Clinical trial NCT02626338
Conditions: Relapsed/Refractory Acute Myeloid Leukemia (AML)
Sponsor: Arog Pharmaceuticals, Inc.
Start date: 2016-02-01; Completion date: 2018-02-01
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed study is designed to combine crenolanib with standard salvage chemotherapy to treat patients with R/R AML irrespective the FLT3 status.

Detailed description:
Open label, dose de-escalation, pilot trial of crenolanib with standard salvage chemotherapy. Subjects may receive up to 2 cycles of induction with standard salvage chemotherapy followed by crenolanib. Each arm will enroll approximately 24 patients (72 total); stratification to each arm will be per physician's choice

Arms: arm 1: * Mitoxantrone
* Cytarabine
* Crenolanib arm 2: * Fludarabine
* Cytarabine
* G-CSF
* Idarubicin
* Crenolanib arm 3: * Mitoxantrone
* Etoposide
* Cytarabine
* Crenolanib
Interventions: intervention 1: Crenolanib intervention 2: Mitoxantrone intervention 3: Cytarabine intervention 4: Etoposide intervention 5: Fludarabine intervention 6: G-CSF intervention 7: Idarubicin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol ARO-011 
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Protocol ARO-011 
 
Pilot study of Crenolanib Combined with Standard Salvage Chemotherapy in Subjects 
with Relapsed/Refractory Acute Myeloid Leukemia 
 
 
 
 
IND Number: 118143 
 
 
 
 
 
 
Version Number: 3.0 
Version Date: June 7, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
AROG Pharmaceuticals, Inc. 
5420 LBJ Freeway, Suite 410 
Dallas, TX 75240 
 
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of AROG Pharmaceuticals, Inc., or its subsidiaries 
and should not be copied by or distributed to persons not involved in the clinical 
investigation of crenolanib besylate, unless such persons are bound by a confidentiality 
agreement with AROG Pharmaceuticals, Inc., or its subsidiaries. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................................................... 0 
LIST OF ABBREVIATIONS ............................................................................................................................... 3 
DEFINITION OF TERMS ................................................................................................................................... 5 
1. 
SYNOPSIS ................................................................................................................................................... 6 
2. 
BACKGROUND AND STUDY RATIONALE......................................................................................... 11 
2.1 
UNMET MEDICAL NEED IN RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA......................................................... 11 
2.2 
PHYSICIAN’S CHOICE OF SALVAGE CHEMOTHERAPY AGENTS IN RELAPSED/REFRACTORY AML........................................... 12 
2.3 
EFFICACY OF HAM, MEC AND FLAG-IDA IN RELAPSED/REFRACTORY AML .................................................................. 12 
2.4 
CLINICAL EVIDENCE OF COMBINING A TYROSINE KINASE INHIBITOR WITH CHEMOTHERAPY IN AML PATIENTS ...................... 13 
2.5 
FLT3 LIGAND LEVELS INCREASE FOLLOWING ADMINISTRATION OF CHEMOTHERAPY ........................................................ 14 
2.6 
OVERVIEW OF CRENOLANIB .................................................................................................................................. 15 
2.7 
RATIONALE FOR COMBINING CRENOLANIB WITH HAM, MEC, OR FLAG-IDA ................................................................. 16 
3. 
STUDY OBJECTIVES ............................................................................................................................. 16 
3.1 
PRIMARY OBJECTIVE ........................................................................................................................................... 16 
3.2 
SECONDARY OBJECTIVES ...................................................................................................................................... 16 
4. 
STUDY DESIGN ....................................................................................................................................... 17 
4.1 
ESTIMATED STUDY DURATION .............................................................................................................................. 17 
5.      STUDY POPULATION ................................................................................................................................... 18 
5.1 
INCLUSION CRITERIA ........................................................................................................................................... 18 
5.2 
EXCLUSION CRITERIA ........................................................................................................................................... 19 
5.3 
SCREENING FAILURES .......................................................................................................................................... 20 
6. 
ASSESSMENTS & SCHEDULE .............................................................................................................. 20 
6.1 
SCREENING ASSESSMENTS .................................................................................................................................... 20 
6.2 
ON-STUDY BASELINE ASSESSMENTS ....................................................................................................................... 21 
6.3 
EVALUATION DURING TREATMENT ......................................................................................................................... 22 
6.4 
EVALUATION DURING FOLLOW-UP ......................................................................................................................... 22 
6.5 
END OF STUDY AND POST-TREATMENT FOLLOW-UP VISITS........................................................................................... 23 
6.6 
STUDY CALENDAR ............................................................................................................................................... 24 
7. 
STUDY TREATMENT ............................................................................................................................. 25 
7.1 
OVERVIEW OF STUDY TREATMENT: INVESTIGATIONAL PRODUCT, CRENOLANIB ............................................................... 25 
7.2 
CRENOLANIB DOSE LEVELS AND DOSE ADJUSTMENTS ................................................................................................ 26 
7.3 
DOSE-LIMITING TOXICITY ..................................................................................................................................... 28 
7.4 
STUDY TREATMENT MANAGEMENT ....................................................................................................................... 29 
7.4.1 
Ordering and site supplies ................................................................................................................... 29 
7.4.2 
Labeling and packaging ....................................................................................................................... 29 
7.4.3 
Subject compliance .............................................................................................................................. 29 
7.4.4 
On site accountability .......................................................................................................................... 29 
7.4.5 
Recall .................................................................................................................................................... 30 
7.4.6 
Unused products .................................................................................................................................. 30 
7.5 
CONCOMITANT MEDICATIONS .............................................................................................................................. 30 
8. 
DISCONTINUATION............................................................................................................................... 32 
8.1 
STUDY TREATMENT DISCONTINUATION AND PREMATURE WITHDRAWAL ........................................................................ 32 
8.2 
STUDY DISCONTINUATION .................................................................................................................................... 33 


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8.3 
SITE DISCONTINUATION ....................................................................................................................................... 33 
9. 
CORRELATIVE STUDIES ...................................................................................................................... 34 
9.1 
PERIPHERAL BLOOD FOR PHARMACOKINETIC ASSAY .................................................................................................. 34 
10. 
CRITERIA FOR RESPONSE .................................................................................................................. 36 
10.1 
RESPONSE CRITERIA ....................................................................................................................................... 36 
11. 
ADVERSE EVENT REPORTING ........................................................................................................... 37 
11.1 
DEFINITIONS ................................................................................................................................................. 37 
11.2 
DETERMINATION OF SEVERITY .......................................................................................................................... 38 
11.3 
DETERMINATION OF RELATEDNESS .................................................................................................................... 38 
11.4 
REPORTING OF ADVERSE EVENTS ....................................................................................................................... 38 
11.5 
REPORTING OF SERIOUS ADVERSE EVENTS ........................................................................................................... 39 
11.6 
PREGNANCY ................................................................................................................................................. 41 
12. 
STATISTICAL CONSIDERATIONS ...................................................................................................... 42 
12.1 
STATISTICAL AND ANALYTICAL PLANS .................................................................................................................. 42 
12.1.1 
General considerations ................................................................................................................... 42 
12.1.2 
Determination of sample size .......................................................................................................... 42 
12.2 
SAFETY MONITORING AND STOPPING RULES FOR THE STUDY .................................................................................. 42 
13. 
DATA QUALITY MANAGEMENT ........................................................................................................ 44 
13.1 
DATA SAFETY MONITORING PLAN .................................................................................................................... 44 
13.2 
DATA QUALITY ASSURANCE ............................................................................................................................. 44 
14. 
REFERENCES .......................................................................................................................................... 45 
15. 
APPENDIX I. ADMINISTRATIVE PROCEDURES .............................................................................. 49 
16. 
APPENDIX II. PATIENT DIARIES: CRENOLANIB ............................................................................ 52 
17. 
APPENDIX III. LABORATORY MANUAL ........................................................................................... 55 
17.1 
FORM 1 ARO-011 INDUCTION 1 DAY __ PHARMACOKINETICS DATA COLLECTION FORM ......................................... 59 
17.2 
FORM 2 ARO-011 INDUCTION 1 DAY __ PHARMACOKINETICS DATA COLLECTION FORM ......................................... 60 
18.    APPENDIX IV. CONTACT INFORMATION .............................................................................................. 61 
19. 
APPENDIX V. HY’S LAW ............................................................................................................................. 62 
20. 
APPENDIX VI. CYP3A4 DRUGS POTENTIALLY AFFECTING CRENOLANIB 
PHARMACOKINETICS ................................................................................................................................... 66 
 
 
 
 
 
 
 
 
 
 


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List of Figures 
Figure 1 Overall survival estimates in the intention-to-treat population of elacytarabine versus 
investigator’s choice of current salvage therapies by Kaplan-Meier test ..................................... 11 
Figure 2 Overall survival in the intention-to-treat population of investigator’s choice of current 
salvage therapies by Kaplan-Meier test ........................................................................................ 12 
Figure 3 Event-free survival in the sorafenib arm vs. placebo ..................................................... 14 
Figure 4 FLT3 ligand levels increase following multiple regimens of intensive chemotherapy .. 14 
Figure 5 Peripheral blast clearance in FLT3 mutant AML patients treated with crenolanib ....... 15 
 
 
List of Tables 
Table 1 30-day, 60-day mortality rates of elacytarabine and investigator’s choice ..................... 11 
Table 2 Pivotal studies using the HAM regimen as salvage ......................................................... 13 
Table 3 Screening Assessments .................................................................................................... 20 
Table 4 On-Study Baseline Assessments ...................................................................................... 21 
Table 5 Post-treatment Discontinuation Visit Assessments ......................................................... 22 
Table 6 Crenolanib dose reduction schedule ................................................................................ 26 
Table 7 Crenolanib dose reduction for non-hematologic toxicities related to crenolanib ............ 26 
Table 8 Crenolanib dose reduction for bilirubin elevation ........................................................... 27 
Table 9 Crenolanib dose reduction for elevation of AST, ALT, Alk Phos .................................. 27 
Table 10 Suggested therapy for nausea and vomiting (ASCO 2011 guidelines [41]) .................. 31 
Table 11 Suggested therapy for diarrhea ...................................................................................... 31 
 
 
 


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LIST OF ABBREVIATIONS 
Term 
Definition 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia  
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BID 
Twice daily 
CBC 
Complete blood count 
Cmax 
Maximum concentration of drug in serum 
CMP 
Complete metabolic panel 
CR 
Complete remission 
CRi 
Complete remission with incomplete count recovery 
CRF 
Case report form  
CTCAE 
Common terminology criteria for adverse events 
DARF 
Drug accountability record form 
DLT 
Dose limiting toxicity 
DoR 
Duration of response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EFS 
Event-free survival 
EKG 
Electrocardiogram 
EOS 
End of study 
FLAG 
Fludarabine, Ara-C, G-CSF 
FLT3 
FMS-like tyrosine kinase 3 
FLT3-ITD 
FMS-like tyrosine kinase 3 – internal tandem duplication 
FLT3-TKD 
FMS-like tyrosine kinase 3 – tyrosine kinase domain 
GCP 
Good clinical practice 
GVHD 
Graft versus host disease 
HAM 
High-dose cytarabine and mitoxantrone 
HiDAC 
High-dose cytarabine 
HR 
Hazard ratio 
HSCT 
Hematopoietic stem-cell transplant 
IB 
Investigator Brochure 


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ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
Ida 
Idarubicin 
IDAC 
Intermediate-dose cytarabine 
IMP 
Investigational medicinal product(s) 
IRB/IEC 
Institutional review board/ Independent ethics committee 
ITT 
Intent-to-treat 
IVRS 
Interactive voice response system 
KM curve 
Kaplan-Meier curve 
LFT 
Liver function test 
MEC 
Mitoxantrone, Etoposide, Cytarabine 
MTD 
Maximum tolerated dose 
MTZ 
Mitoxantrone 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PDGFRα 
 
Platelet-derived growth factor receptor alpha  
PFS 
 
  
Progression-free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PS 
Performance Status 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RFS 
Relapse-free survival 
R/R 
Relapsed/Refractory  
RR 
Response Rate 
RTK 
Receptor tyrosine kinase 
SAE 
Serious adverse event 
SD 
Stable disease 
SOC 
Standard of care 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t1/2  
Half-life 
TID 
Three times daily 
TKI 
 
 
Tyrosine kinase inhibitor 
tmax 
Time that drug is at maximum concentration in serum 
QD 
Once daily 


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ULN 
Upper limit of normal 
WOCBP 
Women of child-bearing potential 
 
DEFINITION OF TERMS 
Term 
Definition 
Adverse Drug 
Reaction 
Any adverse event that is deemed to be at least possibly related to the study 
drug. 
Audit 
A systematic and independent examination of the trial-related activities and 
documents to determine whether the evaluated trial-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s). 
Case Report Form 
(CRF) 
Sometimes referred to as clinical report form:  a printed or electronic form 
for recording study participants’ data during a clinical study, as required by 
the protocol. 
Compliance 
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
Consent 
The act of obtaining informed consent for participation in a clinical trial 
from subjects deemed eligible or potentially eligible to participate in the 
clinical trial.  Individuals entered into a trial are those who sign the informed 
consent document directly or through their legally acceptable 
representatives. 
Enrolled Subject 
An enrolled subject is a subject who has signed the informed consent form, 
completed all screening evaluations, has been deemed eligible for the trial 
by the investigator and sponsor and has been enrolled. 
Ethics Committee 
All appropriate properly constituted committees or boards recognized by the 
appropriate regulatory agencies for approving clinical studies. Including the 
independent ethics committee and institutional review boards. 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site.  If a 
trial is conducted by a team of individuals at a trial site, the investigator is 
the responsible leader of the team and may be called the principal 
investigator. 
Institutional Review 
Board/ Ethics Review 
Board (IRB/ERB) 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that the 
safety, welfare, and human rights of the subjects participating in a clinical 
trial are protected. 
Regulation 
All appropriate regulations, laws and guidelines.  
Screening Period 
The screening period begins when the subject signs the Informed Consent 
Form and continues until randomization. 
Screen Failure 
A screen failure refers to subjects who have signed the Informed Consent 
Form but do not subsequently enroll in the trial. Data from these subjects 
will be recorded in the screening log, but not entered into the study 
database.  
Treatment period 
The time period from administration of the first dose of study drug through 
the end of the one month post-treatment discontinuation visit. 
 
 
 


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1. SYNOPSIS 
Name of Investigational Product 
Crenolanib Besylate  
Title of Study 
Pilot study of Crenolanib Combined with Standard Salvage Chemotherapy in Subjects with 
Relapsed/Refractory Acute Myeloid Leukemia 
Version and Date of Protocol   
Version 3.0, June 7, 2016 
Planned number of subjects and investigational sites 
Approximately 72 subjects (~24 in each cohort) will be enrolled across approximately 10 sites in the U.S. 
Study Rationale 
Treatment of newly-diagnosed acute myeloid leukemia (AML) with standard chemotherapy regimens, 
such as anthracyclines and cytarabine, can lead to high complete remission (CR) rates (ranging from 60-
70%). Unfortunately, the majority of these patients will relapse.  
 
Upon relapse, the prognosis for a second remission or response in these patients significantly worsens. 
Currently, patients who are refractory or relapsed following standard induction therapy have no 
standardized treatment options. Several combinations have been suggested and each achieve similar 
outcome. High-dose cytarabine combined with mitoxantrone (HAM) has been shown to be associated 
with high CR rates in relapsed/refractory (R/R) AML. Two additional aggressive salvage chemotherapies, 
as per National Comprehensive Cancer Network (NCCN) guidelines, are also common options for 
relapsed/refractory patients:  the combination of mitoxantrone, etoposide, and cytarabine (MEC) and the 
combination of fludarabine, cytarabine, G-CSF and idarubicin (FLAG-Ida). However, it has been proven 
difficult to achieve full prolonged responses with these chemotherapy agents alone. 
 
Recent studies have shown that in AML, the addition of a tyrosine-kinase inhibitor (TKI) to standard 
chemotherapy in a sequential manner is feasible and associated with anti-leukemic efficacy. A 
randomized study (SORAML) has shown that the addition of a sorafenib to standard chemotherapy 
resulted in a significantly prolonged event-free survival (EFS) and relapse-free survival (RFS). This data 
has also suggested that this treatment regimen can be beneficial and effective in both FLT3 (Fms-related 
tyrosine kinase 3) wild-type and FLT3 ITD (FLT3 – Internal Tandem Duplication) AML.  
 
Crenolanib besylate is a second generation TKI with high potency and selectivity against both wild-type 
FLT3 and its constitutively active mutant isoforms including FLT3-ITD mutation and also tyrosine kinase 
domain (TKD) point mutations including the D835 TKD mutation.  Clinical safety data of crenolanib is 
available for over 200 patients.  Specifically, there are data in 66 patients with R/R FLT3 ITD and/or 
TKD mutant AML, which demonstrates clinical benefit in approximately 50% of these AML patients 
with responses that included complete remission (CR), complete remission with incomplete blood count 
recovery (CRi) and partial remission (PR).   
 
The proposed study is designed combine crenolanib with salvage chemotherapies, including HAM, MEC 
or FLAG-Ida to treat patients with R/R AML irrespective of FLT3 status. The rationale for this study is as 
follows: 
(1) There is clinical evidence for improved event-free survival in AML with the combination of a TKI 
and chemotherapy; 
(2) HAM, MEC, and FLAG-Ida have been shown to improve the outcome in patients with R/R AML; 


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(3) Sequential administration of chemotherapy followed by a TKI is feasible and can achieve synergistic 
cytotoxicity. 
 
Study Design  
Open label, dose de-escalation, phase 1b pilot trial of crenolanib with standard salvage chemotherapy. 
Subjects may receive up to 2 cycles of induction with standard salvage chemotherapy followed by 
crenolanib. Each arm will enroll approximately 24 patients (72 total); stratification to each arm will be per 
physician’s choice. 
 
 
 
 
 
 
 
 
 
 
Arm A (HAM + crenolanib) 
Subjects 18-60 years of age who have not undergone a prior allogeneic hematopoietic stem cell transplant 
(HSCT): 
 
Mitoxantrone 
 
10 mg/m² IV, over ≤ 30 mins                 days 1-3 
 
Cytarabine 
 
1000 mg/m² IV, over 3 hours 
            days 1-6 
 
Crenolanib                      100 mg TID p.o.                                  starting day 7 (+3 day) 
 
For subjects > 60 years, or subjects who have undergone a prior allogeneic HSCT, or subjects who need a 
second re-induction HAM cycle, the following reduced doses will be used: 
 
Mitoxantrone 
 
8 mg/m² IV, over ≤ 30 mins                   days 1-3 
 
Cytarabine 
 
500 mg/m² IV, over 3 hours 
            days 1-6 
 
Crenolanib                     100 mg TID p.o.                                   starting day 7 (+3 day) 
 
Arm B (MEC + crenolanib) 
Patients >18 years of age: 
 
Mitoxantrone   
8 mg/m² IV, push  
 
 
days 1-5 
 
Etoposide   
 
100 mg/m2 IV  
 
 
days 1-5 
 
Cytarabine   
 
1000 mg/m² IV, over 3 hours    
days 1-5 
 
Crenolanib 
 
100 mg TID  
 
 
 
starting day 7 (+3 day) 
 
Arm C (FLAG-Ida + crenolanib): 
Patients >18 years of age: 
 
Fludarabine     
30 mg/m2 IV    
 
 
day 1-5  
 
Cytarabine    
 
2 g/m2 IV over 2 hrs   
 
 
day 1-5 
 
G-CSF    
 
300 ug s.c. inj or IV/5ug/kg SC    
day 6 - neutrophil recovery           
 
Idarubicin   
 
 8 mg/m2 IV over 30 min   
 
day 1-3 
 
Crenolanib 
 
100 mg TID  
 
 
 
starting day 7 (+3 day) 
Primary Objective 
 
To determine the safety, dose limiting toxicities and maximum tolerated dose (or confirm the 
target dose of 100 mg TID) of crenolanib given sequentially following standard salvage 
chemotherapy regimens in subjects with refractory/relapsed AML 
 
Relapsed / 
Refractory 
AML 
End of 
Treatment 
Visit 


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Secondary Objectives 
 
To determine the response rate, duration of response, progression-free survival, and overall 
survival of crenolanib when given sequentially following standard salvage chemotherapy 
regimens in subjects with refractory/relapsed AML  
 
To determine the pharmacokinetics of crenolanib when given sequentially following standard 
salvage chemotherapy regimens in subjects with refractory/relapsed AML 
 
 
Inclusion Criteria 
1. Confirmed diagnosis of AML, including treatment-related secondary AML (except prior MDS) 
according to World Health Organization (WHO) 2008 classification at treating institution 
2. Subjects who are refractory* or who have relapsed** following first line AML therapy with 
cytarabine/anthracycline based chemotherapy, with or without a tyrosine kinase inhibitor.  
*Refractory to induction therapy is defined as never achieving CR, CRi or CRp (according 
to International Working Group criteria) after one line of intensive regimen for AML (re-
induction, consolidation and/or transplant allowed) including at least one cytarabine 
containing induction block with a total dose no less than 700mg/m² per cycle and 3 days of 
an anthracycline with or without a TKI. 
or 
**First relapse is defined as untreated hematologic relapse (according to International 
Working Group criteria) after one line of intensive regimen for AML (re-induction, 
consolidation and/or transplant allowed) including at least one cytarabine containing 
induction block with a total dose no less than 700mg/m² per cycle and 3 days of an 
anthracycline with or without a TKI that induced a CR/CRi/CRp. Subjects are allowed to 
receive induction, consolidation, transplant and/or maintenance prior to achieving their first 
CR/CRi/CRp. 
3. Subjects considered eligible for intensive chemotherapy 
4. ECOG performance status ≤ 2 
5. Age ≥ 18 years   
6. Adequate liver function within 72 hours of enrollment, defined as:  
• Normal total serum bilirubin 
• ALT and AST ≤ 2.0 x ULN  
7. Adequate renal function, defined as serum creatinine ≤ 1.5x ULN 
8. Women of childbearing potential must have a negative serum or urine pregnancy test with a 
sensitivity of at least 25 mIU/mL within 72 hours prior to enrollment  
 
“Woman of childbearing potential” is defined as any woman who has not undergone a 
hysterectomy and who has had menses at any time in the preceding 24 consecutive 
months 
9. Women of child-bearing potential must either commit to continued abstinence from heterosexual 
intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner’s 
vasectomy) while on crenolanib and for 3 months following the last dose of crenolanib.  
Hormonal contraception alone is not an acceptable method of birth control for the 
purpose of this trial. 
10. Men must use a latex condom during any sexual contact with women of childbearing potential, 
even if they have undergone a successful vasectomy and must agree to avoid to father a child 
(while on therapy and for 3 month after the last dose of crenolanib). 
11. Willing to adhere to protocol specific requirements 
12. Following receipt of verbal and written information about the study, the subject must provide 


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signed informed consent before any study related activity is carried out. 
13. Clinically significant toxic effects of prior therapy (expect hydroxyurea) resolved to Grade ≤ 1 
before the start of study. 
 
 
Exclusion Criteria 
1. < 5% blasts in blood or marrow at screening, except if measurable extramedullary AML is 
confirmed  
2. Acute promyelocytic leukemia (APL) 
3. Known clinically active CNS leukemia 
4. Clinically active or unstable graft-versus-host disease (GvHD) requiring treatment which 
precludes administration of chemotherapy as defined in this protocol 
5. Prior anti-leukemia therapy within 14 days of enrollment for classical cytotoxic agents, and 
within 5x the half-life for other investigational agents 
• Prior use of hydroxyurea or isolated doses of cytarabine for palliation (i.e., control of 
WBC) are allowed but should be discontinued at least 24 hrs prior to enrollment. 
• Other agents used strictly with palliative intent might be allowed during this period after 
discussing with principal investigator 
6. Pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, 
sclerosing cholangitis) 
7. Known HIV infection. 
8. Evidence of ongoing, uncontrolled systemic infection or an uncontrolled local infection requiring 
therapy at the start of study.  
9. “Currently active” second malignancy (other than non-melanoma skin cancer, carcinoma in situ 
of the cervix or prostatic intraepithelial neoplasia within 1 year). Subjects are not considered to 
have a “currently active” malignancy if they have completed therapy and are considered by their 
physician to be at less than 30% risk of relapse within 1 year. 
10. Concurrent participation in another therapeutic clinical trial.  
11. Pregnant or breastfeeding women  
12. Subjects of childbearing potential not willing to use adequate contraception during study and 3 
months after last dose of crenolanib 
13. Subject with uncontrolled cardiac disease including congestive heart failure class III or IV by the 
NYHA, unstable angina (anginal symptoms at rest) or new onset angina (began within the last 
3 months) or myocardial infarction within the past 6 months 
14. Subject with concurrent severe and/or uncontrolled medical or psychiatric conditions that in the 
opinion of the investigator may impair the participation in the study or the evaluation of safety 
and/or efficacy 
15. Inability to give an informed consent 
 
 
Statistical Methods 
Initially, the study will evaluate DLT and determine the maximum tolerated dose (or confirm the target 
dose of 100 mg TID) of crenolanib in combination with either HAM (Arm A), MEC (Arm B) or FLAG-
Ida (Arm C) chemotherapy.  Thereafter, the study will include a dose-expansion cohort. 
For each arm, an initial 6 subjects will be enrolled at a crenolanib dose of 100 mg TID and will be 
evaluated for DLT, as follows: 
 
The DLT period will be 28 days 
o Assessment of potential hematologic DLTs that started during the DLT period will 
extend for up to 6 weeks following the start of the event (see definition of hematologic 
DLT)  
 
DLT will be defined as any clinically significant adverse event or abnormal laboratory value that 


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is not related to concomitant medications, co-morbidities or underlying disease (leukemia), and 
that is not expected for the chemotherapy being used together with crenolanib 
 
The following will be considered to be DLT: 
 
Non-hematologic DLT: 
 
Any grade 3 or 4 non-hematologic toxicity despite optimal supportive care 
o For example, grade 3 or 4 nausea, vomiting, or diarrhea that cannot be controlled with 
standard antiemetic or antidiarrheal medications used at optimal dose within 72 hours of 
onset  
 
Any tumor lysis syndrome    
Hematologic DLT: 
 
Grade ≥ 3 neutropenia and/or thrombocytopenia with a hypocellular bone marrow lasting for 6 
weeks or more after the last dose of therapy in the absence of residual leukemia (i.e., with less 
than 5% blasts) 
o Anemia will not be considered a DLT 
 
For each arm, prior to determining the maximum tolerated dose (or confirming the target dose of 100 mg 
TID) of crenolanib based on DLT, subjects will be enrolled in a sequential manner such that no more than 
6 subjects are within 30 days of starting induction 1 therapy. See Section 12.2.1 for dose de-escalation 
and stopping rules based on dose-limiting toxicity. 
 
For each arm, following the determination of the maximum tolerated dose (or the target dose) of 
crenolanib, subject safety and early mortality will be monitored in cohorts of six throughout the study. 
Enrollment may be halted at any time based on safety reviews. See Section 12.2.2 for the study’s stopping 
rules following the determination of the maximum tolerated dose (or the target dose) for crenolanib. 
 
Descriptive statistics will be used to summarize the safety and efficacy data for this study. Categorical 
data will be summarized by number and percentage of subjects in each category. Time-to-event endpoints 
will be summarized using the cumulative incidence and Kaplan-Meier methodology. 
 


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2. BACKGROUND AND STUDY RATIONALE 
2.1 Unmet Medical Need in Relapsed or Refractory Acute Myeloid Leukemia 
Treatment of newly-diagnosed acute myeloid leukemia (AML) with standard chemotherapy 
regimens, such as anthracyclines and cytarabine, can lead to high complete remission (CR) rates 
(ranging from 60-70%). Unfortunately, the majority of these patients will relapse. Upon relapse, 
the prognosis for a second remission or response in these patients significantly worsens. 
 
Currently, there are multiple commonly used AML salvage regimens: high-dose cytarabine, 
multi-agent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care. Roboz, et 
al conducted a large international, randomized Phase III clinical trial to investigate the efficacy 
of elacytarabine (a novel elaidic acid ester of cytarabine) versus investigator’s choice of 
currently available salvage therapies. A total of 381 patients with relapsed/refractory (R/R) AML 
were enrolled in North America, Europe, and Australia.  
 
The study results showed no significant differences in OS (3.5 v 3.3 months), response rate (23% 
v 21%), or relapse-free survival (RFS) (5.1 v 3.7 months) between the elacytarabine and control 
arms, respectively. As shown in Figure 1, overall survival (OS) in both study arms and for all 
treatments was extremely poor. [36] These results bring to light the need for new treatment 
options in this patient population.  
Figure 1 Overall survival estimates in the intention-to-treat population of elacytarabine 
versus investigator’s choice of current salvage therapies by Kaplan-Meier test 
 
Table 1 30-day, 60-day mortality rates of elacytarabine and investigator’s choice 
 
Total ITT Population (N=381) 
Parameter 
No. of patients 
% 
Early mortality, days 
30 
59 
16 
60 
117 
32 


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2.2 Physician’s Choice of Salvage Chemotherapy Agents in Relapsed/Refractory AML 
As mentioned above in section 2.1, Roboz et al showed that there is not a significant difference 
in OS, RR, or RFS between the elacytarabine and control arm of investigator’s choice salvage 
regimen. Furthermore, figure below, shows the overall survival curves of different salvage 
regimens (including FLAG-Ida and MEC). These curves show the similarity of the effects of the 
different salvage regimens on overall survival. MEC and FLAG-Ida had 30 day mortality rates of 
19% and 11% respectively. As these salvage regimens have shown similar outcomes, physician’s 
choice of salvage regimen allows the treatment to be chosen based on the individual patient and 
disease characteristics/status. 
Figure 2 Overall survival in the intention-to-treat population of investigator’s choice of 
current salvage therapies by Kaplan-Meier test 
 
2.3 Efficacy of HAM, MEC and FLAG-Ida in Relapsed/Refractory AML 
MEC and FLAG-Ida have both been shown to provide responses in refractory or early relapse 
AML patients. In a single-center study, the combination of mitoxantrone, etoposide, and 
cytarabine (MEC) given as first salvage has shown to achieve a CR of 18% in 77 patients 
(median age: 54) who were refractory to conventional induction therapy or relapsed after 
achieving first CR [43]. The efficacy of FLAG-IDA was evaluated as first or second salvage in 
primary refractory or relapsed AML patients, and a CR/CRi of 73% was reported in 48 patients 
(median age: 50) [42].  
 
High-dose cytarabine in combination with mitoxantrone (HAM) has also been shown to improve 
the outcome in patients with R/R AML. Results from a Phase I/II study conducted by the 
German AML Cooperative Group showed that HAM has high antileukemic activity in refractory 
AML. High-dose cytarabine with mitoxantrone was associated with a longer OS in patients with 
poor prognostic features. Of the 40 patients with refractory AML, 21 achieved a complete 
remission (53%) and 1 patient had a partial remission. [32] 
 
Furthermore, in 2 prospective randomized studies, the high-dose cytarabine with mitoxantrone 
(HAM) regimen showed significant clinical activity in R/R AML patients (Table 2). In a 


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prospective randomized pivotal trial, Karanes C et al compared HiDAC (high-dose cytarabine) 
versus HiDAC + MTZ (mitoxantrone) in relapsed/refractory AML patients. 162 patients were 
evaluable for response to induction therapy, with 81 patients on each arm. There was trend 
toward a higher CR rate (from 32% to 44%) with combination HiDAC + MTZ compared to 
single agent HiDAC. [40] 
 
Kern W et al. performed a randomized study comparing high-dose versus intermediate-dose 
cytarabine with mitoxantrone in patients with R/R AML. The remission rate and disease free 
survival were similar in patients getting 3 g/m2 of cytarabine for 8 doses as compared to patients 
getting 1 g/m2 of cytarabine for 8 doses. These data suggest that cytarabine at cumulative doses 
of 6-8 g/m2 in combination with MTZ may provide effective complete remission rates in 
relapsed AML. [31] Hence, this pilot study is using cytarabine at a dose of 6 g/m2 along with 
MTZ as salvage chemotherapy in patients with relapsed AML. 
Table 2 Pivotal studies using the HAM regimen as salvage 
Reference 
Study design 
Regimens 
Number of 
patients 
Refractory/ 
relapsed 
Median age 
(yrs) 
% CR 
Karanes C, et 
al. 1999 [40] 
Phase 3, 
randomized 
HiDAC vs 
HiDAC + 
MTZ 
162 (81 on 
each arm) 
56/106 
48 vs 53 
32 vs 44 
Kern W, et al. 
1998 [31] 
Phase 3, 
randomized 
HiDAC + 
MTZ vs 
IDAC + MTZ 
186 
27/159 
50 
47 
 
2.4 Clinical Evidence of Combining a Tyrosine Kinase Inhibitor with Chemotherapy 
in AML Patients 
Röllig, et al performed a randomized study (SORAML trial) of sorafenib versus placebo as add-
on to standard induction in AML patients (irrespective of the Fms-like tyrosine kinase 3 (FLT3) 
mutation status). Two cycles of induction were allowed (initially with daunorubicin plus 
cytarabine; patients without response after 1 cycle received a 2nd induction with HAM). 
Consolidation treatment consisted of up to 3 cycles of high-dose cytarabine. 267 patients were 
enrolled on the study (134 patients received sorafenib and 133 received placebo). Only 46 of 267 
(17%) were FLT3 internal tandem duplication (ITD) positive. [34] 
 
Addition of sorafenib to cytarabine/anthracycline chemotherapy resulted in a statistically 
significant improvement in event-free survival (EFS) (the median EFS was 20.5 months in the 
sorafenib arm vs. 9.2 months in the placebo arm, p=0.013). These data suggest that in AML 
patients, the addition of a tyrosine kinase inhibitor (TKI) to standard chemotherapy in a 
sequential manner is feasible and associated with anti-leukemic efficacy in both FLT3 wild-type 
and FLT3 ITD AML patients. [34] 
 
 
 


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Figure 3 Event-free survival in the sorafenib arm vs. placebo 
 
2.5 FLT3 Ligand Levels Increase Following Administration of Chemotherapy 
It has been shown that plasma FLT3 ligand levels increase by 2-3 log order following intensive 
chemotherapy in patients with AML. In newly diagnosed AML patients, FLT3 ligand levels rose 
to 488 pg/mL after course one of chemotherapy and as high as 3251 pg/mL after the fourth 
course of chemotherapy. [35] These data suggest that the high level of FLT3 ligand in patients 
following intensive chemotherapy may actually be protective, or even stimulatory, to residual 
stem cells. Thus, it may be beneficial to add a selective FLT3 inhibitor following chemotherapy.  
Figure 4 FLT3 ligand levels increase following multiple regimens of intensive 
chemotherapy