMC within five days.  The DSMC will forward to report to 
the IRB following review. 
12.2.3 Resolving Disputes 
The COH Investigational Drug Service (IDS) cannot release a research agent that would cause a protocol 
deviation without approval by the PI.  Whenever the protocol is ambiguous on a key point, the IDS 
should rely on the PI to clarify the issue. 
In situations where there is misperception or dispute regarding a protocol deviation among the persons 
involved in implementing the protocol, it is the responsibility of the PI to resolve the dispute and the PI 
may consult with the DSMC chair (or designee) to arrive at resolution. 
 
13.0 Statistical Considerations 
13.1 Study Design 
This is an open label Phase I/II study. 
13.1.1 Phase I 
The study design is based on a standard 3 + 3 dose escalation design.  
 
Dose level 1 will be the first dose level tested. Initially three subjects will be treated, if 0/3 experiences a 
dose limiting toxicity (DLT), enter 3 subjects at dose level 2. If 1/3 of the first 3 subjects has DLT, enter 3 
more subjects at dose level 1. If none of these 3 additional subjects has DLT, then proceed to dose level 2. 
If one or more of these 3 additional subjects has DLT, then a dose reduction (to dose level -1) will be 
applied.  
 
Among the patients treated at dose level 2, if 0/3 or 1/3 of the first 3 subjects experiences DLT, enter 3 
more subjects at dose level 2. If ≤ 1/6 subjects on dose level 2 have DLT, dose  level 2 will be declared 
the phase II dose (P2D). If ≥ 2/6 subjects have DLT at dose level 2, dose level 1 will be declared the P2D, 
assuming at least six patients have been treated at dose level 1 and ≤ 1/6 subjects has DLT.  
 
Assuming a dose reduction is necessary, among the patients treated at dose level -1, if 0/3 or 1/3 on the 
first 3 subjects has DLT, enter 3 more subjects at dose level -1. If ≤ 1/6 subjects treated on dose level -1 
has DLT, dose level -1 will be declared the P2D. If ≥ 2/6 subjects have DLT on dose level -1, then the 
study will be terminated.  
 
Dose Level 
Cytarabine* 
Idarubicin# 
Dasatinib^ 
-1 
200mg/m2 
12mg/m2 
70mg/day 
1 
200mg/m2 
12mg/m2 
100mg/day 
2 
200mg/m2 
12mg/m2 
140mg/day 
*: IV QD, days 1-7 
#: IV QD, days 1-3 
^: PO QD, days 1-7 
 


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The phase I study is expected to enroll 9-18 evaluable patients. Toxicities will be monitored, graded, and 
recorded according to the NCI-Common Terminology Criteria for Adverse Events version 4.0.  See 
section 5.7 for dose limiting toxicity (DLT) definition. Patients must complete all 7 days of dasatinib or 
experience a DLT to be evaluable for toxicity.  Phase I patients treated at the P2D will count toward the 
phase II trial accrual goal. 
 
Observed toxicities will be summarized in terms of type (organ affected or laboratory determination such 
as absolute neutrophil count) severity (by NCI CTCAE v4.0), date of onset, duration, reversibility, and 
attribution. Tables will be created to summarize these toxicities and side effects. Baseline information 
(e.g. cytogenetic risk) and demographic information will be presented for all study patients. While not the 
primary objective of the phase I study, a preliminary estimate of complete remission rate (CR) and 
remission duration will be reported. Survival probabilities, overall survival (OS) and event-free (EFS) 
will be estimated. 
13.1.2 Phase II 
This is a single center phase II trial to determine the anti-tumor activity of Dasatinib given in combination 
with cytarabine and idarubicin as assessed by complete remission (CR) rate, the primary endpoint; 
secondary endpoints are remission duration, survival (overall and event-free) and toxicities. Patients with 
high-risk AML will be eligible. This study will implement a single arm SWOG Phase II two-stage design 
to study the activity of Dasatinib plus cytarabine and idarubicin (Green SJ, Benedetti J, and Crowely J, 
1997).  
As noted in the background section, the CR rates for these high risk patient subgroups vary from roughly 
25 to 50%. We will power this study to be able to detect a 20% increase in the CR rate with 
approximately 80% power, assuming a type I error of 5%.  After 20 patients (up to 24 patients can be 
accrued to allow for over accrual while previous patients are under evaluation), we will estimate the 
historical rate for the patient population accrued based on the table below (a weighted average of the 
historically observed CR rate, weighted by percent of accrual in each group).  If the promising rate (20% 
higher than the weighted estimate of the historical CR rate for the patients accrued) can be ruled out with 
a 0.02 false negative rate, the study will stop accrual and be declared unpromising. Otherwise, the study 
will accrue to a total of 40 patients.  A new historical (weighted) estimated weight of the CR rate will be 
calculated based on the number of patients accrued to each group.  If that historical CR rate can be ruled 
out with a 0.05 false positive rate, the study will be declared successful.   
 
For each of the groups below, as examples, we present the operating characteristics based on the above 
rules. The actual operating characteristics will be determined by the actual accrual patterns.  
 
Observed/expected response rates by high risk group are as follows: 
High Risk Group: 
Observed CR 
Rate: 
Expected 
Improvement in 
CR Rate (20%): 
-Power/Alpha/Total N 
-Stage 1/Stage 2 Enrollment 
-Stop if ≤ n responses Stage 1/ 
Promising if ≥ n responses Stage 2 
Newly diagnosed 
patients, aged 60 
and older 
48%, van der 
Holt (2005) 
From 50% to 70% 
.80/.05/40 
20/20 
10/26 
High risk 
cytogenetics <60y  
50%, Mrozek 
(2012) 
From 50% to 70% 
.80/.05/40 
20/20 


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10/26 
High risk 
cytogenetics ≥60y  
39%, Mrozek 
(2012) 
From 40% to 60% 
.79/.05/40 
20/20 
6/22 
Relapsed/refractory 
30%, Becker 
(2013) 
From 30% to 50% 
.78/.05/40 
20/20 
5/18 
Secondary AML 
24%, Leith 
(1997) 
From 25% to 45% 
.79/.05/40 
20/20 
4/16 
Accrual is expected to be complete within 18-24 months. 
Remission rates will be calculated as the percent of evaluable patients that have a confirmed CR, and 
exact 95% confidence intervals will be calculated for these estimates. Time to confirmed complete 
remission, duration of remission, and survival will be estimated using the product-limit method of Kaplan 
and Meier. Toxicity will be monitored on an ongoing basis. If the percentage of unacceptable toxicities 
(using the DLT definition) exceeds 25% with 6 or more patients accrued, patient accrual will be halted 
and a full review of the data by the Data Safety Monitoring Committee will be mandated. Patient accrual 
will not resume until approved by the Data Safety Monitoring Committee to do so. 
Evaluation of Response 
All patients included in the study will be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible. All patients who meet the eligibility criteria (with 
the exception of those who received no study medication) will be included in the main analysis of the 
response rates. An incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate.    
All conclusions will be based on all eligible patients who receive any of the study drug.  Subanalyses may 
then be performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation of treatment, 
major protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis will 
be clearly reported. 
13.2 Sample Size Accrual Rate 
Phase I, Expected: 9, maximum 18 
Phase II, Expected: 14-34 (20-40 including the 6 patients brought forward from Phase I trial) 
Annually approximately 50 AML patients, patients who would meet the protocol eligibility criteria, are 
seen at City of Hope. Based on these numbers, this study expects to accrue 20 patients per year. The study 
is expected to complete the enrollment phase of the study in 24 months, with an additional 24 months of 
follow-up after the completion of study treatment for each patient. With the last patient enrolled at 
approximately month 24, the planned trial activity is scheduled to conclude in month 48. 
13.3 Statistical Analysis Plan 
See Section 13.1 
13.4 Overview and Stopping Rules for Excessive Toxicity 
The following table will be consulted as relevant toxicities are encountered following the phase I study. 
The toxicity/early stopping rule for safety will be assessed for each patient at day 28 post start of dasatinib 


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treatment. The expected rate of unacceptable toxicity should not be ≥33%. The expected rate of regimen-
related death should not be ≥25% (see table below for detailed early stopping rules). Patients with 
ongoing toxicity (beyond day 28) will be followed until resolution or stability.  If more than the specified 
number of patients has unacceptable toxicity (based on DLT definition) or regimen-related death, we will 
lower the dose of dasatinib to 70 mg/day. If the dose was already reduced during the phase I study, patient 
accrual will be halted and a full review of the data by the Data Safety Monitoring Committee will be 
mandated. Patient accrual will not resume until approved by the Data Safety Monitoring Committee to do 
so. The acceptable rate of regimen-related death, defined as <25%, was determined after a review of the 
induction literature for acute myeloid leukemia, in elderly and high risk populations. In a randomized 
phase III study of three induction regimens, the treatment related mortality rate among patients who 
received idarubicin and cytarabine was 22% (Rowe, 2004). Based on this study and preliminary results 
from an ongoing phase II study of induction chemotherapy (daunorubicin/cytarabine) plus dasatinib 
(Marcucci, ASH 2013), the investigators believe that the addition of dasatinib to idarubicin/cytarabine 
should not significantly increase (by more than a few percentage points) the published rate of regimen-
related death among patients treated with idarubicin and cytarabine (Rowe, 2004). 
# of patients 
treated at 
phase II dose 
# of patients 
with 
unacceptable 
toxicity that 
would halt 
enrollment1 
Cumulative probability of early stopping 
given a toxicity rate of: 
15% 
33% 
45% 
  6 
  2 
0.22 
0.64 
0.84 
12 
  4 
0.24 
0.73 
0.92 
18 
  6 
0.25 
0.78 
0.95 
24 
  8 
0.25 
0.81 
0.97 
30 
10 
0.25 
0.83 
0.98 
36 
12 
0.25 
0.84 
0.99 
1: For each unacceptable toxicity, halt enrollment and evaluate if the cumulative # 
of patients reaches or exceeds the specified limits. 
 
14.0 Human Subject Issues 
14.1 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the 
federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 
17,  must review and approve this protocol and the informed consent form prior to initiation of the study.  
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
14.2 Recruitment of Subjects 
Patients with a diagnosis of de novo acute myeloid leukemia, secondary acute myeloid leukemia, and 
therapeutic related acute myeloid leukemia, either newly diagnosed or relapsed after treatment will be 
identified from the new patient services, outpatient clinics or inpatient service of City of Hope Medical 
Center by physicians in the Department of Hematology. Patients will be recruited for the study by the 
principal investigator, co-investigators or participating clinicians.  


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14.3 Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, lay summary to 
be posted on City of Hope’s public Clinical Trials On-LineSM website, etc., will be reviewed and 
approved by the IRB prior to their use to recruit potential study subjects. 
14.4  Study location and Performance Sites 
This study will be performed at COH.   
14.5 Confidentiality  
This research will be conducted in compliance with federal and state of California requirements relating 
to protected health information (PHI). The records related to subject identity will be kept in a separate 
research file and will be stored in a locked file cabinet.  A coded list will be used to link the subject's 
identity to the study data. Any information allowing identification of the subjects will not be included in 
any published report or any computerized records.  Data will be presented as aggregate or group data. The 
principal investigator and co-investigators will be the only one having access to the collected data.  The 
results will not be available to patients, their physicians, insurance carriers or employers.   
14.6 Financial Obligations and Compensation 
The investigational drug Dasatinib, will be provided free of charge by City of Hope.  Should this 
drug become commercially available during the course of your treatment, the research participant 
and/or the insurance carrier may be asked to pay for the costs of the drug. 
The standard of care drugs Cytarabine, Idarubicin, and induction chemo procedures provided will be the 
responsibility of the research participant and/or the insurance carrier.  The research participant will be 
responsible for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set 
forth by the insurance carrier.  The research participant and/or the insurance carrier will be billed for the 
costs of treatment and diagnostic procedures in the same way as if the research participant were not in a 
research study.  However, neither the research participant nor the insurance carrier will be responsible for 
the research procedures related to this study. 
In the event of physical injury to a research participant, resulting from research procedures, appropriate 
medical treatment will be available at the City of Hope to the injured research participant, however, 
financial compensation will not be available. 
The research participant will not be paid for taking part in this study. 
14.7 Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Research subjects will be informed that they may withdraw from the 
study at any time and for any reason without prejudice, including as applicable, their current or future 
care or employment at City of Hope or any relationship they have with City of Hope.  Research subjects 
will be afforded sufficient time to consider whether or not to participate in the research. 
Should sufficient doubt be raised regarding the adequacy of comprehension, further clarifications will be 
made and the questionnaire repeated until a satisfactory result is obtained.  Prospective research subjects 
who cannot adequately comprehend the fundamental aspects of the research study with a reasonable 
amount of discussion, education and proctoring will be ineligible for enrollment.  For those subjects who 
do comprehend the fundamental aspects of the study, consent will be obtained and documented, followed 


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by eligibility testing.  The research team will review the results of eligibility testing and determine if the 
subject is a candidate for study enrollment.  
 
 


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15.0 References 
1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for 
Practice. Pittsburgh, Pa: Oncology Nursing Society. 1999:32–41. 
2. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington, DC; 
Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National 
Institutes of Health; 1992. US Department of Health and Human Services, Public Health Service 
Publication NIH 92-2621. 
3. AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA. 
1985;253:1590–1591. 
4. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic 
Agents. 1987. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on 
Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 
Longwood Avenue, Boston, MA 02115. 
5. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling 
of Antineoplastic Agents. Med J Australia. 1983; 1:426–428. 
6. Jones RB, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the 
Mount Sinai Medical Center. CA Cancer J Clin. 1983;33:258–263. 
7. American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling 
Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033–1049. 
8. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am 
J Health-Syst Pharm. 1996;53:1669–1685. 
9. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication 
No. 83-2621. Superintendent of Documents, U.S. Government Printing Office, Washington, DC 
20402  
10. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics, JAMA, March 15, 
1985.  
11. National Study Commission on Cytotoxic Exposure — Recommendations for Handling 
Cytotoxic Agents, Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic 
Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Ave., 
Boston, Massachusetts 02115.  
12. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling 
of Antineoplastic Agents. Med J Aust 1:426-428, 1983.  
13. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A report from the Mount Sinai 
Medical Center, CA — A Cancer Journal for Clinicians Sept/Oct, 258-263, 1983.  
14. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic 
and Hazardous Drugs. Am J Hosp Pharm 47:1033-1049, 1990.  
15. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines), Am 
J Hosp Pharm, 53:1669-1685, 1996. 
16. Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, Liesveld JL, Abboud 
CN, Dewald G, Hayes FA, Tallman MS, Wiernik PH; Eastern Cooperative Oncology. A phase 3 


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study of three induction regimens and of priming with GM-CSF in older adults with acute 
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