Clinical trial NCT01657682
Conditions: Acute Myeloid Leukemia With FLT3 Activating Mutations That Has Relapsed or Been Refractory After One or More Prior Therapies
Keywords: FLT3 Crenolanib Acute Myeloid AML
Sponsor: Arog Pharmaceuticals, Inc.
Start date: 2012-10-01; Completion date: 2019-04-01
Enrollment: 56 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot Phase II study is designed to evaluate the efficacy and tolerability of crenolanib in two cohorts of AML patients with FLT3 activation mutations (patients whose leukemia has recurred after prior chemotherapy not including a FLT3 TKI and patients whose leukemia has progressed after prior therapy with a FLT3 TKI).

Detailed description:
This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed acute myeloid leukemia (AML) with FLT3 activating mutations. Two cohorts of patients will be enrolled: those whose AML has recurred after prior chemotherapy without a FLT3 TKI, and those whose AML has progressed after prior therapy with FLT3 TKIs. Subjects will take Crenolanib besylate at 100 mg TID until disease progression, death, or unacceptable toxicities. Concurrent hydroxyurea is permitted during the first 28 days of study therapy.

Arms: arm 1: Will enroll relapsed/refractory AML patients with FLT3 activating mutations who progressed on one or more prior chemotherapy regimens excluding any FLT3 TKI. arm 2: Will enroll relapsed/refractory AML patients with FLT3 activating mutations whose leukemia has progressed and have history of prior therapy with one or more FLT3 TKIs.
Interventions: intervention 1: Crenolanib besylate
Intervention descriptions: intervention 1: Crenolanib besylate, 100 mg TID, taken orally at least 30 minutes pre- or post- meal. Patients will complete a daily diary to record the date, time and amount (number of tablets) of crenolanib taken and eating schedule.

Concurrent hydroxyurea (maximum 5g total daily dose x 14 days) is permitted during the first 28 days of study therapy.

Protocol documents:
Prot_SAP_000.pdf: 
1 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Protocol ARO-005 
 
A Phase II Study of Crenolanib in Relapsed/Refractory Acute 
Myeloid Leukemia Patients with FLT3 Activating Mutations 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential Information 
 
 
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 (CP-
868,596), unless such persons are bound by a confidentiality 
agreement with AROG Pharmaceuticals, Inc., or its 
subsidiaries. 
 
 
 
 
 
 
 
 
AROG Pharmaceuticals, Inc. 
5420 LBJ Freeway, Suite 410 
Dallas, TX 75240 
 
 
 
 
 
Version 3.0 


2 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Table of Contents 
List of Tables .................................................................................................................................. 4 
List of Figures ................................................................................................................................. 4 
SPONSOR CONTACT INFORMATION ...................................................................................... 5 
1.  OBJECTIVES ............................................................................................................................ 6 
2.  SYNOPSIS ................................................................................................................................. 7 
3.  BACKGROUND ..................................................................................................................... 11 
4.  CRENOLANIB BESYLATE (CP-868,596-26), PRECLINICAL DATA .............................. 13 
5.  CRENOLANIB BESYLATE (CP-868,596-26), CLINICAL DATA ..................................... 19 
6.  RATIONALE FOR DOSE ...................................................................................................... 22 
7.  STUDY DESIGN..................................................................................................................... 24 
8.  PATIENT SELECTION .......................................................................................................... 25 
8.1 
Inclusion Criteria ............................................................................................................ 25 
8.2 
Exclusion Criteria ........................................................................................................... 26 
9.  TREATMENT PLAN .............................................................................................................. 27 
9.1 
General ........................................................................................................................... 27 
9.2 
Schedule ......................................................................................................................... 27 
9.3 
Crenolanib Administration ............................................................................................. 28 
9.4 
Duration of Therapy ....................................................................................................... 28 
9.5 
Concomitant Medications .............................................................................................. 28 
10.  DOSING AND DOSE MODIFICATIONS OF CRENOLANIB .......................................... 29 
10.1 
Dose Escalation .......................................................................................................... 29 
10.2 
Dose Reductions for Non-Hematologic Toxicities .................................................... 29 
10.3 
Dose Reductions of Crenolanib for Hematologic Toxicities ...................................... 30 
10.4 
Additional Dose Modifications requiring discussion with Sponsors Medical Monitor
 
30 
10.5 
Dose Re-escalation ..................................................................................................... 31 
10.6 
Cycle Delays ............................................................................................................... 31 
10.7 
Continued Access to Study Drug................................................................................ 31 
11. 
AGENT FORMULATION AND PROCUREMENT ....................................................... 32 
11.1 
Dose preparation and Storage of Crenolanib .............................................................. 32 
12.  CORRELATIVE/SPECIAL STUDIES ................................................................................. 33 
12.1 
Plasma Inhibitory Assay ............................................................................................. 33 
12.2 
Pharmacokinetic Assay............................................................................................... 34 
12.3 
Bone Marrow Samples and Other Correlative Studies ............................................... 35 
13.  PATIENT EVALUATION .................................................................................................... 37 
13.1 
Pre-Treatment Evaluation ........................................................................................... 37 
13.2 
Evaluation during Treatment ...................................................................................... 37 
14.  CRITERIA FOR RESPONSE ............................................................................................... 39 


3 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
14.1 
Complete Remission (CR) .......................................................................................... 39 
14.2 
Complete Remission with Incomplete Blood Count Recovery (CRi) ........................ 39 
14.3 
Partial Remission (PR) ............................................................................................... 39 
14.4 
Morphologic Leukemia-Free State ............................................................................. 39 
14.5 
Hematologic Improvement (HI) ................................................................................. 39 
15.  ADVERSE EVENT REPORTING........................................................................................ 40 
15.1 
Adverse Event Reporting............................................................................................ 40 
15.2 
Serious Adverse Event (SAE) Reporting: .................................................................. 42 
15.3 
Reporting to FDA: ...................................................................................................... 43 
16.  STATISTICAL CONSIDERATIONS................................................................................... 44 
16.1 
Determination of Sample Size .................................................................................... 44 
16.2 Toxicity Evaluation ........................................................................................................... 45 
16.3 Statistical and Analytical Plans ......................................................................................... 46 
16.4 General Considerations ....................................................................................................................... 46 
17.  PROTOCOL ADMINISTRATION ....................................................................................... 48 
18.  REFERENCES ...................................................................................................................... 49 
Appendix I. Administrative Procedures ........................................................................................ 51 
Appendix II. Inclusion/Exclusion Criteria Checklist .................................................................... 54 
Appendix III. ECOG Performance Status Criteria ....................................................................... 57 
Appendix IV. Patient Diaries: Crenolanib .................................................................................... 58 
Appendix V. Study Schedule ........................................................................................................ 62 
Appendix VI.  Clinical Laboratory Tests ...................................................................................... 64 
Appendix VII. Common Terminology Criteria for Adverse Events (CTCAE); Version 4.03 ..... 65 
Appendix VIII. Definition of a Serious Adverse Event (SAE) .................................................... 66 
Appendix IX-A. ARO-005 C1D1 Pharmacokinetic Data Collection Form ................................. 68 
Appendix IX-B. ARO-005 C1D1 Plasma Inhibitory Assay Data Collection Form ..................... 69 
Appendix X-A. ARO-005 C1D15 Pharmacokinetic Data Collection Form ................................. 70 
Appendix X-B. ARO-005 C1D15 Plasma Inhibitory Assay Data Collection Form .................... 71 
Appendix XI-A. ARO-005 C__D__ Pharmacokinetic Data Collection Form ............................. 72 
Appendix XI-B. ARO-005 C__D__ Plasma Inhibitory Assay Data Collection Form ................. 73 
Appendix XII. Bone Marrow Aspiration: Data Collection Form (Baseline / C_D_) ................... 74 
Appendix XIII. Shipping Addresses for Serum and Tissue Samples ........................................... 75 
Appendix XIV. CYP3A4 Inducing or Inhibiting Drugs with the Potential to Affect Crenolanib 
Pharmacokinetics .......................................................................................................................... 76 
Appendix XV. Contact Information of Arog Pharmaceuticals ..................................................... 77 
Appendix XVI. FMS-like Tyrosine Kinase 3 Inhibitors Currently Being Studied in the Treatment 
of Leukemia and Their Half-life ................................................................................................... 78 
 


4 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
List of Tables 
Table 4.1. Activity of crenolanib against type-III receptor kinases 
Table 4.2. Kd measurements for the interactions of crenolanib with wild type FLT3 and its 
mutants: FLT3-ITD, FLT3-TKD D835Y, and FLT3-TKD D835H. 
Table 5.1. Incidence of treatment-related AEs occurring in ≥ 5% of the study population treated 
with single agent crenolanib. 
Table 10.1. Crenolanib dose escalation guidelines 
Table 10.2. Crenolanib dose reduction guidelines  
Table 10.3. Crenolanib dose reduction guidelines for All Toxicities (except GI (nausea, vomiting 
and diarrhea)) related to study drug. 
Table 15.1. Sponsor-required baseline information in CRFs. 
Table 16.1  Safety monitoring boundary  
Table 16.2  The operating characteristics  
List of Figures 
Figure 3.1. Schematic of FLT3 representing the domains: transmembrane, juxtamembrane and 
tyrosine kinase and the mutation locations of ITD and KD. 
Figure 4.1. Kd measurements for the interactions of crenolanib, sunitinib, CEP-701, AC-220 
(quizartinib), sorafenib etc, with wild type FLT3 and its mutants: FLT3-ITD, FLT3/D835Y, and 
FLT3/D835H. Assay signals were normalized to facilitate comparison. 
Figure 4.2 Dose response of crenolanib in various models of FLT3 AML cells: (A) SEMK2 
cells, (B) Molm14 cells, (C) MV411 cells, and (D) FLT3-D835Y Ba/F3 cells. 
Figure 4.3. In MTT assays, crenolanib is cytotoxic to MV411 and Molm14 cell lines, with IC50 
values of 8nM and 7nM, respectively. 
Figure 4.4. Immunoblot experiments performed in Molm14 cells show that crenolanib inhibits 
downstream signaling of FLT3 at 10nM. 
Figure 4.5. Immunoblot experiment performed at 20nM comparing the activity of crenolanib 
and sorafenib against leukemic blasts with the FLT3-D835V mutation shows that blasts were 
resistant to sorafenib, while crenolanib provided near complete (>90%) inhibition of 
phosphorylated FLT3. 
Figure 4.6. Crenolanib was active against all 4 patient leukemic blasts that had the FLT3/ITD 
mutation. 
Figure 4.7. Crenolanib was more potent against FLT3 D835 blasts in comparison to sorafenib. 
Figure 5.1. Summary of QTc (Fridericia correction (A) and Bazett correction (B)) both baseline 
and worst on-study 
Figure 6.1. The PK simulation for 100mg TID (median +/- SD) plotted based on a simulation of 
data from 14 patients.  
Figure 6 2. Day 15 Crenolanib Trough Levels (100 mg TID and 200 mg/m2/day) 
Figure 6 3.  Serum Concentrations of Crenolanib following Single Dose in AML Patients (100 
mg TID) 
 
 
 


5 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
SPONSOR CONTACT INFORMATION 
 
 
Protocol Number: 
ARO-005 
Version 
3.0 
Version Date: 
October 27, 2014 
Investigational Product: 
Crenolanib  
Development Phase: 
II 
Sponsor: 
Arog Pharmaceuticals, LLC. 
5420 LBJ Freeway, Suite 410 
Dallas TX 75240 
Phone - (214) 593-0500 
Fax - (214) 594-0002  
Email - info@arogpharma.com 
Medical Monitor: 
Nora Ku, M.D. 
M: 305-283-5896 
 
E-mail: nku@arogpharma.com 
Project Manager 
Abhijit Ramachandran 
O: 214.593.0515  
M: 817.849.0175 
F: 214.594.0002 
E-mail: aramachandran@arogpharma.com 
 
 
 
 
 
 
 
 
 
 


6 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
1.  OBJECTIVES 
 
1.1 
Primary Objectives: 
 
 To determine the response rate to crenolanib, including the rates of complete remission (CR), 
CR with incomplete blood count recovery (CRi), and partial remission (PR), in 
relapsed/refractory AML patients with FLT3 activating mutations after first cycle (28-days) 
and at best response.  
 To determine the safety and tolerability of crenolanib in AML patients with FLT3 activating 
mutations 
 
1.2 
Secondary Objectives:  
 
 To determine the duration of response in AML patients with activating FLT3 mutations 
treated with crenolanib 
 To determine the progression free survival and overall survival of AML patients with 
activating FLT3 mutations treated with crenolanib 
 To characterize crenolanib pharmacokinetics in adult patients with AML and relate 
crenolanib exposure to outcome (e.g.,  toxicity and/or FLT3 inhibition) 
 To analyze phospho-FLT3 and other pharmacodynamic markers from serially collected 
circulating leukemic blasts and/or marrow blast samples 
 
 
 
 
 


7 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
2.  SYNOPSIS 
Study Rationale 
 
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 30%.  Despite the presence of these mutations, there is no approved target specific 
therapy for AML patients who harbor them. 
 
Crenolanib besylate (CP-868,596-26) is an orally bioavailable, selective tyrosine kinase inhibitor 
(TKI) of both wild-type FLT3 as well as FLT3 with activating mutations.  Crenolanib has a high 
affinity for mutant FLT3 with Kd values of 0.43nM, 0.18nM, and 0.4nM for FLT3 ITDs and 
TKD mutations D835Y and D835H, respectively.  This high affinity of crenolanib allows it to 
inhibit aberrant FLT3 signaling at clinically achievable concentrations in AML patients.  The 
activity of crenolanib against wild type FLT3 and FLT3 with activating mutations has been 
confirmed in both myeloid leukemia cell lines as well as in primary leukemic blasts obtained 
from patients.  Crenolanib was found to be cytotoxic to leukemic blasts from treatment naïve 
patients with FLT3 activation as well as patients whose leukemia had progressed after 
chemotherapy or treatment with other FLT3 TKIs.   
 
This pilot Phase II study is designed to evaluate the efficacy and tolerability of crenolanib in two 
cohorts of AML patients with FLT3 activation mutations (patients whose leukemia has recurred 
after prior chemotherapy not including a FLT3 TKI and patients whose leukemia has progressed 
after prior therapy with a FLT3 TKI). 
 
 


8 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Clinical Protocol Synopsis   
 
Protocol Number: ARO-005 
Name of Investigational Product: 
Crenolanib besylate (CP-868,596-26) 
Title of Study:  A Phase II Study of Crenolanib in relapsed/refractory Acute Myeloid 
Leukemia patients with activating FLT3 mutations. 
Number of Planned Patients:   
70 patients 
Length of Study:  1 year 
Objectives:  
Primary Objectives 
 To determine the response rate to crenolanib, including the rates of complete remission 
(CR), CR with incomplete blood count recovery (CRi), and partial remission (PR), in 
relapsed/refractory AML patients with FLT3 activating mutations after first cycle (28-
days) and at best response.  
 To determine the safety and tolerability of crenolanib in AML patients with FLT3 
activating mutations 
Secondary Objectives 
 To determine the duration of response in AML patients treated with crenolanib  
 To determine the progression free survival and overall survival in AML patients with 
FLT3 activating mutations treated with crenolanib 
 To characterize the pharmacokinetics of crenolanib in adult patients and relate drug 
disposition to outcome or pharmacodynamic markers (i.e. toxicity and/or FLT3 inhibition) 
 To analyze phospho-FLT3 and other pharmacodynamic markers from serially 
collected circulating leukemic blasts and/or marrow blast samples 
 
Study Design:   
This is a Phase II open label study of crenolanib besylate given  three times a day 
(preferably every eight hours) continuously until one of the criteria for study 
discontinuation is fulfilled.  
 
The study will enroll 2 different cohorts of patients in parallel. 
 
Cohort A:  Will enroll relapsed/refractory AML patients with FLT3 activating mutations 
who progressed on one or more prior chemotherapy regimens excluding a FLT3 TKI 
 
Cohort B: Will enroll relapsed/refractory AML patients with FLT3 activating mutations 
whose leukemia has progressed and have history of prior therapy with one or more FLT3 
TKIs. 


9 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Diagnosis and Main Criteria for Inclusion and Exclusions:   
 
Inclusion Criteria: 
 Confirmed primary AML relapsed or refractory after prior therapy, AML secondary to 
antecedent chemotherapy or radiation therapy, or AML due to prior myelodysplastic syndrome 
(MDS)/ myeloproliferative neoplasm (MPN) as defined by WHO criteria  with presence of 
either FLT3 ITD and/or other FLT3 activating mutations 
 Patients with secondary AML should have failed no more than two (2) prior regimens 
 Patients with antecedent MDS/MPN, defined by WHO criteria, without any prior therapy for 
AML, regardless of the number of therapies for MDS/ MPN 
 Patients with primary AML should have received no more than two (2) prior cytotoxic 
containing salvage regimens.  Reinduction with the same regimen or stem cell transplant will 
not be considered a separate salvage regimen. Change of drugs will be considered a salvage 
regimen. Unlimited FLT3 TKI therapy (even in combination with cytotoxics/hypomethylating 
agents) is allowed for patients enrolled in cohort B.   
 Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations 
within 30 day screening period. 
 Males and females age ≥18 years 
 ECOG PS 0-2 
 Adequate liver function, defined as bilirubin ≤1.5x ULN, ALT ≤3.0x ULN, and AST ≤3.0x 
ULN.  
 Adequate renal function, defined as serum creatinine ≤1.5x ULN  
 Recovery from non-hematological toxicities of prior therapy (including HSCT) to no more 
than grade 1 (except alopecia) 
 Subjects should have received no anti-leukemic therapy (except hydroxyurea) prior to the first 
dose of crenolanib as follows:  for 14 days for classical cytotoxic agents and for five times the 
t1/2 (half-life) for FLT3 inhibitors and antineoplastic agents that are neither cytotoxic nor FLT3 
inhibitors (e.g. hypomethylating agent or MEK inhibitor).  Refer to Appendix XVI for half-life 
information and drugs considered as FLT3 inhibitors for purposes of this trial. 
 Negative pregnancy test for WOCBP. 
 Able and willing to provide written informed consent. 
Exclusion Criteria: 
 Absence of a FLT3 activating mutation 
 <5% blasts in blood or marrow at screening  
 Concurrent chemotherapy,  or targeted anti-cancer agents, other than hydroxyurea. 
 Patient 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.  
 HIV infection or active hepatitis B (defined as hepatitis B surface antigen positive) or C 
(defined as hepatitis C antibody positive) 
 Known clinically active central nervous system (CNS) leukemia  
 Patients less than 30 days post HSCT.  
 Subjects who have clinically significant graft versus host disease requiring treatment and /or 
have >grade 2 persistent non hematological toxicity related to transplant 
 Prior crenolanib treatment for a non-leukemic indication 
 Major surgical procedures within 14 days of Day 1 administration of crenolanib. 
 Unwillingness or inability to comply with protocol. 


10 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Test Product, Dosage and Mode of Administration:  
Crenolanib besylate, 100 mg TID (preferably every eight hours), taken orally at least 30 
minutes pre or post meal. Patients will complete a daily diary to record the date, time and 
amount (number of tablets) of crenolanib taken and eating schedule. 
 
Concurrent hydroxyurea (maximum 5g total daily dose x 14 days) is permitted during the 
first 28 days of study therapy. 
Planned Duration of Treatment:   
The anticipated duration of patient involvement is a minimum of 28 days with a maximum 
of 365 days but assessed individually for each patient.  Patients will take crenolanib 
besylate daily until their disease has progressed, the patient has died, or the patient 
discontinues for adverse events, investigator’s judgment, or other reasons 
 
Patients who have discontinued study drug will continue to be followed for 30-days post 
last dose.   
Reference Therapy, Dose and Mode of Administration:   
No comparators will be used. 
Criteria for Evaluation:   
International Working Group for AML (Cheson, et. al., JCO, 2003) 
Statistical Methods:   
The primary end-point is overall response rate. The overall response rates in the two 
cohorts will be evaluated along with its 95% confidence interval at the end of cycle 1 (28-
days) and at best response. Analysis of secondary endpoints will be predominantly 
descriptive statistics and will be interpreted as being exploratory and hypothesis 
generating.  Duration of response, Progression Free Survival (PFS) and Overall Survival 
(OS) will be estimated using the method of Kaplan-Meier.   In addition, if at any time 
unacceptable toxicity is encountered in greater than 30% of patients, accrual will be 
stopped and lower doses of crenolanib may be investigated. 
 
 


Protocol:
 
Acute M
 
Acute m
Malignan
marrow 
malignan
 
Targeted
 
During t
diagnose
been app
ozogamic
been app
 
Biologica
 
FMS-like
hematopo
receptor 
receptorα
chromoso
protein o
glycosyla
schemati
 
Figure 3
tyrosine k
  
In norm
progenito
: ARO-005  
Myeloid Leuk
myeloid leuk
ncy is chara
production 
ncies, high le
d Therapy i
the past 30 
d with AML
proved for 
cin were for
proved for th
al Role of F
e tyrosine k
oietic stem/
tyrosine kin
α, and platel
ome 13q12 
of 993 amin
ated isoform
c of FLT3 is
3.1. Schemat
kinase and th
al human h
ors including
                   
kemia (AML
kemia (AML
acterized by 
resulting in
evels of FLT
in AML 
years there
L. New drug
acute prom
r a period ap
e treatment o
FLT3 
kinase 3 (F
/progenitor c
nase (RTK) 
let-derived g
and encom
no acids w
m of 130-143
s provided in
tic of FLT3 
he mutation 
hematopoies
g CD34+ he
 Confidentia
3.  BAC
L) 
L) is a mal
accumulatio
n thrombocy
T3 expression
e has been 
gs like arsen
myelocytic le
pproved for e
of FLT3 mu
FLT3) is a 
cell surviva
family, inc
growth facto
mpasses 24 e
with a molec
3 kDa that i
n Figure 3.1.
representing
locations of
is, FLT3 ex
matopoietic 
al                  
CKGROUN
lignancy of 
on of leukem
ytopenia, an
n have been 
a steady im
nic trioxide 
eukemia and
elderly AML
utant AML.  
receptor ty
l and prolif
cluding FMS
or receptorβ.
exons. It en
cular weigh
is not associ
.5 
g the domai
f ITD and KD
xpression is
stem cells 
   Version –
ND 
f immature 
mic blasts an
nemia, and n
detected in 
mprovement 
and all-trans
d immunoc
L patients. H
 
yrosine kina
feration. FL
S, c-KIT, pl
. 2 The hum
ncodes a me
ht of 158-16
iated with th
ins: transme
D.6 
s restricted 
(HSCs). 7 F
3.0 (Octobe
granulocyte
nd blockade
neutropenia.
AML blasts
t in the surv
s retinoic ac
conjugates l
However, no
ase with im
LT3 belongs
latelet deriv
man FLT3 ge
embrane-bou
60 kDa, as 
he plasma m
embrane, jux
to immatur
FLT3-ligand 
er 27, 2014)
es or monoc
e of normal 
. In hemato
s (70%-100%
vival of pat
cid (ATRA)
ike gemtuzu
o new drugs 
mportant rol
s to the clas
ed growth f
ene is locate
und glycosy
well as a 
membrane.3,4
xtamembrane
re hematopo
(FL) stimul
11 
cytes. 
bone 
ologic 
%).1,2 
tients 
have 
umab 
have 
es in 
ss III 
factor 
ed on 
ylated 
non-
4 The 
e and 
oietic 
lation 


12 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
of hematopoietic progenitors without other growth factors prompts monocytic differentiation, 
whereas combinations of stem cell factor, interleukin (IL)-3, and FL induce proliferation and 
maintenance of human CD34+/ CD38+ progenitor cells.8,9  
 
Downstream Pathways of Normal FLT3  
 
Binding of the FLT3 ligand is followed by receptor autophosphorylation at tyrosine residues, 
thereby creating docking sites for signal transducing effector molecules and activating various 
signaling pathways. The downstream signaling cascade involves the tyrosine phosphorylation 
and activation of multiple cytoplasmic molecules. The FLT3 cytoplasmic domain physically 
associates with the p85 subunit of phosphoinositol-3-kinase (PI3K), Ras GTPase, phospholipase 
C-g, Shc, growth factor receptor bound protein (Grb2) and Src family tyrosine kinase, and results 
in the phosphorylation of these proteins.11 These actions affect the activation of further 
downstream PI3K/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) 
pathways.12  Bruserud et al. reported that exogenous FL increases blast proliferation for not only 
patients with wild-type FLT3 but also patients with FLT3-ITD, as well as, FLT3-TKD 
mutations.13 Therefore, FL-mediated triggering of FLT3 appears to be important for both wild-
type and mutant FLT3 signaling. 
 
FLT3 Mutations in AML 
 
In hematologic malignancies, high levels of FLT3 expression have been detected in AML blasts 
(70%-100%).14,15 Mutations within the FLT3 gene have been detected in up to 35% of acute 
myeloid leukemia (AML) patients and represents one of the most frequently identified genetic 
alterations in AML.16 Two major classes of activating FLT3 mutations have been identified in 
AML patients: internal-tandem duplications (ITDs) and tyrosine kinase domain (TKD) point 
mutations (Figure 3.1).5 ITDs in the juxtamembrane (JM) domain of FLT3 were first described 
by Nakao et al and are detected in 20%-25% of AML patients. ITDs are in-frame duplications of 
3-400 base pairs. 17 Recently, FLT3-ITD insertion sites were systematically reviewed in 753 
unselected patients with AML positive for FLT3-ITD, and it was demonstrated that 28.7% of 
ITDs integrate in the TKD1 and not as previously assumed in the JM domain of FLT3. 18 ITD 
mutations cause constitutive activation of FLT3, leading to aberrant activation of multiple 
downstream pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated 
protein kinase/ extracellular signal-regulated kinase (MAPK/ERK), and signal transducer and 
activator of transcription 5 (STAT5). 18 FLT3-ITD expression confers factor independent growth 
in murine IL-3– dependent cell lines and causes a fatal myeloproliferative disorder in murine 
bone marrow (BM) transplantation models and in FLT3-ITD knock-in mice. 19  
 
A number of FLT3 inhibitors with in vitro and in vivo activity against the FLT3 ITD mutation 
are in clinical development.  However, most AML patients who initially respond to these FLT3 
TKIs experience relapse.  This resistance is mediated through the development of the D835 
FLT3 TKD secondary mutation in approximately 5-10% of relapsed AML patients. No FLT3 
inhibitor currently in development has the ability to inhibit the FLT3 TKD mutation D835 to 
treat patients with relapsed AML 


13 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
4.  CRENOLANIB BESYLATE (CP-868,596-26), PRECLINICAL DATA 
 
Crenolanib is a Potent Inhibitor of Type III Receptor Kinases 
 
Crenolanib besylate (CP-868,596-26) is an orally bioavailable selective and potent inhibitor of 
FLT3, both wild type and FLT3 constitutively active mutations. The chemical name of 
crenolanib 
besylate 
is 
4-piperidinamine, 
1-[2-[5-[(3-Methyl-3-oxetanyl) 
methoxy]-1H-
benzimidazol-1-yl]- 8-quinolinyl]-, monobenzenesulfonate. 26 The CAS registry number is 
670220-93-6.27 
 
Crenolanib is a specific and potent inhibitor of class III receptor tyrosine kinases (RTKs) (Table 
4.1). Crenolanib has sub-nanomolar Kd against wild-type FLT3 (0.74nM) and is potent against 
PDGFRα (3.2 nM) and PDGFRβ (2.1nM) (Table 4.1.). Besides class III RTKs, crenolanib does 
not inhibit any other know RTK (VEGFR, FGFR) or any other serine/threonine kinase (Abl, Raf) 
at clinically achievable concentrations.  
 
          RTK
Crenolanib Kd
FLT3 
0.74 nM 
PDGFRβ 
2.1 nM 
PDGFRα 
3.2 nM 
CFS1R 
30 nM 
Kit 
78 nM 
Table 4.1. Activity of crenolanib against type-III receptor kinases26 
 
 
Crenolanib has high affinity for constitutively active FLT3 mutants,  
 
Crenolanib was evaluated in a KdELECT assay (DiscoverRx, San Diego, CA) to determine its 
affinity against FLT3 and its mutant isoforms. The results demonstrate that crenolanib has 
activity against the FLT3-ITD, the most frequent FLT3 aberration in AML, and the FLT3-TKD 
D835H and D835Y mutations (Table 4.2). 
 
 


14 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
KINOMEscan 
 Gene Symbol 
Publications that first report gene 
aberration in AML 
Crenolanib Kd 
 (nM) 
FLT3 
 
0.74 
FLT3(ITD) 
Leukemia. 10, 1911-1918 (1996). 
0.43 
FLT3(D835H) 
Blood. 97, 2434-2439 (2001); Br J 
Haematol. 113, 983-988 (2001). 
0.4 
FLT3(D835Y) 
Blood. 97, 2434-2439 (2001); Br J 
Haematol. 113, 983-988 (2001). 
0.18 
FLT3(K663Q)  
Leukemia. 20, 2008-2014 (2006). 
1.4  
FLT3(R834Q)  
Cancer Cell. 12, 501–513 (2007). 
0.8  
Table 4.2. Kd measurements for the interactions of crenolanib with wild type FLT3 and its 
mutants: FLT3-ITD, FLT3-TKD D835Y, and FLT3-TKD D835H.26 
 
 
We compared the Kd of crenolanib for wild type and mutant FLT3 with the Kd’s of 72 other 
TKIs.19 Crenolanib binds to FLT3-ITD with a Kd of 0.43, as compared to a Kd of 8.8 nM for 
quizartinib and Kd of 13 nM for sorafenib. Crenolanib binds to FLT3-TKD D835H with a Kd of 
0.4 nM, as compared to a Kd of 3.7nM for quizartinib and Kd of 30nM for sorafenib. Similarly, 
crenolanib also binds to FLT3-TKD D835Y, a mutation that has been shown to cause resistance 
to quizartinib, with a Kd of 0.18nM, as compared to a Kd of 7.1nM for quizartinib and Kd of 
82nM for sorafenib (Figure 4.1).19 In addition to the kinome scan, crenolanib inhibition of the 
FLT3 wild type and FLT3-TKD D835Y mutation was confirmed by Millipore IC50 profiler 
assay, a system that directly measures phosphorylation with superior sensitivity using 
phosphocellulose (PH) filter plates.  Crenolanib showed potency at 2nM against the FLT3 
D835Y mutation and 3 nm against wild type FLT3.         
 
 
 
Figure 4.1. Kd measurements for the interactions of crenolanib, sunitinib, CEP-701, AC-220 
(quizartinib), sorafenib etc, with wild type FLT3 and its mutants: FLT3-ITD, FLT3/D835Y, and 
FLT3/D835H. Assay signals were normalized to facilitate comparison.28 
 


15 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Immunoblot experiments confirm the activity of crenolanib against FLT3 and its mutants 
in different cells 
 
In immunoblots, crenolanib inhibited phosphorylation of the wild type FLT3 receptor (in 
SEMK2 cells), the FLT3-ITD receptor (in Molm 14 and MV411 cells) and the FLT3-D835Y 
TKD mutation (in transfecting Ba/F3 cells), (Figure 4.2).                                                                                                 
                                                    
 
Figure 4.2 Dose response of crenolanib in various models of FLT3 AML cells: (A) SEMK2 
cells, (B) Molm14 cells, (C) MV411 cells, and (D) FLT3-D835Y Ba/F3 cells.27 
 
 
In SEMK2 cells that express wild type FLT3, crenolanib was effective with a p-FLT3 IC50 of 
2.11nM.The IC50 values of crenolanib against the TF/ITD Molm14 and MV411 cell lines, 
derived by transfecting TF-1 cells, were 2.65nM and 1.28 nM, respectively. The IC50 of 
crenolanib against the D835Y, TKD mutation of FLT3 was 8.8nM. 
 
Crenolanib is cytotoxic to myeloid leukemia cell lines with FLT3 mutation with 
concomitant inhibition of FLT3 phosphorylation and its downstream signaling pathways 
 
Crenolanib has been shown to inhibit FLT3 phosphorylation and downstream signaling in both 
myeloid leukemia cell lines with FLT3-ITD as well as in primary leukemic blasts with FLT3 
ITD or TKD mutations. 
 
Metabolic activity as determined in the MTT assay was used to quantitate crenolanib-mediated 
cytotoxicity in a number of AML cell lines.  Crenolanib was determined to be cytotoxic to the 
FLT3/ITD-expressing leukemia cell lines Molm14 and MV411, at IC50 values of 7 nM and 8 
nM, respectively (Figure 4.3). 
A 
B 
C 
D 


16 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
 
Figure 4.3. In MTT assays, crenolanib is cytotoxic to MV411 and Molm14 cell lines, with IC50 
values of 8nM and 7nM, respectively.27 
 
 
Cytotoxicity of crenolanib can be attributed to its ability to cause near complete inhibition of 
phosphorylation of FLT3 and its downstream signaling pathways, demonstrated by p-STAT, p-
ERK and p-AKT (Figure 4.4).  
 
Figure 4.4. Immunoblot experiments performed in Molm14 cells show that crenolanib inhibits 
downstream signaling of FLT3 at 10nM.27 
 
 
Primary leukemic blasts from AML patients bearing mutant FLT3 are killed at clinically 
achievable concentrations of crenolanib 
 
The cytotoxic effects of crenolanib were evaluated on blasts isolated from AML patients. MTT 
assays were performed on AML patient samples procured from the John Hopkins University 
tumor and tissue bank. These included: 
 
a) A newly diagnosed patient with FLT3/D835 mutation 
b) Relapsed, refractory patients with FLT3/ITD AML, who have previously been treated with 
standard or high dose chemotherapy (N=4) 
c) A refractory AML patient with FLT3/D835 who had previously been treated with  FLT3 
inhibitors (N=1) 


17 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Crenolanib has in vitro activity against blasts with FLT3-D835 mutation, resistant to both 
sorafenib and quizartinib 
 
Leukemic blasts from a newly diagnosed patient with the FLT3-D835V mutation were resistant 
to sorafenib and quizartinib but sensitive to crenolanib. Immunoblotting showed that crenolanib 
inhibited phosphorylation of mutant FLT3, while quizartinib and sorafenib did not, suggesting 
the greater in vitro efficacy of crenolanib in this subset of FLT3 mutant AML (Figure 4.5). 
 
 
Figure 4.5. Immunoblot experiment performed at 20nM comparing the activity of crenolanib 
and sorafenib against leukemic blasts with the FLT3-D835V mutation shows that blasts were 
resistant to sorafenib, while crenolanib provided near complete (>90%) inhibition of 
phosphorylated FLT3. 27 
 
 
Crenolanib is cytotoxic to leukemic blasts from relapsed/refractory AML patients with 
FLT3/ITD mutation 
 
Crenolanib was evaluated in an MTT assay against leukemic blasts from relapsed/refractory 
AML patients. Four patient samples were evaluated.  Crenolanib was active against all samples 
with IC50 values ranging from 15-40nM (Figure 4.6). 
 
 
Figure 4.6. Crenolanib was active against all 4 patient leukemic blasts that had the FLT3/ITD 
mutation.27   
 
 
 


18 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Crenolanib was active against leukemic blasts from a patient that had progressed on other 
FLT3 inhibitors including quizartinib and sorafenib 
 
Blasts were obtained from a patient treated with quizartinib and underwent allogeneic 
transplantation. Following which, the patient relapsed and was treated with sorafenib and 
quizartinib, with no benefit. Mutational status was determined and it was discovered that there 
was presence of FLT3/D835 in the background of an FLT3/ITD mutation. In vitro studies 
demonstrated that crenolanib was highly active against the blasts, at therapeutically achievable 
concentrations, with an IC50 value of 26nM (Figure 4.7).    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4.7. Crenolanib was more potent against FLT3 D835 blasts in comparison to sorafenib.27  
 
 


19 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
5.  CRENOLANIB BESYLATE (CP-868,596-26), CLINICAL DATA 
 
Phase I/II clinical study of oral crenolanib showed that it was well absorbed and well 
tolerated 
 
Crenolanib has been clinically evaluated as a single agent in a dose-finding and dose-ranging 
phase-1 study with fifty nine patients treated and was found to have good oral bioavailability. 
Crenolanib was rapidly absorbed on an empty stomach with a median tmax ranging from 1 to 4 
hours.  The half-life of crenolanib in this Phase I trial was found to be between 13-16 hours.  
 
As of 31 May 2013, no treatment related deaths have been reported in 200 patients treated with 
crenolanib both as a single agent and in combination. The most frequent non-hematological 
grade 1/2 toxicities were diarrhea, nausea, and vomiting (Table 5.1). In patients with GIST, 
anemia was the most frequent grade 1/2 hematological toxicity associated with crenolanib 
treatment. Four patients required transfusion, though most of these patients had grade 1/2 anemia 
prior to treatment initiation.  The most commonly reported all-causality events of severity Grades 
3 or 4 have included LFT increase, anemia, hyponatremia, fatigue and headache.. All LFT 
abnormalities resolved to baseline or less upon discontinuation of crenolanib. The AML protocol 
recommends prophylactic antiemetics and anti-diarrheals as well as regular monitoring of 
hepatic enzymes. Table 5.1 summarizes AEs observed in 126 adult and pediatric patients treated 
with single agent crenolanib. 
 
 


20 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
  
NCI CTC Severity Grade 
Total patients = 126 
Adverse Event 
GRADE 
1 
GRADE 
2 
GRADE 
3 
GRADE 
4 
TOTAL 
AEs 
% 
Patients 
Nausea 
86 
19 
2 
1 
108 
63 
Vomiting 
85 
10 
4 
0 
99 
55 
Diarrhea 
62 
13 
1 
0 
76 
45 
Alanine aminotransferase 
increased 
32 
9 
7 
2 
50 
23 
GGT increased 
33 
14 
13 
3 
63 
21 
Fatigue 
16 
12 
2 
0 
30 
18 
Alkaline phosphatase increased 
25 
10 
2 
0 
37 
14 
Anorexia 
15 
5 
1 
0 
21 
13 
Aspartate aminotransferase 
increased 
28 
11 
6 
2 
47 
13 
Lymphocyte count decreased 
22 
10 
7 
2 
41 
13 
Headache 
14 
1 
2 
0 
17 
10 
Anemia 
8 
6 
4 
2 
20 
10 
Abdominal pain 
11 
2 
2 
0 
15 
10 
Dyspepsia 
7 
4 
2 
0 
13 
10 
Dysgeusia 
11 
3 
0 
0 
14 
9 
Constipation 
11 
2 
0 
0 
13 
9 
White blood cell decreased 
16 
4 
1 
0 
21 
8 
Proteinuria 
12 
0 
0 
0 
12 
7 
Edema limbs 
11 
2 
0 
0 
13 
6 
Hypophosphatemia 
10 
0 
1 
0 
11 
6 
Hypoalbuminemia 
8 
0 
0 
0 
8 
6 
Periorbital edema 
8 
0 
0 
0 
8 
6 
Serum amylase increased 
4 
3 
0 
0 
7 
6 
Dizziness 
7 
0 
0 
0 
7 
5 
Platelet count decreased 
4 
0 
0 
2 
6 
5 
Table 5.1. Incidence of treatment-related AEs occurring in ≥ 5% of the study population treated 
with single agent crenolanib. 
 
 
ECG data from patients treated with single agent crenolanib in the phase I trial 
 
Fifty nine patients were treated in the phase I single agent study of crenolanib. ECGs were 
obtained on all subjects at screening done in triplicate at 2 to 5 minute intervals. Baseline ECG 
was defined as the closest evaluations prior to the first dose of study drug. The summary of QTc 
at baseline and on-treatment was provided by overall and dose level for the mean, median, range 
(minimum, maximum) and the frequencies (n [%] of males with (i) QTc within 431 to 450 msec, 
(ii) QTc>450 msec; females with (i) QTc within 451 to 470 msec, (ii) QTc>470 msec. Of all 
subjects examined for ECG at baseline 50.85% had normal values and 49.15% had abnormal 
value.  
 
Using the Fridericia QTc correction critertia, at baseline, there were no females with >470 msec 
QTc interval, however 1 male subject reported to have a QTc interval of >450 msec. On study, 4 
male subjects had a QTc interval between 431 and 450 msec and 2 female subjects had a QTc 
interval between 451 and 470 msec. Baseline and worst on study QTc (Fridericia correction) is 
given in Figure 5.1. 


21 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
 
For the Bazett QTc correction, 2 male subjects had a QTc interval >450 msec at baseline and on 
study 6 male subjects had a QTc interval >450 msec. There were no female subjects with a QTc 
interval >470 msec at baseline however 1 female subject had a QTc interval >470 msec while 
on-study. Baseline and worst on study QTc (Bazett correction) is given in Figure 5.1. 
 
Summary of QTc (A. Fridericia correction) Baseline and Worst On-Study Summary of QTc (B. Bazett correction) Baseline and Worst On-Study 
 
A. Treatment Group: Over All 
 
B. Treatment Group: Over All 
 
QTc interval 
(msec) 
Baseline 
 
(N=59) 
Crenolanib  
(CP-868,596) 
Worst On-Study 
 
(N=59) 
QTc interval (msec) 
Baseline 
 
(N=59) 
Crenolanib  
CP-868,596 
Worst On-Study 
 
(N=59) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
 
Total (males) 
 
29 
(49.2) 
29 
(49.2) 
 
Total (males) 
 
29 
(49.2) 
29 
(49.2) 
Mean QTc 
400 
 
408 
 
Mean QTc 
418 
 
432 
 
Median QTc 
398 
 
408 
 
Median QTc 
413 
 
428 
 
Min QTc 
356 
 
370 
 
Min QTc 
365 
 
368 
 
Max QTc 
459 
 
448 
 
Max QTc 
489 
 
481 
 
Total (females) 
30 
(50.8) 
30 
(50.8) 
Total (females) 
30 
(50.8) 
30 
(50.8) 
Mean QTc 
402 
 
411 
 
Mean QTc 
425 
 
436 
 
Median QTc 
400 
 
413 
 
Median QTc 
429 
 
437 
 
Min QTc 
357 
 
336 
 
Min QTc 
393 
 
374 
 
Max QTc 
449 
 
457 
 
Max QTc 
460 
 
497 
 
 
431-450 (males) 
2 
(3.4) 
4 
(6.8) 
431-450 (males) 
6 
(10.2) 
8 
(13.6) 
451-470 (females) 
0 
 
2 
(3.4) 
451-470 (females) 
3 
(5.1) 
9 
(15.3) 
 
>450 (males) 
1 
(1.7) 
0 
 
>450 (males) 
2 
(3.4) 
6 
(10.2) 
>470 (females) 
0 
 
0 
 
>470 (females) 
0 
 
1 
(1.7) 
Figure 5.1. Summary of QTc (Fridericia correction (A) and Bazett correction (B)) both baseline 
and worst on-study 
 
 
There were only two actual grade 1 QT interval prolongations observed in the 59 patients treated,  
which resolved without need for study drug interruption. No grade 2/3/4 QT interval 
prolongation has  been observed. The grade 1 QT prolongation was observed in 1/6 patients in 
the 200mg QD without food cohort and in 1/4 patients in the 60mg BID without food cohort.  
However no QT prolongation was observed in 280mg QD (N=7) and 340mg QD (N=5) without 
food cohorts and 60 mg BID (N=8) and 100 mg BID (N=12) with food cohorts. 
 
In the pediatric phase I study of crenolanib being conducted at St. Jude’s Children Cancer Center 
(Memphis, TN) in children with gliomas, no episodes of QT prolongations have been observed 
to date.  
 
No myelosuppression has been observed, as yet, in patients treated with single agent 
crenolanib 
 
Crenolanib has a Kd for c-kit of 78nM as compared to FLT3 of 0.74nM and could potentially not 
inhibit c-kit at doses that are adequate to inhibit FLT3. Crenolanib because of its lower affinity 
for c-kit may have a lower potential to cause delayed marrow recovery in patients with AML.  
No grade 3/4 myelosuppression has been seen in the adult patients treated to date with 
crenolanib. In addition, no grey hairs have been observed in any patients treated till-date. 


22 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
6.  RATIONALE FOR DOSE 
 
 
As of July 1st, 2014, 51 AML patients (combined ARO-004 study and ARO-005 study) have 
received crenolanib monotherapy . Among these 51 AML patients, the first 26 patients received 
100 mg TID and the rest 25 patients received 200 mg/ m2/day. PK parameters are available in all 
26 patients at 100 mg TID and in 16 of 25 patients at 200 mg/ m2/day. 
  
PK analysis showed the following: (1) The median planned dose intensity at 200 mg/ m2/day 
(based on patient BSA) was 340 mg/day (range 300-400mg/day), which is approximately 11% 
higher than that at 100 mg TID (300 mg/day). (2) The median delivered dose intensity taking all 
dose reductions and dose delay into account was 314 mg/day (range 214-397 mg/day) at 200 mg/ 
m2/day and 276 mg/day (range 204-298 mg/day) at 100 mg TID, respectively. (3) The median 
Day 15 trough level in patients treated with 200 mg/ m2/day were similar to that of patients who 
received 100 mg TID [median 363 nM (range 40.6-3134) vs. median 419 nM (range 74-3720 
nM)]. This suggests that there is no significant difference in median drug exposure among these 
two dosing groups (Figure 6-2), and more patient convenience within the 100 mg TID. 
Figure 6-1.  Day 15 Crenolanib Trough Levels (100 mg TID and 200 mg/m2/day) 
 
Thus, a fixed dose regimen of 100 mg TID will be utilized for future clinical studies. Dose 
reductions to 80 mgTID and 60 mg TID will be applied should certain toxicities emerge in study 
individuals.  
 
Serum concentrations of crenolanib in AML patients following a single dose of 100 mg is shown 
in Figure 6-3. 
 
 
 
 


Protocol:
Figure 
 
*The media
: ARO-005  
6-2.  Serum
an concentrati
                   
m Concentra
ion for each tim
 Confidentia
ations of Cr
P
me point is dep
al                  
enolanib fol
Patients  
icted by the thi
   Version –
llowing Sin
ick black line.
3.0 (Octobe
gle Dose (10
er 27, 2014)
00 mg) in A
 
23 
AML 


24 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
7.  STUDY DESIGN 
 
This is a Phase II open label study of crenolanib besylate given at 100 mg TID (preferably every 
eight hours) continuously until one of the criteria for study discontinuation is fulfilled. Study 
drug should be taken at least 30 minutes prior to or following a meal.   Patients will complete a 
daily diary to record the date, time, and amount (number of tablets) of crenolanib taken and 
relation to eating schedule (Appendix IV). 
 
The study will enroll 2 different cohorts of patients in parallel. 
 
Cohort A:  Will enroll AML patients with FLT3 activating mutations who have progressed on 
one or more prior chemotherapy regimen who have not received previously a FLT3 TKI  
 
Cohort B: Will enroll AML patients with FLT3 activating mutations whose leukemia has 
progressed and have received prior therapy with one or more FLT3 TKIs.  
 
Cycles will be repeated approximately every 28 days, and therapy will be continued until 
clinically significant disease progression or documentation of unacceptable toxicity as 
determined by the investigator.  If the drug is discontinued for toxicity, patient should be 
reassessed until toxicity has resolved.   
 
In the setting where hematopoietic stem cell transplant is anticipated study drug will be 
discontinued at least 72 hours prior to start of conditioning. 
 
Counting Cycle Days:  If drug is held or a dose missed, the missed/held dose should not be 
made up.  Dosing will resume with the next scheduled dose.  The patient should enter in the 
diary the doses missed.  If drug is held for a day or more, the counting of cycle days should 
continue as if uninterrupted.  The start of cycle 1 is denoted by the ingestion of study drug.  The 
scheduled procedures/visits should comply with the study calendar regardless of amount of study 
drug administered in a 28 day cycle. 
 
 


25 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
8.  PATIENT SELECTION 
 
Patients must have baseline evaluations performed within 14 days prior to the first dose of study 
drug and must meet all inclusion and exclusion criteria. The exception to this is determination of 
FLT3 mutation status which can be done within 30 day screening period.  Results of all baseline 
evaluations must be reviewed by the Principal Investigator or his/her designee prior to 
enrollment of that patient. In addition, the patient must be thoroughly informed about all aspects 
of the study, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The written informed consent must be obtained from the 
patient prior to initiating treatment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
 
8.1 
Inclusion Criteria 
1. Confirmed primary  with primary AML relapsed or refractory after prior therapy, AML 
secondary to antecedent chemotherapy or radiation therapy, or AML due to prior  
myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) as defined by WHO 
criteria with the presence of either FLT3-ITD and/or other FLT3 activating mutations, whose 
leukemia has recurred after prior chemotherapy but never received a FLT3 inhibitor (Cohort 
A) or whose leukemia has progressed after prior therapy  and have history of prior exposure 
to one or more FLT3 TKIs (Cohort B).  
2. Patients with secondary AML should have failed no more than two (2) prior cytotoxic 
chemotherapy containing regimens. 
3. Patients with antecedent MDS/MPN defined by WHO criteria, without any prior therapy for 
AML regardless of the number of therapies for MDS/MPN.   
4. Patients with primary AML should have received no more than two (2) prior cytotoxic drug 
containing salvage regimens.  Reinduction with the same regimen or a stem cell transplant 
following salvage therapy is not considered a separate salvage regimen. Change of drugs will 
be considered a salvage regimen. Unlimited FLT3 TKI therapy (even in combination with 
cytotoxics/hypomethylating agents) is allowed for patients enrolled in cohort B.   
5. Patients must have tested positive for FLT3-ITD and/or other FLT3 activating mutations 
within the 30 day screening period. 
6. Males and females age ≥18 years 
7. ECOG PS 0-2 
8. Adequate liver function, defined as bilirubin ≤1.5x ULN, ALT ≤3.0x ULN, and AST ≤3.0x 
ULN.  
9. Adequate renal function, defined as serum creatinine ≤1.5x ULN  
10. Recovery from non-hematological toxicities of prior therapy (including HSCT) to no more 
than grade 1 (except alopecia) 
11. Subjects should have received no anti-leukemic therapy except hydroxyurea prior to the first 
dose of crenolanib as follows:  for 14 days for classical cytotoxic agents and for five times 
the half-life for FLT3 inhibitors  and antineoplastic agents that are neither cytotoxic nor 
FLT3 inhibitors (e.g. hypomethylating agents or MEK inhibitors) Refer to Appendix XVI for  
half-life information and drugs considered as FLT3 inhibitors for purposes of this trial. 
 
 
12.  


26 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
12.1 
Negative pregnancy test for women of childbearing potential (WOCBP). 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, and abstention.   
12.2 
Male patients with female partners who are of childbearing potential: 
Recommendation is for male and partner to use effective contraceptive methods, 
as described above, during the study.   
12.3 
Women considered not of childbearing potential include any of the following: no 
menses for at least 5 years or menses within 5 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.   
13. Able and willing to provide written informed consent. 
 
8.2 
Exclusion Criteria 
 
1. Absence of a FLT3 activating mutation 
2. <5% blasts in blood or marrow at screening  
3. Concurrent chemotherapy,  or targeted anti-cancer agents, other than hydroxyurea. 
4. Patient 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. HIV infection or active hepatitis B or C (defined as positive hepatitis B surface antigen 
positive or hepatitis C antibody positive)  
6. Known clinically active central nervous system (CNS) leukemia  
7. Patients who are <30 days of a  HSCT.   
8. Subjects who have clinically significant graft-versus-host disease requiring treatment, and/or 
have >Grade 2 persistent non hematological toxicity related to the transplant 
9. Prior crenolanib treatment for non-leukemic indication 
10. Major surgical procedures within 14 days of Day 1 administration of crenolanib. 
11. Unwillingness or inability to comply with protocol. 
 
 
 


27 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
9.  TREATMENT PLAN 
 
9.1 
General 
 
The study will enroll patients with primary AML relapsed/ refractory after prior therapy, 
secondary AML (due to prior chemo- or radiation therapy) or prior transformed MDS/MPN with 
FLT3 activating mutations.  Patients will be treated with crenolanib three times daily, preferably 
every eight hours, continuously until they fulfill one of the criteria for study discontinuation. The 
objective will be to administer crenolanib at full dose starting at 100 mg TID. Other dose levels 
will be used for dose adjustments for toxicity (refer to section 10) during therapy. The only 
exception to this will occur on course 1 day 1, when doses 2 and 3 will be held in order to 
analyze the pharmacokinetics of the first dose administered out to 24 hours. 
 
Patients currently enrolled at 100mg TID (protocol v1.1) may be dose escalated based on BSA, 
see table 10.2.  
 
Up to 70 evaluable patients will be enrolled on this study: 30 patients in Cohort A and 40 
patients in Cohort B. Patients receiving less than 28 days of study dug will be replaced for 
efficacy evaluation. All patients will be assessed for toxicity. 
 
9.2 
Schedule 
 
Patients will be treated according to the following schedule:  
 The starting dose will be 100 mg TID.  Dose reductions for adverse events are listed in table 
10.2. 
 Dose reduction guidelines for adverse events are listed in table 10.2 and 10.3 in Section 10.2.  
Dose reductions beyond those mentioned in these tables or different than those specified, 
should be discussed with the sponsor and documentation of the justification recorded. 
 One cycle of therapy is defined as 28 consecutive days regardless of whether study drug is 
taken or not. 
 Subsequent cycles may be delayed for recovery of toxicity.  Delays in start of subsequent 
cycles greater than 8 weeks will be acceptable only for patients who are deriving clinical 
benefit and after determination of the principal investigator of potential risk/benefit ratio.  
 If prolonged (more than 60 days) grade 4 neutropenia or thrombocytopenia with evidence of 
a hypocellular marrow (marrow cellularity less than 5% without evidence of leukemia) is 
observed, protocol treatment may be interrupted until recovery to ANC > 0.5 x 109/L and 
platelets >25 x 109/L . If the peripheral counts do not recover ANC <0.5 x109/L and/or 
platelets <25 x109/L  but there is evidence of residual leukemia in the bone marrow, 
subsequent cycles can be administered at the discretion of the investigator.  
 For patients who discontinue therapy, the reason for treatment discontinuation will be 
captured.  
 
 
 
 


28 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
9.3 
Crenolanib Administration 
 
 Prophylactic antiemetic therapy is recommended to be used as needed for nausea and/or 
vomiting.  
 If a dose is missed or vomited, it should not be taken again.  The next dose should not be 
increased to account for missing a dose.  The patient should take the next regular dose at the 
regularly scheduled time.  
 
9.4 
Duration of Therapy 
 
Treatment may continue until one of the following criteria applies: 
 
1. Clinically significant progressive disease, or 
2. Intercurrent illness that in the opinion of the investigator prevents further administration of 
treatment, or 
3. Patient request, or 
4. General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator, or 
5. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to continue 
therapy, or 
6. Treatment interruption due to toxicity that has not recovered to at least grade 1 within 8 
weeks.  
 
It is planned that up to a total of 12 cycles of therapy will be administered for patients deriving 
benefit from this regimen. Continuation of therapy for patients completing 12 cycles of therapy 
may be considered on a case by case basis after discussion with the sponsor’s medical monitor.  
 
A minimum of 1 full course (defined as the administration of crenolanib for 28 days) will be 
required for a patient to be considered as having received an adequate trial to evaluate efficacy. 
Patients who do not complete one cycle of crenolanib therapy will be replaced. All patients 
receiving at least one dose of study drug will be considered evaluable for toxicity.   
 
9.5 
Concomitant Medications 
 
In general, the use of any concomitant medication/therapies deemed necessary for patient 
supportive care and safety are permitted. Other anticancer agents including systemic 
chemotherapy, radiation therapy, or biologic response modifiers are not permitted during the 
study, with the exception of hydroxyurea which is allowed for 14 days anytime during the first 
28 days on study.  
 
Prophylactic intrathecal therapy is allowed to prevent recurrence of CNS disease. Patients with 
active CNS disease are excluded.   
 
No other investigational drugs are allowed during the study without consent of the medical 
monitor.  


29 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
10.  DOSING AND DOSE MODIFICATIONS OF CRENOLANIB 
 
Toxicities will be graded using the NCI CTCAE, Version 4.03 (see partial representation in 
Appendix VII). 
 
The starting dose for all patients will be 100 mg TID. 
10.1 
Dose Escalation 
 
There will be one level dose escalation allowed for patients who do not experience grade 3 or 4 
toxicity and who have no response based on investigator evaluation. 
 
Dose level 
Crenolanib dosing 
0 
100 mg TID 
+1 
120 mg TID 
Table 10.1. Crenolanib dose escalation guidelines 
  
Dose escalation can occur as early as cycle 1 day 15. 
10.2 
Dose Reductions for Non-Hematologic Toxicities  
Dose reductions for non-hematologic toxicities due to crenolanib, will be done according to the 
schema outlined in Table 10.1. 
 Reductions below 60mg TID are not planned; dose reductions beyond those mentioned in 
this table or different than those specified, should be discussed with the sponsor and 
documentation justifying the specified dose recorded. If an appropriate dose is not 
determined, then it will lead to patients’ withdrawal from the study drug, in which the patient 
will stop taking crenolanib, but will still be followed for outcomes. 
 
Dose level 
Crenolanib dosing 
0 
100 mg TID 
-1 
80 mg TID 
-2 
60 mg TID  
Table 10.2. Crenolanib dose reduction guidelines  
 
Toxicity  
 
(NCI Criteria) 
Dose Modification 
Grade 1 or 2 
 
No dose modification 
 Clinically significant 
persistent grade 2 
despite optimal therapy 
Hold drug until toxicity resolves to grade 1 or less. Restart drug 
at same dose level (Table 10.2). 


30 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Table 10.3. Crenolanib dose reduction guidelines for All Toxicities (except GI (nausea, vomiting 
and diarrhea)) related to study drug. 
 
Starting dose (dose level 0) for all patients will be 100 mg TID. A maximum of two (2) dose 
reductions are allowed in a single patient for toxicity management. 
10.3 
Dose Reductions of Crenolanib for Hematologic Toxicities 
 
Patients with leukemia usually present with abnormal peripheral blood counts at the time therapy 
is started and myelosuppression is an expected event during the course of therapy for acute 
leukemia. Thus, no dose adjustments or treatment interruptions for myelosuppression will be 
planned for the first cycle of therapy. After this time, treatment interruptions and dose 
adjustments may be considered according to the following guidelines: 
 
Patients with neutropenia or thrombocytopenia as a consequence of the disease do not require 
treatment interruptions for myelosuppression. Dose-reductions in these patients should be 
considered in an individual case and discussed with the medical monitor. The following 
guidelines can be used for these patients:  
 Patients with pre-cycle counts of neutrophils >1x109/L and platelets >100 x109/L and no 
evidence of residual leukemia who have sustained neutropenia <0.5 x109/L or platelet counts 
<25 x x109/L for more than 4 consecutive weeks in the current cycle, may receive a 
subsequent cycle at 1 dose level reduction.  A reduction of 2 dose levels may be considered if 
the myelosuppression was deemed severe and life threatening by the treating physician, and 
if it is in the patient's best interest. 
 If there are persistent peripheral blood blasts, or the bone marrow shows >5% blasts, 
treatment may continue regardless of neutrophil and platelet count with supportive care as 
needed.  
 Patients with pre-cycle counts of neutrophils <1x109/L and platelets <100 x109/L and no 
evidence of  residual leukemia, consider holding therapy until recovery of granulocytes to ≥1 
x109/L and platelets ≥ 60 x109/L, then resume at same or 1 lower dose level according to 
guidelines mentioned in Table 10.2. 
 
10.4 
Additional Dose Modifications requiring discussion with Sponsors Medical Monitor 
 
Modification of dose schedules for toxicities other than the above will be allowed within the 
following guidelines: 
 
Dose reductions beyond dose level (-2) should be discussed with the sponsor and 
documentation of the justification recorded. 
 
Dose adjustments by more than 1 dose level at a time can be considered when judged in the 
best interest of the patient (e.g., neutropenia with sepsis, bleeding requiring platelet 
transfusions) when toxicity has resolved. The reason for this reduction will be reviewed by 
the PI and documented in the medical record. Dose re-escalation may be reconsidered. 
 
 Grade 3 or 4 
Hold drug until toxicity resolves to grade 1 or less. Restart drug 
at next lower dose level (Table 10.2). 


31 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
10.5 
Dose Re-escalation 
 
 
A patient who has had a dose reduction for any reason may have their dose re-escalated 
provided the patient has remained free of toxicity requiring dose adjustments for at least  1 
month. Escalation will be made by 1 dose-level increments only, and not more frequent 
than every cycle. Re-escalation cannot exceed the patient’s previous highest dose.. 
 
10.6 
Cycle Delays 
 
 A cycle of therapy may be delayed for a maximum of 8 weeks to allow recovery from 
toxicities.  
 Inability to re-start therapy within 8 weeks after a treatment interruption for toxicity will 
constitute grounds for removing the patient from protocol.  
10.7 
Continued Access to Study Drug 
 
At AROG’s discretion, patients receiving crenolanib at the time of study closure may 
continue to receive crenolanib until disease progression or initiation of other therapy. 
However, if a serious adverse event (SAE) occurs during this time, AROG may request 
additional information (such as local lab results, concomitant medications, and 
hospitalizations) in order to evaluate the reported SAE. 


32 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
11. AGENT FORMULATION AND PROCUREMENT 
 
11.1 
Dose preparation and Storage of Crenolanib 
 
Crenolanib is supplied as 100 mg and/or 20 mg tablets for oral dosing, in 42-count bottles or 30-
count bottles. Crenolanib 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 and unused tablets and bottles should be returned to the treating physician before 
starting a new therapeutic cycle to assess treatment compliance. Study drug will be supplied by 
AROG Pharmaceuticals LLC.  Study drug may be packaged by a third party.  Clinical trial 
materials will be labeled according to regulatory and institutional requirements. 
 
 
 
 


33 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
12.  CORRELATIVE/SPECIAL STUDIES 
 
12.1 
Plasma Inhibitory Assay 
 
Sampling Strategy 
Samples collected during study of crenolanib therapy will be collected into heparinized (green 
op) vacutainers and will be transported to the laboratory. 
 
Peripheral blood for plasma inhibitory assay will be drawn pre and post administration of first 
crenolanib dose on day1 cycle 1 at the following time points: pre dose and at 30 (± 10), 60 (± 
15), 120 (± 15) minutes, 4 (±1) hours, 8 (±2), and 24 (±6) hours (Day 2) after crenolanib 
administration.   
In order to obtain the 24-hour time point, all other day 1 dosing (2 doses) will be held. It is 
also crucial that the 24-hour time point be obtained prior to dose administration on day 2.  
 
Blood samples will also be drawn for plasma inhibitory analysis pre and post administration of 
first crenolanib dose on day 15 of cycle 1 at the following time points: pre dose, 30 (± 10) 
minutes, and 4 (±1) hours after administration of first crenolanib dose.  
Do not administer second or third dose of crenolanib until after 4 hour timepoint is 
obtained on day 15 of cycle 1.  
 
On subsequent courses, samples may be obtained at the discretion of the investigator (e.g., pre-
dose), and whenever possible every 2-4 cycles. (Appendix V).   
 
Sampling Collection and Processing Instructions for Plasma Inhibitory Assay Analysis 
 
Please refer to the lab manual provided by AROG Pharmaceuticals.    The date and time of 
sample collection, crenolanib dose, and date and time of the last crenolanib dose should be 
recorded on the appropriate Plasma Inhibitory Assay Data Collection Form    (Appendix IX-B, 
X-B and XI-B) 
 
 
Sampling Handling and Shipping Instructions 
 
The participating institution will arrange for shipments of samples collected for plasma 
inhibitory assay for each patient enrolled on the study. 
 
Samples should be shipped within 30 days of the last sample collection.  Specimens collected 
should be shipped via FedEx Priority Overnight shipping for delivery Monday through 
Thursday.  Weekend and holiday deliveries should be avoided.  In preparation of sample 
shipment, contact AROG Pharmaceuticals (refer to appendix XV) and Levis lab (Appendix XIII) 
to notify of sample shipment and to provide the FedEx tracking number.  AROG 
Pharmaceuticals will confirm shipment from the site.  Ship all plasma inhibitors assay samples 
on dry ice, along with a completed Data Collection Form (Appendix IX-B, X-B and XI-B) 
 
 


34 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
12.2 
Pharmacokinetic Assay 
 
Description of the Assay 
 
Samples collected during study of crenolanib therapy will be collected into no additives added 
(red top) vacutainers and will be transported to the laboratory. 
 
Sampling Strategy 
 
Peripheral blood for pharmacokinetic studies will be drawn pre and post administration of first 
crenolanib dose  Day 1 of cycle 1 at the following time points:  
pre dose and at 30 (± 10), 60 (± 15), 120 (± 15) minutes, 4 (±1) hours, 8 (±2) hours, and 24 (±6) 
(Day 2) hours after crenolanib administration.  
 
In order to obtain the 24-hour time point, all other day 1 dosing (2 doses) will be held. It is 
also crucial that the 24-hour time point be obtained prior to dose administration on day 2.  
 
Blood samples will also be drawn for pharmacokinetic analysis pre and post administration of 
first crenolanib dose on day 15 of cycle 1 at the following time points:  pre dose, 30 (± 10) 
minutes, and 4 (±1) hours after administration of the first crenolanib dose.  
 
Do not administer second or third dose of crenolanib until after 4 hour timepoint is 
obtained on day 15 of cycle 1.  
 
Blood samples will also be drawn for pharmacokinetic analysis pre and post administration of 
first crenolanib dose on day 1 of cycle 2 and day 1 of cycle 3 at the following time points: 
 Pre dose 
 4 ±1 hour 
 
Do not administer second or third dose of crenolanib until after 4 hour timepoint is 
obtained on day 1 of cycle 2 and day 1 of cycle 3. 
 
Peripheral blood sampling for pharmacokinetic assay and bone marrow aspiration for day 1 of 
cycle 2 should be done on the same day 
 
On subsequent courses, samples may be obtained at the discretion of the investigator (e.g., pre-
dose), and whenever possible every 2-4 cycles. (Appendix V).   
 
Sampling Collection and Processing Instructions  
 
Please refer to the lab manual provided by AROG Pharmaceuticals. The date and time of sample 
collection, crenolanib dose, and date and time  of the last crenolanib dose should be recorded on 
the appropriate Pharmacokinetics Data Collection Form (Appendix IX-A, X-A and XI-A). 
 
 
 


35 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Sampling Handling and Shipping Instructions 
 
In preparation of shipping samples, contact AROG Pharmaceuticals (refer to appendix XV) and 
MicroConstants (Appendix XIII) to notify of sample shipment and to provide FedEx tracking 
number.  AROG Pharmaceuticals will confirmation shipment from site.   
Samples should be shipped within 60 days of the last sample collection, whenever feasible. 
Specimens collected should be shipped via FedEx Priority Overnight shipping for delivery 
Tuesday through Thursday. Weekend and holiday deliveries should be avoided.  Ship all 
pharmacokinetic samples on dry ice, along with a completed Pharmacokinetics Data Collection 
Form (Appendix IX-A, X-A and XI-A).  
 
12.3 
Bone Marrow Samples and Other Correlative Studies 
 
Sampling collection schedule: 
Prior to start of first dose of crenolanib, a baseline sample of bone marrow or peripheral blood 
containing blasts should be obtained.  If entry bone marrow aspiration was done per eligibility 
criteria (within 30 days prior to study drug initiation) as part of screening but no aspirate is 
available at time of enrollment, obtain 1 green top tube of blood and process per bone marrow 
aspirate instructions in AROG Pharmaceuticals laboratory manual. 
 
It is preferable that bone marrow aspiration for screening baseline evaluation be done within 14 
days of start of study drug and a sample of this marrow should also be shipped as per 
instructions below.  
 
Additional bone marrow aspirations (x2) should be taken at the following time points: 
 Cycle 2 day 1 +4 days* 
 Cycle 3 day 1 ±7 days 
 Then every 3 cycles ±1 cycle as long as criteria for CR is maintained. 
*bone marrow sampling day 1 cycle 2 should match sampling days for plasma inhibitory assay 
and pharmacokinetic assay. 
 
Sampling Collection: 
Bone marrow aspiration (BMA) will be done as per institutional protocol.  Please refer to lab 
manual provided by AROG Pharmaceuticals for additional information. 
 
Refrigerated BMA samples should be shipped within 24 hours of collection along with Data 
Collection Form. 
 
Shipping of bone marrow samples: 
 
In preparation of marrow sample shipment, contact AROG Pharmaceuticals (refer to appendix 
XV) and ProPath (Appendix XIII ) to notify of sample shipment and provide the FedEX tracking 
number.  AROG Pharmaceuticals will provide confirmation regarding shipment from site.  Ship 
all bone marrow samples on dry ice, along with a completed Data Collection Form (Appendix 
XII). 


36 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
 
At loss of CR, bone marrow biopsy should be performed as clinically indicated to exclude 
toxicity issues such as persistent pancytopenia due to study drug vs progressive AML.  For 
patients remaining on study drug without significant toxicity for more than 12 months, 
subsequent evaluations during study may be modified after discussion with the sponsor.   
 
Blood samples will also be drawn for future correlative science research studies at the following 
two time point’s:  
 Pre administration of first dose of crenolanib on day 1 of cycle 1  
 Day (+14days) at which patient is determined to have progressive disease by the PI  
 
In preparation of sample shipment, contact AROG Pharmaceuticals (refer to appendix XV) and 
ProPath (Appendix XIII ) to notify of sample shipment and provide the FedEX tracking number. 
See lab manual/instructions for more details. 
 
Tissue cells and blood samples may be requested for immediate assessment in other tests which 
assess study drug activity on the biologic targets or samples will be banked for future correlative 
science research studies. Additional correlative science research may be performed at the 
discretion of the investigators or AROG, including assays for resistance studies for cases in 
which responses are noted but are not durable.  The total blood drawn for these studies will be 
less than 400ml in any month. 
 


37 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
13.  PATIENT EVALUATION 
 
13.1 
Pre-Treatment Evaluation 
 
All pretreatment studies should be obtained within 14 days of entry into the trial, unless 
otherwise stated. 
 
1. Medical history (includes documentation of current medications and allergies) 
2. Height, weight, vital signs 
3. Physical examination with baseline laboratory tests 
4. ECOG Performance Status (Appendix III) 
5. Serum or urine pregnancy test for women of child bearing capacity 
6. A complete history and physical, documentation of all disease, concomitant medications and 
performance status 
7. CBC, platelet count, differential (differential may be omitted if WBC is <0.5 x109/L) 
8. Creatinine, total bilirubin, ALT, and AST 
9. HIV infection or hepatitis B or C screening. (positive defined as hepatitis B surface antigen 
positive or hepatitis C antibody positive) 
10. Bone marrow aspirate during the last 30 days preceding study initiation is acceptable for 
study entry as long as blast count is available from that marrow. Cytogenetics will be 
obtained prior to therapy (results from prior analysis can be used for this purpose, if done 
within 6-months of enrollment) 
11. Evaluation of FLT3 mutation status (if not done < 30 days of start of study drug).   
12. Peripheral blood for optional procedures  
 
* Every effort will be made to collect optional procedures at all time points for all patients; 
however, missing collection in one or more of these time points in occasional patients will not be 
considered a protocol deviation/violation.  
 
13.2 
Evaluation during Treatment 
 
1. Physical exam at the start of each cycle (± 4 days) for the first 2 cycles, then every 2 cycles 
and documentation of all concomitant medications. 
2. CBC, platelet count, differential (differential may be omitted if WBC is <0.5 x109/L) twice 
weekly (at least 24 hours apart) for the first two weeks of cycle 1, once weekly (± 3 days) for 
the second two weeks of cycle 1, bi-weekly (± 4 days) for the second cycle and once a month 
thereof from cycle 3 until cycle 12 (± 14 days). 
3. Creatinine, total bilirubin, ALT, AST, twice weekly (at least 24 hours apart) for the first two 
weeks of cycle 1, once weekly (±3 days) for the second two weeks of cycle 1, bi-weekly (± 4 
days) for the second cycle and once a month thereof from cycle 3 until cycle 12 (± 14 days). 
4. Bone marrow aspiration x 2 should be taken at these timepoints:  cycle 2 day 1 (+4 days) , 
then cycle 3 day 1 (+/- 7 days), then every 3 cycles (+/- 1 cycle) as long as criteria for CR is 
maintained.  At loss of CR, bone-marrow aspiration would be performed only as clinically 
indicated to exclude toxicity issues like persistent pancytopenia due to study drug vs from 
progressive AML.   


38 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
5. Peripheral blood for correlative studies will be drawn on day1 at the following time points: 
pre dose and at 30 (± 10), 60 (± 15), 120 (± 15) minutes, 4 (±1) hours, 8 (±2), and 24 (±6) 
hours after crenolanib administration.  Blood samples will also be drawn on day 15 of cycle 1 
at the following time points: pre dose, 30 (± 10) minutes, and 4 (±1) hours after crenolanib 
administration. Blood samples will also be drawn on day 1 cycle 2 (±2 days), day 1 cycle 3 
(±2  days) at the following time points: pre dose, 4 ±1 hours after crenolanib administration.  
On subsequent courses, samples may be obtained at the discretion of the investigator, pre-
dose, and whenever possible every 2-4 cycles. 
6. For patients that remain on study with no significant toxicity for more than 12 months, 
subsequent evaluations during study may be modified after discussion with the sponsor.  
These may include a decrease in frequency of bone marrow aspirations to every 6-12 months 
(or as clinically indicated), correlative studies to every 6-12 months (or suspension of sample 
collection for correlative studies), and other laboratory tests to once every cycle. 
 
* Every effort will be made to collect optional procedures at all time points for all patients; 
however, missing collection in one or more of these time points in occasional patients will not be 
considered a protocol deviation/violation.  
 
Labs obtained with the local physician can be used for monitoring; PI must review and sign 
source documents within 24 hours of performance of lab at local physician’s office unless 
performed on a Friday in which case review on the following Monday is acceptable.  It is 
encouraged that labs be performed on Monday thru Thursday. 
 
 


Protocol:
Response
Respond
hematolo
 
14.1 
C
 Perip
 
No ci
 
Neutr
 
Plate
 Bone
 
≤5% 
 
No A
 
No ex
 
14.2 
C
 Perip
 
No ci
 
Neutr
 
Plate
 Bone
 
≤ 5%
 
No A
 
No ex
 
14.3 
P
 All C
50 %
 
Marr
 
14.4 
M
 Bone
 
14.5 
H
Hematolo
 Eryth
 
Hgb i
 Plate
 
Abso
            In
 Neut
 
At lea
 Blast
 
At lea
: ARO-005  
e criteria w
ers are patie
ogic improve
Complete Re
pheral blood
irculating bl
rophil count
let count ≥1
e marrow as
blasts 
Auer rods 
xtramedullar
Complete Re
pheral blood
irculating bl
rophil count
let count <1
e marrow as
% blasts 
Auer rods 
xtramedullar
Partial Remi
CR criteria if
% reduction 
ow blasts <5
Morphologic
e marrow: 5
Hematologic
ogic respons
hroid respo
increase by 
elet response
olute increase
ncrease from
trophil respo
ast 100% inc
t response (B
ast a 50% re
                   
14.
will be mo
ents who ob
ements, and 
emission (CR
d counts: 
asts 
 ≥1.0 x109/L
00 x109/L 
spirate and 
ry leukemia 
emission wit
d counts: 
asts 
 <1.0 x109/L
00 x109/L 
spirate and 
ry leukemia 
ission (PR):
f abnormal b
in bone mar
5% with pers
c Leukemia-
5% myelobla
c Improvem
se must be d
onse (E) (pre
1.5 g/dL 
e (P) (pretre
e of 30 x 1
m < 20 x 109/
onse (N) (pr
crease and a
B) 
eduction in b
 Confidentia
.  CRITERI
odified from
btain a CR, 
morphologic
R):  
L 
 
biopsy: 
th Incomple
L, or 
biopsy: 
:  
efore treatm
rrow blast bu
sistent Auer 
-Free State:
asts   
ment (HI): 
escribed by 
etreatment H
eatment plate
09/L for pati
/L to > 20 x 
retreatment A
n absolute in
blast percenta
al                  
IA FOR RE
m the Inter
CRi, or PR
c leukemia-f
ete Blood C
ment  except:
ut still >5% o
rods 
: 
the number 
Hgb <11 g/dL
elets <100 x
ients starting
109/L and by
ANC <1.0 x
ncrease > 0.5
age in periph
   Version –
ESPONSE 
rnational W
R, with or w
free state. Br
Count Recov
or 
of positively
L) 
109/L) 
g with > 20 x
y at least 10
109/L) 
5 x 109/L 
heral blood (
3.0 (Octobe
Working Gro
without cytog
riefly, criteri
very (CRi): 
y affected ce
x 109/L plate
00% 
(if > 5%) or 
er 27, 2014)
oup for AM
genetic resp
ia are as foll
ell lines. 
elets 
bone marrow
39 
ML.27 
ponse, 
lows: 
w 


40 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
15.  ADVERSE EVENT REPORTING 
 
Adverse event is any untoward medical occurrence that may present during treatment with a 
pharmaceutical product but which does not necessarily have a causal relationship with this 
treatment.  
 
Adverse drug reaction is a response to a drug which is noxious and unintended and which occurs 
at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the 
modification of physiologic function.  
 
Assessing causal connections between agents and disease is fundamental to the understanding of 
adverse drug reactions. In general, a drug may be considered a contributory cause of an adverse 
event if, had the drug not been administered, 1) the event would not have happened at all, 2) the 
event would have occurred later than it actually did, or 3) the event would have been less severe. 
 
15.1 
Adverse Event Reporting 
 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all subjects 
enrolled on the trial. 
 
For clarity the information required by the sponsor at baseline is to be captured in the CRFs is: 
 
Forms Title 
Content to be captured 
‘Relevant Medical History’ (SC_5_Screening) 
Any prior important medical history 
‘Physical Examination’ (SC_6_Screening) 
From physical examination during screening 
‘Baseline Medical history’ (SC_7_Screening) 
Any current medical history 
‘Baseline Symptoms’ (SC_8_Screening) 
Any current symptoms 
Table 15.1. Sponsor-Required Baseline Information in CRFs. 
 
 
Adverse Events (AEs) will be evaluated according to the latest CTCAE version 4.03 and 
documented in medical record.  Principal investigator should review and provide 
documentation of all baseline comorbidites related to the preexisting conditions and/or 
current medications prior to initiation of cycle one. These events will not be considered as 
related to crenolanib treatment. If these events continue during the treatment phase they 
do not need to be captured in the case report form. Captured AEs include:  
  
1) Any new AE regardless of its grade or expectedness post study drug initiation 
2) Worsening of any expected or unexpected AEs determined by the principal 
investigator as related to crenolanib 
  
 


41 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Expected events during leukemia therapy are (all other are considered unexpected and should be 
captured for reporting as outlined above): 
 
1) Febrile or infection episodes 
2) Coagulation abnormalities 
3) Epistaxis or bleeding except for catastrophic CNS or pulmonary hemorrhage 
4) Preexisting side effects related to prior disease specific therapy or ongoing medications 
for management of non-leukemia conditions 
5) Myelosuppresion and myelosuppression-related events (due to disease) 
6) Bone, joint, or muscle pain 
7) Fatigue/malaise 
8) Weakness 
9) Shortness of breath 
10) Nausea and vomiting 
11) Anorexia 
12) Electrolyte abnormalities (sodium, potassium, bicarbonate, CO2, magnesium) 
13) Chemistry abnormalities (LDH, phosphorus, calcium, BUN, protein, albumin, uric acid, 
alkaline phosphatase, glucose) 
14) Coagulation abnormalities 
15) Alopecia 
 
General Therapy Related Events: 
 
1) Catheter related events (thrombosis, bleeding, infection) 
2) Renal failure related to tumor lysis syndrome or antibiotic/ antifungal therapy 
3) Rash related to antibiotic use 
4) Hospitalization for the management of any of the above expected events 
 
Reporting Hematology and Blood Chemistry Results: 
 
 Hematology and blood chemistry results for every scheduled visit or for the most 
contiguous to the scheduled visit should be reported on case report form.Data captured in 
addition to the protocol specified scheduled visit is to be captured, only if any abnormal 
hematological or chemical values resulted in dose modification or dose delay. 
 Transfusion information is to be captured throughout the study. 
 
Adverse Event Reporting in 30-day Follow-up Period: 
 
 Adverse events will be captured from the time the patient signs consent until 30 days 
after the last dose of study drug.  
 If patients goes on to another clinical study or standard therapy, if possible, adverse 
events should continue to be captured for 30 days, including name of new therapy.  
 Patients who do not have progressive disease but stop crenolanib for toxicity, should be 
followed until resolution of toxicity. 


42 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
o Patients who have progressive disease and do not receive further therapy 
do not need to be followed, unless there is toxicity related to study drug 
which is unresolved at the time patient is taken off study 
 
15.2 
Serious Adverse Event (SAE) Reporting: 
 
A serious adverse event is – any adverse drug experience occurring at any dose that results in 
any of the following outcomes:  
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant disability/incapacity – a substantial disruption of a person’s ability 
to conduct normal life functions. 
 A pregnancy or congenital anomaly/birth defect. 
 Important medical events that do not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 
CFR 312.32). 
 
Any important medical event may be reported as an SAE if deemed appropriate by the Principal 
Investigator and the IND Sponsor.  .  
 
All serious adverse events occurring during the conduct of a protocol will be reported (either via 
expedited report or log) to the IRB in accordance with the timeframes and procedures.    
 
All serious adverse events will be recorded in the case report form.  
 
Hospitalizations for the management of any expected adverse events (previously described) 
will be reported to the sponsor as SAE and follow SAE reporting requirements  
 
 All life-threatening or fatal events, expected or unexpected, and regardless of attribution to 
the study drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event  to AROG.   
 The institution’s Internal SAE Report Form for Prompt Reporting will be used for reporting  
to AROG.  
 Serious adverse events will be captured from the time the patient signs consent until 30 days 
after the last dose of drug. Serious adverse events must be followed until clinical recovery is 


43 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
complete and laboratory tests have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event. 
Additionally, any serious adverse event that occur after the 30 day time period that is related to 
the study treatment must be reported to IRB and to AROG. This may include the development of 
a secondary malignancy. 
 
15.3 
Reporting to FDA: 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (AROG) according to 21 
CFR 312.32. 
 
It is the responsibility of the PI and the research teams to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
 


44 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
16.  STATISTICAL CONSIDERATIONS 
 
16.1 
Determination of Sample Size 
 
The primary endpoint of the study is the overall response rate to crenolanib. The outcome may 
be different for patients with or without the previous FLT3 TKI therapy. Therefore, patients will 
be stratified according to whether they have recurred after prior chemotherapy without a FLT3 
TKI treatment or they have progressed after prior therapy with a FLT3 TKIs.  
 
Based on the promising results observed to date, the sample size for each cohort will be 
expanded to include a total of 30 patients in Cohort A and 40 patients in Cohort B.  Such 
additional patients will permit a more accurate assessment of the efficacy and safety of 
crenolanib in these populations. The total sample size for the two cohorts is 70 patients.  
 
Cohort B (N=40): Two parallel Simon minimax two-stage Phase II designs will be used for the 
two cohorts of patients. For the patients who progressed after prior chemotherapy with FLT3 
TKI, the null response rate will be 5%, and target response rate will be 20%.  With alpha of 0.05 
and beta of 0.08, the first stage will require 28 patients. If there is 1 or no patient responding, the 
trial will be stopped. If 2 or more out of the first 28 patients respond, accrual will continue until a 
total of 40 patients have been enrolled. At the end of the study, if 5 or more patients out of 40 
respond, the regimen will be considered active. With this design, the probability of early 
termination is 59% if the true response rate is only 5%. 
 
Cohort A (N=30): For the patients who progressed after prior chemotherapy without FLT3 TKI, 
the null response rate will be 5%, and target response rate will be 30.  With alpha of 0.06 and 
beta of 0.01, the first stage will require 24 patients. If there is 1 or no patient experiencing the 
response, the trial will be stopped. If 2 or more out of the first 24 patients respond, accrual will 
continue until a total of 30 patients have been enrolled. At the end of the study, if 4 or more 
patients out of 30 respond, the regimen will be considered active. With this design, the 
probability of early termination is 66% if the true response rate is only 5%. 
 
The method of Thall, Simon, and Estey will be employed to perform interim safety monitoring.  
We will assume a Beta (0.6, 1.4) prior distribution for the toxicity rate which in particular has 
mean of 30%.  The toxicity is defined as any grade 3 or greater non-hematologic toxicities 
attributed to the study drug. 
 
The following decision criteria will be applied continuously up to the 70 patient. The two cohorts 
of patients will be jointly monitored for the safety. Targeting a 30% toxicity rate as a trade-off, 
the trial will be stopped early according to the following monitoring rule. 
 
Pr{toxicity  rate > 30%| data} > 0.93 
 
That is, if at any time during the study we determine that there is more than a 93% chance that 
the toxicity rate  is more than 30% we will stop the study.   
 


45 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
The design software Multc Lean Desktop (version 2.1) developed by the Department of 
Biostatistics at M. D. Anderson Cancer Center (MDACC) was used to generate the toxicity 
stopping boundaries and the OC table. The stopping rule boundary is shown in table 16.1. 
Table 16.1 Safety monitoring boundary 
#patient 
Stop the trial if there are this 
many toxicities total: 
5 
4-5 
10 
6-10 
15 
8-15 
20 
10-20 
25 
12-25 
30 
14-30 
35 
15-35 
40 
17-40 
45 
19-45 
50 
21-50 
55 
22-55 
60 
24-60 
65 
26-65 
 
The operating characteristics of this rule in the trial are shown in the following table 
 
Table 16.2 The operating characteristics 
True toxicity 
Early Stopping Probability 
Average number of patients treated 
0.2 
0.02 
69.1 
0.25 
0.06 
67.0 
0.3 
0.18 
61.8 
0.35 
0.42 
52.2 
0.4 
0.71 
39.9 
0.5 
0.98 
20.4 
 
 
16.2 Toxicity Evaluation 
Crenolanib has been well tolerated in studies including over 100 patients and toxicity patterns are 
relatively well understood.  
 


46 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
16.3 Statistical and Analytical Plans 
The primary end-point is overall response rate.   The overall response rates in the two cohorts 
will be evaluated along with its 95% confidence interval. Analysis of secondary endpoints will 
be predominantly descriptive statistics and will be interpreted as being exploratory and 
hypothesis generating. Progression free survival (PFS) and overall survival (OS) will be 
estimated using the method of Kaplan-Meier.   Cox regression models will be used to determine 
the relationship with the time-to-events (e.g. PFS and OS) and the potential prognostic factors.  
Exploratory logistic regression will be used to identify the prognostic factors that are 
significantly correlated with the response rate.   
 
16.4 General Considerations 
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. 
 
Safety endpoints will be reported with descriptive statistics for overall study population. For 
continuous variables, summary statistics will include number of patients, mean, median, standard 
deviation, minimum, and maximum.  Categorical endpoints will be summarized using number of 
patients, frequency, and percentages.   
 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 
 
 
 
Patient Disposition 
 
A detailed description of patient disposition, broken by cohort, will be provided. It will include: 
 Summary of patients entered  
 Total number of patients entered 
 Total number of patients enrolled 
 Summary of reasons for patients entered, but not enrolled 
 Summary of reasons for patient discontinuation from study treatment 
 Summary of all identified important protocol violations 
 
Patient Characteristics 
 
Patient characteristics will be reported for each cohort, and include a summary of the following: 
 Patient demographics 
 Baseline disease characteristics 
 Pre-existing conditions 


47 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
 Prior therapies 
 
Other patient characteristics will be summarized as deemed appropriate. 
 
 
Concomitant Therapy 
 
Concomitant medication will be reported at each visit with start/stop dates. If warranted, an 
attempt may be made to determine how concomitant medications are related to observed study 
outcomes. 
 
Treatment Compliance 
 
Treatment compliance information will be collected through pill counts at each tumor assessment 
visit and also by analyzing patient diaries where patients will record their daily drug intake.  The 
estimate of percent compliance will be given by: 
 
Percent Compliance =         Actual number of pills taken            x100 
                        Number of pills expected to be taken 
 
The number of tablets taken will be determined by counting the number of tablets returned at 
each visit and subtracting that number from the number of tablets dispensed.  The number of 
tablets expected to be taken will be determined by the assigned dose and taking into account any 
prescribed dose reductions and omissions. 
 
No minimal level of compliance will be defined for patient inclusion in efficacy analyses.  An 
exploratory analysis of compliance may be performed by regressing percent compliance on 
selected efficacy endpoints.  If significant results are indicated, analysis may be performed to 
determine the level of compliance that best delineates each endpoint. 
 
 
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 patients are continuing to benefit from study treatment, they will be 
allowed to continue receiving study treatment.  If patients continue on crenolanib beyond study 
closure, safety data must be collected.  If further data are collected that are not included as part of 
the final locked database, the post hoc data will eventually be combined with the locked database 
and stored in a data library separate from the locked database. 
 
 


48 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
17.  PROTOCOL ADMINISTRATION 
 
Protocol amendments 
 
Changes to the protocol will be made only when protocol amendments have been signed by the 
principal investigator and approved by the sponsor and the IRB of the study center. 
 
Archival of data 
 
All patient data (including source data) generated in connection with this study will be kept in 
the archives of each respective institution per policy or for at least 2 years after the approval of 
crenolanib. All data will be available for inspection by company representatives of the Medical 
Department and by regulatory authorities. 
 


49 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
18.  REFERENCES 
 
1.   
Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J  
Clin Oncol 2011;29:487-94. 
2. 
Lemmon MA, Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases. Cell  
2010;141:1117-34. 
3. 
Markovic A, MacKenzie KL, Lock RB. FLT-3: a new focus in the understanding of acute  
leukemia. Int J Biochem Cell Biol 2005;37:1168-72. 
4. 
Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev  
Cancer 2003;3:650-65. 
5. 
Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematol Educ  
Program 2006:178-84. 
6. 
Rosnet O, Buhring HJ, deLapeyriere O, et al. Expression and signal transduction of the  
FLT3 tyrosine kinase receptor. Acta Haematol 1996;95:218-23. 
7. 
Gabbianelli M, Pelosi E, Montesoro E, et al. Multi-level effects of flt3 ligand on human  
hematopoiesis: expansion of putative stem cells and proliferation of granulomonocytic 
progenitors/monocytic precursors. Blood 1995;86:1661-70. 
8. 
Shah AJ, Smogorzewska EM, Hannum C, Crooks GM. Flt3 ligand induces proliferation 
of quiescent human bone marrow CD34+CD38- cells and maintains progenitor cells in vitro. 
Blood 1996;87:3563-70. 
9. 
Sitnicka E, Buza-Vidas N, Larsson S, Nygren JM, Liuba K, Jacobsen SE. Human CD34+ 
hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: 
distinct flt3 and c-kit expression and response patterns on mouse and candidate human 
hematopoietic stem cells. Blood 2003;102:881-6. 
10. 
Takahashi S. Inhibition of the MEK/MAPK signal transduction pathway strongly impairs 
the growth of Flt3-ITD cells. Am J Hematol 2006;81:154-5. 
11. 
Takahashi S. Downstream molecular pathways of FLT3 in the pathogenesis of acute 
myeloid leukemia: biology and therapeutic implications. J Hematol Oncol 2011;4:13. 
12. 
Bruserud O, Hovland R, Wergeland L, Huang TS, Gjertsen BT. Flt3-mediated signaling 
in human acute myelogenous leukemia (AML) blasts: a functional characterization of Flt3-ligand 
effects in AML cell populations with and without genetic Flt3 abnormalities. Haematologica 
2003;88:416-28. 
13. 
Armstrong SA, Mabon ME, Silverman LB, et al. FLT3 mutations in childhood acute 
lymphoblastic leukemia. Blood 2004;103:3544-6. 
14. 
Wellmann S, Moderegger E, Zelmer A, et al. FLT3 mutations in childhood acute 
lymphoblastic leukemia at first relapse. Leukemia 2005;19:467-8. 
15. 
Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging 
after all these years. Blood 2010;116:5089-102. 
16. 
Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in 
acute myeloid leukemia. Leukemia 1996;10:1911-8. 
17. 
Breitenbuecher F, Schnittger S, Grundler R, et al. Identification of a novel type of ITD 
mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor. Blood 
2009;113:4074-7. 
18. 
Li L, Piloto O, Nguyen HB, et al. Knock-in of an internal tandem duplication mutation 
into murine FLT3 confers myeloproliferative disease in a mouse model. Blood 2008;111:3849-
58. 


50 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
19. 
Chillon MC, Fernandez C, Garcia-Sanz R, et al. FLT3-activating mutations are 
associated with poor prognostic features in AML at diagnosis but they are not an independent 
prognostic factor. Hematol J 2004;5:239-46.20. 
Kindler T, Breitenbuecher F, Kasper S, et al. 
Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in 
patients with acute myeloid leukemia (AML). Blood 2005;105:335-40. 
21. 
Frohling S, Scholl C, Levine RL, et al. Identification of driver and passenger mutations of 
FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles. 
Cancer Cell 2007;12:501-13. 
22. 
Reindl C, Bagrintseva K, Vempati S, et al. Point mutations in the juxtamembrane domain 
of FLT3 define a new class of activating mutations in AML. Blood 2006;107:3700-7. 
23. 
Millipore IC50 Profiler Assay. Activity of crenolanib against mutant kinases of FLT3, 
PDGFRA and c-KIT. Data available on file 2011. 
24. 
Lewis NL, Lewis LD, Eder JP, et al. Phase I Study of the Safety, Tolerability, and 
Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor 
Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers. Journal of Clinical 
Oncology 2009;27:5262-9. 
25. 
Ramachandran A, Marshall H, Jain V.  Crenolanib, a novel type I, mutant specific 
inhibitor of class III receptor tyrosine kinases, preferentially binds to phosphorylated kinases.  
AACR 2012. Abstract #3683. 
26. 
Galanis A, Rajkhowa T, Muralidhara C., et al. Crenolainb: A next generation FLT3 
inhibitor.  AACR 2012. Abstract #3660. 
 
 


51 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix I. Administrative Procedures 
 
Protocol Amendments, Other Changes to the Protocol 
 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by the investigator before implementation. Amendments significantly affecting the 
safety of subjects, the scope of the investigation or the scientific quality of the study, require 
additional approval by the IRB/IEC/REB of all centers, and, in some countries, by the regulatory 
authority. A copy of the written approval of the IRB/IEC/REB, which becomes part of the 
protocol, must be given to all the monitors and supporters of the protocol. Examples of 
amendments requiring such approval are: 
 
1. an increase in drug dosage or duration of exposure of subjects 
2. a significant change in the study design (e.g. addition or deletion of a control group) 
3. an increase in the number of invasive procedures to which subjects are exposed 
4. addition or deletion of a test procedure for safety monitoring. 
 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator in the interests of preserving the safety of all subjects included in the 
trial. If an immediate change to the protocol is felt to be necessary by the investigator and is 
implemented by him/her for safety reasons, the sponsor should be notified and the IRB/IEC/REB 
at the center should be informed within 10 working days or per institutional policy. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC/REB approval but the IRB/IEC/REB of each center must be kept 
informed of such administrative changes. Examples of administrative changes not requiring 
formal protocol amendments and IRB/IEC/REB approval that can be treated as administrative 
amendments include: 
 
1. changes in the staff used to monitor trials (e.g. AROG Pharmaceuticals staff versus a CRO) 
2. minor changes in the packaging or labeling of study drug. 
 
Publication of Results 
 
Any formal presentation or publication of data from this trial will be considered as a joint 
publication by the investigator(s) and appropriate AROG Pharmaceuticals personnel. Authorship 
will be determined by mutual agreement. For multicenter studies it is mandatory that the first 
publication is based on data from all centers, analyzed as stipulated in the protocol, and not by 
the investigators. Investigators participating in multicenter studies agree not to present data 
gathered from one center or a small group of centers before the full publication, unless formally 
agreed to by all other investigators and AROG Pharmaceuticals. 
AROG Pharmaceuticals must receive copies of any intended communication in advance of 
publication (at least 15 working days for an abstract or oral presentation and 45 working days for 
a journal submission). AROG Pharmaceuticals will review the communications for accuracy 
(thus avoiding potential discrepancies with submissions to health authorities), verify that 
confidential information is not being inadvertently divulged and provide any relevant 
supplementary information.  


52 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Disclosure and Confidentiality 
 
The investigator agrees to keep all information provided by AROG Pharmaceuticals in strict 
confidence and to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study 
documents provided by AROG Pharmaceuticals (protocols, investigators' brochures, case report 
forms and other material) will be stored appropriately to ensure their confidentiality. The 
information provided by AROG Pharmaceuticals to the investigator may not be disclosed to 
others without direct written authorization from AROG Pharmaceuticals as applicable, except to 
the extent necessary to obtain informed consent from patients who wish to participate in the trial. 
  
Discontinuation of Study 
 
AROG Pharmaceuticals reserves the right to discontinue any study under the conditions 
specified in the clinical trial agreement. 
 
Ethics and Good Clinical Practice 
 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in AROG Pharmaceuticals standard operating procedures and: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
3. Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects). 
4. The investigator agrees when signing the protocol to adhere to the instructions and 
procedures described in it and thereby to adhere to the principles of Good Clinical Practice 
that it conforms to. 
 
Institutional Review Board/Independent Ethics Committee 
 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the IRB/IEC/REB 
must be given to AROG Pharmaceuticals before study initiation.  Any amendments to the 
protocol, other than administrative ones, must be approved by this committee. 
 
Informed consent 
 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 


53 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC/REB approval. AROG Pharmaceuticals supplies a proposed 
informed consent form, which complies with regulatory requirements and is considered 
appropriate for the study. Any changes to the proposed consent form suggested by the 
Investigator must be agreed to by AROG Pharmaceuticals before submission to the 
IRB/IEC/REB, and a copy of the approved version must be provided to the AROG 
Pharmaceuticals monitor after IRB/IEC/REB approval. 
 
Declaration of Helsinki 
 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request 
or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html 
 
 


54 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix II. 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.  Alternatively MD Anderson internal 
form can be used. 
 
I. Study Information 
Protocol Title: 
A Phase II Study of Crenolanib in Acute Myeloid Leukemia 
Patients with FLT3 Activating Mutations 
Protocol Number: 
ARO-005 
 
II. Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
 
III. Inclusion/Exclusion Criteria:Inclusion 
Criteria 
(From IRB approved protocol) 
Yes 
No 
N/A 
Supporting 
Documentation* 
1. Confirmed primary AML relapsed or 
refractory after prior therapy, AML 
secondary to antecedent chemotherapy or 
radiation therapy, or AML due to MDS/ 
MPN as defined by WHO criteria with 
presence of FLT3 ITD and or/other FLT3 
activating mutations, whose leukemia has 
recurred after prior chemotherapy but 
never received a FLT3 inhibitor (Cohort 
A) or whose leukemia has progressed 
after prior therapy  and have history of 
prior exposure to one or more FLT3 TKIs 
(Cohort B). 
 
 
 
 
2. Patients with secondary AML who have 
failed no more than two prior cytotoxic 
chemotherapy containing regimens. 
 
 
 
 
3. Patients with antecedent MDS/MPN, 
defined by WHO criteria, without any 
prior therapy for AML, regardless of the 
number of therapies for MDS/MPN. 
 
 
 
 


55 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
4. Patients with primary AML with no more 
than two prior cytotoxic drug containing 
salvage regimens. Reinduction with the 
same agents is not considered a salvage 
regimen.  Change of drugs will be 
considered a salvage regimen. Unlimited 
FLT3 TKI therapy (even in combination 
with cytotoxics/hypomethylating agents) 
is allowed for patients enrolled in cohort 
B.   
 
 
 
 
5. Positive for AML with FLT3-ITD and/or 
other FLT3 activating mutations as tested 
within 30 days of enrollment. 
 
 
 
 
6. Age ≥18 years 
 
 
 
 
7. ECOG Performance Status 0 - 2 
 
 
 
 
8. Liver function: 
ALT ≤ 3.0x ULN 
AST ≤ 3.0x ULN 
Bilirubin ≤ 1.5x ULN  
 
 
 
 
9.  
Serum creatinine ≤ 1.5x ULN 
 
 
 
 
10. Recovery from toxicities of prior therapy 
(including HSCT) to no more than grade 
1 (except alopecia) 
 
 
 
 
11. Subjects should have received no anti-
leukemic therapy (except hydroxyurea) 
for 14 daysfor classical cytotoxic agents 
and for five times the half life of  FLT3 
inhibitorsprior to first dose of crenolanib 
and antineoplastic agents that are neither 
cytotoxic nor FLT 3 inhibitors. 
 
 
 
 
12. Negative pregnancy test for women of 
childbearing potential 
 
 
 
 
13. Able and willing to provide written 
informed consent 
 
 
 
 


56 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Exclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
N/A 
Supporting 
Documentation* 
1. Absence of FLT3 activating mutation 
 
 
 
 
2. <5% blasts in blood or marrow at 
screening (i.e. only extra-medullary 
leukemia) 
 
 
 
 
3. Concurrent chemotherapyor targeted anti-
cancer agents, other than hydroxyurea. 
 
 
 
 
4. Patient 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. HIV infection or active hepatitis B or C  
 
 
 
 
6. Known clinically active central nervous 
system (CNS) leukemia 
 
 
 
 
7. Subjects who are <30 days of an HSCT. 
 
 
 
 
8. Subjects who have clinically significant 
graft-versus-host disease requiring 
treatment, and/or have >Grade 2 
persistent non hematological toxicity 
related to the transplant 
 
 
 
 
9. Prior crenolanib treatement for a non-
leukemia indication 
 
 
 
 
10. Major surgical procedures within 14 days 
of Day 1 administration of crenolanib 
 
 
 
 
11. Unwillingness or inability to comply with 
protocol 
 
 
 
 
 
*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 [
 eligible / 
 ineligible] for participation in the study. 
Signature: 
Date: 
Printed Name: 
 
 


57 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix III. 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 
 
 
 


58 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix IV. Patient Diaries: Crenolanib 
 
 


59 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 


60 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 


61 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
 
 


62 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix V. Study Schedule 
 
screening 
Therapy
End 
of 
Study 
visit 
Follow‐
up visit 
Cycle No.  
 
1
2
3
n
Duration 
28d
28d
28d
28d
Relative day 
within cycle 
(‐)14 
1 
2 
8
15
22
1
15
1
1
 
Informed Consent 
X 
  
 
  
Inclusion/Exclusion 
X 
  
 
  
Demography 
X 
 
 
 
Relevant medical 
history, current 
medical conditions 
including AML‐
specific history 
X 
X 
 
  
Evaluation of FLT3‐
D835, FLT3‐ITD, 
and other 
mutational status 
X 
 
 
 
Height 
X 
 
 
 
Prior/Concomitant 
medications, 
significant non‐
drug therapies 
X 
X 
X 
X
X
X
X
X
X
X
X
X 
Physical 
examination1 
X 
X 
 
X
X
X
X
X 
Vitals, ECOG 
Performance 
Status, Weight 
X 
X 
 
X
X
X
X
X
X
X
X
X 
AEs and SAEs 
X 
X 
X 
X
X
X
X
X
X
X
X
X 
Laboratory tests 
  
  
 
  
Hematology2 
X 
X 
X 
 
XX
X
 
X
 
X
 
X
 
X
 
X
X
X 
Serum Chemistries2 
X 
XX 
 
XX
X
 
X
 
X
 
X
 
X
 
X
X
X 
HIV, HepB/C 
X 
 
 
 
Urine or serum 
Pregnancy test 
X 
 
 
X
  
Peripheral blood 
for PK analysis3 
  
X 
X 
X
X
X
  
Peripheral blood 
for correlative 
analysis3 
 
X 
X 
X
  
Disease 
assessment 
  
  
 
  
Bone marrow 
aspirations (x2)4 
X 
X 
 
X
X
X
  
1Physical examination = .Day 1 +/- 4 days 
 
2 CBC includes platelet count, differential (differential may be omitted if WBC is <0.5 x109/L), Chemistry panel 
including AST, ALT, and total bilirubin to be drawn twice weekly (at least 24 hours apart) for the first two weeks of 


63 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
cycle 1, once weekly (± 3 days) for the second two weeks of cycle 1, bi-weekly (± 4 days) for the second cycle and 
once a month thereof from cycle 3 until cycle 12 (± 14 days). 
 
Labs obtained with the local physician can be used for monitoring; PI must review and sign source documents 
within 24 hours of performance of lab at local physician’s office unless performed on a Friday in which case review 
on the following Monday is acceptable.  It is encouraged that labs be performed on Monday thru Thursday. 
At the time of any dose escalation, labs should be drawn twice per week for at least one week. 
 
3Peripheral blood for translational research and correlative analysis including Pharmacokinetics Assay and Plasma 
Inhibitory Assay will be obtained at multiple time points on Day 1 of Cycle 1, the 24 hour drug level would be 
obtained on Day 2 of Cycle 1. Samples will also be obtained at multiple time points on Day 15 of Cycle 1, Day 1 of 
Cycle 2, and Day 1 of Cycle 3. Further collections may be as requested by sponsor.  Additional samples may be 
drawn at the discretion of the investigator. At the time of any dose escalation, labs should be drawn twice per week 
for at least one week. 
 
4Baseline bone marrow aspirations (two aspirates at each time point, see section 12.3) or a sample of peripheral 
blood containing blasts should be collected prior to start of crenolanib therapy.  Ideally, entry bone marrow should 
be done within 14 days of Cycle 1 Day 1 (baseline.), however a marrow done within 30 days of enrollment is 
allowed if baseline blast count can be assessed.   Additional aspirations should be taken at cycle 2 day 1 (+ 4 days), 
cycle 3 day 1 (+/- 7 days), then every 3 cycles (+/- 1 cycle) as long as criteria for CR is maintained.  At loss of CR, 
bone-marrow biopsy would be performed only as clinically indicated to exclude toxicity issues (such as persistent 
pancytopenia due to study drug vs from progressive AML.) 
 
 
 
 


64 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix VI.  Clinical Laboratory Tests 
 
Hematology
a 
Clinical Chemistry
b
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Leukocytes (WBC) 
Total bilirubin 
Neutrophils, segmented  
Direct bilirubin 
Lymphocytes 
Indirect bilirubin 
Monocytes  
Alkaline phosphatase 
Eosinophils  
Alanine aminotransaminase (ALT/SGPT) 
Basophils  
Platelets 
Aspartate aminotransferase (AST/SGOT) 
Gamma-glutamyltransferase (GGT) 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Phosphorus 
 
Calcium 
 
Glucose, random  
 
Albumin 
 
Lactate dehydrogenase 
 
 
 
 
 
Pregnancy Test (serum or urine; females only)
a,c,d 
 
 
Abbreviations:  RBC = red blood cells, WBC = white blood cells. 
a Performed by local lab 
b Local Lab results may be used for enrollment or dosing decisions 
c Required for women of childbearing potential. Women are considered not of childbearing 
potential if they are surgically sterile or are postmenopausal.  Patients may be entered and 
enrolled on the basis of a local serum or urine pregnancy test 
d Repeat test as clinically indicated 
e Repeat test on Day 1 of each cycle of therapy. 
Note:  Patients may be enrolled on the basis of local chemistries. 
Investigators must document their review of each lab report. 
 
 
 


65 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix VII. Common Terminology Criteria for Adverse Events 
(CTCAE); Version 4.03 
 
 


66 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix VIII. Definition of a Serious Adverse Event (SAE) 
 
Life threatening: “Life threatening” means that the patient was at immediate risk of death from 
the adverse event as it occurred or it is suspected that use or continued use of the product would 
result in the patient’s death. “Life threatening” does not mean that had an adverse event occurred 
in a more severe form it might have caused death (i.e., hepatitis that resolved without hepatic 
failure). 
 
Hospitalization: Outpatient treatment in an emergency room is not in itself a serious adverse 
event, although the reasons for it may be (e.g., bronchospasm, laryngeal edema). Hospital 
admissions and/or surgical operations planned before or during a study are not considered 
adverse events if the illness or disease existed before the patient was enrolled on the study, 
provided that it did not deteriorate in an unexpected way during the study. 
 
Important medical event or medical intervention: Medical and scientific judgment should be 
exercised in deciding whether a case is serious in a situation where important medical events 
may not be immediately life threatening or result in death, hospitalization, disability or 
incapacity but may jeopardize the patient or may require medical intervention to prevent one or 
more outcomes listed in the definition of serious. These should usually be considered as serious. 
 
Examples of such events are: 
・ Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment 
・ Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine 
・ Intensive treatment in an emergency room or at home for allergic bronchospasm 
・ Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
・ Development of drug dependency or drug abuse 
 
Disease progression: Any events or hospitalizations that are unequivocally due to progression of 
disease must not be reported as serious adverse events. 
 
The following factors should be considered when deciding if there is a “reasonable possibility” 
that an adverse event may have been caused by the investigational product. 
・ Time course of events and exposure to suspect drug: Has the patient actually received the 
suspect drug? Did the adverse event occur in a reasonable temporal relationship to the 
administration of suspect drug? 
・ Consistency with known drug profile: Was the adverse event consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the adverse event be anticipated from its 
pharmacological properties? 


67 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
・ De-challenge experience: Did the adverse event resolve or improve on stopping or 
reducing the dose of the suspect drug? 
・ No alternative cause: The adverse event cannot be reasonably explained by another 
etiology, such as the underlying disease, other drugs, other host, or environmental factors. 
・ Re-challenge experience: Did the adverse event reoccur if the suspected drug was 
reintroduced after having been stopped? Laboratory tests: Has a specific laboratory 
investigation confirmed the relationship? 
 
A “reasonable possibility” could be considered to exist for an adverse event when 1 or more of 
these factors exist. 
 
In contrast, there would not be a “reasonable possibility” of causality if none of the above criteria 
apply, or if there is evidence of exposure and a reasonable time course, but any de-challenge (if 
performed) is negative or ambiguous, or there is another more likely cause of the adverse event. 
 
In difficult cases, other factors could be considered such as the following: 
・ Is this a recognized feature of overdose of the drug? 
・ Is there a known mechanism? 
 
Ambiguous cases should be considered as having a “reasonable possibility” of causal 
relationship, unless additional evidence becomes available to refute this. 
 
If true progression is determined by subsequent imaging, then the date of progression returns to 
the earlier date with increasing mass. 
 
 
 
 
 
 


68 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix IX-A. ARO-005 C1D1 Pharmacokinetic Data Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA:   
Crenolanib Dose (mg):   
Today’s Date:     
 
List the name, dose, and regimen of other drugs the patient has received within 48 hours of crenolanib 
therapy, including any vitamins and herbal supplements (St. John’s Wort, etc.).  If more space is needed, 
please use an additional sheet: 
Drug Name 
Drug Dose 
Date and Time Administered 
 
 
 
 
 
 
 
 
 
 
List the type, quantity, and time of food/drink consumed 1 hour prior to crenolanib dose until 2 hours post 
Day 1 crenolanib dose.  Use an additional sheet if necessary.   
_____________________________________________________________________________________
_____________________________________________________________________________________
________________________________________________________________ 
 
Fill in crenolanib dose date, time, and tolerance in the spaces below.  HOLD SECOND AND THIRD 
DOSE of crenolanib on day 1. Obtain 24 hour sample prior to administration of crenolanib doses on 
day 2. List the scheduled and actual times of the pharmacokinetic samples in the chart below.  Scheduled 
time refers to the time that blood should be collected, and actual time refers to the actual time the blood 
was collected whether it is the same or different than the scheduled time.  Blood should be collected as 
close to the scheduled time as possible.   
Date of Dose: _______________________________________________________________    
Dose Administration Time: _____________________________________________________ 
Describe Dose Tolerance:  ______________________________________________________ 
 
 
Name of person completing form: ____________________________________ 
Phone Number: __________________________________________________ 
Email: _________________________________________________________ 
Date: __________________________________________________________ 
Course 1 Day 1 Samples 
Date 
Scheduled Time 
Actual Time 
Prior to crenolanib dose (pre) 
 
 
 
30 (± 10) minutes after dose 
 
 
 
60 (± 15) minutes after dose 
 
 
 
120 (±15) minutes after dose 
 
 
 
4 (±1) hours after dose 
 
 
 
8 (±2) hours after dose 
 
 
 
24 (±6) hours after dose (C1D2)  
 
 


69 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix IX-B. ARO-005 C1D1 Plasma Inhibitory Assay Data Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA:   
Crenolanib Dose (mg):   
Today’s Date:     
 
List the name, dose, and regimen of other drugs the patient has received within 48 hours of crenolanib 
therapy, including any vitamins and herbal supplements (St. John’s Wort, etc.).  If more space is needed, 
please use an additional sheet: 
Drug Name 
Drug Dose 
Date and Time Administered 
 
 
 
 
 
 
 
 
 
List the type, quantity, and time of food/drink consumed 1 hour prior to crenolanib dose until 2 hours post 
Day 1 crenolanib dose.  Use an additional sheet if necessary.   
_____________________________________________________________________________________
_____________________________________________________________________________________
________________________________________________________________ 
Fill in crenolanib dose date, time, and tolerance in the spaces below.  HOLD SECOND AND THIRD 
DOSE of crenolanib on day 1. Obtain 24 hour sample prior to administration of crenolanib doses on 
day 2. List the scheduled and actual times of the pharmacokinetic samples in the chart below.  Scheduled 
time refers to the time that blood should be collected, and actual time refers to the actual time the blood 
was collected whether it is the same or different than the scheduled time.  Blood should be collected as 
close to the scheduled time as possible.   
Date of Dose: _______________________________________________________________    
Dose Administration Time: _____________________________________________________ 
Describe Dose Tolerance:  ______________________________________________________ 
 
 
Name of person completing form: ____________________________________ 
Phone Number: __________________________________________________ 
Email: _________________________________________________________ 
Date: __________________________________________________________ 
Course 1 Day 1 Samples 
Date 
Scheduled Time 
Actual Time 
Prior to crenolanib dose (pre) 
 
 
 
30 (± 10) minutes after dose 
 
 
 
60 (± 15) minutes after dose 
 
 
 
120 (±15) minutes after dose 
 
 
 
4 (±1) hours after dose 
 
 
 
8 (±2) hours after dose 
 
 
 
24 (±6) hours after dose (C1D2) 
 
 
 


70 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix X-A. ARO-005 C1D15 Pharmacokinetic Data Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex:
Date of Birth: 
Height (cm): 
Weight (kg):
Height (cm): 
Crenolanib Dose (mg):   
Today’s Date:     
 
List the name, dose, and regimen of other drugs the patient has received within 48 hours of crenolanib 
therapy, including any vitamins and herbal supplements (St. John’s Wort, etc.).  If more space is needed, 
please use an additional sheet: 
Drug Name 
Drug Dose 
Date and Time Administered 
 
 
 
 
 
 
 
 
 
 
List the type, quantity, and time of food/drink consumed 1 hour prior to crenolanib dose until 2 hours post 
Day 15 crenolanib dose.  Use an additional sheet if necessary.   
_____________________________________________________________________________________
_____________________________________________________________________________________
______________________________________________________________________________ 
 
Fill in exact dose dates, times, and tolerances for the prior 4 crenolanib doses in the spaces below.   
 
Crenolanib Date Administered  
Time Administered 
Crenolanib Tolerance 
 
 
 
 
 
 
 
 
 
 
 
 
 
List the scheduled and actual times of the pharmacokinetic samples in the chart below.  List exact date 
and time of day 15 crenolanib administration. Scheduled time refers to the time that blood should be 
collected, and actual time refers to the actual time the blood was collected whether it is the same or 
different than the scheduled time.  Blood should be collected as close to the scheduled time as possible. 
Note: Do not administer second or third crenolanib dose until after 6 hour sample is collected. 
 
 
Name of person completing form: ____________________________________ 
Phone Number: __________________________________________________ 
Email: _________________________________________________________ 
Date: __________________________________________________________ 
 
Cycle 1 Day 15 Samples 
Date 
Scheduled Time 
Actual Time 
Prior to Day 15 crenolanib dose  
 
 
 
30 (±10) minutes after dose  
 
 
 
4 (± 1) hours after dose  
 
 
 


71 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix X-B. ARO-005 C1D15 Plasma Inhibitory Assay Data Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex:
Date of Birth: 
Height (cm): 
Weight (kg):
Height (cm): 
Crenolanib Dose (mg):   
Today’s Date:     
 
List the name, dose, and regimen of other drugs the patient has received within 48 hours of crenolanib 
therapy, including any vitamins and herbal supplements (St. John’s Wort, etc.).  If more space is needed, 
please use an additional sheet: 
Drug Name 
Drug Dose 
Date and Time Administered 
 
 
 
 
 
 
 
 
 
 
List the type, quantity, and time of food/drink consumed 1 hour prior to crenolanib dose until 2 hours post 
Day 15 crenolanib dose.  Use an additional sheet if necessary.   
_____________________________________________________________________________________
_____________________________________________________________________________________
______________________________________________________________________________ 
 
Fill in exact dose dates, times, and tolerances for the prior 4 crenolanib doses in the spaces below.   
 
Crenolanib Date Administered  
Time Administered 
Crenolanib Tolerance 
 
 
 
 
 
 
 
 
 
 
 
 
 
List the scheduled and actual times of the pharmacokinetic samples in the chart below.  List exact date 
and time of day 15 crenolanib administration. Scheduled time refers to the time that blood should be 
collected, and actual time refers to the actual time the blood was collected whether it is the same or 
different than the scheduled time.  Blood should be collected as close to the scheduled time as possible. 
Note: Do not administer second or third crenolanib dose until after 6 hour sample is collected. 
 
 
Name of person completing form: ____________________________________ 
Phone Number: __________________________________________________ 
Email: _________________________________________________________ 
Date: __________________________________________________________ 
Cycle 1 Day 15 Samples 
Date 
Scheduled Time 
Actual Time 
Prior to Day 15 crenolanib dose  
 
 
 
30 (±10) minutes after dose  
 
 
 
4 (± 1) hours after dose  
 
 
 


72 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
 
Appendix XI-A. ARO-005 C__D__ Pharmacokinetic Data Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex:
Date of Birth: 
Height (cm): 
Weight (kg):
Height (cm): 
Crenolanib Dose (mg):   
Today’s Date:     
 
List the name, dose, and regimen of other drugs the patient has received within 48 hours of crenolanib 
therapy, including any vitamins and herbal supplements (St. John’s Wort, etc.).  If more space is needed, 
please use an additional sheet: 
Drug Name 
Drug Dose 
Date and Time Administered 
 
 
 
 
 
 
 
 
 
 
List the type, quantity, and time of food/drink consumed 1 hour prior to crenolanib dose until 2 hours post 
crenolanib dose.  Use an additional sheet if necessary.   
_____________________________________________________________________________________
_____________________________________________________________________________________
______________________________________________________________________________ 
 
Fill in exact dose dates, times, and tolerances for the prior 4 crenolanib doses in the spaces below.   
 
Crenolanib Date Administered  
Time Administered 
Crenolanib Tolerance 
 
 
 
 
 
 
 
 
 
 
 
 
 
List the scheduled and actual times of the pharmacokinetic samples in the chart below.  List exact date 
and time of crenolanib administration. Scheduled time refers to the time that blood should be collected, 
and actual time refers to the actual time the blood was collected whether it is the same or different than 
the scheduled time.  Blood should be collected as close to the scheduled time as possible. Note: Do not 
administer second or third crenolanib dose until after 6 hour sample is collected. 
 
 
Name of person completing form: ____________________________________ 
Phone Number: __________________________________________________ 
Email: _________________________________________________________ 
Date: __________________________________________________________ 
Samples 
Date 
Scheduled Time 
Actual Time 
Prior to crenolanib dose  
 
 
 
4 (± 1) hours after dose  
 
 
 
 
 
 
 
 
 
 
 


73 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix XI-B. ARO-005 C__D__ Plasma Inhibitory Assay Data Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex:
Date of Birth: 
Height (cm): 
Weight (kg):
Height (cm): 
Crenolanib Dose (mg):   
Today’s Date:     
 
List the name, dose, and regimen of other drugs the patient has received within 48 hours of crenolanib 
therapy, including any vitamins and herbal supplements (St. John’s Wort, etc.).  If more space is needed, 
please use an additional sheet: 
Drug Name 
Drug Dose 
Date and Time Administered 
 
 
 
 
 
 
 
 
 
 
List the type, quantity, and time of food/drink consumed 1 hour prior to crenolanib dose until 2 hours post 
crenolanib dose.  Use an additional sheet if necessary.   
_____________________________________________________________________________________
_____________________________________________________________________________________
______________________________________________________________________________ 
 
Fill in exact dose dates, times, and tolerances for the prior 4 crenolanib doses in the spaces below.   
 
Crenolanib Date Administered  
Time Administered 
Crenolanib Tolerance 
 
 
 
 
 
 
 
 
 
 
 
 
 
List the scheduled and actual times of the pharmacokinetic samples in the chart below.  List exact date 
and time of crenolanib administration. Scheduled time refers to the time that blood should be collected, 
and actual time refers to the actual time the blood was collected whether it is the same or different than 
the scheduled time.  Blood should be collected as close to the scheduled time as possible. Note: Do not 
administer second or third crenolanib dose until after 6 hour sample is collected. 
 
 
Name of person completing form: ____________________________________ 
Phone Number: __________________________________________________ 
Email: _________________________________________________________ 
Date: __________________________________________________________ 
Samples 
Date 
Scheduled Time 
Actual Time 
Prior to crenolanib dose 
 
 
 
4 (± 1) hours after dose  
 
 
 
 
 
 
 
 
 
 
 


74 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix XII. Bone Marrow Aspiration: Data Collection Form (Baseline / C_D_) 
 
Study Acc #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA:   
Crenolanib Dose(mg):   
Crenolanib Dosage (mg/m2):   
Today’s Date:     
 
 
 
Please fill in crenolanib dose date, time, and tolerance in the spaces below.  List the actual times 
of the bone marrow aspiration, sample volume or estimated mass, and note any collection issues 
in the chart below.  Use an additional sheet if necessary.     
 
Dateof Dose: _______________________________________________________________    
Dose Administration Time: _____________________________________________________ 
Describe Dose Tolerance:  ______________________________________________________ 
 
 
Name of person completing form: ____________________________________ 
Phone Number: __________________________________________________ 
Email: _________________________________________________________ 
Date: __________________________________________________________ 
 
 
Bone Marrow 
Aspiration 
Actual Time 
Sample Volume or 
Estimated Mass 
Note any  
collection issues 
Sample – 1 
 
 
 
Sample – 2 
 
 
 


75 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix XIII. Shipping Addresses for Serum and Tissue Samples 
 
A. Pharmacokinetics Samples 
 
Cynthia Gomez 
Senior Project Coordinator 
MicroConstants, Inc. 
9050 Camino Santa Fe 
San Diego, CA 92121 
P (858) 652-4600 
F (858) 652-4699 
 
CGomez@microconstants.com 
www.microconstants.com 
 
 
B. Plasma Inhibitory Assay Samples 
 
Mark Levis, MD PhD 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital 
Cancer Research Building 1, Room 230 
1650 Orleans Street 
Baltimore, MD 21231 
(410) 955-8964 
LevisMa@jhmi.edu 
 
 
C. Bone Marrow Aspirate Samples 
 
Debrah Cohen 
Cytogenetis and Molecular Laboratory Manager 
ProPath 
1355 River Bend Drive 
Dallas TX 75247 
214.237.1739 
Fish@propath.com 
www.ProPath.com 
 
 


76 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix XIV. CYP3A4 Inducing or Inhibiting Drugs with the Potential to Affect 
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) 
oxcarbamazepine (anticonvulsants and mood 
stabilizers) 
ketoconazole (azole antifungals) 
phenobarbital (barbiturates) 
itraconozole (azole antifungals) 
rifampicin (bactericidal) 
Posaconazole (azole antifungals) 
modafinil (stimulant) 
dexamethasone 
Voriconazole (azole antifungals) 
hyperforin (constituent of St. John’s Wort) 
nefadozone (antidepressant) 
 
 
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 
 
 
 
 


77 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix XV. Contact Information of Arog Pharmaceuticals  
 
Contact Information of Medical Monitor 
 
Nora Ku, M.D. 
Telephone: 305.283.5896 
 
E-mail: nku@arogpharma.com 
 
 
Contact Information of Study Manager 
 
Abhijit Ramachandran 
AROG Pharmaceuticals, LLC 
E:aramachandran@arogpharma.com  
O: 214.593.0515  
M: 817.849.0175 
F: 214.594.0002 
 
Contact Information of Study Monitors 
 
Pritam Kambuj 
AROG Pharmaceuticals, LLC 
E:pkambuj@arogpharma.com  
M: 214.593.0512 
 
 
 
Contact Information for notification of shipment of correlative studies samples 
 
Justin Rains 
AROG Pharmaceuticals, LLC 
E: jrains@arogpharma.com 
O: +1 214.593.0500  
M: +1 817.849.0175 
F: +1 214.594.0002 
 
 
 
 


78 
Protocol: ARO-005                      Confidential                    Version – 3.0 (October 27, 2014) 
Appendix XVI. FMS-like Tyrosine Kinase 3 Inhibitors Currently Being Studied in the 
Treatment of Leukemia and Their Half-life 
 
Following are few examples of FLT3 inhibitors and their half-lives based on current available 
data: 
 
Trade name 
Compound 
Half-life 
5X Half-life 
Days 
Dovitinib 
TKI258 
18 hours 
90 hours 
4 
KW-2449* 
KW-2449 
3.5 hours 
17.5 hours 
1 
Lestaurtinib 
CEP-701 
9.2 hours 
46 hours 
2 
Midostaurin 
PKC412 
38.4 hours 
192 hours 
8 
PLX3397* 
PLX3397 
20 hours 
100 hours 
4 
Quizartinib 
AC220 
36 hours 
180 hours 
8 
R406* 
R406 
15 hours 
75 hours 
3 
Sorafenib 
BAY-43-9006 
27 hours 
135 hours 
6 
Sunitinib 
SU11248 
86 hours 
430 hours 
18 
Tandutinib 
MLN518 
33 hours 
165 hours 
7 
 
*No trade name is currently available