Clinical trial NCT02283177
Conditions: Newly Diagnosed AML With FLT3 Activating Mutations
Sponsor: Arog Pharmaceuticals, Inc.
Start date: 2015-01-01; Completion date: 2019-12-01
Enrollment: 44 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot study is designed to evaluate the safety and tolerability of oral crenolanib besylate given sequentially during standard induction and consolidation chemotherapy in patients with newly diagnosed AML with FLT3 activating mutations.

Detailed description:

Arms: arm 1: Patients will be given cytarabine and daunorubicin during induction therapy plus crenolanib at 100 mg TID. arm 2: Patients will be given cytarabine and idarubicin during induction therapy plus crenolanib at 100 mg TID.
Interventions: intervention 1: crenolanib intervention 2: cytarabine intervention 3: daunorubicin intervention 4: idarubicin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
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A Study of Crenolanib and Chemotherapy with Cytarabine 
and Anthracyclines in Patients with Newly Diagnosed Acute 
Myeloid Leukemia with FLT3 Activating Mutations 
 
PROTOCOL ARO-006 
 
VERSION 2.0 
 
Date: January 4, 2017 
 
 
AROG PHARMACEUTICALS, INC. 
TWO LINCOLN CENTRE 
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 
(AR-868,596), unless such persons are bound by a confidentiality agreement with AROG 
Pharmaceuticals, Inc., or its subsidiaries. 
 
 
 


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SIGNATURE PAGES 
 
Protocol Lead responsible for designing the clinical trial: 
I approve the design of the clinical trial. 
 
__________________________________ _______________________________ 
Signature 
 
 
 
 
 
Date of Signature 
 
Name, academic degree 
Vinay Jain, MD 
 
 
 
 
Chief Executive Officer 
Institution 
 
 
Arog Pharmaceuticals, Inc. 
Address 
 
 
5420 Lyndon B Johnson Freeway, Suite 410, Dallas, TX 75240 
Telephone number 
 
214-207-8003 
Fax number 
 
 
214-594-0002 
E-mail address 
 
vjain@arogpharma.com 
 
 
 
 
 


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Trial Title  
A Study of Crenolanib and Chemotherapy with 
Cytarabine and Anthracyclines in Patients with 
Newly Diagnosed Acute Myeloid Leukemia with 
FLT3 Activating Mutations 
 
IND Number   
 
 
 
118,143 
Clinical Trial Protocol Version Date  
4 January, 2017 
Center Number 
 
_______________________________________ 
Principal Investigator 
 
_______________________________________ 
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that: 
 
 
I understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, ICH Good Clinical Practice (ICH Topic E6 GCP) and all applicable Health Authority 
requirements and national laws. 
 
I will not deviate from the clinical trial protocol without prior written permission from the Sponsor and 
prior review and written approval from the Institutional Review Board or Independent Ethics Committee, 
except where necessary to prevent immediate danger to the subject. 
 
I understand that some Health Authorities require the Sponsors of clinical trials to obtain and supply, when 
required, details about the Investigators’ ownership interests in the Sponsor or Investigational Medicinal 
Product and information regarding any financial ties with the Sponsor.  
 
The Sponsor will use any such information that is collected solely for the purpose of complying with the 
regulatory requirements. I therefore agree to supply the Sponsor with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent children), and to provide 
updates as necessary. 
 
__________________________________ ____________________________ 
Signature  
 
 
 
 
 
Date of Signature 
Name, academic qualifications  
 
 
____________________________ 
Position (job title)  
 
 
 
 
____________________________ 
Address of Institution  
 
 
 
____________________________ 
Phone and fax  
 
 
 
 
____________________________ 
E-mail  
 
 
 
 
 
____________________________ 
 
 
 
 
 
 


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Table of Contents 
1. 
OVERVIEW OF THE TREATMENT PLAN ................................................................................................ 7 
2. 
SPONSOR CONTACT INFORMATION ...................................................................................................... 9 
3. 
SYNOPSIS .................................................................................................................................................... 10 
3.1. 
Rationale for the Proposed Study .................................................................................................... 10 
3.2. 
Study Synopsis ................................................................................................................................ 11 
4. 
ABBREVIATIONS AND DEFINITIONS ................................................................................................... 14 
5. 
BACKGROUND ........................................................................................................................................... 17 
5.1. 
Crenolanib inhibits wild-type FLT3 and its constitutively active mutations .................................. 17 
5.2. 
Crenolanib has reduced activity against KIT .................................................................................. 17 
5.3. 
Synergistic activity of crenolanib in combination with cytarabine ................................................. 18 
5.4. 
Antileukemic activity of crenolanib in combination with daunorubicin ......................................... 19 
5.5. 
Clinical studies of crenolanib in AML ............................................................................................ 19 
5.5.1. 
Clinical summary of crenolanib in relapsed/refractory FLT3 mutated AML ................... 19 
5.6. 
Tolerability of crenolanib in AML patients who had undergone prior allogeneic bone marrow 
transplant ......................................................................................................................................... 20 
5.7. 
Long-term Safety Data of Crenolanib ............................................................................................. 20 
5.8. 
Rationale for Crenolanib Dose and Schedule.................................................................................. 20 
6. 
STUDY OBJECTIVES ................................................................................................................................. 22 
6.1. 
Primary Objective ........................................................................................................................... 22 
6.2. 
Secondary Objectives ...................................................................................................................... 22 
6.3. 
Exploratory Objectives ................................................................................................................... 22 
7. 
SUBJECT ELIGIBILITY .............................................................................................................................. 23 
7.1. 
Inclusion Criteria ............................................................................................................................ 23 
7.2. 
Exclusion Criteria ........................................................................................................................... 23 
7.3. 
Protocol Registration....................................................................................................................... 24 
7.4. 
Discontinuations ............................................................................................................................. 24 
7.4.1. 
Discontinuations of Study Drugs and Disease status/Survival Follow up of Patients ...... 24 
7.4.2. 
Discontinuation of Study Sites ......................................................................................... 25 
7.4.3. 
Discontinuation of the Study ............................................................................................ 25 
8. 
TREATMENT PLAN ................................................................................................................................... 26 
8.1. 
Summary of Treatment ................................................................................................................... 26 
8.2. 
Study Design ................................................................................................................................... 26 
8.2.1. 
Induction ........................................................................................................................... 26 
8.2.2. 
Consolidation .................................................................................................................... 27 
8.2.3. 
Maintenance ...................................................................................................................... 27 
8.3. 
Treatment with Crenolanib (AR-868,596) ...................................................................................... 28 
8.4. 
Dosing and Dose Modification of Crenolanib ................................................................................ 29 
8.4.1. 
Dose Reductions for Non-hematologic Toxicities ............................................................ 29 
8.4.2. 
Dose Reductions of Crenolanib for Hematologic Toxicities ............................................ 30 
8.5. 
Other Dose Hold and Dose Reduction ............................................................................................ 30 
8.6. 
Concomitant Therapy ...................................................................................................................... 30 
9. 
DRUG FORMULATION, AVAILABILITY, AND PREPARATION ........................................................ 32 
9.1. 
Crenolanib ....................................................................................................................................... 32 


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9.1.1. 
Drug-Drug Interaction ...................................................................................................... 32 
9.2. 
Chemotherapy ................................................................................................................................. 32 
9.2.1. 
Cytarabine ......................................................................................................................... 32 
9.2.2. 
Idarubicin .......................................................................................................................... 32 
9.2.3. 
Daunorubicin .................................................................................................................... 32 
10. 
STUDY PROCEDURES ............................................................................................................................... 33 
10.1. 
Screening......................................................................................................................................... 33 
10.2. 
Baseline… ....................................................................................................................................... 33 
10.3. 
Evaluation during treatment ............................................................................................................ 34 
10.4. 
At time of progression or completion of study................................................................................ 35 
11. 
PHARMACOKINETIC AND CORRELATIVE STUDIES ......................................................................... 36 
12. 
RESPONSE DEFINITIONS ......................................................................................................................... 38 
12.1. 
Response Criteria ............................................................................................................................ 38 
13. 
STATISTICAL CONSIDERATIONS .......................................................................................................... 39 
13.1. 
Statistical and analytical plans ........................................................................................................ 39 
13.1.1. General considerations ...................................................................................................... 39 
13.1.2. Determination of sample size ........................................................................................... 39 
13.2. 
Safety monitoring during the initial safety phase ............................................................................ 40 
13.2.1. Excessive early mortality .................................................................................................. 40 
13.2.2. Excessive expected crenolanib-related toxicity ................................................................ 41 
13.2.3. Excessive unexpected crenolanib-related toxicity ............................................................ 41 
13.3. 
Assessments during the expansion phase ........................................................................................ 42 
13.3.1. Safety monitoring during the expansion phase ................................................................. 42 
13.3.2. Response Rate Evaluation ................................................................................................ 42 
13.4. 
Subject Disposition ......................................................................................................................... 42 
13.5. 
Subject Characteristics .................................................................................................................... 42 
13.6. 
Concomitant Therapy ...................................................................................................................... 42 
13.7. 
Response Outcome and Methodology............................................................................................. 42 
13.8. 
Safety Analyses ............................................................................................................................... 42 
13.9. 
Criteria for End of Study ................................................................................................................. 43 
14. 
SAFETY EVALUATIONS AND APPROPRIATENESS OF MEASUREMENTS .................................... 44 
14.1. 
Definitions of Adverse Events ........................................................................................................ 44 
14.1.1. Adverse Event (AE) .......................................................................................................... 44 
14.1.2. Serious AE (SAE) ............................................................................................................. 44 
14.2. 
Attribution to Study Drug ............................................................................................................... 44 
14.3. 
Determination of Severity ………………………………………………………………………...45 
14.4. 
Adverse Event Reporting ................................................................................................................ 45 
14.5. 
Serious Adverse Event Reporting ................................................................................................... 46 
14.6. 
Follow-up of Adverse Events.......................................................................................................... 47 
14.7. 
Miscellaneous adverse events ......................................................................................................... 48 
14.8. 
Deaths ……………………………………………………………………………………………48 
14.9. 
Pregnancy ........................................................................................................................................ 49 
14.9.1. Maternal exposure ............................................................................................................ 49 
14.9.2. Paternal exposure .............................................................................................................. 49 


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14.10. 
Overdose ......................................................................................................................................... 49 
15. 
DATA COLLECTION AND MANAGEMENT .......................................................................................... 51 
15.1. 
Data Capture System ....................................................................................................................... 51 
15.2. 
Data Safety Monitoring Plan ........................................................................................................... 51 
16. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY CONSIDERATIONS ................. 52 
16.1. 
Informed Consent ............................................................................................................................ 52 
16.2. 
Document Review ........................................................................................................................... 52 
16.3. 
Confidentiality ................................................................................................................................ 52 
16.4. 
Investigator Information ................................................................................................................. 53 
16.5. 
Protocol Signatures ......................................................................................................................... 53 
16.6. 
Final Report Signature .................................................................................................................... 53 
16.7. 
Publication Statement ..................................................................................................................... 53 
17. 
REFERENCES .............................................................................................................................................. 54 
APPENDIX I. INCLUSION/EXCLUSION CRITERIA CHECKLIST ...................................................................... 55 
APPENDIX II. ECOG PERFORMANCE STATUS CRITERIA ............................................................................... 58 
APPENDIX III. PATIENT DIARIES: CRENOLANIB.............................................................................................. 59 
APPENDIX IV. STUDY SCHEDULE ....................................................................................................................... 64 
I. 
Induction ......................................................................................................................................... 64 
II. 
Consolidation .................................................................................................................................. 65 
III. 
Maintenance .................................................................................................................................... 66 
APPENDIX V. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS; VERSION 4.03 ................ 67 
APPENDIX VI. CYP3A4 DRUGS POTENTIALLY AFFECTING CRENOLANIB PHARMACOKINETICS ...... 69 
APPENDIX VII. THE WHO CLASSIFICATION OF ACUTE MYELOID LEUKEMIA[12] .................................. 70 
APPENDIX VIII. CONTACT INFORMATION AROG PHARMACEUTICALS .................................................... 72 
 
 
 


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Table of Tables 
Table 1 Dissociation constants of crenolanib with constitutively active FLT3 mutations ......................... 17 
Table 2 Cohort A: Cytarabine, daunorubicin induction .............................................................................. 26 
Table 3 Cohort B: Cytarabine, idarubicin induction ................................................................................... 27 
Table 4 Crenolanib dose reduction schedule .............................................................................................. 29 
Table 5 Crenolanib dose reduction for non-hematologic toxicities related to crenolanib .......................... 29 
Table 6 Crenolanib dose reduction for bilirubin elevation ......................................................................... 29 
Table 7 Crenolanib dose reduction for elevation of AST, ALT, Alk Phos ................................................. 30 
Table 8 Suggested therapy for nausea and vomiting (ASCO 2011 guidelines) .......................................... 31 
Table 9 Suggested therapy for diarrhea ...................................................................................................... 31 
Table 10 95% confidence interval based on response rate expected in approximately 120 patients .......... 40 
 
Table of Figures 
Figure 1 Schematic of inactive and active FLT3 with most common resistance mutations in AML.[8] ... 17 
Figure 2 Effects of crenolanib on uptake of cytarabine in AML cells. ....................................................... 18 
Figure 3 Crenolanib and cytarabine combination synergistically inhibit FLT3-ITD-positive cell 
viability in vitro. ............................................................................................................... 18 
Figure 4 Viability of FLT3 ITD cell lines treated with crenolanib and daunorubicin ................................ 19 
Figure 5 Peripheral blast clearance in FLT3 mutant AML patients treated with crenolanib. ..................... 20 
Figure 6 Pharmacokinetics analyses in AML patients on 100 mg crenolanib. ........................................... 21 
Figure 7 Representative PIA analysis of patient plasma samples after taking crenolanib single agent. ..... 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. OVERVIEW OF THE TREATMENT PLAN 
 
INDUCTION  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONSOLIDATION 
 
 
* Daunorubicin dose:  
 
90 mg/m2: Age < 60  
 
60 mg/m2: Age ≥ 60 or for 
patients who are <60 and 
receiving a second cycle of 
induction (per physician’s 
discretion) 
D1  D2  D3   D4   D5  D6  D7  D8  D9                                                                                                              D28 
Idarubicin 12 mg/m
2
 or Daunorubicin* 90/60 mg/m2 IV daily on days 1, 2, 3 
Cytarabine 100 or 200 mg/m
2
/day CIV days 1, 2, 3, 4, 5, 6, 7 
*Crenolanib 100 mg TID PO starting approximately 24-48 hrs after completion of Cytarabine 
D1  D2  D3   D4   D5  D6  D7                                                                                                                              D28 
High dose Cytarabine IV Q12 hours on days 1, 3, 5  
Crenolanib 100 mg TID PO starting approximately 24-48 hrs after completion of Cytarabine  
 
Crenolanib starts approximately 24-48 hours after completion of 
Cytarabine (+7-day window). Normal total bilirubin and ALT and 
AST ≤2.0x ULN are required within 24 hours prior to crenolanib 
commencement. Crenolanib can be delayed until these criteria are 
met. (If crenolanib will be delayed longer day 16, a discussion with PI 
and sponsor should be conducted to determine the best options for the 
patient) 
 
On first day of crenolanib, only one 100 mg dose given; from second 
day on, all three doses given (100 mg TID) 
 
A total of two cycles of induction will be allowed.  
 
Crenolanib should be held 72 hours prior to subsequent chemotherapy 
 
Cytarabine dose: 
o Age < 60: 3000 mg/m2 (3g/m2)  
o Age ≥ 60: 1000 mg/m2 (1 g/m2) 
 
On days 1,3,5 every 12 h (total of 6 doses) 
 
Up to 4 cycles of consolidation allowed with 
HiDAC  
 
 
Crenolanib starts approximately 24-48 hours after completion 
of cytarabine (+7-day window).  
 
Normal total bilirubin and ALT and AST ≤2.0x ULN are 
required within 24 hours prior to crenolanib 
commencement. Crenolanib can be delayed until these 
criteria are met. (If crenolanib will be delayed longer day 14, 
a discussion with PI and sponsor should be conducted to 
determine the best options for the patient) 
 
Crenolanib should be held 72 hours prior to subsequent 
chemotherapy 


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MAINTENANCE 
 
 
A total of 12 cycles of maintenance will be allowed.  
 
During maintenance, patients will take continuous crenolanib. Cycles will be 28 days long. 
 
Patients who have received HSCT and remain in remission may receive crenolanib maintenance therapy. 
Crenolanib should be restarted no sooner than 30 days post-HSCT and should be administered at the same 
dose of crenolanib last taken by the patient.  
 
Patients not undergoing hematopoietic stem cell transplant who are in remission may continue on crenolanib 
after induction and/or HiDAC consolidation. 
 
 
D1   
 
 
 
                                                                                                                              D28 
Crenolanib 100 mg TID (or last tolerated dose during induction/consolidation) PO starting on Day 1 continuously for 28 day cycles 


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2. SPONSOR CONTACT INFORMATION 
 
Protocol Number: 
ARO-006 
Version 
2.0 
Version Date: 
January 4, 2017 
Investigational Product: 
Crenolanib Besylate 
Development Phase: 
Phase II 
Sponsor: 
Arog Pharmaceuticals, Inc. 
5420 LBJ Freeway, Suite 410, Dallas TX 75240 
O: (214) 593-0500 
F: (214) 594-0002  
Email: info@arogpharma.com 
Medical Monitor: 
 John Eckardt, MD 
O: (214) 451-4520 
M: (314) 614-5124 
F: (214) 594-0002 
Email: jeckardt@arogpharma.com 
 
 


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3. SYNOPSIS 
3.1. 
Rationale for the Proposed Study 
This study is designed to evaluate the safety and clinical benefit of oral crenolanib besylate given 
sequentially during standard induction and consolidation chemotherapy in patients with newly 
diagnosed AML with FLT3 activating mutations. Acute myelogenous leukemia (AML) has a 
significant resistance to primary chemotherapy with a cure rate of only 30-40%.[1] The prognosis 
varies according to cytogenetic status. Activating mutations of FLT3 including internal tandem 
duplication (ITD) mutations within the juxtamembrane domain and single base pair mutations 
within the tyrosine kinase domain (TKD) of the receptor are the most frequent mutations described 
in AML, with a prevalence of approximately 24-30%.[2, 3] Despite the presence of these 
mutations, there is no approved target specific therapy for AML patients who harbor them. 
 
Crenolanib besylate (AR-868,596-26) is an orally bioavailable benzimidazole that was designed 
to be a selective and potent inhibitor of type III receptor kinases FLT3, PDGFRα and PDGFRβ. 
Molecular binding data support that crenolanib is a type I kinase inhibitor that binds preferentially 
to the active kinase conformation of FLT3.[4] As a result of this property, crenolanib potently 
inhibits both wild type and constitutively active mutant FLT3 kinase.  In vitro studies in cell lines 
and a xenograft model have shown that crenolanib has higher binding affinity (Kd) for and potency 
(IC50) against FLT3 kinase with internal tandem duplication (ITD) and tyrosine kinase domain 
(TKD) mutations.[2, 4, 5] A saturation mutagenesis screen of FLT3-ITD failed to recover any 
resistant colonies in the presence of crenolanib at a concentration significantly lower than what 
has been safely achieved in patients.[4] This high affinity of crenolanib allows it to inhibit aberrant 
FLT3 signaling at clinically achievable concentrations in AML patients.  
 
Two phase II clinical trials administered single-agent crenolanib to a total of 69 patients with FLT3 
mutant AML. Encouraging single-agent activity, safety and PK was observed with crenolanib in 
this patient population. Amongst 18 evaluable who had relapsed AML patients after chemotherapy 
or allogeneic stem cell transplant (but who had not received prior FLT3 inhibitors), crenolanib 
therapy resulted in an overall response rate of 50% (39% CR/CRi and 11% PR).  Median overall 
survival was almost eight months (234 days).  The overall response to crenolanib monotherapy 
was 31% in 36 patients who progressed after a median of three prior regimens (including 
chemotherapy and FLT3 inhibitors like sorafenib, midostaurin and quizartinib). Crenolanib had a 
half-life of 7.5hrs and no crenolanib accumulation seen with repeated dosing.  Common adverse 
events (AEs) included nausea/vomiting, transaminitis and fluid retention (majority Grade 1/2) and 
only 2 patients discontinued crenolanib due to related AEs (fatigue and nausea). No patient 
acquired a secondary FLT3 mutation at the time of relapse following crenolanib. 
 
For patients with newly diagnosed AML, the standard chemotherapy induction regimen used in 
this study (7+3, cytarabine and anthracyclines) is considered universally as effective as any other 
regimen.[8] For this trial, crenolanib will be added to standard induction and consolidation 
chemotherapy regimens. This study will initially have a safety phase with two cohorts designated 
by anthracycline: in cohort A daunorubicin will be given at 90 mg/m2 for patients younger than 60 
years of age and 60 mg/m2 for patients ≥60 and in cohort B idarubicin will be given at 12 mg/m2. 
Once the safety of the combination has been established an expansion of an additional 72 patients 
will be initiated. During the expansion, patients will be eligible for either anthracycline regimen 
per physician’s discretion.   
 


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3.2. 
Study Synopsis 
 
 
Title of Study:  A Study of Crenolanib and Chemotherapy in Patients with Newly Diagnosed Acute Myeloid 
Leukemia with FLT3 Activating Mutations 
 
Number of Planned Subjects: 120  
 
Approximately 48 patients will be enrolled into two cohorts during an initial safety phase: 
Cohort A: 24 patients receiving cytarabine/daunorubicin followed by crenolanib 
Cohort B: 24 patients receiving cytarabine/idarubicin followed by crenolanib 
 
Once safety of adding crenolanib to cytarabine/daunorubicin and cytarabine/idarubicin has been established, an 
expansion phase of 72 additional patients will be treated with either cytarabine/daunorubicin or with 
cytarabine/idarubicin induction chemotherapy followed by crenolanib to further assess the safety and clinical benefit 
of the combination.  
 
Length of Study:  2-3 years 
 
Primary Objectives 
 
To determine the safety and tolerability of crenolanib given sequentially with chemotherapy for newly 
diagnosed AML 
 
To determine the response rate to induction therapy in newly diagnosed AML subjects with FLT3 activating 
mutations when crenolanib is given sequentially with standard induction/consolidation chemotherapy, 
including the rates of complete remission (CR), CR with incomplete blood count recovery (CRi), and partial 
response (PR).  
 
Secondary Objectives 
 
To determine the overall survival (OS) in newly diagnosed AML subjects with FLT3 activating mutations 
when crenolanib is given sequentially with standard induction/consolidation chemotherapy 
 
In those patients achieving response, assess parameters of response including: remission duration and relapse-
free survival (RFS) 
 
Pharmacokinetic analysis of crenolanib when given with chemotherapy 
 
Exploratory Objectives 
To evaluate the impact of crenolanib given in combination with chemotherapy: 
 
Determine steady-state serum crenolanib concentration 
 
Identify and correlate specific molecular markers with clinical outcomes 
 
Determine changes in molecular markers during treatment and their correlations with clinical outcomes 
 
Measure minimal residual disease (MRD) and correlate with post-remission outcomes 
 
Inclusion Criteria: 
1. Unequivocal diagnosis of AML based on the WHO classification, excluding acute promyelocytic leukemia  
2. No prior therapy for AML, except for hydroxyurea and/or leukapheresis, in this setting is allowed.  
3. Subjects with AML evolving from MDS with or without prior MDS therapy with demethylating agents will 
be allowed in the safety phase only.  
4. Subjects must have tested positive for FLT3-ITD and/or other FLT3 activating mutations.   
5. Age ≥18 years will be allowed in the safety phase; during the expansion phase, subjects must be ≥18 - ≤70 
years of age. 


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6. ECOG PS 0 – 2 
7. Adequate liver function, defined as normal total bilirubin, ALT ≤2.0x ULN, and AST ≤2.0x ULN. 
8. Adequate renal function, defined as serum creatinine ≤1.5x ULN or GFR >50 mL/min 
9. Negative pregnancy test (serum or urine) for women of childbearing potential (WOCBP).  
 
Women considered not of childbearing potential include any of the following: no menses for at least 
2 years or menses within 2 years but amenorrheic for at least 2 months and luteinizing hormone 
(LH) and follicular stimulating hormone (FSH) values within normal range (according to definition 
of postmenopausal for laboratory used) or bilateral oophorectomy or radiation castration and 
amenorrheic for at least 3 months or with bilateral tubal ligation. 
10. WOCBP must practice contraception. Acceptable methods of contraception are double barrier methods 
(condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, 
or injectable contraceptives, intrauterine devices, tubal ligations, and abstention.  
11. Male patients (except those with prior surgical contraceptive procedures) with female partners who are of 
childbearing potential: Recommendation is for male and partner to use effective contraceptive methods, such 
as latex condoms, during the study.  
12. Able and willing to provide written informed consent 
 
Exclusion Criteria: 
1. Pre-existing liver diseases (i.e., cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, and 
sclerosing cholangitis, etc.)  
2. Known active CNS leukemia  
3. During the expansion phase subjects with therapy-related AML, AML with prior history of MDS with or 
without prior HMA therapy or AML in the setting of antecedent hematologic disorder. 
4. Subject with concurrent severe and/or uncontrolled medical conditions that may impair the participation in 
the study or the evaluation of safety and/or efficacy  
5. NYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry, and/or serious 
arrhythmia requiring anti-arrhythmic therapy 
6. Major surgical procedures within 14 days of enrollment (does not include line placement as needed for 
chemotherapy administration). 
7. Unwillingness or inability to comply with protocol. 
8. Concurrent use of other investigational agents. 
9. Subjects who are not eligible for standard chemotherapy 
 
Test Product, Dosage and Mode of Administration:  
Crenolanib besylate will be taken at a starting dose of 100 mg TID, orally. Patient, nursing or research staff will 
complete documentation to record the date, time and amount (number of tablets) of crenolanib taken. 
 
Drug Information: 
Crenolanib besylate will be provided in 100 mg and/or 20 mg tablets by Arog Pharmaceuticals, Inc. 
 
Study Design: 
Patients will initially be enrolled to the safety phase of the study. During the safety phase, patients will be enrolled to 
either cohort A: cytarabine/daunorubicin or cohort B: cytarabine/idarubicin. Each cohort will enroll independently 
and patients will be treated with crenolanib following either cytarabine/daunorubicin or cytarabine/idarubicin.  
 
Once safety of adding crenolanib to cytarabine/daunorubicin and cytarabine/idarubicin has been established, an 
expansion phase of an additional 72 patients will be treated with standard 7+3 (either cytarabine/daunorubicin or with 
cytarabine/idarubicin, per physician’s discretion) induction chemotherapy followed by crenolanib. 
 
Per physician’s discretion, patients may receive up to 2 cycles of the same induction therapy. Following induction, 
eligible patients can receive up to four cycles of consolidation with HiDAC followed by crenolanib. Following either 


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induction or consolidation, eligible patients may receive maintenance therapy with crenolanib up to an additional 12 
cycles.  
 
Eligible patients should receive allogeneic stem cell transplant following induction and/or consolidation with HiDAC. 
Those who have received transplant may receive maintenance therapy with crenolanib following transplant.  
 
Planned Duration of Treatment:   
If patients receive all available therapy options, patients may stay on trial for approximately 20 months. Information 
for survival and disease status (until progression of disease) on patients who have discontinued study drug for any 
reason should be obtained at least every 6 months for a maximum of 24 months or until the end of the study, whichever 
is later. 
 
Statistical Plan:  
During the initial safety phase, there will be two cohorts (based on chemotherapy regimen). Each cohort will enroll 
independently. To confirm the safety of each combination (cytarabine/daunorubicin with crenolanib and 
cytarabine/idarubicin with crenolanib), approximately 24 patients will be enrolled onto each cohort, if early stopping 
criteria are not met. Following analysis of the initial safety phase, an expansion phase of an additional 72 patients will 
be initiated to further assess safety and clinical benefit of this combination.  
 
Safety analysis: 
During the initial safety phase, twelve patients will be enrolled onto each cohort and if the early stopping rule criterion 
are not met than approximately 12 additional patients will be enrolled onto each cohort. Safety monitoring will be 
performed separately for each cohort and enrollment will be halted within a cohort if stopping rules are met for early 
mortality due to any cause, increase in expected non-hematologic crenolanib-related grade 4 adverse events, or any 
unexpected non-hematologic crenolanib-related grade 4 adverse events.  
 
Stopping rules during the initial safety phase are the following: If the observed mortality rate exceeds 10 % and 20% 
at day 30 and 60, respectively, enrollment will be halted pending Protocol Safety Committee review. If an observed 
increase of expected non-hematologic crenolanib-related grade 4 adverse events exceeds 20% during the first 60 days 
of treatment further enrollment will be halted pending Protocol Safety Committee review. If an observed increase of 
unexpected non-hematologic crenolanib-related grade 4 adverse event exceeds 15% during the first 60 days of 
treatment further enrollment will be halted pending Protocol Safety Committee review. 
 
During the expansion phase, safety monitoring will be performed for the entire per protocol patient population (defined 
as those who receive at least one dose of study drug) and in a separate analysis dictated by chemotherapy agent used.  
 
Response rate analysis: 
This study will enroll approximately 120 patients with the following confidence intervals based on projected response 
rate. A response rate of 90% will have a 95% CI of ±5%. That is to say that if we treat 120 patients and observe a 90% 
response rate, we are 95% sure that the true response rate is between 85% to 95%.  
 
Analysis method: 
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 patients in each category. Time – to – event endpoints will be summarized 
using the cumulative incidence and Kaplan-Meier methodology.  


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4. ABBREVIATIONS AND DEFINITIONS 
Adverse Event 
(AE) 
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally occurring during the use of a 
medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
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). 
Compliance 
Adherence to all the trial-related requirements, good clinical practice 
(GCP) requirements, and the applicable regulatory requirements. 
Complaint 
A complaint is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, purity, durability, 
reliability, safety or effectiveness, or performance of a drug or drug 
delivery system. 
Confirmation 
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that 
AROG is confident that results are accurate.  Confirmation will either 
occur immediately after initial testing or will require that samples be 
held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results. 
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. 
Consent 
The act of obtaining informed consent for participation in a clinical 
trial from patients deemed eligible or potentially eligible to participate 
in the clinical trial.  [Patients/Subjects] entered into a trial are those 
who sign the informed consent document directly or through their 
legally acceptable representatives. 
End of Study (trial) 
The date of the last visit or last scheduled procedure shown in the 
Study Schedule for the last active subject in the study.  
Enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled 
in the trial are those who have been assigned to a treatment. 
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/Ethical 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 patients participating 
in a clinical trial are protected. 


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Legal Representative 
An individual, judicial, or other body authorized under applicable law 
to consent on behalf of a prospective patient, to the patient’s 
participation in the clinical trial. 
Patient 
A study participant who has the disease or condition for which the 
investigational product is targeted. 
Screen 
The act of determining if an individual meets minimum requirements 
to become part of a pool of potential candidates for participation in a 
clinical trial.  In this study, screening involves invasive or diagnostic 
procedures and/or tests (for example, radiology and blood draws).  
For this type of screening, informed consent for these screening 
procedures and/or tests shall be obtained. 
Treatment-Emergent 
Adverse Event 
(TEAE) 
Any untoward medical occurrence that either occurs or worsens at 
any time after treatment baseline and which does not necessarily have 
to have a causal relationship with this treatment (also called 
treatment-emergent signs and symptoms [TESS]). 
 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
Ara-C 
cytarabine 
ASCO 
American society of clinical oncology 
AST 
aspartate aminotransferase 
BMA 
bone marrow aspiration 
BUN 
blood urea nitrogen 
CALGB 
cancer and leukemia group b 
CBC 
complete blood count 
CIV 
continuous intravenous therapy 
CNS 
Central nervous system 
CR 
complete response 
CRi 
complete remission with incomplete blood count recovery 
CYP3A4 
Cytochrome P450 3A4 
DNA 
deoxyribonucleic acid 
ECOG -PS 
Eastern Cooperative Oncology Group performance status 
EFS 
Event free survival 
EKG 
Electrocardiogram 
FLT3 
FMS-like Tyrosine Kinase 3 
GCP 
good clinical practice 
GVHD 
Graft versus host disease 
HI 
Hematologic improvement 
HiDAC 
High dose cytarabine 
HSCT 
Hematologic stem cell transplant 
IC50 
Half maximal inhibitory concentration 
ICD 
informed consent document 
ICH 
International Conference on Harmonization 
IRB 
Internal review board 
ITD 
internal tandem duplication 
IV 
Intravenous therapy 
Kd 
Dissociation constant 
KIT 
Stem cell growth factor receptor 


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LDH 
Lactate dehydrogenase 
MDS 
Myelodysplastic syndrome 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.03 
NYHA 
New York Heart Association 
OS 
Overall survival 
PD 
progressive disease 
PIA 
Pharmacologic inhibitory assay 
PK 
Pharmacokinetics 
PO 
By mouth 
PR 
Partial response 
RFS 
relapse-free survival 
SAE 
Serious adverse event 
TID 
Three times a day 
TKD 
tyrosine kinase domain 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
UPIN 
Unique patient identification number 
WBC 
White blood count 
WOCBP 
Woman of child bearing potential 


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5. BACKGROUND  
5.1. 
Crenolanib inhibits wild-type FLT3 and its constitutively active mutations 
Crenolanib besylate (also known as AR-868,596-26) is an orally bioavailable class III RTK 
inhibitor that potently targets FLT3. Crenolanib inhibits wild-type FLT3, and its constitutively 
active mutations at clinically achievable concentrations. [4, 5]  
 
Crenolanib has heightened binding affinity against the FLT3-ITD mutation (the most frequent 
FLT3 aberration in AML) and TKD point mutations FLT3 (D835H), FLT3 (D835Y) and FLT3 
(D835V). Crenolanib binds to FLT3-ITD and FLT3-TKD D835H with Kd values of 0.43 and 0.4 
nM, respectively. Similarly, crenolanib also binds to FLT3-TKD D835Y with a Kd of 0.18 nM. A 
saturation mutagenesis screen of FLT3 ITD showed that crenolanib is a “pan-FLT3 inhibitor” that 
has the ability to successfully suppress all resistance-conferring TKD mutants.[4] Crenolanib 
inhibitory activity has been verified in human AML cell lines. [4] 
 
Table 1 Dissociation constants of crenolanib with constitutively active FLT3 mutations 
Gene Symbol 
Crenolanib Kd  (nM) 
FLT3(ITD) 
0.43 
FLT3(D835H) 
0.4 
FLT3(D835Y) 
0.18 
FLT3 (D835V) 
0.048 
 
Crenolanib is a type 1 tyrosine kinase inhibitor that binds to both the active and inactive 
conformation of FLT3.  
Figure 1 Schematic of inactive and active FLT3 with most common resistance mutations in 
AML.[8] 
 
5.2. 
Crenolanib has reduced activity against KIT 
Crenolanib has been found to be approximately 100-fold more selective for FLT3 than for KIT 
and is therefore highly selective toward FLT3 relative to KIT [9] and elicits cytotoxicity in FLT3–
mutant AML while largely sparing KIT inhibition (100-fold offset in both viability and 
biochemical assays) with limited activity against other kinases. As a result, crenolanib may be 
associated with less myelosuppression than the available type II FLT3 TKIs.   


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5.3. 
Synergistic activity of crenolanib in combination with cytarabine 
The effect of crenolanib on nucleoside analogue uptake in AML cells was evaluated.  Cells were 
incubated for 2 h with 1.25 uM of radiolabeled cytarabine combined with DMSO control or in 
combination with crenolanib at 0.1 uM for 5 minutes and 2 h (Figure 2). Combining cytarabine 
with crenolanib in FLT3 wild-type OCI-AML3 cells and FLT3-ITD MV411 cells showed that 
crenolanib does not decrease cytarabine accumulation in AML cells, despite length of crenolanib 
incubation time.[5] 
Figure 2 Effects of crenolanib on uptake of cytarabine in AML cells. 
 
(A) 5 minute incubation; (B) 2 hour incubation.  Histogram shows mean and SD. 
 
Further combination experimentation was undertaken to give insight into the potential sequence 
of crenolanib and cytarabine administration in future clinical studies. Assays were performed to 
measure cell viability of FLT3 ITD cell lines (MOLM13 and MV4-11) that were incubated for 4 h 
with cytarabine followed by 68 h of crenolanib (Figure 3). Results suggested synergistic activity 
with the combination [5]. 
 
Figure 3 Crenolanib and cytarabine combination synergistically inhibit FLT3-ITD-positive 
cell viability in vitro.  
 
(A) simultaneous 72 h drug exposure; (B) simultaneous 4 h drug exposure followed by 68 h crenolanib exposure; 
(C) (pre-AraC) 4 h AraC exposure followed by 68 h crenolanib exposure; or (D) (pre-crenolanib) 24 h crenolanib 
exposure followed by 48 h AraC exposure. [5]. 
 


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5.4. 
Antileukemic activity of crenolanib in combination with daunorubicin 
In vitro combination studies with crenolanib and daunorubicin also suggest antileukemic synergy 
in AML cell lines with mutant FLT3 (Figure 4, unpublished data on file, Dr. Sharyn Baker). 
 
Figure 4 Viability of FLT3 ITD cell lines treated with crenolanib and daunorubicin  
 
(A) Molm 13 cell line; (B) MV4-11 cell line 
 
5.5. 
Clinical studies of crenolanib in AML 
 
5.5.1. 
Clinical summary of crenolanib in relapsed/refractory FLT3 mutated AML 
 
Crenolanib has been studied in relapsed/refractory FLT3 mutant AML (NCT01522469, 
NCT01657682). Crenolanib was administered as single-agent in 69 patients with 
relapsed/refractory FLT3 mutated AML in two clinical trials, NCT01522469/ARO-004 and 
NCT01657682/ARO-005. Encouraging single-agent activity, safety and PK was observed with 
crenolanib in this patient population. Amongst 18 evaluable who had relapsed AML patients after 
chemotherapy or allogeneic stem cell transplant (but who had not received prior FLT3 inhibitors), 
crenolanib therapy resulted in an overall response rate of 50% (39% CR and 11% PR).  Median 
overall survival was almost eight months (234 days).  The overall response to crenolanib 
monotherapy was 31% in 36 patients who progressed after a median of three prior regimens 
(including chemotherapy and FLT3 inhibitors like sorafenib, midostaurin and quizartinib). 
Crenolanib had a half-life of 7.5hrs and no crenolanib accumulation seen with repeated dosing.  
Common adverse events (AEs) included nausea/vomiting, transaminitis and fluid retention 
(majority Grade 1/2) and only 2 patients discontinued crenolanib due to related AEs (fatigue and 
nausea). No patient acquired a secondary FLT3 mutation at the time of relapse following 
crenolanib. 
 
 


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Figure 5 Peripheral blast clearance in FLT3 mutant AML patients treated with crenolanib.  
 
 
In conclusion, crenolanib is a FLT3 TKI showing preliminary clinical activity in a heavily 
pretreated population with FLT3-ITD, FLT3-D835, and compound FLT3-ITD/D835 mutant 
AML. Importantly, crenolanib is the first agent to demonstrate clinical activity in patients with 
FLT3-D835 activating mutations. 
 
5.6. 
Tolerability of crenolanib in AML patients who had undergone prior allogeneic bone 
marrow transplant 
A retrospective analysis of those patients who, following hematopoietic cell transplant (HCT), 
received monotherapy crenolanib on the relapsed/refractory AML studies (ARO-004 and ARO-
005) was performed and reported at ASH 2015. This analysis showed that crenolanib at the full 
therapeutic dose of 100 mg TID was well tolerated in this heavily pre-treated patient population 
following HCT. A phase II clinical trial of crenolanib in the post-HCT maintenance setting 
(NCT02400255 / ARO-009) is on-going. 
 
5.7. 
Long-term Safety Data of Crenolanib  
In a Phase I pediatric glioma study conducted at the St. Jude Children's Research Hospital, 6 
children received crenolanib for at least 12 cycles. Four children have stayed on study for more 
than 24 cycles. No dose reduction was required. Long-term exposure to crenolanib seems to be 
tolerable and safe.     
 
5.8. 
Rationale for Crenolanib Dose and Schedule  
Crenolanib has been tested in 51 AML patients as single agent., Two dosing schedules have been 
studied: 100 mg TID (28 patients) and 200 mg/m2/day (23 patients). Crenolanib was safe and well 
tolerated in this patient population. The most common adverse events were low-grade nausea, 
vomiting, diarrhea, and transaminitis.  
 
To date, 28 AML patients have been treated with 100 mg TID crenolanib. Day 1 pharmacokinetics 
data is shown in Figure 6. Trough crenolanib levels were measured in 25 patients on Day 15 by 
which time steady state levels should have been achieved. Only 2 patients had > 1000 nM 
crenolanib, but neither required dose de-escalation due to adverse events. Thus, a fixed dose 
ITD
ITD
ITD
ITD
ITD
ITD
ITD
ITD
ITD
ITD
D835
D835
D835
ITD + D835
ITD + D835
ITD + D835
ITD + D835
ITD + D835
ITD + D835
ITD + D835
ITD + D835
ITD + D835
ITD + D835
D835
ITD
ITD
ITD
ITD
ITD + D835
ITD + D835
ITD
ITD
ITD + D835
ITD
ITD + D835
ITD + D835
ITD + D835
ITD + D835
ITD
ITD
ITD
D835
ITD + D835
ITD + D835
ITD
ITD
ITD
ITD + D835
ITD + D835
D835
ITD
ITD
ITD + D835
ITD + D835
D835
ITD
ITD
ITD + D835
ITD
ITD + D835
D835
D835
ITD + D835
ITD
ITD + D835
ITD + D835
D835 * baseline of 0
ITD + D835 * baseline of 0
D835
-100%
-75%
-50%
-25%
0%
25%
Maximum Change in Peripheral Blasts from Baseline
ITD
D835
ITD+D835


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regimen of 100 mg TID will be utilized for this trial. Dose reductions to 80 mg TID and 60 
mg TID will be applied should toxicities emerge in study individuals.  
 
Figure 6 Pharmacokinetics analyses in AML patients on 100 mg crenolanib.  
 
 
Previous plasma inhibitory assays have shown that FLT3 phosphorylation is inhibited for 
approximately 8 hours after each dose of crenolanib (see representative PIA assay below in Figure 
7). Hence, crenolanib will be given in this protocol in a TID schedule.  
 
Figure 7 Representative PIA analysis of patient plasma samples after taking crenolanib 
single agent.  
 
The study by Robert J, et al. in 16 leukemia patients showed that the major metabolites of 
idarubicin or daunorubicin were the 13-dihydroderivative of each drug, idarubicinol or 
daunorubicinol. The elimination half-life of idarubicinol was two times higher than that of 
daunorubicinol (80.7 h versus 37.3 h). [6] During 7+3 induction in this protocol, idarubicin or 
daunorubicin will be administered on days 1, 2, and 3. By the time crenolanib is started (Day 9), 
idarubicinol level should have declined by 75% (2 half-lifes) and daunorubicinol levels will have 
dropped by 93.5% (4 half-lifes). Crenolanib will be discontinued 3 days (9 half-lifes) prior to 
initiation of subsequent chemotherapy.  
 
 
 
1.0
10.0
100.0
1000.0
10000.0
0
10
20
30
Crenolanib 
concentration (nM)
Time (h)


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6. STUDY OBJECTIVES  
6.1. 
Primary Objective 
 
 
To determine the safety and tolerability of crenolanib given sequentially with cytarabine and 
anthracycline chemotherapy for newly diagnosed FLT3 mutant AML. 
 
To determine the response rate to induction therapy in newly diagnosed AML subjects with 
FLT3 activating mutations when crenolanib is given sequentially with standard 
induction/consolidation chemotherapy, including the rates of complete remission (CR), CR 
with incomplete blood count recovery (CRi) and partial remission (PR). 
 
6.2. 
Secondary Objectives 
 
 
To determine the overall survival (OS) in newly diagnosed AML subjects with FLT3 activating 
mutations when crenolanib is given sequentially with standard induction/consolidation 
chemotherapy 
 
In those patients achieving response with crenolanib, assess parameters of response including 
remission duration and relapse-free survival (RFS) 
 
Pharmacokinetic analysis of crenolanib when given with chemotherapy 
 
6.3. 
Exploratory Objectives 
 
To evaluate the impact of crenolanib given in combination with chemotherapy: 
 
Determine steady-state serum crenolanib concentration 
 
Identify and correlate specific molecular markers with clinical outcomes 
 
Determine changes in molecular markers during treatment and their correlations with 
clinical outcomes 
 
Measure minimal residual disease (MRD) and correlate with post-remission outcomes 
 
 


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7. SUBJECT ELIGIBILITY 
All patients must meet eligibility as defined. Clarifications of eligibility should be directed to the 
sponsor’s medical monitor.  
 
7.1. 
Inclusion Criteria 
 
1. Unequivocal diagnosis of AML based on WHO classification, excluding acute 
promyelocytic leukemia. 
2. No prior therapy for AML, except for hydroxyurea and/or leukapheresis, in this setting is 
allowed. 
3. Subjects with AML evolving from MDS with or without prior MDS therapy with 
demethylating agents will be allowed in the safety phase only.  
4. Subjects must have tested positive for FLT3-ITD and/or other FLT3 activating mutations.     
5. Age ≥18 years will be allowed in the safety phase; during the expansion phase, subjects 
must be ≥18 - ≤70 years of age. 
6. ECOG PS 0 – 2 
7. Adequate liver function, defined as normal bilirubin, ALT ≤2.0x ULN, and AST ≤2.0x ULN 
measured within 24 hours prior to crenolanib commencement.  
8. Adequate renal function, defined as serum creatinine ≤1.5x ULN or GFR >50 mL/min 
9. Negative pregnancy test (serum or urine) for women of childbearing potential (WOCBP).  
 Women considered not of childbearing potential include any of the following: 
no menses for at least 2 years or menses within 2 years but amenorrheic for at 
least 2 months and luteinizing hormone (LH) and follicular stimulating hormone 
(FSH) values within normal range (according to definition of postmenopausal 
for laboratory used) or bilateral oophorectomy or radiation castration and 
amenorrheic for at least 3 months or with bilateral tubal ligation. 
10. WOCBP must practice contraception. Acceptable methods of contraception are double 
barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal 
jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, tubal 
ligations, and abstention.  
11. Male patients (except those with prior surgical contraceptive procedures) with female 
partners who are of childbearing potential: Recommendation is for male and partner to use 
effective contraceptive methods, such as latex condoms, during the study.  
12. Able and willing to provide written informed consent. 
 
7.2. 
Exclusion Criteria 
 
1. Pre-existing liver diseases (i.e., cirrhosis, chronic hepatitis B or C, nonalcoholic 
steatohepatitis, and sclerosing cholangitis, etc.) 
2. Known active CNS leukemia  


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3. During the expansion phase subjects with therapy-related AML, AML with prior history 
of MDS with or without prior HMA therapy or AML in the setting of antecedent 
hematologic disorder. 
4. Subjects with concurrent severe and/or uncontrolled medical conditions that in the opinion 
of the investigator may impair the participation in the study or the evaluation of safety and/or 
efficacy.  
5. NYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry 
and/or serious arrhythmia requiring anti-arrhythmic therapy 
6. Major surgical procedures within 14 days of enrollment (does not include line placement as 
needed for chemotherapy administration). 
7. Unwillingness or inability to comply with protocol. 
8. Concurrent use of other investigational agents.  
9. Subjects who are not eligible for standard chemotherapy. 
 
7.3. 
Protocol Registration 
To register, a form 1572 listed physician involved in the care of the potential participant must 
contact either the Principal Investigator or the Study Coordinator to complete the Eligibility 
Checklist for the Sponsor (Appendix I). For registration, a completed Checklist is to be provided 
to the sponsor who will provide the site with a Confirmation of Enrollment form which will assign 
a patient study number (UPIN). 
 
7.4. 
Discontinuations 
 
7.4.1. 
Discontinuations of Study Drugs and Disease status/Survival Follow up of Patients 
The criteria for enrollment must be followed explicitly. If a patient who does not meet enrollment 
criteria is inadvertently enrolled, that patient should be immediately discontinued from the study 
drug.   
 
Study drug may be held for an extended period of time for comorbidities including but not limited 
to infections, ICU admissions, severe graft vs host disease, and other comorbidities typically seen 
in patients undergoing induction, consolidation or allogeneic transplant therapies for AML.  Such 
prolonged drug hold will not require the patient to be taken off study. Study drug can be restarted, 
even after prolonged drug holds, at the same dose as was last received by the patient. Restart of 
study drug will require a discussion with the sponsor. 
 
Study drug may be held for an extended period of time if requested by the patient without 
necessitating the patient to be taken off study. Study drug can be restarted, even after prolonged 
drug holds, at the same dose as was last received by the patient. Patients will be continued to be 
followed for survival and disease status per protocol. Safety will be followed as per section 14. 
 


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Patients, who for any reason, require treatment with another therapeutic agent for AML or 
investigational agent will be discontinued from the study drug prior to introduction of the new 
agent. Restart of study drug will require a discussion with the sponsor. 
 
Patients who have disease refractory to induction or consolidation therapy will be taken off 
crenolanib but be followed for survival.  Similarly, patients who relapse after achieving a response 
will be taken off crenolanib but be followed for survival.   
 
7.4.2. 
Discontinuation of Study Sites 
Study site participation may be discontinued if AROG, the investigator, or the ethical review board 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and good clinical practice. Sites may also be discontinued if unable 
to accrue an adequate number of patients on the trial. 
 
7.4.3. 
Discontinuation of the Study 
The study will be discontinued if the site IRB judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical practice. The study 
could also be discontinued at any time at the sole discretion of the sponsor, AROG 
Pharmaceuticals, Inc.  


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8. TREATMENT PLAN 
 
8.1. 
Summary of Treatment 
This is a non-randomized, open label, phase II study enrolling newly diagnosed AML subjects 
with FLT3 activating mutations. Along with chemotherapy, subjects will be treated with 
crenolanib divided in three divided doses (preferably every 8 h) continuously until they fulfill one 
of the criteria for study discontinuation (see Section 7.4).  
 
Study subjects, nursing or research staff will complete documentation (i.e patient diary) during 
induction and first cycle of consolidation to record the date, time and amount (number of tablets) 
of crenolanib taken and when taken relative to food. While study subjects are hospitalized, medical 
records, such as Medication Administration Record, may be used to enter data requested. Once 
subject is discharged from the hospital, they must submit the crenolanib administration 
documentation as required during induction 1 (and 2 if applicable), consolidation 1 (Appendix III). 
All subjects will be assessed for efficacy and toxicity. 
 
8.2. 
Study Design 
This will be a Phase II multi-center study assessing the safety and clinical benefit of crenolanib 
given with standard 7+3 induction chemotherapy in newly diagnosed in FLT3 mutated AML.  
 
Safety Phase: Patients will receive either daunorubicin/cytarabine (Cohort A) or idarubicin/ 
cytarabine (Cohort B) per the treating hospitals SOP.  
 
Expansion Phase: Patients may receive either daunorubicin/cytarabine or idarubicin/cytarabine per 
physician’s discretion. During the expansion phase, patients may receive their standard 7+3 chemo 
of either anthracycline with cytarabine.  
 
8.2.1. 
Induction 
Patients with newly diagnosed AML with FLT3 activating mutations will be treated with 
crenolanib following induction with either daunorubicin/cytarabine or idarubicin/cytarabine. 
During the initial safety phase the anthracycline options will be separated into Cohort A and B. 
Induction treatment schedules combining standard 7+3 chemotherapy with crenolanib are listed in 
Tables 2 (Cohort A) and 3 (Cohort B). During the expansion phase, the choice of anthracycline 
will not be separated into different cohorts.  
 
Crenolanib will start approximately 24-48 hours after completion of cytarabine (+7 day window). 
Adequate liver function including normal total bilirubin ALT and AST ≤2.0x ULN are required 
within 24 hours prior to crenolanib commencement. Crenolanib can be delayed until this criterion 
is met. (If crenolanib will be delayed longer day 16, a discussion with PI and sponsor should be 
conducted to determine the best options for the patient) 
 
 
Table 2 Cohort A: Cytarabine, daunorubicin induction   
Drug 
Dose 
Mode 
Days 
Cytarabine  
100 - 200 mg/m2/day 
IV continuous infusion over 24 hrs 
Days 1-7 
Daunorubicin  
90 mg/m2 (<60 years old) 
IV bolus over 10-15 mins 
Days 1-3 


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60 mg/m2 (≥60 years old or for 
patients who are <60 and 
receiving a second cycle of 
induction (per physician’s 
discretion)) 
 
 
Table 3 Cohort B: Cytarabine, idarubicin induction  
Drug 
Dose 
Mode 
Days 
Cytarabine  
100 - 200 mg/m2/day 
IV continuous infusion over 24 hrs 
Days 1-7 
Idarubicin 
12 mg/m2  
intravenously daily over 10-15 mins  
Days 1-3 
 
If after induction 1, the bone marrow is hypoplastic (<10 % cellularity) on day 14-28 and contains 
less than 5 percent blast cells, further chemotherapy treatment can be deferred and the marrow 
examination repeated weekly until marrow recovery, or per the discretion of the treating physician. 
A repeat bone marrow should be performed at time of hematological remission or Day 42, 
whichever occurs first. Crenolanib treatment may be continued during this period as per the 
discretion of the treating physician.  
 
If after induction 1, the bone marrow shows residual disease without a hypocellular marrow, a 
second course of the same induction remission therapy (or lower dose of anthracycline per Tables 
2 and 3) can be given at the decision of the treating physician. Timing and/or necessity of bone 
marrow evaluation following second induction will follow the same schedule as induction 1. 
Crenolanib must be held for 72 hours prior to the start of the next chemotherapy.  
 
8.2.2. 
Consolidation 
Therapy with crenolanib will be held for 72 hours prior to the start of the first dose of cytarabine 
given for consolidation. Crenolanib treatment should be continued during the period of marrow 
recovery.  
 
Subjects on both cohorts A and B may have up to 4 consolidation courses with: 
 High dose cytarabine (HiDAC) given as 3 g/m2 (<60 years old) or 1 g/m2 (for ≥60) 
intravenously over 3 h every twelve hours on days 1, 3, 5 (total of 6 doses).  
 
Crenolanib will start approximately 24-48 hours after completion of cytarabine (+7 day window). 
Adequate liver function including normal total bilirubin ALT and AST ≤2.0x ULN are required 
within 24 hours prior to crenolanib commencement. Crenolanib can be delayed until this criterion 
is met (If crenolanib will be delayed longer day 14, a discussion with PI and sponsor should be 
conducted to determine the best options for the patient). 
 Dose of crenolanib will be the same as that given in induction(s). 
 Dose modification of crenolanib is allowed based on treating physician discretion 
according to Section 8.4 of this protocol. 
 
8.2.3. 
Maintenance 


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Subjects not undergoing hematopoietic stem cell transplant who are in remission may continue on 
crenolanib after induction and/or HiDAC consolidation. Following the last dose of cytarabine 
given for consolidation, crenolanib can be given continuously for an additional twelve cycles.  
 
Patients who undergo allogeneic transplant may receive maintenance crenolanib after transplant if 
they fulfill prerequisites. Subjects in remission who are scheduled for allogeneic hematopoietic 
stem cell transplant (HSCT) should discontinue crenolanib at least 72 hours prior to start of 
conditioning therapy. Start of maintenance therapy is intended no sooner than 30 days after 
allogeneic HSCT. 
 
Prerequisites for start of maintenance are: 
 a stable dose of immunosuppressive drugs for management or prophylaxis of GVHD or 
 no escalation of therapy for GVHD within 14 days of starting study drug  
 have no more than grade 2 persistent non-hematological toxicity related to the transplant 
 must have received crenolanib during induction for AML prior to HSCT to continue on to 
maintenance 
 
Maintenance therapy, whether following transplant or not will start at the last dose tolerated during 
induction/consolidation therapy. For example, if the patient was taking 80 mg TID prior to 
proceeding with HSCT, maintenance therapy will resume at 80 mg TID. If well tolerated, 
crenolanib can be escalated to 100 mg TID. Crenolanib maintenance can be given for up to 12 
cycles and additional therapy can be provided after discussion with the sponsor.   
 
8.3. 
Treatment with Crenolanib (AR-868,596) 
The investigator or his/her designee is responsible for explaining the correct use of the 
investigational agent(s) to the subject or other site personnel such as inpatient staff, verifying that 
instructions are followed properly, maintaining accurate records of study drug dispensing and 
collection, and returning all unused and unopened medication to AROG or its designee at the end 
of the study. Study medication that has been dispensed but remains unused at the end of each cycle 
is recorded by the site personnel and either safely discarded if opened or returned to AROG if 
unopened with intact packaging. 
 
Subjects will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be handled.  
 
Missed Doses/Counting Cycle Days: If a subject vomits after drug ingestion, no replacement dose 
is to be taken; the subject can continue to take the remaining doses as planned. If drug is held or a 
dose is missed by more than 3 hours after the scheduled time, the missed/held dose should not be 
made up. Dosing will resume with the next scheduled dose. The subject/nursing or research staff 
should enter in the diary the doses as missed and reason for missed dose. If drug is held or missed 
for a day or more, treatment should continue as if uninterrupted. As pill count for compliance 
assessment will be performed at each patient follow up; leftover drug should be returned to the 
study site by the subject upon follow up. 
 
During induction and consolidation, one cycle is defined by start of chemotherapy and will 
continue until the start of next chemotherapy (i.e. induction 1 = cycle 1 and may exceed 28 days) 


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regardless whether drug is held. During maintenance, cycles will be 28 days in maximum duration 
(28 days = 1 cycle = 1 month).  
 
“Days” of a cycle are to be counted sequentially from start of chemotherapy (not study drug) until 
start of next chemotherapy cycle. During maintenance, the start of a cycle is denoted by ingestion 
of the first dose of crenolanib after evaluation of efficacy at the end of induction or consolidation. 
The scheduled procedures/visits should comply with the study calendar regardless of amount of 
study drug administered. 
 
8.4. 
Dosing and Dose Modification of Crenolanib 
Subjects will be given a starting dose of 100 mg TID. Crenolanib should be held starting 72 hours 
prior to start of next induction chemotherapy cycle.   
 
Table 4 Crenolanib dose reduction schedule  
Dose level 
Crenolanib dosing 
0 
100 mg TID 
-1 
80 mg TID 
-2 
60 mg TID 
 
Reductions below 60 mg TID are not planned; dose reductions beyond those mentioned in Table 
4 should be discussed with the sponsor and documentation justifying the specified dose should be 
recorded.  
 
8.4.1. 
Dose Reductions for Non-hematologic Toxicities 
Dose reductions for non-hematologic toxicities attributed to crenolanib will be done as outlined in 
Table 5. The starting dose (dose level 0) of crenolanib will be 100 mg TID. A maximum of two 
(2) dose reductions are allowed in a single subject for toxicities related to crenolanib. Please refer 
to Table 6 and 7 for specific instructions for dose modifications for elevated bilirubin, ALT, AST 
and/or Alkaline Phosphatase.  
 
Table 5 Crenolanib dose reduction for non-hematologic toxicities related to crenolanib 
Toxicity (CTCAE v4.03) 
Dose Modification 
Grade 1 or 2  
No dose modification 
Grade 3 or 4 (except nausea, vomiting 
or diarrhea)  
Hold drug until toxicity resolves to grade 1 or less. Restart drug 
at next lower dose level (see Table 4) 
Grade 3 or 4 nausea, vomiting or 
diarrhea despite optimal therapy within 
72 hours of onset 
Hold drug until toxicity resolves to grade 1 or less. Restart drug 
at next lower dose level (see Table 4) 
 
Table 6 Crenolanib dose reduction for bilirubin elevation 
Worst toxicity (CTCAE Grade) 
Recommended Dose Modifications 
Grade 1 bilirubin elevation (ULN- 1.5 x ULN) 
Continue crenolanib at current dose 
Grade ≥2 or bilirubin elevation (>1.5 x ULN) 
Stop crenolanib. Restart drug at next lower dose 
level (-1) (Table 4) once bilirubin returns to normal. 
Following re-challenge: 
 
Grade ≥2 or bilirubin elevation (>1.5 x ULN) 
Stop crenolanib. Restart drug at next lower dose 
level (-2) once bilirubin returns to normal. 
 


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Table 7 Crenolanib dose reduction for elevation of AST, ALT, Alk Phos 
Worst toxicity (CTCAE Grade) 
Recommended Dose Modifications 
Grade 1 ALT or AST elevation (ULN - 3.0 x ULN) 
and/or Alk phos (ULN - 2.5 x ULN) 
Continue crenolanib at current dose 
Grade ≥2 ALT or AST elevation (>3.0 x ULN) and/or 
Alk phos (>2.5 x ULN) 
Stop crenolanib. Restart drug at next lower dose 
level (-1) (Table 4) once ALT, AST and/or Alk 
Phos returns to ≤ grade 1 
Following re-challenge: 
 
Grade ≥2 ALT or AST elevation (>3.0 x ULN) and/or 
Alk phos (>2.5 x ULN) 
Stop crenolanib. Restart drug at next lower dose 
level (-2) once ALT, AST and/or Alk Phos returns 
to ≤ grade 1 
 
8.4.2. 
Dose Reductions of Crenolanib for Hematologic Toxicities 
Subjects with neutropenia or thrombocytopenia as a consequence of the disease or chemotherapy 
do not require treatment interruptions for myelosuppression. Drug hold or dose reduction in these 
subjects may be considered in an individual case and should be discussed with the medical monitor 
at AROG prior to the drug hold. All dose holds and reductions should be captured in CRFs. Dose 
re-escalation is not allowed on this protocol, any exception must be approved by the sponsor in 
writing. 
 
8.5. 
Other Dose Hold and Dose Reduction  
Dose hold due to toxicity unrelated to crenolanib or other medical interventions may be allowed 
on a case by case basis. Investigator should discuss with sponsor prior to any dose hold for reasons 
other than toxicity related to crenolanib. All dose hold should be captured in CRFs.    
 
8.6. 
Concomitant Therapy 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented with 
source documents on CRFs as concomitant medication. 
 
Supportive measures including blood and platelet transfusions, antimicrobials including 
prophylaxis, etc. are permitted. The use of growth factors is allowed per institutional practice 
guidelines or the preference of the attending physician.  
 
Chemotherapy not specified on this protocol, investigational cytotoxic agents, radiation, or 
biologic therapy is prohibited while the subject is on study with the following exceptions during 
induction:  
1. Leukapheresis is allowed within the first 10 days of induction of the study only. Please 
notify the study’s medical monitor if leukapheresis is required beyond this specification. 
2. Hydroxyurea (up to a maximum of 5 g/d) for a maximum of 10 days within the first 28 
days on trial may be administered during induction. 
3. Leukapheresis and hydroxyurea may be administered together according to the guidelines 
above. 
 
The parameters of exposure to leukapheresis and/or hydroxyurea apply as of cycle 1, day 1 of 
first induction.  Patients who commenced hydroxyurea and/or leukapheresis prior to enrollment 
are allowed to participate.   
 


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Except for the chemotherapy or hydroxyurea specified in this protocol no other anticancer therapy 
including immunotherapy, hormonal cancer therapy, or experimental medications will be 
permitted while patients are participating in this study. Any disease progression requiring other 
forms of specific antitumor therapy will be cause for discontinuation of study therapy. 
 
In clinical trials, crenolanib caused nausea and vomiting in >60% patients (2-5% Grade 3/4 events, 
data unpublished, on file at AROG) and diarrhea in 50% of patients (4% Grade 3/4 events, data 
unpublished, on file at AROG). Therefore, the recommendation is made that standard anti-emetic 
premedication is given (see Table 8). Prophylaxis can be discontinued if subject tolerates 
crenolanib without significant nausea and vomiting. Infectious work-up for diarrhea will be left to 
the discretion of the Investigator, using institutional guidelines. Treatment with antidiarrheal drugs 
is recommended once the onset of the earliest signs of diarrhea is present (see Table 9).  
 
It has not been established whether enzyme inducing drugs alter the dosing of crenolanib in 
patients. However, CYP3A4 is required for the metabolism of crenolanib in experiments done with 
hepatic microsomes. Therapeutic agents which are potential hepatic enzyme CYP3A4 inducing or 
inhibiting drugs should be used with caution in patient participation on the study, see Appendix 
VI. 
Table 8 Suggested therapy for nausea and vomiting (ASCO 2011 guidelines)  
Escalation of therapy 
Drug or class 
Directions 
0 
5-HT3 receptor antagonist  
30 minutes prior to crenolanib 
administration 
1 
Metoclopramide 
2 
Dexamethasone 
  
Table 9 Suggested therapy for diarrhea 
Escalation of therapy 
Drug or class 
Directions 
0 
Loperamide  
As per investigators discretion, not 
to exceed maximum recommended 
dose 
1 
Lomotil 
 
These are suggested guidelines; subjects should be treated according to investigator/treating 
physician discretion.  
 
 


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9. DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
9.1. 
Crenolanib 
Crenolanib besylate is supplied as 100 mg and/or 20 mg tablet for oral administration. Study drug 
will be supplied by AROG Pharmaceuticals, Inc. Study drug may be packaged by a third party. 
Clinical trial materials will be labeled according to regulatory requirements. 
 
Crenolanib besylate tablets should be refrigerated at a temperature between 2C and 8C (35.6F 
and 46.4F). Standard household refrigeration is considered adequate for drug storage. Crenolanib 
should be stored in the vials provided by the pharmacy and kept out of the reach of children. Used 
bottles, unused tablets and bottles and drug diaries should be returned to the study site.  
 
9.1.1. 
Drug-Drug Interaction 
It has not been established whether enzyme inducing drugs alter the dosing of crenolanib in 
patients. However, CYP3A4 is required for the metabolism of crenolanib in experiments done with 
hepatic microsomes. Therapeutic agents which are potential hepatic enzyme CYP3A4 inducing or 
inhibiting drugs should be used with caution in patient participation on the study, see Appendix 
VI. 
 
9.2. 
Chemotherapy 
Only qualified personnel familiar with procedures that minimize undue exposure to themselves or 
the environment should undertake the preparation, handling, and safe disposal of chemotherapeutic 
agents in a self-contained, protective environment. Institutional protocols for preparation, dosing 
and discarding chemotherapeutic agents should be followed. 
 
9.2.1. 
Cytarabine  
Please see package insert for additional information.  
 
9.2.2. 
Idarubicin  
Please see package insert for additional information.  
 
9.2.3. 
Daunorubicin 
Please see package insert for additional information.  
 
 


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10. STUDY PROCEDURES 
After providing informed consent, screening procedures may start with the patients assigned 
unique patient identification number (UPIN). The UPIN will consist of an eight-digit number 
where the first three digits will mark the protocol ID (006). The second two numbers will mark the 
site and will be determined by the sponsor. And the third will mark the patient sequentially. (ie. 
00601001 will be the first patient enrolled from site 1 onto protocol ARO-006). The Sponsor 
should be provided with the complete “Enrollment Checklist” indicating the request to enroll the 
patient to the trial. After review, the sponsor will provide the site a “Confirmation of Enrollment” 
signifying enrollment of the patient to the trial and formal verification of the study unique patient 
identifier number (UPIN).   
 
10.1. Screening 
The following assessments will be performed after completion of the informed consent and within 
28 days of enrollment except as otherwise specified. Any test or procedure performed as per 
standard of care can be used for screening purposes as long as done within the window required.  
 
1. Medical history and physical exam (includes documentation of current medications, prior 
relevant surgeries or treatments, allergies and prior or existing relevant medical conditions) 
2. Height, weight, vital signs 
3. Demographics 
4. ECOG Performance Status (Appendix II) 
5. Serum or urine pregnancy test for women of child bearing capacity (within 7 days of 
enrollment) 
6. Chemistry panel including creatinine, total bilirubin, ALT, and AST (within 7 days of 
enrollment) 
7. CBC with differential (within 7 days of enrollment) 
8. Bone marrow aspirate and biopsy (within 21 days of enrollment).  
9. Evaluation of FLT3-D835, FLT3-ITD and other mutational status (within 21 days of 
enrollment).   
 
10.2. Baseline 
Baseline (first day of crenolanib) should be performed as follows: 
1. Chemistry panel including total bilirubin, ALT and AST should be collected within 24 
hours of initiation of crenolanib. Eligibility criteria (Section 7.1.7) should be reconfirmed 
at this time point. If patient does not have normal total bilirubin and ALT/AST ≤ 2x ULN 
at this time point, crenolanib can be delayed until these criteria are met (section 1 overview 
of treatment plan). 
2. Baseline EKG should be collected after completion of chemotherapy (within 24 hours of 
start of crenolanib) and a second EKG should be performed 2 hour (± 30 minutes) post first 
dose of crenolanib 
3. Active concomitant medications within 24 hours of initiation of crenolanib 
4. CBC with differential collected after completion of chemotherapy and prior to initiation of 
crenolanib 
5. PS, Physical exam with vitals after completion of chemotherapy and prior to initiation of 
crenolanib 
6. Active toxicities or medical conditions after completion of chemotherapy and prior to 
initiation of crenolanib  


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7. Blood and marrow samples for translational research including pharmacokinetic analysis 
will be obtained as defined in Section 11 and lab manual. Every effort should be made to 
collect correlative studies at all time points for all patients; however, missing collection in 
one or more of these time points will not be considered a protocol deviation/violation. 
 
10.3. Evaluation during treatment  
Counting Cycle Duration: During induction and consolidation, one cycle is defined by start of 
chemotherapy and will continue until the start of next chemotherapy (i.e. induction 1 = cycle 1 and 
may exceed 28 days). During maintenance, cycles will be 28 days in maximum duration (28 days 
= 1 cycle).  
 
It is assumed subjects will be in the hospital for chemotherapy (induction and consolidation). 
Required study patient evaluations should be performed as an inpatient or outpatient including: 
 
1. Physical examination (with ECOG PS, vital signs and weight) and medical history update 
(including concomitant medications), and documentation of adverse events: 
a. During induction(s): Routinely per institutional standard of care , at response 
assessment visit (Day 14-28), and at count recovery (or day 42) whichever occurs 
first.  
b. During consolidation(s) Day 1 of crenolanib and then routinely per institutional 
standard of care   
c. During maintenance: Day 1 and then per site standard schedule but no less frequent 
than every 2 months (±1 month). 
2. EKG measurements to be obtained during induction and consolidation therapy.  
a. EKG to be obtained 2 hour (± 30 minutes) post first dose of crenolanib in consolidation 
1. 
3. CBC with platelet count and differential (differential may be omitted if WBC is <0.5 
x109/L) must be obtained at least 
 
a. During induction(s): Routinely per institutional standard of care (at least once 
weekly), at response assessment visit (Day 14-28), and at count recovery (or day 
42) whichever occurs first.  
b. During consolidation(s): Routinely per institutional standard of care (at least once 
weekly). 
c. During maintenance: Day 1 of each cycle 
4. Chemistry panel including creatinine, total bilirubin, ALT and AST must be obtained at 
least 
a. During induction(s): Routinely per institutional standard of care (at least once 
weekly), at response assessment visit (Day 14-28), and at count recovery (or day 
42) whichever occurs first. 
b. During consolidation(s): Routinely per institutional standard of care (at least once 
weekly). 
c. During maintenance: Day 1 of each cycle  
5. Bone marrow aspirations will be taken as follows:  
a. During induction (s): Between days 14-28, bone marrow is obtained per standard 
of care to evaluate for remission/response to therapy and at time of count recovery 
or Day 42 (whichever occurs first)  
b. Bone marrow sampling during consolidations should occur per institutional 
standard of care.   


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c. During maintenance: should occur per institutional standard of care (reference 
study calendar appendix IV).   
6. Blood and marrow samples for translational research including pharmacokinetic analysis 
will be obtained as defined in Section 11 and lab manual. Every effort should be made to 
collect correlative studies at all time points for all patients; however, missing collection in 
one or more of these time points will not be considered a protocol deviation/violation. 
7. Serum or urine pregnancy test for women of child bearing capacity should be done every 
six months while on study.  
 
10.4. At time of progression or completion of study 
1. Medical history and physical exam (includes documentation of current medications) 
2. Weight, vital signs, ECOG Performance Status (Appendix II) 
3. Adverse event documentation 
4. CBC with platelet count, differential (differential may be omitted if WBC is <0.5 x109/L) 
5. Chemistry panel including creatinine, total bilirubin, ALT, and AST 
6.  bone marrow and whole blood samples  
7. Evaluation of FLT3-D835, FLT3-ITD and other mutational status when available 
 
* Every effort should be made to collect optional procedures at all time points for all patients; 
however, missing collection in one or more of these time points will not be considered a protocol 
deviation/violation. 
Procedures that are to be performed at the planned subject visits will be granted an exemption if 
the subject is hospitalized and unstable, or otherwise medically unstable as determined by 
investigator and unable to travel to the study sites. In the latter case, the investigator is responsible 
to ensure that the planned protocol procedures are performed at a local hospital and provide 
oversight. Appropriate documentation and source documents shall be obtained and information 
recorded onto study CRFs. 
 
 
 
 
 


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11. PHARMACOKINETIC AND CORRELATIVE STUDIES 
The participating institution will receive a laboratory kit containing blood collection tubes, labels, 
and a lab manual with collection instructions from AROG for the collection, processing and 
shipping of samples from consenting subjects. Site should contact AROG (Appendix VIII) to 
request lab kits in anticipation of each patient enrolled on the study. 
 
Correlative samples to be collected include but are not limited to: 
1. Serum for pharmacokinetic (PK) analysis (selected sites only) 
2. Bone marrow aspirate (BMA) samples 
3. Bone marrow smears 
4. Whole blood sample  
 
Sampling Schedule for PK (selected sites only) 
Serial blood samples for PK will be drawn for correlative research. See lab manual for forms. 
During crenolanib treatment, PK will be drawn for the following time points:  
 
Day 1 of crenolanib administration following Induction 1 
a. 
pre-dose 
b. 
post-dose 2 hours (± 15 minutes)   
c. 
post-dose 4 hours (± 30 minutes)  
d. 
post-dose 8 hours (± 2 h)  
e. 
post-dose 24 hours (± 6 h) prior to first dose of the day 
 
Day 15 of crenolanib administration following Induction 1 
a. pre-dose 
b. post-dose 4 hours (±30 minutes)  
For patients who proceed to consolidation with HiDAC: 
Day 1 of crenolanib administration following Consolidation 1 
a. pre dose 
b. post-dose 4 hours (±30 minutes)  
c. post-dose 8 hours (± 2 h)  
 
Please make sure that the time and dose of last four crenolanib administrations are captured 
on PK forms.  
 
Sampling Schedule for Bone Marrow Aspirates 
At the time of each routine marrow sampling, an additional aspiration of 2.5 mL should be drawn 
for research purposes and placed in a heparinized cell preparation tube. See lab manual for required 
form.  
 
Scheduled bone marrow time points per protocol: 
a. During induction(s): day 14-28 and at time of count recovery (or Day 42), 
whichever occurs first 
b. During consolidations: as per the institutional standard of care 


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c. Maintenance: as per the institutional standard of care. 
d. When patient is determined to have progressive disease by the treating 
physician (loss of CR/CRi). 
 
Sampling Schedule for Whole Blood Collection 
Samples of 5-10 mL of whole blood are drawn and placed in heparinized cell preparation tubes for 
other correlative science research studies. See lab manual for required form. Samples should be 
drawn at the following two time points: 
 
a. Pre-administration of first dose of anthracycline in induction 1 (when applicable), 
b. Upon progression 
 
Sample Processing Instructions  
See lab manual for processing, storage and shipment of samples.  
 
Sampling Schedule for Other Correlative Studies 
Additional samples for correlative research may be collected at any time while the patient is on 
study, at the discretion of the investigator or as requested by the sponsor. These may include assays 
for resistance studies for cases in which responses are noted but not durable. Samples can be stored 
and collected and send at interim intervals. AROG may request the investigator obtain additional 
samples from the patients; the total blood drawn for these studies will be less than 200 ml in any 
month. 
 
Samples will be stored at AROG or its designated facility for future correlative science research 
studies.  
 
 
 


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12.  RESPONSE DEFINITIONS 
12.1. Response Criteria 
Response criteria will be adapted from the International Working Group for AML. [9] Responders 
are newly diagnosed patients receiving study drug who obtain a CR, CRi, or PR, with or without 
cytogenetic response, hematologic improvements, and morphologic leukemia-free state. Briefly, 
criteria are as follows: 
 
1. Complete remission (CR):  
a. Peripheral blood counts: 
i. No circulating blasts 
ii. Neutrophil count ≥1.0 x109/L  
iii. Platelet count ≥100 x109/L 
b. Bone marrow aspirate and biopsy: 
i. < 5% blasts 
ii. No Auer rods 
iii. No extramedullary leukemia 
 
2. Complete remission with incomplete blood count recovery (CRi): 
a. Peripheral blood counts: 
i. No circulating blasts 
ii. Neutrophil count <1.0 x109/L, or 
iii. Platelet count <100 x109/L 
b. Bone marrow aspirate and biopsy: 
i. < 5% blasts 
ii. No Auer rods 
iii. No extramedullary leukemia 
 
3. Partial remission:  
a. All CR criteria except: 
b. 50 % reduction in bone marrow blast but within 5-25% or  
c. Marrow blasts < 5% with persistent Auer rods 
 
4. Morphologic leukemia-free state:  
a. Bone marrow: <5% myeloblasts   
 
5. Hematologic Improvement (HI):  
Hematologic response must be described by the number of positively affected cell lines. 
a. Blast response (B) 
i. At least a 50% reduction in blast percentage in peripheral blood (if > 5%) 
or bone marrow  
 
 


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13.  STATISTICAL CONSIDERATIONS 
13.1. Statistical and analytical plans 
The statistical analysis of this study will be the responsibility of AROG Pharmaceuticals or its 
designees. The clinical research physician/scientist and statistician will jointly be responsible for 
the appropriate conduct of an internal review process for the final study report and any study-
related material to be authorized for publication by AROG or its designees. A statistical analysis 
plan (SAP) will be prepared as a separate document that details the planned analyses and 
presentation of the study results. 
 
13.1.1. General considerations 
The statistical analyses will be performed by cohort and in some cases, with the cohorts combined. 
Descriptive statistics will be used to summarize the safety and efficacy data for this study. 
Continuous data will be summarized by the number of patients, mean, standard deviation, median, 
minimum, and maximum value. Categorical data will be summarized by the number and 
percentage of patients in each category. Time-to- event endpoints will be summarized using the 
cumulative incidence and Kaplan-Meier methodology, as appropriate. 
 
13.1.2. Determination of sample size 
A total of approximately 120 patients will be enrolled. The study consists of a safety phase and an 
expansion phase. The safety phase has two arms in which patients will receive cytarabine in 
combination with daunorubicin (Cohort A) or with idarubicin (Cohort B) during standard 7+3 
therapy with Crenolanib. The safety of each arm will be evaluated separately and once the safety 
is established, an expansion phase will be opened in which patients can receive either 
chemotherapy regimens. 
 
During the initial safety phase, the two cohorts, each consisting of approximately 24 patients, will 
be analyzed separately and initially enroll 12 patients to receive crenolanib with 1-2 courses of 
standard induction chemotherapy. If the early safety stopping criteria are not met for a cohort, then 
12 additional patients may be enrolled in that cohort in order to further characterize the safety and 
tolerability of the combination.  
 
Once the safety of the combinations is determined, a single arm expansion phase will be initiated 
to further confirm the safety and assess the clinical benefit of the combination of standard induction 
chemotherapy with crenolanib.  
 
Historically, patients with newly diagnosed FLT3+ve AML achieve a 66% - 69% response rate 
with induction chemotherapy only. (Mandelli et al. J Clin Oncol. 2009;27(32):5397-403) In recent 
years, Midostaurin (a FLT3 TKI) has shown an improvement of response rate to 74-76% with the 
combination of Midostaurin to standard induction chemotherapy. (Schlenk et al. Blood 2016; 
128(22): 449) This study will enroll approximately 120 patients with the following confidence 
intervals based on projected response rate. A response rate of 90% will have a 95% CI of ±5%. 
That is to say that if we treat 120 patients and observe a 90% response rate, we are 95% sure that 
the true response rate is between 85% to 95%.  
 
 


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Table 10 95% confidence interval based on response rate expected in approximately 120 
patients 
Response Rate 
95% CI 
True response rate interval  
90% 
±5% 
85%-95% 
85% 
±6% 
84%-96% 
80% 
±7% 
83%-97% 
75% 
±8% 
82%-98% 
 
13.2. Safety monitoring during the initial safety phase 
Adverse events, as defined in Section 14.1, will be monitored during the treatment and post-
treatment follow up periods. Adverse events will be monitored on a continuous basis by the 
sponsor. 
 
The Protocol Safety Committee will review safety data from this trial on a periodic basis. The 
committee also will monitor the safety outcomes listed below for purposes of determining if 
enrollment in one or both cohorts should continue or be halted. Within each cohort, up to 6 patients 
will be initially enrolled. For the first 6 patients, patients will be enrolled in a sequential manner 
such that no more than 3 patients are within 30 days of starting induction 1 therapy. Enrollment 
will be halted within a cohort if an apparent increase is observed in the occurrence of one or more 
of the following outcomes: 
 Early mortality due to any cause  
 Expected, non-hematologic, crenolanib-related toxicity (CTCAE Grade 4) 
 Unexpected, non-hematologic, crenolanib-related toxicity (CTCAE Grade 4) 
 
The criteria used to determine if enrollment will be halted are described in sections 13.2.1, 13.2.2 
and 13.3.3.  
 
13.2.1. Excessive early mortality 
Early stopping rules for excessive mortality will be applied in the safety phase of the study. Early 
mortality is defined for this study as death due to any cause within 30 and 60 days of the initiation 
of study treatment. In the VALOR trial, all-cause mortality rates of 7.9% and 19.7% were reported, 
respectively, for patients with relapsed/refractory AML who received cytarabine and placebo as 
induction therapy. [14]  The 30-day mortality rate of 7.9% from the VALOR trial is similar to the 
28-day mortality rate of 10.3% that was reported from a retrospective analysis of more than 3000 
patients with newly diagnosed AML, the majority of whom were treated with cytarabine-based 
regimens as induction therapy.[11] 
 
Based on the above considerations, enrollment in a cohort will be halted if the observed 30- and 
60-day early mortality rate exceeds 10% and 20%, respectively, as follows: if 1 or more of the first 
6 patients enrolled within a cohort die prior to Day 30 then enrollment of additional patients within 
that cohort will be halted pending review by the Protocol Safety Committee. Additionally, 
enrollment will be halted within a cohort if 2 or more of the patients die prior to Day 60. Otherwise, 
6 additional patients will be enrolled within the cohort provided none of the other stopping criteria 
have been met. 
 
For the second group of 6 patients within a cohort, if 2 or more of the patients enrolled within a 
cohort die prior to Day 30, then enrollment of additional patients will be halted pending review by 
the Protocol Safety Committee. Similarly, if 3 or more of the patients enrolled within a cohort die 


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prior to Day 60, then enrollment of additional patients will be halted for that cohort. If these and 
the other early stopping criteria are not met, then the 12 additional patients will be enrolled within 
the cohort. 
 
13.2.2. Excessive expected crenolanib-related toxicity  
Early stopping rules for excessive expected crenolanib-related toxicity will be applied in the safety 
phase of the study. In clinical studies of crenolanib as single-agent therapy, the following 
treatment-related, non-hematologic, adverse events were the most frequently reported, irrespective 
of severity:  
 hepatic dysfunction 
 nausea, vomiting, and diarrhea  
 ascites, edema, and effusions 
  
The majority of these events were CTCAE severity grade 1-3, with grade 4 representing less than 
5% of total cases reported. It’s anticipated that these or similar adverse events also occur with 
relatively higher frequency for AML induction regimens that include cytarabine, idarubicin, or 
daunorubicin. Nonetheless, for purposes of monitoring enrollment in this study, the adverse events 
listed above represent the expected non-hematologic crenolanib-related toxicities. If the observed 
rate of expected, non-hematologic, crenolanib-related toxicity with CTCAE severity grade 4 
exceeds 20% during the first 60 days of treatment, then enrollment will be halted as follows: 
 
If 2 or more of the first 6 patients enrolled within a cohort experience a CTCAE grade 4, non-
hematologic, expected crenolanib-related adverse event prior to Day 60 then enrollment of 
additional patients within that cohort will be halted pending review by the Protocol Safety 
Committee. Otherwise, 6 additional patients will be enrolled within the cohort provided none of 
the other stopping criteria have been met. Upon enrollment of the 6 additional patients within a 
cohort, if 3 or more of the patients enrolled within a cohort experience such an event prior to Day 
60, then enrollment of additional patients will be halted pending review by the Protocol Safety 
Committee. If these and the other early stopping criteria are not met, then 12 additional patients 
will be enrolled to the cohort. 
 
13.2.3. Excessive unexpected crenolanib-related toxicity 
Early stopping rules for excessive unexpected crenolanib-related toxicity will be applied in the 
safety phase of the study. An unexpected crenolanib-related toxicity is defined as any non-
hematologic, adverse event considered related to crenolanib (exclusive of those listed in Section 
13.2.2). If the observed rate of unexpected, non-hematologic, crenolanib-related toxicity with 
CTCAE severity grade 4 exceeds 15% during the first 60 days of treatment then enrollment within 
a cohort will be halted as follows: 
 
If 1 or more of the first 6 patients enrolled within a cohort experience a CTCAE grade 4, non-
hematologic, unexpected crenolanib-related adverse event prior to Day 60 then enrollment of 
additional patients within that cohort will be halted pending review by the Protocol Safety 
Committee. Otherwise, 6 additional patients will be enrolled within the cohort provided none of 
the other stopping criteria have been met. Upon enrollment of the 6 additional patients within a 
cohort, if 2 or more of the patients enrolled within a cohort experience such an event prior to Day 
60, then enrollment of additional patients will be halted pending review by the Protocol Safety 
Committee. If these and the other early stopping criteria are not met, then 12 additional patients 
will be enrolled to complete the cohort. 


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13.3. Assessments during the expansion phase 
Once the safety of the combinations is determined, a single arm expansion phase will be initiated 
to further confirm the safety and assess the clinical benefit of the combination of standard induction 
chemotherapy with crenolanib.  
 
13.3.1. Safety monitoring during the expansion phase 
During the expansion phase, safety monitoring will be performed for the entire per protocol patient 
population (defined as those who receive at least one dose of study drug) and in a separate analysis 
dictated by chemotherapy agent used.  
 
13.3.2. Response Rate Evaluation 
At the expansion phase, the primary end-point is overall response rate. Patients must have received 
at least one dose of study drug and have at least one bone marrow disease assessment to be included 
in the complete response rate.   
 
13.4. Subject Disposition 
A summary of patient disposition will be provided for each cohort and will include the following: 
 Number of patients enrolled 
 Number of patients who participate in each study phase (induction, consolidation, 
maintenance) 
 Reasons for discontinuation from study treatment and follow-up 
 Summary of major protocol violations 
 
13.5. Subject Characteristics 
Patient characteristics will be reported for each cohort, and will include a summary of the 
following: 
 Demographics 
 Baseline disease characteristics 
 Pre-existing conditions 
Other characteristics will be summarized as deemed appropriate. 
 
13.6. Concomitant Therapy 
Concomitant medication will be reported overall as well as summarized in a frequency table using 
the terms recorded on the CRF. If warranted, an attempt may be made to determine how 
concomitant medications are related to observed study outcomes. 
 
13.7. Response Outcome and Methodology 
Response criteria will be adapted from the International Working Group for AML, as stated in 
section 12.1. 
 
13.8. Safety Analyses 
All subjects will be evaluable for safety. Adverse events that occur after a subject is entered (signs 
informed consent), but before the patient receives study drug, will not be recorded on the CRF 
unless the investigator believes that the events may have been caused by a protocol procedure. 
Safety analyses will include summaries of the incidence of adverse events by maximum CTCAE 


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grade (version 4.03; NCI 2010) that occur during the study treatment period or within 30 days of 
the last dose of study treatment or until alternate therapy is started, regardless of causality or 
relatedness to study drug. The safety-related outcomes that will be summarized include: 
 Adverse events, 
 TEAEs, 
 SAEs, 
 Deaths, 
 Discontinuations due to adverse events, 
 Extent of exposure to study drug treatment, 
 Hospitalizations, 
 Use of key concomitant medications. 
 
Analyses for data with discrete dates (for example, death date and start/stop dates of concomitant 
medications) will be performed through 30 days after the patient has been discontinued from study 
treatment or until alternate therapy is started. Adverse events will also be analyzed in this time 
frame. After 30-day post-discontinuation follow-up, only those SAEs that are thought to be related 
to study treatment or protocol procedure should be reported immediately to AROG or its designee. 
For these events, the patient must be followed until the event has resolved or stabilized. 
 
13.9. Criteria for End of Study 
This study will be considered complete following the data cut-off date for the final analysis.  
Documentation of the data cut-off will be included in the master study file. After the final analysis, 
if subjects are continuing to benefit from study treatment, they will be allowed to continue 
receiving study treatment for up to one year as part of planned maintenance. Patient is considered 
“off therapy” when study drug stops for any reason and crenolanib therapy is not continued.  
Patient is considered “off study” after completion of the 30-day safety follow up, 2 year follow-up 
period or upon death or upon start of a new therapy, whichever comes first. 
 
 
 
 


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14. SAFETY EVALUATIONS AND APPROPRIATENESS OF MEASUREMENTS 
14.1. Definitions of Adverse Events 
 
14.1.1. Adverse Event (AE) 
Any harm or untoward medical occurrence in a research participant administered a medical 
product, medical treatment or procedure even if it does not necessarily have a causal relationship 
with the product, treatment, or procedure. An adverse event can be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medical product, medical treatment, or procedure whether or not 
considered to be related. All adverse events regardless of grade must be recorded, graded, and 
reported to the Sponsor. 
 
14.1.2. Serious AE (SAE) 
An adverse event that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening adverse event (real risk of dying) 
• 
Hospital admission 
• 
Prolongation of hospitalization 
• 
Persistent or significant disability/incapacity/or change in psychosocial status 
• 
Congenital anomaly 
• 
Requirement of intervention to prevent permanent impairment or damage 
 
14.2. Attribution to Study Drug 
For reporting purposes, attribution is the assessment of the likelihood that an adverse event is 
caused by the research agent or protocol intervention. The attribution is assigned by the principal 
investigator after considering the clinical information, the medical history of the subject, and past 
experience with the research agent/intervention. This is recorded using one of the following four 
categories:  
 Related 
 Possibly Related 
 Not Related 
 Unknown 
 
Related means that the adverse event was most certainly caused by the procedures involved in the 
research. 
 
Possibly related means that there is reasonable possibility that the adverse events may have been 
caused by the procedures involved in the research. 
Not related means that the adverse event was due to an underlying disease, disorder, or condition 
of the subject, or may have been caused by other circumstances unrelated to the research or any 
underlying disease, disorder, or condition of the subject. 
 
Unknown means that it is unclear whether the adverse event was related to procedures involved in 
the research, either because more information is needed, and will be provided in follow-up, or 
because there is no way to make a determination. 
 


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An AE is “related or possibly related to the study drug or research procedures” if in the opinion of 
the principal investigator, it was more likely than not caused by the research procedures. AEs that 
are solely caused by an underlying disease, disorder or condition of the subject or by other 
circumstances unrelated to the research or any underlying disease, disorder or condition of the 
subject are not “related or possibly related”. If there is any question whether or not an AE is related 
or possibly related, the AE should be reported. 
 
14.3. Determination of Severity 
The severity of AEs will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.03. If the AE is not defined in the CTCAE, the investigator will 
determine the severity based on the following definitions from the CTCAE: 
 Grade 1 (Mild): Asymptomatic or mild symptoms, clinical or diagnostic observations only 
with no intervention indicated 
 Grade 2 (Moderate): Minimal, local or noninvasive intervention indicated, limiting 
instrumental ADL 
 Grade 3 (Severe): Medically significant but not immediately life-threatening, causing 
hospitalization or prolongation of hospitalization, disabling and limiting self-care AL 
 Grade 4 (Life-Threatening): Urgent intervention indicated 
 Grade 5 (Death) 
 
14.4. Adverse Event Reporting 
AROG has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent. Lack of drug effect is not an AE in clinical trials, because 
the purpose of the clinical trial is to establish drug effect. 
 
Adverse Events (AEs) will be evaluated according to CTCAE version 4.03 and documented in 
medical record.  After the Informed Consent Document (ICD) is signed, study site personnel will 
record the occurrence and nature of each patient’s pre-existing conditions, including clinically 
significant signs and symptoms of the disease. During the study, site personnel will record any 
change in the pre-existing condition(s) and the occurrence and nature of any new adverse events.  
 
All AEs related to protocol procedures are reported to AROG or designee. All AEs occurring after 
the patient receives the first dose of study drug must be reported to AROG or its designee via CRF. 
Investigators will be instructed to report to AROG or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, studied disease state, study drug, and/or drug 
delivery system via CRF.  
 
For all AEs, the investigator should specify: 
1. Seriousness: Seriousness of an AE is defined by the criteria described in Section 10.1. A 
severe AE should not always be considered as serious. 
2. Date of onset and its duration (start and end dates): The investigator should follow up the 
outcome of any AEs until they return to normal or consolidation of the subject's condition. 
All adverse events still evolving at the end of the study are to be followed up by the 
investigator until their resolution or stabilization.  
3. Severity: (using NCI CTCAE v.4.03),  


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4. Action taken with respect to study drug: (no action taken; study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; hospitalization/prolonged hospitalization), corrective treatment/therapy given, 
additional investigations performed 
5. Outcome: 
Resolved/Recovered, 
recovering/resolving, 
not 
recovered/resolved, 
recovered/resolved with sequelae, unknown 
6. Relatedness: If an AE is related or not related to study drug  
 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study are to be followed up by the 
investigator for as long as medically indicated. The sponsor retains the right to request additional 
information for any subject with ongoing AE(s) at the end of the study, if judged necessary. 
 
CASE OF ROUTINE LABORATORY MEASUREMENTS 
A value outside the normal or reference range in a routine safety assessment, such as clinical 
laboratory may be considered as an AE. However, laboratory, as well as vital signs abnormalities, 
are to be recorded into the eCRF as AEs only if they are considered medically relevant by the 
investigator: 
i.e. 
symptomatic, 
requiring 
corrective 
treatment, 
leading 
to 
IMP 
discontinuation/dose modification (reduction and/or delay), and/or fulfilling a seriousness 
criterion. Deterioration of a laboratory value that is unequivocally due to disease progression 
should not be reported as an AE. If the findings contribute to a clinical diagnosis (such as hepatitis 
in case of increased liver enzymes) this diagnosis should be recorded as an adverse event.  
 
14.5. Serious Adverse Event Reporting 
Serious adverse event collection begins after the patient has signed informed consent and has 
received a tablet or more of study drug. If a patient experiences an SAE after signing informed 
consent, but prior to receiving study drug, the event will NOT be collected unless the investigator 
feels the event may have been caused by a protocol procedure. 
 
In case of a SAE, the investigator, within 24 hours of learning of the SAE or subject death, must 
notify the sponsor (Arog Pharmaceuticals by e-mail: SAE@arogpharma.com or Fax: 214-594-
0002) and transmit the following information (within a signed SAE report form): 
 Subject identification code, demographics and vitals 
 Description of event with onset and duration (with CTCAE event term & severity) 
 Dates, dose and frequency of study drug administered 
 Assessment of the seriousness and causality of the event with the study drug using the 
causality criteria (EVCTM): related versus not related 
 Study drug status (dose interrupted or discontinued) 
 Date of death (if applicable) 
 Concomitant therapy and interventions 
 Pertinent laboratory data/diagnostic tests 
 Pertinent medical history including underlying diagnosis 


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All SAEs must be followed by the investigator until resolution or stabilization until the subject’s 
death. This may mean that follow-up will be extended beyond the subject’s withdrawal from the 
trial. The investigator must provide follow-up information (outcome, more precise medical details, 
results of investigations, copy of discharge summary, etc…) within 24 hours of information 
becoming available to Arog Pharmaceuticals and to the study monitor, again using the SAE Report 
Form indicating follow-up. When this information is passed on, care must be taken to continue to 
respect subject anonymity. The study monitor may contact, or visit the investigator, in order to 
obtain details of the event.  
 
The sponsor will report all SUSAR to the country specific regulatory authorities within the request 
period. The evaluation of expectedness is based on knowledge of the adverse reaction on the 
reference document: the current reference document is the latest version of the Investigator’s 
Brochure of crenolanib. 
 
The sponsor will also inform the IRB of any SAE with the potential to modify the benefit/risk ratio 
of the present study. The sponsor will be responsible for reporting of New Safety Issues and Annual 
Safety Reports to IRBs. 
 
The following events are not to be considered as a SAE: 
 Any event requiring short consultation in a hospital 
 An external treatment in a hospital emergency service 
 Any event clearly related to disease progression  
o Disease progression can be considered as a worsening of a patient’s condition 
attributable to the disease for which the investigational product is being studied. It 
may be an increase in the severity of the disease under study and/or increases in the 
symptoms of the disease. The development of new, or progression of existing 
metastasis to the primary cancer under study should be considered as disease 
progression and not an AE or SAE. Events that are unequivocally due to disease 
progression should not be reported as AEs or SAEs during the study. 
 Hospitalization (1 night or more) or hospitalization prolongation for one of the following 
reasons: 
o Planned hospitalization for routine intervention 
o Hospitalization or intervention requested by the protocol 
o Hospitalization for explorations not related to a modification of the subject’s health 
o Hospitalization for comfort or for social reasons (for example: hospitalization of an 
elderly person due to dependence on his partner who was hospitalized) 
o Hospitalization not related to a subject’s health worsening and not related to the 
study objectives (for example: plastic surgery) 
 
14.6. Follow-up of Adverse Events 
All adverse events will be followed up according to Good Clinical Practice. 


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During Treatment:  During study, site personnel will track any change in the condition(s) and 
the occurrence and nature of any AEs and record the highest grade of the adverse event per cycle 
on the CRF. CTCAE grading will be assigned before each visit for any adverse events experienced 
during the previous visit period. 
 
Preparation for transplant: Once patient enters conditioning prior to transplant, crenolanib will 
be held (72 hours prior to start of conditioning). Patients will not be followed for safety once 
conditioning starts. If patient receives maintenance crenolanib following transplant, safety will be 
assessed once patient restarts crenolanib (per protocol).  
 
Discontinuation due to relapse: 
Patients who have discontinued therapy due to relapse will be followed for safety for 30 days post 
last dose of crenolanib or until start of another therapy or death, whichever comes first. 
 
Discontinuation due to toxicity:  
Patients who have discontinued therapy due to toxicities attributable to study drug will be followed 
for safety for 30 days post last dose of crenolanib or until start of another therapy or death, 
whichever comes first.  
 
Long-Term Follow-Up Period:  Only new and ongoing serious adverse events (SAEs) thought 
to be related to study treatment or protocol procedures should be documented on the CRF and 
immediately reported to AROG or its designee via the designated transmission method. If drug-
related toxicity is present beyond 30 days post-discontinuation, patients must be followed at least 
for 30 days or until the toxicity resolves.  
 
14.7. Miscellaneous adverse events 
New safety issues: Any new safety data that could lead to re-evaluate the ratio between the benefits 
and the risks of the research, or that could be sufficiently important to consider modifications of 
the research documents, the research management or, if need be, the drug utilization. 
 
New cancers: The development of a new cancer should be regarded as an AE and will generally 
meet at least one of the serious criteria. New cancers are those that are not the primary reason for 
the administration of the study treatment and have been identified after the subject’s inclusion in 
this study. They do not include metastases of the original cancer. 
 
14.8. Deaths 
All deaths that occur during the study should be reported as follows: 
• Death, which is unequivocally due to disease progression, should be communicated to 
the study monitor at the next monitoring visit and should be documented in the CRF 
module, but should not be reported as a SAE during the study 
• Where death is not clearly due to disease progression of the disease under study the AE 
causing the death should be reported to the study monitor as an SAE within 24 hours of 
becoming aware of the event. The report should contain a comment regarding the co-


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involvement of progression of disease, if appropriate, and should assign a single 
primary cause of death together with any contributory causes 
• Deaths with an unknown cause should always be reported as a SAE (within 24 hours of 
becoming aware of the event) but every effort should be made to establish a cause of 
death. A post-mortem may be helpful in the assessment of the cause of death, and if 
performed, a copy of the post-mortem results (with translation of important parts into 
English) should be reported in an expedited fashion to the sponsor within the usual 
timeframes 
 
14.9. Pregnancy 
Nothing is known about the effects of crenolanib on reproductive function. Women of reproductive 
potential and fertile men will be informed as to the potential risk of procreation while participating 
in this trial. 
If the investigator has been informed that a female subject is pregnant during the study period: 
1. The investigational product should be immediately discontinued and the planned safety 
assessments should be performed 
2. The investigator must immediately notify the study monitor, complete the Pregnancy 
Report Form, and send it to Arog Pharmaceuticals by e-mail: SAE@arogpharma.com or 
Fax: 214-594-0002. 
3. Follow-up of the pregnancy will be mandatory until the outcome has been determined.  
Nota bene: In order to follow the pregnancy of the wife of a subject included in the study, consent 
or agreement of the subject’s wife should appear in the medical file of the subject.   
 
14.9.1. Maternal exposure 
Pregnancy itself is not regarded as an adverse event. Congenital abnormalities/birth defects and 
spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of a pregnancy should be followed up 
and documented even if the patient was withdrawn from the study. 
 
If a pregnancy occurs during exposure to investigational product or in the 30 days after 
discontinuing investigational product, then investigators or other site personnel must inform the 
sponsor immediately, or no later than 24 hours of when he or she becomes aware of it. The same 
timelines apply when outcome information is available. 
 
14.9.2. Paternal exposure 
Pregnancy of a patient’s partner is not considered to be an adverse event. However, any conception 
occurring from the date of dosing until 16 weeks after dosing should be reported to the sponsor and 
followed up for its outcome. 
 
14.10. Overdose 
To date there have been no instances of patients who were inadvertently overdosed. Clinical 
studies have shown an apparent crenolanib half-life of approximately 8 hours. It is anticipated that 


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crenolanib would be metabolized and excreted within 5 half-lives of the drug. No specific antidote 
exists for the treatment of crenolanib overdose. Investigators will be advised that any patient who 
receives a higher dose than that intended should be monitored closely, managed with appropriate 
supportive care and followed up expectantly.  
 
If an overdose occurs in the course of the study, then investigators or other site personnel must 
inform the sponsor immediately, or no later than 24 hours of when he/she becomes aware of it.  
 
Such overdoses should be recorded as follows: 
 An overdose with associated AEs/SAEs is recorded as the AE diagnosis/symptoms on the 
relevant AE/SAE modules in the eCRF. 
 An overdose with no associated symptoms should be documented on the eCRF module for 
dosing of study drug. 
 
 
 


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15.  DATA COLLECTION AND MANAGEMENT 
To ensure accurate, complete, and reliable data, AROG or its representatives will do the following: 
 Provide instructional material to the study site, as appropriate. 
 Sponsor a start-up training session to instruct the investigators and study coordinators. 
This session will give instruction on the protocol, the completion of the CRFs, and 
study procedures. 
 Conduct periodic teleconferences (approximately twice a month) with each study site 
to discuss current patients on trial, available pharmacodynamics/pharmacokinetic 
data, regulatory issues and other updates as applicable. 
 Make periodic visits to the study site. 
 Be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax. 
 Review and evaluate CRF data and use audits to detect errors in data collection. 
 Conduct a quality review of the database. 
 
In addition, AROG or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by AROG or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study. If requested, the investigator 
will provide the sponsor, applicable regulatory agencies, and applicable ethical review boards 
(ERBs) with direct access to original source documents. 
 
15.1. Data Capture System 
An electronic data capture system will be used in this trial. Case report form (CRF) data will be 
encoded and stored in a clinical trial database. Any data that will serve as the source document 
will be identified and documented in the site’s study file.  
 
15.2. Data Safety Monitoring Plan 
AROG and Investigator, or his/her designee, will have periodic teleconferences (approximately 
twice a month) with each study site to discuss current patients on trial, available 
pharmacodynamics/pharmacokinetic data, regulatory issues and other updates as applicable.  
   
AROG will have Data Safety Monitoring meetings at least every six months or for every 6 patients 
enrolled per cohort. At these meetings, compiled patient data including responses and safety 
analysis will be discussed. 
 
 


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16. INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
16.1. Informed Consent 
The Principal Investigator or designee is responsible for explaining verbally and in writing the 
nature, duration, and purpose of the study and possible consequences for treatment. In addition, 
the Principal Investigator or designee must ensure that the patient understands the potential risks 
and benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial. Patients must also be 
informed that they may withdraw from the study at any time and for any reason without 
jeopardizing their future treatment. In accordance with federal regulations (21 CFR 50), all patients 
enrolled in the study must sign the IRB-approved consent form. 
 
The informed consent document (ICD) will be used to explain the potential risks and benefits of 
study participation to the patient in simple terms before the patient is entered into the study, and 
to document that the patient is satisfied with his or her understanding of the risks and benefits of 
participating in the study and desires to participate in the study. 
 
The investigator is responsible for ensuring that informed consent is given by each patient or legal 
representative. This includes obtaining the appropriate signatures and dates on the ICD prior to the 
performance of any protocol procedures and prior to the administration of study drug. 
 
16.2. Document Review 
In accordance with federal regulations (21 CFR 312.66), an Institutional Review Board (IRB) that 
complies with regulations in 21 CFR 56 must review and approve this protocol and the informed 
consent form prior to initiation of the study. Documentation of IRB approval of the protocol and 
the ICD must be provided to AROG.   
 
Prior to IRB submission and review, AROG must review and approve all ICDs. All informed 
consent documents must be compliant with the International Conference on Harmonization (ICH) 
guideline on good clinical practice (GCP). Informed consent obtained under special circumstances 
may occur only if allowed by local laws and regulations and performed in accordance with a 
written process approved by AROG. 
 
Any member of the IRB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the IRB’s vote on the approval of the protocol. 
As well as documentation required by the study site’s IRB(s), the following will be provided:   
 Current Study Protocol 
 The current Investigator’s Brochure or package labeling and updates during the 
course of the study 
 Informed consent document 
 
16.3. Confidentiality 
Patient medical information obtained for the purposes of this study is confidential, and disclosure 
to third parties, other than those noted above, is prohibited. Upon the patient’s request and written 
permission, medical information may be given to his/her personal physician or other appropriate 
medical personnel responsible for the patient’s welfare. Data generated for this study must be 


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available for inspection on request to representatives of the national or local health authorities, and 
the associated IRB/IEC. Release of research results or data that reveal patient names or other 
identifiers, such as photographs, audio or videotapes, must be carried out in accordance with 
Department of Health and Human Services Final Standards for Privacy of Individual Health 
Information, 45 CFR 164.508. Written authorization must be obtained from the patient and 
IRB/IEC prior to the release of such information. Identifiable patient data may not be used for 
purposes of promoting any drugs used in this trial. 
 
16.4. Investigator Information 
Physicians with a specialty in oncology will participate as investigators in this clinical trial. 
 
16.5. Protocol Signatures 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to an AROG representative. 
 
16.6. Final Report Signature 
The clinical study report coordinating investigator, which may be the Principal Investigator, will 
sign the final clinical study report for this study, indicating agreement that, to the best of his or her 
knowledge, the report accurately describes the conduct and results of the study.  
 
The sponsor’s responsible medical officer will sign the final clinical study report for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study. The final clinical study report will be written by the sponsor. 
 
16.7. Publication Statement 
The results of this clinical trial may be used for public dissemination in the form of papers, 
abstracts, posters, or other informational materials to be presented at scientific meetings, or 
published in professional journals, or as a part of an academic thesis by an investigator. 
 
Identifiable patient data may not be used for any of these presentations, manuscripts, or reports 
unless directed by law. 
 
 
 
 


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17.  REFERENCES 
1. 
Rowe, J.M. and M.S. Tallman, How I treat acute myeloid leukemia. Blood, 2010. 116(17): 
p. 3147-56. 
2. 
Galanis, A., et al., Crenolanib is a potent inhibitor of FLT3 with activity against resistance-
conferring point mutants. Blood, 2014. 123(1): p. 94-100. 
3. 
Schlenk, R.F., et al., Mutations and treatment outcome in cytogenetically normal acute 
myeloid leukemia. N Engl J Med, 2008. 358(18): p. 1909-18. 
4. 
Smith, C.C., et al., Crenolanib is a selective type I pan-FLT3 inhibitor. Proceedings of the 
National Academy of Sciences of the United States of America, 2014. 111(14): p. 5319-
24. 
5. 
Zimmerman, E.I., et al., Crenolanib is active against models of drug-resistant FLT3-ITD-
positive acute myeloid leukemia. Blood, 2013. 122(22): p. 3607-15. 
6.        Robert J, et al., Comparative pharmacokinetic study of idarubicin and daunorubicin in 
leukemia patients. Hematol Oncol. 1992.10(2): p.111-6.7. Collins, R., et al., Clinical 
activity of Crenolanib in patients with D835 mutant FLT3-positive relapsed/refractory 
acute myeloid leukemia (AML). J Clin Oncol, 2014. 32:5s(suppl; abstr 7027). 
8. 
Lichtman, M.A., A historical perspective on the development of the cytarabine (7days) and 
daunorubicin (3days) treatment regimen for acute myelogenous leukemia: 2013 the 40th 
anniversary of 7+3. Blood cells, molecules & diseases, 2013. 50(2): p. 119-30. 
9. 
Cheson, B.D., et al., Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. Journal of clinical oncology 
: official journal of the American Society of Clinical Oncology, 2003. 21(24): p. 4642-9. 
10. 
Kottaridis, P.D., et al., The presence of a FLT3 internal tandem duplication in patients with 
acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk 
group and response to the first cycle of chemotherapy: analysis of 854 patients from the 
United Kingdom Medical Research Council AML 10 and 12 trials. Blood, 2001. 98(6): p. 
1752-9. 
11. 
Walter, R.B., et al., Prediction of early death after induction therapy for newly diagnosed 
acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment 
assignment. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology, 2011. 29(33): p. 4417-23. 
12.  
Mandelli et al. J Clin Oncol. 2009;27(32):5397-403 
13.  
Schlenk et al. Blood 2016; 128(22): 449 
 
 
 
 
 


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Appendix I. Inclusion/Exclusion Criteria Checklist 
All subjects enrolled must meet eligibility criteria based on the inclusion/exclusion criteria 
detailed in the application and approved by the IRB. 
 
I. Study Information 
 
Protocol Title: 
A Study of Crenolanib and Chemotherapy with Cytarabine and 
Anthracyclines in Patients with Newly Diagnosed Acute Myeloid 
Leukemia  
with FLT3 Activating Mutations 
Protocol Number: 
ARO-006 
 
II. Subject Information: 
 
Subject Name/ID: 
 
Gender:    x Male     x  Female 
 
III. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
N/A 
Supporting 
Documentation* 
1. Unequivocal diagnosis of AML based on the 
WHO classification, excluding acute 
promyelocytic leukemia. 
 
 
 
 
2. No prior therapy for AML, except for 
hydroxyurea and/or leukapheresis, in this 
setting is allowed. 
 
 
 
 
3. Subjects with AML evolving from MDS with or 
without prior MDS therapy with demethylating 
agents will be allowed in the safety phase only. 
 
 
 
 
4. Subjects must have tested positive for FLT3-ITD 
and/or other FLT3 activating mutations. 
 
 
 
 
5. Age ≥18 years will be allowed in the safety 
phase; during the expansion phase, subjects 
must be ≥18 - ≤70 years of age. 
 
 
 
 
6. ECOG PS 0 – 2 
 
 
 
 
7. Adequate liver function, defined as normal 
bilirubin, ALT ≤2.0x ULN, and AST ≤2.0x ULN 
measured within 24 hours prior to the induction 
chemotherapy. 
 
 
 
 
8. Adequate renal function, defined as serum 
creatinine ≤1.5x ULN or GFR >50 mL/min 
 
 
 
 


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9. Negative pregnancy test (serum or urine) for 
women of childbearing potential (WOCBP). 
 
Women considered not of 
childbearing potential include any of 
the following: no menses for at least 
2 years or menses within 2 years but 
amenorrheic for at least 2 months 
and luteinizing hormone (LH) and 
follicular stimulating hormone 
(FSH) values within normal range 
(according to definition of 
postmenopausal for laboratory used) 
or bilateral oophorectomy or 
radiation castration and amenorrheic 
for at least 3 months or with bilateral 
tubal ligation. 
 
 
 
 
10. WOCBP must practice contraception. 
Acceptable methods of contraception are double 
barrier methods (condoms with spermicidal jelly 
or foam and diaphragm with spermicidal jelly or 
foam), oral, depo provera, or injectable 
contraceptives, intrauterine devices, tubal 
ligations, and abstention. 
 
 
 
 
11. Male patients (except those with prior surgical 
contraceptive procedures) with female partners 
who are of childbearing potential: 
Recommendation is for male and partner to use 
effective contraceptive methods, such as latex 
condoms, during the study. 
 
 
 
 
12. Able and willing to provide written informed 
consent. 
 
 
 
 
Exclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
N/A 
Supporting 
Documentation* 
1. Pre-existing liver diseases (i.e., cirrhosis, chronic 
hepatitis B or C, nonalcoholic steatohepatitis, 
and sclerosing cholangitis, etc.)  
 
 
 
 
2. Known active CNS leukemia 
 
 
 
 
3. During the expansion phase subjects with 
therapy-related AML, AML with prior history of 
MDS with or without prior HMA therapy or 
AML in the setting of antecedent hematologic 
disorder. 
 
 
 
 
4. Subject with concurrent severe and/or 
uncontrolled medical conditions that in the 
opinion of the investigator may impair the 
participation in the study or the evaluation of 
safety and/or efficacy. 
 
 
 
 


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5. NYHA Class III-IV heart failure, myocardial 
infarction <6 months prior to study entry and/or 
serious arrhythmia requiring anti-arrhythmic 
therapy 
 
 
 
 
6. Major surgical procedures within 14 days of 
enrollment (Does not include line placement as 
needed for chemotherapy administration) 
 
 
 
 
7. Unwillingness or inability to comply with 
protocol. 
 
 
 
 
8. Concurrent use of other investigational agents. 
 
 
 
 
9. Subjects who are not eligible for standard 
chemotherapy. 
 
 
 
 
 
*All subject files must include supporting documentation to confirm subject eligibility. The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.   
 
IV. Statement of Eligibility 
 
This subject is [x eligible / x ineligible] for participation in the study. 
 
Signature:  
Date:  
 
Printed Name:  
 
 
 


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Appendix II. ECOG Performance Status Criteria 
Performance Status Criteria 
ECOG (Zubrod) 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory, and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of self-care, but unable to carry out any work activities, up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair for more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self care; totally confined to bed or chair 
 
 
 


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Appendix III. Patient Diaries: Crenolanib 
Cycle No:_________ This section to be completed by Site Study Staff ONLY      
Investigational Drug: Crenolanib 
Besylate (AR-868,596-26) 
Protocol ID: ARO-006 
Prescribed Dose:_________ mg TID, Dosing:______100 mg tablets_________20 mg tablets    
 
SUBJECT ID                                                                       SUBJECT INITIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
Date 
___/___/___ 
m     d      y 
Time 
Taken 
(HR-
MIN 
AM/PM 
Number of 
Tablets 
Taken (100 
mg Tablet) 
Number of 
Tablets 
Taken (20 
mg Tablet) 
If Dose Skipped 
Please Provide the 
Reason/s 
With Food 
If Yes, please 
provide 
Description of 
Meal 
Any Side 
Effects (Please 
Complete 
Adverse Events 
Form in Detail) 
1 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
2 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
3 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
4 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
5 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
6 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
7 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
 


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Cycle No:_________ This section to be completed by Site Study Staff ONLY      
Investigational Drug: Crenolanib 
Besylate (AR-868,596-26) 
Protocol ID: ARO-006 
Prescribed Dose:_________ mg TID, Dosing:______100 mg tablets_________20 mg tablets    
 
SUBJECT ID                                                                      SUBJECT INITIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
Date 
___/___/___ 
m     d      y 
Time 
Taken 
(HR-
MIN 
AM/PM 
Number of 
Tablets 
Taken (100 
mg Tablet) 
Number of 
Tablets 
Taken (20 
mg Tablet) 
If Dose Skipped 
Please Provide the 
Reason/s 
With Food 
If Yes, please 
provide 
Description of 
Meal 
Any Side 
Effects (Please 
Complete 
Adverse Events 
Form in Detail) 
8 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
9 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
10 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
11 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
12 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
13 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
14 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Cycle No:_________ This section to be completed by Site Study Staff ONLY      
Investigational Drug: Crenolanib 
Besylate (AR-868,596-26) 
Protocol ID: ARO-006 
Prescribed Dose:_________ mg TID, Dosing:______100 mg tablets_________20 mg tablets    
 
SUBJECT ID                                                                        SUBJECT INITIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
Date 
___/___/___ 
m     d      y 
Time 
Taken 
(HR-
MIN 
AM/PM 
Number of 
Tablets 
Taken (100 
mg Tablet) 
Number of 
Tablets 
Taken (20 
mg Tablet) 
If Dose Skipped 
Please Provide the 
Reason/s 
With Food 
If Yes, please 
provide 
Description of 
Meal 
Any Side 
Effects (Please 
Complete 
Adverse Events 
Form in Detail) 
15 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
16 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
17 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
18 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
19 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
20 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
21 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
 
 
 


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Cycle No:_________ This section to be completed by Site Study Staff ONLY      
Investigational Drug: Crenolanib 
Besylate (AR-868,596-26) 
Protocol ID: ARO-006 
Prescribed Dose:_________ mg TID, Dosing:______100 mg tablets_________20 mg tablets    
 
SUBJECT ID                                                                        SUBJECT INITIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
Date 
___/___/___ 
m     d      y 
Time 
Taken 
(HR-
MIN 
AM/PM 
Number of 
Tablets 
Taken (100 
mg Tablet) 
Number of 
Tablets 
Taken (20 
mg Tablet) 
If Dose Skipped 
Please Provide the 
Reason/s 
With Food 
If Yes, please 
provide 
Description of 
Meal 
Any Side 
Effects (Please 
Complete 
Adverse Events 
Form in Detail) 
22 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
23 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
24 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
25 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
26 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
27 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
28 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
 
 
 
 
  


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Cycle No:_________ This section to be completed by Site Study Staff ONLY      
Investigational Drug: Crenolanib 
Besylate (AR-868,596-26) 
Protocol ID: ARO-006 
Prescribed Dose:_________ mgTID, Dosing:______100 mg tablets_________20 mg tablets    
 
SUBJECT ID                                                                       SUBJECT INITIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
Date 
___/___/___ 
m     d      y 
Time 
Taken 
(HR-
MIN 
AM/PM 
Number of 
Tablets 
Taken (100 
mg Tablet) 
Number of 
Tablets 
Taken (20 
mg Tablet) 
If Dose Skipped 
Please Provide the 
Reason/s 
With Food 
If Yes, please 
provide 
Description of 
Meal 
Any Side 
Effects (Please 
Complete 
Adverse Events 
Form in Detail) 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
___/___ 
AM/PM 
 
 
 
___/___ 
YES/NO 
 
 
 
 


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Appendix IV. Study Schedule 
I. 
Induction 
 
Assessment 
Screening a 
Baseline 
On Treatment - Induction 1 and 2 
Day 
-28 days of 
enrollment, unless 
otherwise specified 
First day of 
crenolanib 
Weekly 
following 
start of 
crenolanib 
Day 14-28 
(response 
assessment visit) 
Day 42 ± (3 days) 
or at count 
recovery+ 
(whichever is first) 
Weekly until end 
of cycle (if cylce 
is extended past 
42 days) 
Demographics 
X 
 
 
 
 
 
Relevant medical history, current medical conditions 
including AML-specific history 
X 
 
 
 
 
 
Evaluation of FLT3 and other mutational status  
X 
 
 
 
X 
 
Prior/Concomitant medications and significant non-drug 
therapies 
X 
X 
Per SOC 
X 
X 
Per SOC 
Physical examination with ECOG PS  
X 
X 
Per SOC 
X 
X 
Per SOC 
EKG b 
 
X** 
  
 
 
  
Vitals, Weight, and Height (only at screening) 
X 
X 
Per SOC 
X 
X 
Per SOC 
Assessment of adverse events, toxicities  
 
X 
Per SOC 
X 
X 
Per SOC 
Hematology (CBC with differential) 
X* 
X 
X d 
X 
X 
X d 
Serum Chemistries (CMP with bilirubin, ALT/AST and 
creatinine) 
X* 
X 
X d 
X 
X 
X d 
Urine or serum pregnancy test 
X 
 
Every 6 months while patient is on study 
Blood collections for PK and correlative sciences c 
 
X** (drawn per Section 11) 
Bone marrow biopsy and aspirate 
X* 
 
 
X e 
X 
 
 
Key: 
+ count recovery is defined as : ANC ≥1000 and platelets ≥100,000 
a Screening assessments should be performed within 28 days of enrollment with the following exceptions: CBC, CMP and pregnancy test (when applicable) should be performed within 7 days of enrollment, 
bone marrow biopsy and aspirate and evaluation of FLT3 and other mutational status should be performed within 21 days of enrollment 
* If screening assessments were performed while patient was receiving induction chemotherapy, the following assessments performed prior to starting induction, if done per standard of care, may be 
requested by the sponsor: CBC with differential, CMP with bilirubin, ALT/AST, and bone marrow biopsy and aspiration 
b EKG is to be performed pre-dose crenolanib (baseline on the first day of crenolanib) as well as 2 hours (± 30 minutes) post first dose of crenolanib during Induction 1 
c Peripheral and whole blood samples for translation research (including PK analysis) should be collected as defined in Section 11.  
** EKG, Peripheral blood for PK analysis and Whole blood sample will only be collected during Induction 1  
d CBC with differential and CMP should be performed at least weekly while patients are receiving crenolanib during induction. Additional labs may be performed per SOC, for safety, the sponsor may 
request additional labs done per SOC be captured 
e Bone marrow biopsy and aspirate performed on day 14-28 should have FLT3 testing and mutational status if available 
Per SOC: Physician visits (with ECOG PS, vitals, weight, concomitant medication assessment and adverse events assessments) should be performed as per SOC while patients are receiving crenolanib 
during induction. At a minimum adverse events and concomitant medications should be reported to the sponsor (per EDC) monthly.  
 


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II. 
Consolidation  
 
Assessment 
Baseline - Consolidation 1-4 
On Treatment - Consolidation 1-4 
Day 
First day of HiDAC 
consolidation 
First day of 
crenolanib 
Weekly following start of crenolanib 
Prior/Concomitant medications and significant non-drug therapies 
X 
X 
Per SOC 
Physical examination with ECOG PS  
X 
X 
Per SOC 
EKG a 
 
X* 
  
Vitals and Weight 
X 
X 
Per SOC 
Assessment of adverse events, toxicities  
X 
X 
Per SOC 
Hematology (CBC with differential) c 
X 
X 
X 
Serum Chemistries (CMP with bilirubin, ALT/AST and creatinine) c 
X 
X+ 
X 
Urine or serum pregnancy test 
Every 6 months while patient is on study 
Blood collections for PK and correlative sciences b 
 
X* 
 
Bone marrow biopsy and aspirate d 
Per SOC 
 
Key: 
a EKG is to be performed 2 hours (± 30 minutes) post first dose of crenolanib during Consolidation 1 
b Blood samples for translation research (including PK analysis) should be collected as defined in Section 11.  
* EKG and blood for PK will only be collected during Consolidation 1  
c CBC with differential and CMP should be performed at least weekly while patients are receiving crenolanib during induction. Additional labs may be performed per SOC, for safety, the sponsor may 
request additional labs done per SOC be captured 
+ Prior to initiation of crenolanib (within 24 hours of first dose) following HiDAC consolidation, bilirubin, ALT and AST must meet eligibility criteria as depicted in section 1 treatment overview 
d Bone marrow biopsy and aspirate performed should have FLT3 testing and mutational status if available 
Per SOC: Physician visits (with ECOG PS, vitals, weight, concomitant medication assessment and adverse events assessments) should be performed as per SOC while patients are receiving crenolanib 
during induction. At a minimum adverse events and concomitant medications should be reported to the sponsor (per EDC) monthly. 
 
 
 


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III. 
Maintenance  
 
Assessment 
Maintenance 1-12 
At time of progression or 
completion of study 
Day within cycle 
Day 1 (± 14 days) 
 
Prior/Concomitant medications, 
significant non-drug therapies  
X a 
X 
Physical examination with ECOG PS  
X a 
X 
Vitals and weight  
X a 
X 
Assessment of adverse events, 
toxicities  
X a 
X 
Hematology (CBC with differential) 
X 
X 
Serum Chemistries (CMP with 
bilirubin, ALT/AST and creatinine) 
X 
X 
Urine or serum Pregnancy test 
Every 6 months while patient 
is on study 
 
Whole blood sample b 
 
X 
Bone marrow biopsy and aspirate c 
Per SOC 
X 
 
Key: 
a Day 1 and then per site standard schedule but no less frequent than every 2 months (±1 month). 
b Whole blood samples for translation research should be collected as defined in Section 11.  
c Bone marrow biopsy and aspirate performed should have FLT3 testing and mutational status if available 


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Appendix V. Common Terminology Criteria for Adverse Events; Version 4.03 
Cardiac Disorders 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Anorexia 
Definition: A disorder 
characterized by loss of 
appetite. 
Loss of appetite in eating 
habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g. 
inadequate oral caloric 
and/or fluid); tube feeding 
or TPN indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Diarrhea 
Definition: A disorder 
characterized by frequent and 
watery bowel movements 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4-6 stools per 
day over baseline; 
moderate increase in 
ostomy output compared 
to baseline 
Increase of ≥7 stools per 
day over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self care 
ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Fatigue 
Definition: A disorder 
characterized by a state of 
generalized weakness with a 
pronounced inability to 
summon sufficient energy to 
accomplish daily activities. 
Fatigue releved by rest 
 
Fatigue not releved by 
rest, limiting instrumental 
ADL 
 
Fatigue not releved by 
rest, limiting self care 
ADL 
_ 
_ 
Nausea 
Definition: A disorder 
characterized by queasy 
sensation and/or the urge to 
vomit.  
Loss of appetite without 
altering in eating habits 
Oral intake decrease 
without significant weight 
loss, dehydration or 
mainutrition 
Inadequate oral caloric or 
fluid intake; tube feeding, 
TPN, or hospitalization 
indicated 
_ 
_ 
Vomiting 
Definition: A disorder 
characterized by the reflexive 
act of ejecting the contents of 
the stomach throught the 
mount. 
1-2 episodes (separated 
by 5 minutes) in 24 hrs 
3-5 episodes (separated by 
5 minutes) in 24 hrs 
≥6 episodes (separated by 
5 minutes) in 24 hrs; tube 
feeding, TPN or 
hospitalization indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Alanine 
aminotransferance 
increased 
Definition: A finding based 
on laboratory test results that 
indicate an increase in the 
level of alanine 
aminotransferance (ALT or 
SGPT) in the blood 
specimen. 
>ULN-3.0 x ULN 
>3.0-5.0 x ULN 
>5.0-20.0 x ULN 
>20.0 x ULN 
_ 
Aspartate 
aminotransferance 
increased 
Definition: A finding based 
on laboratory test results that 
indicate an increase in the 
level of alanine 
aminotransferance (ALT or 
SGPT) in the blood 
specimen. 
>ULN-3.0 x ULN 
>3.0-5.0 x ULN 
>5.0-20.0 x ULN 
>20.0 x ULN 
_ 
Blood bilirubin 
increased 
Definition: A finding based 
on laboratory test results that 
indicate an increase in the 
level of aspartate 
aminotransferance (AST or 
SGOT) in the blood 
specimen. 
>ULN-1.5 x ULN 
>1.5-3.0 x ULN 
>3.0-10.0 x ULN 
>10.0 x ULN 
_ 
 
 
 
 
 


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Cardiac Disorders 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Pleural effusion 
Definition: A disorder 
characterized by an amounts 
of fluid within the pleural 
cavity. Symptoms include 
shortness of breath, cough 
and market chest discomfort 
Asymptomatic; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Symptomatic; intervention 
indicated (e.g. diuretics or 
limited therapeutic 
thoracentesis 
Symptomatic with 
respiratory distress and 
hypoxia; surgical 
intervention including 
chest tube or pieurodesis 
indicated 
Life-threatening 
respiratory or 
hemodynamic 
compromise; intubation or 
urgent intervention 
indicated 
Death 
Pericardial effusion 
Definition: A disorder 
characterized by fluid 
collection within the 
pericardial sac, usually due 
to inflammation. 
_ 
Asymptomatic effusion 
size small to moderate 
Effusion with physiologic 
consequences 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Edema face 
Definition: A disorder 
characterized by swelling 
due to excessive fluid 
accumulation in face tissues. 
Localized facial edema 
 
Moderated localized facial 
edema; limiting 
instrumental ADL 
 
Severe swelling; limiting 
self care ADL 
_ 
_ 
Edema limbs 
Definition: A disorder 
characterized by swelling 
due to excessive fluid 
accumulation in the upper or 
lover extremities. 
5-10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible difference; 
swelling or obscuration of 
anatomic architecture on 
close inspection 
>10-30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible difference; 
readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour; 
limiting instrumental 
ADL 
≥30% inter-limb 
discrepancy in volume; 
gross deviation from 
normal anatomic contour, 
limiting self care ADL 
_ 
_ 
Edema trunk 
Definition: A disorder 
characterized by swelling 
due to excessive fluid 
accumulation in the trunk 
area. 
Swelling or obscuration of 
anatomic architecture on 
close inspection 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; deadly 
apparent deviation from 
normal anatomic contour, 
limiting instrumental 
ADL 
Gross deviation from 
normal anatomic contour; 
limiting self care ADL 
_ 
_ 


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Appendix VI. CYP3A4 drugs potentially affecting crenolanib pharmacokinetics 
 
The following are few examples of therapeutic agents which are potential hepatic enzyme (CYP3A4) 
inducing or inhibiting drugs and should be used with caution in patient participation on the study): 
 
Strong Inducers 
Strong Inhibitors 
phenytoin (anticonvulsants and mood stabilizers) 
telithromycin (macrolide antibiotics) 
carbamazepine (anticonvulsants and mood 
stabilizers) 
clarithromycin (macrolide antibiotics) 
oxcarbazepine (anticonvulsants and mood 
stabilizers) 
ketoconazole (azole antifungals) 
phenobarbital (barbiturates) 
itraconozole (azole antifungals) 
rifampin (bactericidal) 
nefadozone (antidepressant) 
modafinil (stimulant) 
dexamethasone 
Saquinavir (HIV protease inhibitor) 
hyperforin (constituent of St. John’s Wort) 
Suoxone (analgesic)  
glucocorticoids 
Telithromycin (antibiotic) 
Rifabutin (antimycobiotic) 
 
Troglitazone (anti-diabetic and anti-inflammatory 
drug) 
 
 
 
Moderate Inducers 
Moderate Inhibitors 
pioglitazone (Thiazolidinedione) 
erythromycin (macrolide antibiotics) 
 
fluconazole (azole antifungals) 
 
aprepitant (antiemetic) 
 
bergamottin (constituent of grapefruit 
juice) 
 
verapamil (calcium channel blocker) 
 
Diltiazem (calcium channel blocker) 
 
 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
 
 


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Appendix VII. The WHO Classification of Acute Myeloid Leukemia[12] 
 
Name 
Description 
Acute myeloid leukemia with recurrent 
genetic abnormalities 
Includes:  
 
AML with translocations between chromosome 8 and 21 - 
[t(8;21)(q22;q22);] RUNX1/RUNX1T1;  
 
AML with inversions in chromosome 16 - [inv(16)(p13.1q22)] or internal translocations in it - 
[t(16;16)(p13.1;q22);] CBFB/MYH11; (ICD-O 9871/3); 
 
Acute promyelocytic leukemia with translocations between chromosome 15 and 17 - 
[t(15;17)(q22;q12);] RARA/PML; (ICD-O 9866/3); 
 
AML with translocations between chromosome 9 and 11 - [t(9;11)(p22;q23);] MLLT3/MLL; 
 
AML with translocations between chromosome 6 and 9 - [t(6;9)(p23;q34);] DEK/NUP214; 
 
AML with inversions in chromosome 3 - [inv(3)(q21q26.2)] or internal translocations in it - 
[t(3;3)(q21;q26.2);] RPN1/EVI1; 
 
Megakaryoblastic AML with translocations between chromosome 1 and 22 - 
[t(1;22)(p13;q13);] RBM15/MKL1; 
 
AML with mutated NPM1 
 
AML with mutated CEBPA 
AML with myelodysplasia-related changes 
 
This category includes patients who have had a prior documented myelodysplastic 
syndrome (MDS) or myeloproliferative disease (MPD) that then has transformed into AML, or 
who have cytogenetic abnormalities characteristic for this type of AML (with previous history of 
MDS or MPD that has gone unnoticed in the past, but the cytogenetics is still suggestive of 
MDS/MPD history). This category of AML occurs most often in elderly patients and often has a 
worse prognosis.  
Includes: 
 
AML with complex karyotype 
 
Unbalanced abnormalities 
 
AML with deletions of chromosome 7 - [del(7q);] 
 
AML with deletions of chromosome 5 - [del(5q);] 
 
AML with unbalanced chromosomal aberrations in chromosome 17 - [i(17q)/t(17p);] 
 
AML with deletions of chromosome 13 - [del(13q);] 
 
AML with deletions of chromosome 11 - [del(11q);] 
 
AML with unbalanced chromosomal aberrations in chromosome 12 - [del(12p)/t(12p);] 
 
AML with deletions of chromosome 9 - [del(9q);] 
 
AML with aberrations in chromosome X - [idic(X)(q13);] 
 
Balanced abnormalities 
 
AML with translocations between chromosome 11 and 16 - [t(11;16)(q23;q13.3);], 
unrelated to previous chemotherapy or ionizing radiation 
 
AML with translocations between chromosome 3 and 21 - [t(3;21)(q26.2;q22.1);], 
unrelated to previous chemotherapy or ionizing radiation 
 
AML with translocations between chromosome 1 and 3 - [t(1;3)(p36.3;q21.1);] 
 
AML with translocations between chromosome 2 and 11 - [t(2;11)(p21;q23);], unrelated 
to previous chemotherapy or ionizing radiation 
 
AML with translocations between chromosome 5 and 12 - [t(5;12)(q33;p12);] 
 
AML with translocations between chromosome 5 and 7 - [t(5;7)(q33;q11.2);] 
 
AML with translocations between chromosome 5 and 17 - [t(5;17)(q33;p13);] 
 
AML with translocations between chromosome 5 and 10 - [t(5;10)(q33;q21);] 
 
AML with translocations between chromosome 3 and 5 - [t(3;5)(q25;q34);] 
 


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Name 
Description 
Therapy-
related 
myeloid 
neoplasms 
This category includes patients who have had prior chemotherapy and/or radiation and 
subsequently develop AML or MDS. These leukemias may be characterized by specific 
chromosomal abnormalities, and often carry a worse prognosis. 
AML not otherwise categorized 
Includes subtypes of AML that do not fall into the above categories 
 
AML with minimal differentiation 
 
AML without maturation 
 
AML with maturation 
 
Acute myelomonocytic leukemia 
 
Acute monoblastic and monocytic leukemia 
 
Acute erythroid leukemia 
 
Acute megakaryoblastic leukemia 
 
Acute basophilic leukemia 
 
Acute panmyelosis with myelofibrosis 
 


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Appendix VIII. Contact Information AROG Pharmaceuticals 
 
Contact Information of Chief Medical Officer 
 
John Eckardt, MD 
AROG Pharmaceuticals, Inc. 
Email: jeckardt@arogpharma 
Phone: 214. 451.4520 
 
Contact Information of Director of Clinical Operations 
 
Abhijit Ramachandran 
AROG Pharmaceuticals, Inc. 
Email: aramachandran@arogpharma.com  
Office: 214.593.0515  
Mobile: 817.849.0175 
Fax: 214.594.0002 
 
Contact Information of Study Monitors 
 
Vinoo Urity 
AROG Pharmaceuticals, Inc. 
Email: vurity@arogpharma.com  
Office: 214.593.0521  
Fax: 214.594.0002 
 
Contact Information for notification of shipment of correlative studies samples 
 
AROG Pharmaceuticals, LLC 
Email: info@arogpharma.com 
Office: +1 214.593.0500  
Fax: +1 214.594.0002