Conditions: Relapsed or Refractory Acute Myeloid Leukemia With FLT3 Activating Mutations
Keywords: FLT3 Crenolanib Acute myeloid leukemia relapsed refractory
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed or refractory AML with FLT3 activating mutations. Prior treatment with other FLT3 TKIs is allowed. Subjects will take crenolanib 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who are able to proceed to allogeneic stem cell transplant will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Crenolanib Besylate (CP-868,596-26)
Intervention descriptions: intervention 1: Subjects will take crenolanib 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who are able to proceed to allogeneic stem cell transplant will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission.

Protocol document:
Prot_SAP_000.pdf: 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Protocol ARO-004 
 
A Phase II Study of Crenolanib Besylate in Subjects with 
Relapsed/Refractory Acute Myeloid Leukemia 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, LLC, 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, LLC, or its 
subsidiaries. 
 
 
 
 
 
 
 
 
AROG Pharmaceuticals, LLC 
12400 Coit Road, Suite 570 
Dallas, TX 75251 
 
 
 
Version 4.0 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Table of Contents 
1. Objectives ................................................................................................................................... 6 
1.1 Primary Objectives ................................................................................................................ 6 
1.2 Secondary Objectives............................................................................................................ 6 
2. Sponsor Contact Information ...................................................................................................... 7 
3. Synopsis ...................................................................................................................................... 8 
Study Rationale .................................................................................................................... 8 
4. Abbreviations and Definitions .................................................................................................. 13 
5. Background ............................................................................................................................... 16 
5.1 Acute Myeloid Leukemia (AML) ....................................................................................... 16 
5.2 Targeted Therapy in AML .................................................................................................. 16 
5.3 FMS-like Tyrosine Kinase 3 (FLT3) .................................................................................. 16 
5.4 FLT3 in AML ..................................................................................................................... 17 
5.4.1 Downstream Pathways of Normal FLT3 .................................................................. 17 
5.5 Crenolanib is a Potent Inhibitor of Type III Receptor Kinases and their Constitutively 
Active Mutations ...................................................................................................................... 17 
5.5.1 Crenolanib has High Binding Affinity against the FLT3 Mutant Isoforms D835H 
and D835Y ......................................................................................................................... 18 
5.5.2 Crenolanib is Active against Leukemic Cell Lines and Primary Blasts with FLT3-
D835 ................................................................................................................................... 19 
5.5.3 Leukemic Blasts from Patients who Relapsed on FLT3 TKI Therapy Were Inhibited 
by Crenolanib ..................................................................................................................... 20 
5.5.4 Phase I/II Clinical Studies of Oral Crenolanib Show that it is well absorbed and well 
tolerated.............................................................................................................................. 20 
6. Patient Eligibility ...................................................................................................................... 24 
6.1 Inclusion Criteria ................................................................................................................ 24 
6.2 Exclusion Criteria ............................................................................................................... 24 
6.3 Discontinuations ................................................................................................................. 25 
6.3.1 Discontinuations of Patients ..................................................................................... 25 
6.3.2 Discontinuation of Study Sites ................................................................................. 25 
6.3.3 Discontinuation of the Study .................................................................................... 26 
7. Treatment Plan .......................................................................................................................... 27 
7.1 Summary of Treatment ....................................................................................................... 27 
7.2 Study Design ....................................................................................................................... 27 
7.3 Supportive Care Guidelines ................................................................................................ 27 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
8. Study Procedures ...................................................................................................................... 29 
8.1 Baseline Screening .............................................................................................................. 29 
8.2 Evaluation during Treatment and Post Allogeneic Transplant ........................................... 29 
8.3 Treatment with Crenolanib (CP-868,596) .......................................................................... 30 
8.4 Materials and Supplies ........................................................................................................ 32 
8.5 Method of Assignment to Treatment .................................................................................. 32 
8.6 Rationale for Selection of the Baseline Dose for Current Protocol Version 4 ................... 32 
8.7 Dosing and Dose Modification of Crenolanib .................................................................... 34 
8.7.1 Dose Reductions for Crenolanib for Non-hematologic Toxicities During 
Reinduction and Post Allogeneic Transplant ..................................................................... 35 
8.7.2 Dose Reductions for Crenolanib for Hematologic Toxicities For Patients Taking 
Crenolanib as Reinduction and Post Allogeneic Transplant .............................................. 37 
8.7.3 Dose Re-escalations for Crenolanib  during induction and maintenance ................. 38 
8.7.4 Cycle Delays ............................................................................................................. 38 
8.7.5 Continued Access to Study Drug .............................................................................. 38 
8.8 Blinding............................................................................................................................... 38 
8.9 Concomitant Therapy.......................................................................................................... 39 
8.10 Treatment Compliance ...................................................................................................... 39 
8.11 Sample Collection and Testing ......................................................................................... 39 
8.11.1 Samples for Standard Laboratory Testing .............................................................. 40 
8.12 Follow Up Visits ............................................................................................................... 40 
8.13 Translational Research ...................................................................................................... 40 
9.1 Response Criteria ................................................................................................................ 42 
10. Statistical Considerations ........................................................................................................ 43 
10.1 Determination of Sample Size .......................................................................................... 43 
10.2 Toxicity Evaluation ........................................................................................................... 43 
10.3 Statistical and Analytical Plans ......................................................................................... 43 
10.3.1 General Considerations ........................................................................................... 43 
10.3.2 Patient Disposition .................................................................................................. 43 
10.3.3 Patient Characteristics ............................................................................................. 44 
10.3.4 Concomitant Therapy .............................................................................................. 44 
10.3.5 Treatment Compliance ............................................................................................ 44 
10.3.6 Primary Outcome and Methodology ....................................................................... 44 
10.3.7 Efficacy Analysis .................................................................................................... 45 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
10.3.9 Safety Analyses ....................................................................................................... 45 
10.3.10 Criteria for End of Study ....................................................................................... 45 
11. Safety Evaluations and Appropriateness of Measurements .................................................... 46 
11.1 Safety Evaluations ............................................................................................................ 46 
11.1.1 Adverse Event Definition ....................................................................................... 46 
11.1.2 Serious Adverse Event Definition .......................................................................... 46 
11.1.3 Unexpected Adverse Events Definition .................................................................. 46 
11.1.4 Attribution ............................................................................................................... 47 
11.1.5 Adverse Event Reporting ........................................................................................ 47 
11.1.6 Serious Adverse Event Reporting ........................................................................... 48 
11.1.7 Follow-up ................................................................................................................ 49 
11.1.8 Other Safety Measures ............................................................................................ 50 
11.2 Appropriateness of Measurements .................................................................................... 51 
12. Data Quality Assurance .......................................................................................................... 52 
12.1 Data Capture System......................................................................................................... 52 
13. Informed Consent, Ethical Review, and Regulatory Considerations ..................................... 53 
13.1 Informed Consent .............................................................................................................. 53 
13.2 Ethical Review .................................................................................................................. 53 
13.3 Regulatory Considerations ................................................................................................ 53 
13.3.1 Investigator Information ......................................................................................... 53 
13.3.2 Protocol Signatures ................................................................................................. 54 
13.3.3 Final Report Signature ............................................................................................ 54 
14. References ............................................................................................................................... 55 
Appendix I. Inclusion/Exclusion Criteria Checklist ..................................................................... 57 
Appendix II. ECOG Performance Status Criteria ......................................................................... 60 
Appendix III. Patient Diaries: Crenolanib .................................................................................... 61 
Appendix IV. Study Schedule ....................................................................................................... 65 
Appendix V.  Clinical Laboratory Tests ....................................................................................... 67 
Appendix VI. Common Terminology Criteria for Adverse Events (CTCAE); Version 4.03 ...... 68 
Appendix VII. Definition of a Serious Adverse Event (SAE) ...................................................... 69 
Appendix VIII-A. ARO-004 C1D1 Pharmacokinetics Data Collection Form ............................. 71 
Appendix VIII-B. ARO-004 C1D1 Plasma Inhibitory Assay Data Collection Form .................. 72 
Appendix VIII-C. ARO-004 C1D1 Whole Blood Phospho-Flow Data Collection Form ............ 73 
Appendix IX-A. ARO-004 C1D15 Pharmacokinetics Data Collection Form .............................. 74 
Appendix IX-B. ARO-004 C1D15 Plasma Inhibitory Assay (PIA) Data Collection Form ......... 75 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix IX-C. ARO-004 C1D15 Whole Blood Phospho-Flow Data Collection Form............. 76 
Appendix X-A. ARO-004 C_D_ Pharmacokinetics Data Collection Form ................................. 77 
Appendix X-B. ARO-004 C_D_ Plasma Inhibitory Assay Data Collection Form ...................... 78 
Appendix X-C. ARO-004 C_D_ Whole Blood Phospho-Flow Data Collection Form ................ 79 
Appendix XI. C_D_ Bone Marrow Aspiration: Data Collection Form ........................................ 80 
Appendix XII. Shipping Addresses for Serum and Tissue Samples ............................................ 81 
Appendix XIII. CYP3A4 Inducing or Inhibiting Drugs  with the Potential to Affect Crenolanib 
Pharmacokinetics .......................................................................................................................... 82 
Appendix XIV. Contact Information of Arog Pharmaceuticals ................................................... 83 
Appendix XV. Dosing Instructions for Relapsed/Refractory ....................................................... 84 
AML Patients  ............................................................................................................................... 84 
Appendix XVI. Dosing Instructions for Patients post HSCT ....................................................... 85 
Appendix XVII. Fms-like Tyrosine Kinase 3 Inhibitors Currently Being Studied in the Treatment 
of Leukemia and Their Half-life ................................................................................................... 86 
 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
1. Objectives 
1.1 Primary Objectives 
• 
Overall response rate defined as Complete remission (CR) including  incomplete blood count 
recovery (CRi) 
• 
Duration of response  
• 
Progression-free survival  
 
1.2 Secondary Objectives 
• 
Safety and tolerability of crenolanib 
• 
Pharmacokinetic analysis of crenolanib in patients with AML 
• 
Analysis of phospho-FLT3 and other pharmacodynamic markers from serially collected 
circulating leukemic blasts and/or marrow blast samples 
• 
Pharmacogenetic analyses, correlation of remission with genomic abnormalities including 
but not limited to mutant FLT3 allelic ratio 
• 
Impact of crenolanib on hematological improvement, bridge to transplant, duration of 
leukemia control, blood and platelet transfusions, infections, days of hospitalization, 
performance status 
 
 
 
 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
2. Sponsor Contact Information 
  
  
 
 
Protocol Number: 
ARO-004 
Version 
4.0 
Version Date: 
August 30 , 2013 
Investigational Product: 
Crenolanib  
Development Phase: 
II 
Sponsor: 
Arog Pharmaceuticals, LLC. 
12400 Coit Road Suite 570 
Dallas TX 75251 
Phone - (214) 593-0500 
Fax - (214) 594-0002  
Email - info@arogpharma.com 
Medical Monitor: 
Nora Ku, M.D. 
M: 305-283-5896 
F: 214:594.0002 
 
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 
 
 
 
 
 
 
 
 
 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
3. Synopsis 
Study Rationale 
A number of FLT3 inhibitors with in vitro and in vivo activity against the FLT3 internal tandem 
duplication (ITD) mutation are in clinical development.  These include midostaurin (PKC412, in 
phase III development), sorafenib (in phase III development), and quizartinib (AC220, in phase 
II development). 
 
However, most AML patients who initially respond to these FLT3 tyrosine kinase inhibitors 
(TKIs) relapse.  One of the mechanisms of resistance to FLT3 inhibitors is the development of 
secondary mutations in the FLT3 tyrosine kinase domain (TKD). The most common secondary 
TKD mutations that have been identified are substitutions of aspartic acid at the position 835 of 
FLT3 (D835Y/V).  The D835 substitution mutation in FLT3 results in ligand-independent 
constitutive phosphorylation of the tyrosine residues present in the kinase domains of FLT3 
protein. This mutation is resistant to midostaurin, sorafenib and even quizartinib. Thus, there 
exists a need to develop FLT3 inhibitors with the ability to inhibit FLT3-D835 signaling to treat 
patients with relapsed AML. 
 
Crenolanib besylate (CP-868,596-26) is an orally bioavailable benzimidazole that was designed 
to be a selective and potent inhibitor of type III receptor kinases FLT3, PDGFRα and PDGFRβ. 
Crenolanib not only inhibits the wild type FLT3, but also its constitutively active mutations. In 
vitro studies have shown that Crenolanib has a high affinity for mutant FLT3 with Kd values of 
0.43nM. In addition, crenolanib has high affinity for TKD mutations D835H at 0.4nM Kd in 
contrast to that of 3.7nM for quizartinib and Kd of 30nM for sorafenib, and for D835Y at 0.18nM 
and known to cause resistance to quizartninb with a Kd of 7.1nM and Kd of 82nM for sorafenib.  
This high affinity of crenolanib allows it to inhibit aberrant FLT3 signaling at clinically 
achievable concentrations in AML patients.  Crenolanib was able to inhibit phosphorylation of 
FLT3-D835Y transfected in Ba/F3 cells, with an IC50 of 8.8nM. 
 
This activity of crenolanib against both wild type as well as mutant FLT3 has been confirmed in 
primary AML blast obtained from patients.  In these assays, crenolanib was found to be 
cytotoxic to leukemic blasts with FLT3 activating mutations with concurrent inhibition of FLT3 
phosphorylation and downstream signaling pathways like AKT and STAT. The potential ability 
of crenolanib to overcome resistance developed by patients treated with other FLT3 inhibitors 
has been assessed by exposing leukemic blasts from patients whose AML had progressed on 
other FLT3 inhibitors including quizartinib and sorafenib.  These leukemic blasts had not only 
the ITD of FLT3 but also FLT3-D835 mutation.  Crenolanib was able to inhibit FLT3 
phosphorylation in these blasts as well as inhibit MTT metabolism by these leukemic blasts.  
 
These data suggest that crenolanib could potentially provide therapeutic benefit to the patients 
with activated FLT3, whether due to ITD or due to TKD mutations like D835, which could be 
present at the time of diagnosis or be acquired secondary to exposure to other FLT3-TKIs.  
 
This pilot Phase II study is designed to evaluate the efficacy and tolerability of oral crenolanib 
besylate in patients with relapsed Acute Myeloid Leukemia with FLT3 activating mutations as 
retreatment of relapsed/refractory AML and in maintaining remission after allogeneic stem cell 
transplant. 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Name of Investigational Product: 
Crenolanib besylate (CP-868,596-26) 
Title of Study:  A Phase II Study of Crenolanib Besylate in Subjects with Relapsed/Refractory 
Acute Myeloid Leukemia with FLT3 Activating Mutations  
Number of Planned Subjects:   
14 evaluable subjects  
Length of Study:  3 years 
 
Objectives:  
 
Primary Objectives 
• 
Overall response rate including Complete remission (CR) including  incomplete blood count 
recovery (CRi) 
• 
Duration of response  
• 
Progression-free survival  
 
Secondary Objectives:  
• 
Safety and tolerability of crenolanib 
• 
Pharmacokinetic analysis of crenolanib in patients with AML 
• 
Analysis of phospho-FLT3 and other pharmacodynamic markers from serially collected 
circulating leukemic blasts and/or marrow blast samples 
• 
Pharmacogenetic analyses, correlation of remission with genomic abnormalities including 
but not limited to mutant FLT3 allelic ratio 
• 
Impact of crenolanib on hematological improvement, bridge to transplant, duration of 
leukemia control, blood and platelet transfusions, infections, days of hospitalization, 
performance status 
 
Study Design:   
 
This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with 
relapsed or refractory AML with FLT3  activating mutations. Prior treatment with other FLT3 
TKIs is allowed. Subjects will take crenolanib 200mg/m2/day  divided in three  doses daily 
(preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease 
progression, death, or the patient discontinues treatment for adverse events, investigator’s 
judgment, or other reasons.  Patients who are able to proceed to allogeneic stem cell transplant 
will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission. 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Diagnosis and Main Criteria for Inclusion and Exclusions:   
 
Inclusion Criteria: 
 
 Relapsed/refractory primary AML or AML secondary to antecedent hematologic disorder 
with an expected survival of 3 months or greater  
 Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations 
within < 60 days of the screening period.  
 Age ≥18 years 
 ECOG PS 0 – 2 
 Adequate liver function, defined as total or direct bilirubin ≤1.5x ULN, ALT ≤3.0x ULN, 
AST ≤3.0x ULN. Exceptions for ALT and AST restrictions will be made in the setting of 
documented liver involvement with leukemia. 
 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 XVII for half-life information and drugs considered as FLT3 inhibitors for 
purposes of this trial.. 
 Negative pregnancy test for women of childbearing potential. 
 Able and willing to provide written informed consent. 
 Subjects who received crenolanib prior to and are within 30-90 days of an allogeneic stem 
cell transplant (HSCT) and have either no active GVHD where therapy has been initiated or 
GVHD where therapy has not been escalated within 14 days prior to start of study drug. 
 
Exclusion Criteria: 
 
 Absence of FLT3 activating mutation 
 <5% blasts in blood or marrow at screening  
 Concurrent chemotherapy, systemic immunosuppressants, 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 manifested as hepatitis surface antigen positive (HepBs 
Ag) or hepatitis C manifested as hepatitis C antibody positive  
 For post HSCT, subjects who are within 29 days of an allogeneic transplant, and/or are on an 
unstable dose of immunosuppressive drugs for management or prophylaxis of GVHD or have 
escalated therapy for GVHD within 14 days of starting study drug and/or have >/=Grade 2 
persistent non hematological toxicity related to the transplant or did not receive crenolanib 
prior to HSCT 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 Evidence of lack of engraftment if post allogeneic transplant  
 Unable to swallow pills 
 Major surgical procedures within 14 days of Cycle 1 Day 1 administration of crenolanib. 
 Unwillingness or inability to comply with protocol. 
 


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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Test Product, Dosage and Mode of Administration:  
Crenolanib besylate taken as follows: 
1.  For patients with active relapse and given as reinduction, 200mg/m2/day  divided in three  
doses daily (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. (Appendix III) Concurrent hydroxyurea (maximum 
5g total daily dose) is permitted for the first 14 days of study therapy. 
2. For patients continuing therapy as maintenance after allogeneic stem cell transplant 
(HSCT), the same dose of crenolanib most recently tolerated by the patient during induction 
will be restarted.  Patients will complete a daily diary to record the date, time and amount 
(number of tablets) of crenolanib taken and eating schedule (Appendix III) 
 
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.  Subjects will take crenolanib besylate daily 
as reinduction and may resume as maintenance after allogeneic stem cell transplant, until their 
disease has progressed, the patient has died, or the patient discontinues for adverse events, 
investigator’s judgment, or other reasons.  
 
Subjects who have discontinued will continue to be followed 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.  Descriptive statistics will be presented for all 
categories of each best response category.  Duration of response and PFS will be listed and 
additionally summarized using Kaplan-Meier methodology. In addition, if at any time 
unacceptable toxicity is encountered in more than 33% of patients, the accrual will stop and 
lower doses may be investigated. 
 
 
 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
4. Abbreviations and Definitions 
Adverse Event 
(AE) 
Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
 
Audit 
A systematic and independent examination of the trial-related activities 
and documents to determine whether the evaluated trial-related 
activities were conducted, and the data were recorded, analyzed, and 
accurately reported according to the protocol, applicable standard 
operating procedures (SOPs), good clinical practice (GCP), and the 
applicable regulatory requirement(s). 
 
Compliance 
Adherence to all the trial-related requirements, good clinical practice 
(GCP) requirements, and the applicable regulatory requirements. 
 
Complaint 
A complaint is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, purity, durability, 
reliability, safety or effectiveness, or performance of a drug or drug 
delivery system. 
 
Confirmation 
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that 
AROG is confident that results are accurate.  Confirmation will either 
occur immediately after initial testing or will require that samples be 
held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results. 
 
Case Report Form 
(CRF) 
Sometimes referred to as clinical report form:  a printed or electronic 
form for recording study participants’ data during a clinical study, as 
required by the protocol. 
 
Consent 
The act of obtaining informed consent for participation in a clinical 
trial from patients deemed eligible or potentially eligible to participate 
in the clinical trial.  [Patients/Subjects] entered into a trial are those 
who sign the informed consent document directly or through their 
legally acceptable representatives. 
 
End of Study (trial) 
The date of the last visit or last scheduled procedure shown in the 
Study Schedule for the last active subject in the study.  
 
 
 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled 
in the trial are those who have been assigned to a treatment. 
 
Interim Analysis 
 
An interim analysis is an analysis of clinical trial data, separated into 
treatment groups, that is conducted before the final reporting database 
is created/locked. 
 
Investigator 
A person responsible for the conduct of the clinical trial at a trial site. 
If a trial is conducted by a team of individuals at a trial site, the 
investigator is the responsible leader of the team and may be called the 
principal investigator. 
 
Institutional Review 
Board/Ethical 
Review/Board 
(IRB/ERB) 
A board or committee (institutional, regional, or national) composed of 
medical and nonmedical members whose responsibility is to verify that 
the safety, welfare, and human rights of the patients participating in a 
clinical trial are protected. 
 
Legal Representative 
An individual, judicial, or other body authorized under applicable law 
to consent on behalf of a prospective patient, to the patient’s 
participation in the clinical trial. 
 
Patient 
A study participant who has the disease or condition for which the 
investigational product is targeted. 
 
Screen 
The act of determining if an individual meets minimum requirements 
to become part of a pool of potential candidates for participation in a 
clinical trial.  In this study, screening involves invasive or diagnostic 
procedures and/or tests (for example, radiology and blood draws).  For 
this type of screening, informed consent for these screening procedures 
and/or tests shall be obtained. 
 
Subject 
An individual who is or becomes a participant in clinical research, 
either as a recipient of the investigational product(s) or as a control.  A 
subject may be either a healthy human or a patient. 
 
Treatment-Emergent 
Adverse Event 
(TEAE) 
Any untoward medical occurrence that either occurs or worsens at any 
time after treatment baseline and which does not necessarily have to 
have a causal relationship with this treatment (also called treatment-
emergent signs and symptoms [TESS]). 
 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
CN-AML 
cytogenetically normal acute myeloid leukemia 
CT 
computerized tomography 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
CR 
complete response 
CRF 
case report form 
CRi 
complete remission with incomplete hematological recovery 
CRp 
complete remission with incomplete platelet recovery 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
FDR 
fixed dose rate 
FLT3 
FMS-like Tyrosine Kinase 3 
GCP 
good clinical practice 
GGTP 
gamma glutamyl transpeptidase 
ICD 
informed consent document 
ICH 
International Conference on Harmonization 
IHC 
immunohistochemistry 
ITD 
internal tandem duplication 
LFTs 
liver function tests 
mm 
millimeter 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 4.03 
NONMEM 
nonlinear mixed effect modeling 
ORR 
overall response rate 
PD 
progressive disease 
PDGFR 
platelet-derived growth factor receptor 
 
PET 
positron emission tomography 
PFS 
progression free survival 
PR 
partial response 
SD 
stable disease 
SEER 
Surveillance Epidemiology and End Results 
SUV 
standardized uptake value 
TKD 
Tyrosine Kinase Domain 
TKI 
Tyrosine Kinase Inhibitor 
ULN 
upper limit of normal 
 
 
 
 
 
 


 
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17 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
5.4 FLT3 in AML 
Mutations within the FLT3 gene have been detected in up to 35% of AML patients and represent 
one of the most frequently identified genetic alterations in AML.5 In addition, approximately 
5%-10% of AML patients harbor point mutations within the second TKD. In most cases, these 
mutations result in a substitution of tyrosine for aspartic acid at codon 835. FLT3-TKD 
mutations cause constitutive activation of the FLT3 receptor, aberrant activation of downstream 
signaling pathways. 
 
5.4.1 Downstream Pathways of Normal FLT3 
Binding of its ligand, FLT3-ligand (FL) 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.6 These actions affect the 
activation of further downstream PI3K/protein kinase B (Akt) and mitogen-activated protein 
kinase (MAPK) pathways.7 Bruserud et al. reported that exogenous FL increases blast 
proliferation for not only patients with wild-type FLT3 but also patients with FLT3-TKD 
mutations.8 Therefore, FL-mediated triggering of FLT3 appears to be important for both wild-
type and mutant FLT3 signaling. 
 
Significant literature is available that implicates FLT3-D835 mutations as a key activating 
mechanism in a subset of AML and which thus could be targeted for therapy. 9-14 In addition, the 
FLT3–TKD mutations are associated with poor clinical outcome emphasizing the potential 
benefit in targeting cells with FLT3 targeted TKI.15  
 
In 2008, Whitman et al. determind the prognostic relevance of FLT3 D835 mutations (FLT3-
TKD) in cytogenetically normal acute myeloid leukemia (CN-AML).16 They excluded patients 
with FLT3 internal tandem duplications and compared treatment outcome of 16 de novo CN-
AML patients with FLT3-TKD with that of 123 patients with wild-type FLT3 (FLT3- WT), less 
than 60 years of age and similarly treated. Although all FLT3-TKD patients and 85% of FLT3-
WT patients achieved a complete remission (P = 0.13). Disease-free survival (DFS) of FLT3- 
TKD patients was worse than DFS of FLT3-WT patients (P=0.01; estimated 3-year DFS rates, 
31% vs 60%, respectively). 
 
5.5 Crenolanib is a Potent Inhibitor of Type III Receptor Kinases and their 
Constitutively Active Mutations 
Crenolanib besylate is an orally bioavailable benzimidazole, selective and potent inhibitor of 
type III receptor kinase FLT3 and its 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. 17 The CAS registry number is 
670220-93-6.18 


 
18 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 
Crenolanib is a specific and potent inhibitor of class III receptor tyrosine kinases (RTKs) (Table 
5.1). Crenolanib has sub-nanomolar Kd against the wild-type receptors FLT3 (0.74nM, Table 
5.1.). 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. 
 
 
Table 5.1. Activity of crenolanib against type-III receptor kinases22  
 
RTK 
Crenolanib Kd 
FLT3 
0.74 nM 
PDGFRβ 
2.1 nM 
PDGFRα 
3.2 nM 
Kit 
78 nM 
CSF1R 
30 nM 
 
5.5.1 Crenolanib has High Binding Affinity against the FLT3 Mutant 
Isoforms D835H and D835Y  
Crenolanib was evaluated in a KdELECT assay (DiscoverRx, San Diego, CA) to determine its 
affinity against wild type FLT3 as well as its mutant isoforms. In these assays, crenolanib was 
found to have sub-nanomolar Kd for both FLT3-D835H and D835Y, which are found in about 
7% of AML cases. These FLT3-TKD mutations, D835Y and D835H, are intrinsically resistant to 
almost all currently available FLT3-targeted TKIs. In clinical trials, patients progressing on 
sorafenib and quizartinib have been found to develop resistance through secondary D835H and 
D835Y mutations respectively.  
 
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-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-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 5.2).19 
 


 
19 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 
Figure 5.2. Kd measurements of crenolanib, sunitinib, CEP-701(lestaurtinib), AC-220 
(quizartinib), sorafenib etc, with FLT3/D835Y and FLT3/D835H. Assay signals were 
normalized to facilitate comparison. 19, 22 
Activity of crenolanib against both wild-type as well as D835Y FLT3 kinase was evaluated in 
the Millipore IC50 profiler assay. This system allows for the direct measurement of 
phosphorylation with superior sensitivity using phosphocellulose (PH) filter plates. This assay 
system is a direct enzymatic measurement with “gold standard” radiometric filter binding format.  
In this assay, the IC50 of crenolanib against wild type FLT3 was 3nM and was even lower at 2nM 
against FLT3 with the D835Y mutation, confirming the activity of crenolanib against both the 
wild type and mutant FLT3 receptors 
  
In contrast to sorafenib and quizartinib, which bind to the non-phosphorylated form of kinases 
(classified as type II TKI), crenolanib preferentially  binds to the phosphorylated from of kinases 
(type I TKI).19   Such constitutively phosphorylated FLT3 receptors are a consequence of D835 
TKD mutations which makes resistant to both sorafenib and quizartinib but potentially sensitive 
to crenolanib. This high affinity of crenolanib to constitutively phosphorylated TKD mutants is 
not limited to just FLT3 but has also been seen in analogous activating mutants found in 
PDGFRA (D842V) as well c-kit (D816V).   
 
5.5.2 Crenolanib is Active against Leukemic Cell Lines and Primary Blasts 
with FLT3-D835  
Crenolanib not only inhibited phosphorylation of the wild type FLT3 receptor in SEMK2 cells, 
but also inhibited phosphorylation of the FLT3-D835Y TKD mutation in Ba/F3 cells transfected 
with vectors expressing FLT3-D835Y (Figure 5.3). The IC50 of crenolanib against the D835Y, 
TKD mutation of FLT3 was found to be 8.8nM. 
 
 
Figure 5.3. Activity of crenolanib against FLT3-D835Y mutation transfected in Ba/F3 cells 
(Unpublished, data on file). 
 


 
20 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
In leukemic blasts from a newly diagnosed AML patient with the FLT3-D835V mutation, FLT3 
phosphorylation was inhibited by crenolanib but was resistant to sorafenib and quizartinib 
(Figure 5.4). 
 
 
 
 
 
 
 
Figure 5.4. Leukemic blasts with the FLT3-D835V mutation were incubated with 20nM of 
crenolanib (Cren) or  sorafenib (Sor)  In contrast to sorafenib, crenolanib was able to provide 
near complete (>90%) inhibition of phosphorylated FLT3.23 
 
5.5.3 Leukemic Blasts from Patients who Relapsed on FLT3 TKI Therapy 
Were Inhibited by Crenolanib  
Leukemic blasts were obtained from a patient who had been treated with quizartinib and 
subsequently underwent an allogeneic transplantation.  The patient’s leukemic blasts had a 
FLT3/D835 mutation in the background of a FLT3/ITD mutation. Leukemic blasts obtained at 
the time of post-transplant relapse showed sensitivity to crenolanib in an MTT assay (IC50 of 
26nM); with no sensitivity to sorafenib (Figure 5.5).    
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5.5. In primary patient blasts, crenolanib was the most potent inhibitor against 
FLT3/D835 in comparison to sorafenib.23  
 
5.5.4 Phase I/II Clinical Studies of Oral Crenolanib Show that it is well 
absorbed and well tolerated 
Crenolanib has been clinically evaluated as a single agent in a dose-finding and dose-ranging 
phase-I 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.  
 


 
21 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
As of 31 May 2013, one treatment related death has reported in 200 patients treated with 
crenolanib both as a single agent and in combination.  This death occurred during phase Ib 
evaluation of crenolanib with docetaxel and axitinib in a patient with metastatic NSCLC and 
liver metastases who developed progressive liver failure and died.  This death was classified as 
possibly related to study drug although progressive metastatic disease in the liver was not 
excluded. 
 
The most frequent non-hematological grade 1/2 toxicities were diarrhea, nausea, and vomiting 
(Table 5.2). 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, and decreased 
lymphocyte count. 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 5.2. Incidence of treatment-related AEs occurring in ≥ 5% of the study population treated 
with single agent crenolanib, data as of May 2013 
 
  
NCI CTC Severity Grade 
Total patients = 
125 
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 


 
22 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
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 
 
QT prolongation has been observed in only two patients  treated with single agent crenolanib  
 
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 criteria, 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  Table 5.3. 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 Table 5.3. 
 
There were two grade 1 QT interval prolongations observed in the 59 patients treated, that 
resolved without need for study drug interruption. No grade 2/3/4 QT interval prolongation have 
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. 
 


 
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24 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
6. Patient Eligibility 
6.1 Inclusion Criteria 
 Relapsed/refractory primary AML or AML secondary to antecedent hematologic disorder  
with an expected survival of 3 months or greater 
 Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations 
within < 60 day screening period age ≥18 years 
 ECOG PS 0 – 2 (Appendix II) 
 Adequate liver function, defined as total or direct bilirubin ≤1.5x ULN, ALT ≤3.0x ULN, 
and AST ≤3.0x ULN. Exceptions for ALT and AST restrictions will be made in the setting of 
documented liver involvement with leukemia 
 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 antileukemic 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 XVII for 
half-life information and drugs considered as FLT3 inhibitors for purposes of this trial.  
 Negative pregnancy test for women of childbearing potential 
 Able and willing to provide written informed consent 
 Subjects who received crenolanib prior to and are within 30 to 90 days of receipt of a 
allogeneic stem cell transplant (HSCT) and have either no active GVHD where therapy has 
been initiated or GVHD where therapy has not been escalated within 14 days prior to start of 
study drug. 
 
6.2 Exclusion Criteria 
 Absence of FLT3 activating mutation 
 <5% blasts in blood or marrow at screening  
 Concurrent chemotherapy, systemic immunosuppressants, 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 manifested as hepatitis B surface antigen (hepBs Atg) 
positivity or hepatitis C manifested as hepatitis C antibody positive. 
 
For post HSCT, subjects within 29 days of an allogeneic transplant, and/or are on an unstable dose of 
immunosuppressive drugs for management or prophylaxis of GVHD or have escalated therapy for GVHD 
within 14 days of starting study drug, and/or have >/=Grade 2 persistent non hematological toxicity related to 
the transplant or did not receive crenolanib prior to HSCT 
 Evidence of lack of engraftment if post allogeneic transplant 


 
25 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 Unable to swallow pills 
 Major surgical procedures within 14 days of Cycle 1 Day 1 administration of crenolanib. 
 Unwillingness or inability to comply with protocol 
 
6.3 Discontinuations 
6.3.1 Discontinuations of Patients 
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient should be immediately discontinued 
from the study drug unless specific approval is obtained from the IRB.   
 
In addition, patients will be discontinued from the study drug but continued to be followed for 
survival data in the following circumstances: 
 The patient experiences unacceptable toxicity as defined in Section 8.7 The patient is 
non-compliant (see Section 8.10). 
 The investigator decides that the patient should be withdrawn, for example due to 
intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree.  If this decision is made because of a serious 
adverse event or a clinically significant laboratory value, the study drug is to be 
discontinued and appropriate measures are to be taken.  AROG or its designee is to be 
alerted immediately (see Section 11.1). 
 The patient or attending physician requests that the patient be withdrawn from the study. 
 Enrollment in any other clinical trial involving an off-label use of an investigational drug 
or device or enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study. 
 The patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for treatment of the study indication.  In this case, 
discontinuation from the study occurs prior to introduction of the new agent. 
 The investigator or AROG stops the study or stops the patient’s participation in the study 
for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and good clinical practice. 
 
Patients in these circumstances will be followed as per the Study Schedule (appendix IV) and 
section 11.1.7.   
 
For patients lost to follow-up or undergoing initiation of another drug therapy including  
allogeneic HSCT, the study schedule will be stopped but patients should be followed for survival 
data if at all possible. 
6.3.2 Discontinuation of Study Sites 
Study site participation may be discontinued if AROG, the investigator, or the ethical review 
board of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice. Sites may also be 
discontinued if it is unable to accrue an adequate number of patients on the trial. 


 
26 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 
6.3.3 Discontinuation of the Study 
The study will be discontinued if the site IRB judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical practice.  The 
study could also be discontinued at any time at the sole discretion of the sponsor, AROG 
Pharmaceuticals, LLC.  
 
 


 
27 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
7. Treatment Plan 
7.1 Summary of Treatment 
The study will enroll AML patients with FLT3 D835 and/or other FLT3 activating mutations. 
Patients in relapse will be treated with crenolanib at 200mg/m2/day divided as three times a day 
(preferably every eight hours) continuously until they fulfill one of the criteria for study 
discontinuation (see Section 6.3) or proceed to allogeneic stem cell transplant. 
 
Patients currently enrolled at 100mg TID (protocol v3.0) can be switched to the dosing based on 
BSA, see table 8.4, as per investigators discretion. If patients enrolled under v3.0 are continued 
on their current dose without BSA based dosing, continue study procedures from the current time 
point as outlined under Study Schedule (Appendix IV) of this version of the protocol (v4.0) 
 
After allogeneic HSCT, patients who received crenolanib prior to transplant may resume  
crenolanib as maintenance on study post-transplant, if in remission at the same dose which was 
tolerated at the time of study drug hold prior to HSCT. 
 
Patients who did not receive crenolanib preHSCT will not be able to receive crenolanib as 
maintenance therapy under this protocol. 
 
Patients receiving less than 28 days of study dug as induction therapy will be replaced for 
efficacy evaluation.  All patients will be assessed for toxicity 
 
Study drug will be stopped if patients demonstrate evidence of relapsed disease as determined by 
the investigator. 
 
7.2 Study Design 
Fourteen relapsed/ refractory AML patients with FLT3  activating mutations will be treated with 
crenolanib daily as reinduction until they meet one of the criteria for discontinuation.  After 
HSCT, patients who received crenolanib prior to transplant and achieved response may continue 
on study post-transplant with maintenance crenolanib. Until they meet one of the criteria for 
discontinuation. Subject efficacy evaluations will be performed at scheduled time points. These 
include: monthly bone marrow biopsy in the first two months, and then every three months for as 
long as criteria for CR/CRi is maintained.  At loss of CR/CRi, bone-marrow biopsy will be 
performed only as clinically indicated to exclude toxicity issues such as pancytopenia due to 
study drug versus myelosuppression from progressive AML. Subjects’ best clinical response will 
be recorded, as well as the response at 2 months.  Subjects not in CR/Cri by the end of month 2 
but showing clinical benefit will be allowed to continue therapy at the discretion of the 
physician. 
7.3 Supportive Care Guidelines 
Supportive measures including blood and platelet transfusions, antimicrobials, etc. are permitted. 
The administration of hematopoietic colony stimulating factors is not permitted. 


 
28 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Other chemotherapy, investigational cytotoxic agents, radiation, or biologic therapy is prohibited 
while the subject is on study with the following exceptions during cycle 1:  
1.  During the first 5 days of cycle 1 of study only, subjects may receive leukapheresis (not more 
than three procedures per week and not more than five procedures in total) to control elevated 
blast and/or platelet counts  
2. hydroxyurea (up to a maximum of 5 gm /day) for a maximum of 14 days may be administered 
during cycle 1. 
3. Leukapheresis and hydroxyurea may be administered together according to the guidelines 
above. 


 
29 
Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
8. Study Procedures 
After providing informed consent, if meeting the screening inclusion/exclusion criteria, and after 
having baseline evaluations performed within 28 days prior to first dose of study drug patients 
will be enrolled in the study. 
The following assessments will be performed after completion of the informed consent and 
within 28 days of start of study drug except as otherwise specified: 
8.1 Baseline Screening 
1. Medical history (includes documentation of current medications and allergies) 
2. Height, weight, vital signs 
ECOG Performance Status (Appendix II) 
3. Pregnancy test for women of child bearing capacity 
4. A complete history and physical, documentation of all disease, concomitant medications 
and performance status 
5. CBC, platelet count, differential  
6. Creatinine, total bilirubin, ALT, and AST 
7. Bone marrow aspirate within 14 days preceding study drug initiation. Cytogenetics will 
be obtained prior to therapy (results from prior analysis can be used for this purpose, if 
done within 6-months of enrollment) 
8. Evaluation of FLT3-D835, FLT3-ITD and other mutational status (if not done < 60 days 
preceding study drug initiation).   
9. Baseline EKG assessment 
 
8.2 Evaluation during Treatment and Post Allogeneic Transplant  
1. Patient visits are weekly (± 2 days) for Cycle-1, bi-weekly (± 4 days) for Cycle-2, once 
every cycle (±14 days) from Cycle-3 to Cycle-6, once every two cycles (± 1 cycle) 
thereafter.  The flexibility is applied to all instances unless specified. 
2. 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. 
3. EKG measurements to be obtained at 1 hour (± 30 mins) post first or second dose, in 
accordance to the visit.  If new drugs with known effect on QTc are to be co-
administered with crenolanib, EKGs including a baseline prior to start of the new agent 
and 2-3 days after starting patient on combination of drugs is recommended. Weekly 
EKG x3 is also recommended for follow up and as needed for assessment based on 
patient’s clinical condition.  EKG can then be resumed per study schedule. 
4. CBC with 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). 
5. 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). 


 
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6. Bone marrow aspiration (with two additional aspirates) should be taken at these time 
points:  cycle 2 day 1 (+4 days), then cycle 3 day 1 (+/- 4 days). Following which every 
3 cycles (+/- 1 cycle) as long as criteria for CR are maintained.  At loss of CR, bone-
marrow biopsy would be performed only as clinically indicated to exclude toxicity 
issues like persistent pancytopenia due to study drug vs. from progressive AML. 
Aspiration sample for study purposes may also be submitted for patients not in CR if a 
marrow will be done for clinical purposes. Handling of bone marrow specimens is 
outlined in section 8.13, lab manual, and appendix XI. 
7. Samples for translational research including pharmacokinetic analysis, whole-blood 
phospho-flow cytometry and plasma inhibitory assay will be obtained as defined in 
section 8.13.and lab manual. 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. 
8. Procedures that are to be performed at the planned patient visits will be granted an 
exception only if the patients are hospitalized and unable to travel to the study sites. In 
that case, the investigator is responsible to ensure that the planned protocol procedures 
are performed at a local hospital.  Source documents shall be obtained and information 
recorded onto study CRFs. 
8.3 Treatment with Crenolanib (CP-868,596) 
This study involves an assessment of crenolanib administered orally for the treatment of relapsed 
/refractory AML with FLT3 activating mutations.  Responding patients who proceed to 
allogeneic stem cell transplant may be candidates to continue crenolanib as maintenance post-
transplant. 
 
All patients receiving study drug in relapse or with refractory disease will be administered 
200mg/m2/day divided as  three times a day (preferably every eight hours) daily, 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 if it was taken either with or without 
food. (Appendix III). Tablets should be swallowed whole and not be crushed or dissolved.   
 
Dosing will be three times daily, beginning on Day 1 through Day 28, for a 28 day cycle.  The 
starting dose will be 200mg/m2/day divided as  three times a day (preferably every eight hours) 
(Table 8.1).  The start of a cycle is denoted by the ingestion of study drug. 
 
Table 8.1. Baseline Treatment Regimen  
Regimen 
Dose 
All patients 
Day 1 through Day 28 
200mg/m2/day divided as  three times a day 
(preferably every eight hours)taken orally at 
least 30 minutes pre or post meal 
 
Patients may receive multiple cycles of treatment as described in Section 8.7.5. 


 
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The investigator or his/her designee is responsible for explaining the correct use of the 
investigational agent(s) to the patient/site personnel, verifying that instructions are followed 
properly, maintaining accurate records of study drug dispensing and collection, and returning all 
unused medication to AROG or its designee at the end of the study. Study medication that has 
been dispensed but remains unused at the end of the cycle is recorded by the site personnel and 
either safely discarded, if opened, or returned, if unopened. 
 
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be handled.  If a patient vomits after drug 
ingestion, no replacement dose is to be taken; the patient can continue to take the remaining 
doses as planned.  Missed doses will not be made up, and leftover drug should be returned to the 
study site upon patient follow up. 
 
Counting Cycle Days: If drug is held or a dose is 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 as missed. If drug is held or missed for a day or more, the cycle should continue 
as if uninterrupted.  Counting days of a cycle should be ongoing without disruption. 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. 
 
Continuation of crenolanib after allogeneic transplantation as maintenance therapy:  
Crenolanib will be held during the transplant period by stopping drug 72 hours prior to start of 
conditioning and resuming no sooner than 30 days post stem cell infusion. 
 
For patients in CR/CRi after allogeneic transplant, crenolanib may be resumed at the same dose 
of crenolanib tolerated as induction when crenolanib was held.  Patients will complete a daily 
diary to record the date, time and amount (number of tablets) of crenolanib taken and if it was 
taken either with or without food (Appendix III). Tablets should be swallowed whole and not be 
crushed or dissolved/ 
 
Patients may receive multiple cycles of treatment as described in Section 8.7.5.  Follow up of 
patients on post-transplant crenolanib is outlined in section 8.2 
 
The investigator or his/her designee is responsible for explaining the correct use of the 
investigational agent(s) to the patient/site personnel, verifying that instructions are followed 
properly, maintaining accurate records of study drug dispensing and collection, and returning all 
unused medication to AROG or its designee at the end of the study. Study medication that has 
been dispensed but remains unused at the end of the cycle is recorded by the site personnel and 
either safely discarded, if opened, or returned, if unopened.  
 
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be handled.  If a patient vomits after drug 
ingestion, no additional tablets should be taken on that day.  Missed doses will not be made up, 
and leftover drug should be returned to the study site upon patient follow up 
 


 
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Counting Cycle Days: If drug is held or a dose is 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 as missed. If drug is held or missed for a day or more, the cycle should continue 
as if uninterrupted.  Counting days of a cycle should be ongoing without disruption. 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. 
8.4 Materials and Supplies 
Crenolanib besylate is supplied as 100mg and/or 20mg tablets for oral administration in 42 count 
bottles or 30-count bottles.  Crenolanib besylate tablets should be refrigerated at a temperature 
between 2C and 8C (35.6F and 46.4F).  Standard household refrigeration is considered 
adequate for drug storage.  Crenolanib should be stored in the vials provided by the pharmacy 
and kept out of the reach of children. Used bottles 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 
requirements. 
 
8.5 Method of Assignment to Treatment 
All patients will receive crenolanib.  Patients who meet all criteria for enrollment will be 
considered enrolled into the study at Day 1 of Cycle 1. 
 
8.6 Rationale for Selection of the Baseline Dose for Current Protocol Version 4 
Dose of 200mg/m2/day divided as three times a day 
 
In vitro experiments have demonstrated that crenolanib inhibits the phosphorylation of FLT3- 
D835 (FLT3-D835Y/H) and FLT3-ITD mutations with an IC50 of approximately 9nM and 2nM, 
respectively, in culture medium.  In studies performed on plasma, the IC50 observed was 34nM 
against the FLT3-ITD mutation (23).  FLT3 inhibition studies suggest that sustained inhibition of 
FLT3 phosphorylation approximately 10-15 fold above IC50 is required to achieve meaningful 
clinical benefit, taking into account FLT3 expression in both stromal and blast cells.  We 
hypothesize that at least 680nM, or 20-fold the IC50, is needed for crenolanib to penetrate into 
bone marrow and maintain a sustained minimum concentration.   
 
Crenolanib serum concentration-time data were modeled with a two-compartment structural 
model using a maximum likelihood estimation method as implemented in ADAPTII. Individual 
Bayesian post hoc parameter estimates were obtained for the volume of distribution of the central 
compartment (Vc), elimination rate constant (Ke), and the intercompartmental transfer rate 
constants (Kcp and Kpc). These parameter values were then extrapolated to a new population of 
1,000 patients by pooling and random resampling. The concentration-time curves were then 
simulated out to steady-state (100 mg TID) using a differential equation solver for a two 
compartment model with first-order absorption and first-order elimination scripted in R. This 
Monte Carlo resampling scheme accounts for the variability in pharmacokinetic parameters and 


 
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allows for estimation of 95% confidence intervals of the concentration-time estimates indicated 
by the shaded regions on the plots below (figure 8.1).  
 
The modeling/simulation cycle described above was performed with combined data from two 
adult studies (19 patients, ARO-BRE-001 (NCT01229644) and 002 (NCT01243346)) and one 
pediatric study ARO-003 (NCT01393912). This data was used to perform distribution of the 
BSA-normalized crenolanib pharmacokinetic parameters and the expected distribution of BSA in 
an adult population to perform 1,000 Monte Carlo simulations for each regimen. In figure 8.1, 
the shaded regions represent the 95% CIs for each simulation. The patients’ dosing interval is 
considered to be every eight hours. Although the drug would be administered three times a day 
on a “TID” schedule, it is important to understand that the simulation was performed using an 
every eight hour dosing schedule and every attempt should be made to dose the drug on this 
schedule.  
 
 
 
Figure 8.1. The PK simulation for TID (median +/- SD) plotted based on a simulation of data 
from 19 adult patients and pediatric patients.  
 
The serum PK results of the 16 AML patients  enrolled to date at 100mg TID across two clinical 
studies show that fifteen have cycle 1 day 15 average trough levels of 444nM (standard error 
±15nM), below the theoretical target of 680nM required to inhibit FLT3 signaling in bone 
marrow.  In addition, the Pk data suggest that crenolanib is slowly absorbed with a t-max of 2-4 
hours and mean terminal half-life ranging from 8.6-9.5 hours.  This suggests the currently 
administered crenolanib dose of 100mg TID (protocol v3) is insufficient to achieve adequate 
sustained inhibition of FLT3 kinase activity.  As of May 2013, of the 16 patients enrolled across 
two clinical studies,  4 have achieved a CR (1CR/3CRi) with 6 others having some short lived 
reduction in blast cells in either blood or marrow and another 4 patients showing no response.  In 
the 6 patients with blast decrease, blast reduction occurred by 21 days but was not sustained.  
These results suggest pharmacologic failure for most patients at this initially selected dose of 
300mg/day (100mg/TID). In addition, AML patients over 85kg did not achieve sustained 
responses and are potentially underdosed on a flat-dose schedule.  
 
In contrast to the flat mg/day dosing schedule currently given on this trial under protocol v3, an 
ongoing phase I trial (NCT01393912) in pediatric patients with malignant brainstem glioma has 
treated 49 patients at four escalating dose levels of single agent using mg/m2/day dosing. Nine 
patients have received crenolanib at 220mg/m2 QD as a single daily dose.  Six out of these 9 
patients were on study drug for the DLT period of 28 days.  Two patients experienced DLT of 
transaminase elevations and stopped crenolanib therapy with subsequent resolution of abnormal 


 
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labs. Thus in the pediatric population 220mg/m2 given as one single daily dose approaches MTD 
but otherwise yields no other significant toxicities.   
 
Because a single daily dose achieves higher peak concentrations of drug, we have hypothesized 
that once daily dosing is associated more commonly with potential toxicities such as LFT 
elevations; and a BID or TID schedule will lower peak drug concentrations potentially allowing 
more sustained dosing, less toxicity and improved pharmacokinetic profiles.  At the current 
100mg TID dose prescribed in this trial (protocol version 31) no substantial drug related 
toxicities have been observed. The most common drug related adverse events (AEs) reported as 
grade 1 or 2 nausea and vomiting. Two patients required dose reductions for Grade 3 and 4 
transaminitis, which resolved once drug was held. Both were on two CYP3A4 inhibitors which 
may interfere with drug metabolism. Both patients tolerated 80 mg TID without transaminitis.  A 
crenolanib dose of 200mg/m2/day given as a TID schedule is postulated to result in a lower peak 
drug concentration and potential toxicities but provide adequate sustained dosing levels to reduce 
pharmacologic failure.  Pharmacokinetic data will continue to be collected.   
 
8.7 Dosing and Dose Modification of Crenolanib 
Toxicities will be graded using the NCI CTCAE, Version 4.03 (see partial representation in 
Appendix VI). 
 
All patients with relapsed/refractory AML will receive crenolanib induction therapy at a starting 
oral dose of 200mg/m2/day divided three times a day (preferably every eight hours)  
continuously for 28 days for each cycle of treatment.  Study drug should be taken at least 30 
minutes prior to or following a meal.. 
Crenolanib will be held starting 72 hours prior to start of planned conditioning for HSCT.  Study 
drug will be held for a minimum of 30 days post infusion of stem cells (day of HSCT). 
 
Post HSCT crenolanib will resume at the dose level last tolerated prior to HSCT. 
 
BSA will be capped at 2m2 for large patients and 1.5m2 for small patients.  Therefore the 
highest starting study drug dose will be 400mg/day (2m2 x 200mg/m2/day) and lowest drug 
dose will be 240mg/day (1.5m2 x 160mg/m2/day-see dose reduction scheme table 8.4).   
 
Because dosing increments based on BSA may not result in uniform doses given TID, the 
sponsor will provide detailed dosing instructions to the site.  Upon enrollment, the site will 
provide the sponsor the patient’s height, weight and BSA.  Along with the acknowledgement of 
enrollment, the sponsor will provide the site with a dosing information sheet (Appendix XV)   
on which will be the calculated starting dose (dose level 0) with instructions for how much drug 
should be taken at each TID ingestion.  Similar instructions will be provided on the dosing 
instruction sheet for dose level (+1), (-1) and (-2) should the patient require dose modification 
while participating on the study. 
 
Patients currently enrolled under protocol version 3 can be continued at their current dose and 
dose escalated as defined in this protocol version 4 if without grade 3 or 4 toxicity and lack of 
response to study drug at the current dose. 


 
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Patients are strongly encouraged to be premedicated as for moderate to highly emetogenic 
therapy per ASCO 2011 guidelines. Patients will complete a daily diary to record the date, time 
and amount (number of tablets) of crenolanib taken, and if it was taken with or without food. 
(Appendix III) 
 
Dose Escalation during induction and maintenance 
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. 
 
Table 8.2: Dose escalation guidance 
Dose level 
Crenolanib dosing 
0 
200 mg/m2/day  
+1 
220 mg/m2/day 
  
Dose escalation can occur as early as cycle 1 day 15. 
 
Counting Cycle Days:  If drug is held or a dose is 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 as missed. If drug is held or missed for a day or more, the cycle should continue 
as if uninterrupted.  Counting days of a cycle should be ongoing without disruption. 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. 
8.7.1 Dose Reductions for Crenolanib for Non-hematologic Toxicities During 
Reinduction and Post Allogeneic Transplant 
Toxicities will be graded using the NCI CTCAE, Version 4.03 (Appendix VI). 
 
For patients receiving crenolanib for reinduction therapy:  Dose reductions for non-
hematologic toxicities except nausea, vomiting, and diarrhea due to crenolanib will be done 
according to the schema in Table 8.3. Dose reductions are summarized in Table 8.4 and 
reductions below 160mg/m2/day will lead to withdrawal from the study drug, in which case the 
patient will stop taking crenolanib, but will still be followed for outcomes as outlined in 8.12. 
 
 
 
 
 
 
 
Table 8.3. Based on NCI CTCAE v4.03, Crenolanib Dose Reduction for Non Hematologic 
Toxicities Except Nausea, Vomiting, and Diarrhea related to study drug.  Use toxicity grade 
at time of start of next planned cycle.  Reassessment may be performed weekly to determine 
when to restart drug or dose modify.  A 28-day deferment window is allowed to assess toxicities. 


 
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Table 8.4. Dose levels of Crenolanib During Reinduction 
 
Dose Level 
Crenolanib Daily Dose 
Baseline 
200mg/m2/day 
First dose reduction (-1) 
180 mg/m2/day 
Second dose reduction (-2) 
160 mg/m2/day  
 
For patients receiving maintenance crenolanib after allogeneic transplant:  Start of 
maintenance crenolanib therapy is intended at the earliest time no sooner than 30 days but no 
longer than 90 days after allogeneic HSCT. Prerequisites for start of maintenance are a stable 
dose of immunosuppressive drugs for management or prophylaxis of GVHD or no escalation of 
therapy for GVHD within 14 days of starting study drug and/or have no more than Grade 2 
persistent non hematological toxicity related to the transplant.  Patients must have received 
crenolanib prior to HSCT to continue on to maintenance. 
 
Maintenance therapy will start at the last dose tolerated during reinduction therapy.  For 
example, if the patient was taking 180mg/m2/day prior to proceeding with HSCT, maintenance 
therapy will resume at 180mg/m2/day.   
  
Dose reductions for non-hematologic toxicities except nausea, vomiting or diarrhea due to 
crenolanib will be done according to the schema in Table 8.5. For dose level reductions please 
refer to Table 8.6, and appendix XV. Dose reductions below 140 mg/m2/day are not planned and 
crenolanib will be stopped. 
Table 8.5. Based on NCI CTCAE v4.03, Crenolanib Dose Reduction for Non-Hematologic 
Toxicities Post Allogeneic Transplant except Nausea, Vomiting, or Diarrhea related to 
study drug.  Use toxicity grade at time of start of next planned cycle.  Reassessment may be 
Toxicity 
(NCI Criteria) 
Dose modification for patients taking crenolanib as reinduction 
Grade 1 or 2 
No dose modification 
Clinically significant or 
persistent grade 2 
despite optimal 
therapy 
Hold drug until toxicity resolves to grade 1 or less. Restart drug at 
same dose level (Table 8.4). 
Grade 3 or 4 
Hold drug until toxicity resolves to grade 1 or less. Restart drug at 
next lower dose level (Table 8.4). 


 
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performed weekly to determine when to restart drug or dose modify.  A 28-day deferment 
window is allowed to assess toxicities. 
 
Table 8.6. Dose adjustments  of Crenolanib Post Allogeneic Transplant Maintenance 
therapy will start at the last dose level tolerated during reinduction therapy and dose 
adjustments made from that dose. 
Current crenolanib dose: 
Change crenolanib dose to: 
100 mg PO TID* 
80 mg PO TID 
220 mg/m2/day 
200 mg/m2/day 
200 mg/m2/day 
180 mg/m2/day 
180 mg/m2/day 
160 mg/m2/day 
160 mg/m2/day 
140 mg/m2/day  
*for patients enrolled on v3 of this protocol, not on BSA-based dosing 
 
8.7.2 Dose Reductions for Crenolanib for Hematologic Toxicities for Patients 
Taking Crenolanib as Reinduction and Post Allogeneic Transplant 
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 two cycles 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:  
Toxicity 
(NCI Criteria) 
Dose modification for patients taking crenolanib post allogeneic 
transplant  
Grade 1 or 2 
No dose modification 
Clinically significant or 
persistent grade 2 
despite optimal 
therapy 
Hold drug until toxicity resolves to baseline or grade 1 or less. 
Restart drug at same dose level (Table 8.6). 
Grade 3 or 4 
Hold drug until toxicity resolves to baseline or grade 1 or less. 
Restart drug at next lower dose level (Table 8.6). 


 
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 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 above.  
 
For patients taking crenolanib post allogeneic transplant, dose modification for 
hematologic toxicity will follow those outlined in Section 8.7.1 and tables 8.5 and 8.6 
 
8.7.3 Dose Re-escalations for Crenolanib during induction and maintenance 
In patients for whom the dose has been reduced due to toxicity, the dose may be re-escalated 
provided the patient has shown no clinical benefit and 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 to a max of 220 mg/m2..   
 
8.7.4 Cycle Delays  
A cycle of therapy may be delayed for a maximum of 28 days to allow recovery from toxicities.  
If drug has been held for total duration of 56 days or more, patient will be discontinued from 
study.  
 
8.7.5 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. 
 
8.8 Blinding 
This is an open-label study. 
 


 
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8.9 Concomitant Therapy 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
source documents as concomitant medication. 
 
No other anticancer therapy including immunotherapy, hormonal cancer therapy, or experimental 
medications other than hydroxyurea (which is allowed during the first two weeks) will be 
permitted while patients are participating in this study.  Radiation therapy will not be allowed.  
No hematopoietic growth factors will be permitted while patients are participating in this study. 
Any disease progression requiring other forms of specific antitumor therapy will be cause for 
discontinuation of study therapy. 
 
At the discretion of the investigator, crenolanib can be administered with standard anti-emetic 
and anti-diarrheal premedication.  Prophylaxis can be discontinued if patient tolerates crenolanib 
without significant nausea and vomiting.   
 
Donor lymphocyte infusion (DLI) will be permitted after 2 cycles (56 days) of crenolanib 
therapy exclusive of any drug hold for resolution of toxicity. 
 
8.10 Treatment Compliance 
Patient compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by counting returned tablets.  Deviation(s) from the prescribed dosage regimen should 
be recorded in the CRF. 
 
Definition of noncompliance:  Patients who are significantly noncompliant will be discontinued 
from the study.  A patient will be considered significantly noncompliant if he or she takes <60% 
of the total amount of expected study drug taken in a visit interval. 
 
In addition, to monitor patient compliance during the two first cycles, patients will be asked to 
complete a diary to record the date, time, and amount (the number of tablets) of crenolanib taken 
(Appendix III). 
 
The following procedures will be employed to assure appropriate drug accountability: 
 Drug accountability will be emphasized at the start-up meeting. 
 Drug accountability will be monitored throughout the study. 
 Each patient should be instructed to return all study drug packaging and unused 
material to the study site at each visit.  The study site personnel will keep a record 
of all drug dispensed to and returned by the patients throughout the study.  Study 
site personnel will return or destroy (as requested) all used, unused, and expired 
study drug for all patients. 
 
8.11 Sample Collection and Testing 
Appendix V lists the specific standard tests to be performed for this study. 


 
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8.11.1 Samples for Standard Laboratory Testing 
 
Blood samples will be collected at the times specified in the Study Schedule (Appendix IV).  
Standard laboratory tests, including chemistry, liver function tests, and hematology panels, will 
be performed as outlined below.  
 
 Cycle 1: labs twice weekly (at least 24 hours apart) for the first two weeks of cycle 1, then 
weekly (±3 days) for the second two weeks of cycle 1 
 Cycle 2: labs every 14 days ±4 days 
 Cycle 3 to Cycle 6: labs every 28 days ±14 days 
 Cycle 6 onwards: once every two cycles (± 1 cycle) 
 
A pregnancy test should be performed at study entry and at any time during the study if clinically 
indicated by history or clinical exam.   Other clinical laboratory tests will be analyzed by either a 
central or a local laboratory. Appendix V lists the specific tests that will be performed for this 
study. 
 
Investigators must document their review of each laboratory safety report 
 
8.12 Follow up Visits 
The Study Schedule in Appendix IV lists the specific follow up visits for this study. 
The Study Schedule applies to patients receiving study drug. The calendar should re-commence 
as start of cycle 1 when drug is resumed post allogeneic transplant.  Patients who have 
discontinued study drug for any reason should be followed for survival. 
 
8.13 Translational Research 
Translational studies to be evaluated include but are not limited to: 
1. Pharmacokinetic analysis (Pk) 
2. Whole-blood phospho-flow cytometry to detect activation of FLT3 and other signal 
transduction molecules in leukemic blasts from patients  
3. Plasma inhibitory assay to assess if therapeutically adequate concentrations of crenolanib 
were achieved in each patient (PIA) 
4. Bone marrow aspirate samples 
 
Bone marrow samples will be collected at the time of marrow sampling with 2 additional 
aspirations drawn and placed in heparinized tubes.  These samples will be refrigerated and 
shipped at 4-8oC within 24 hours of collection to the laboratory specified in Appendix XII. 
 
The participating institution will receive a laboratory kit containing blood collection tubes, 
labels, collection instructions from AROG for the collection of samples from consenting patients.  
Site should contact  AROG (Appendix XIV)at  to request a lab  kit for each patient enrolled on 
the study.   


 
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Serum and blood for translational research will be obtained at multiple time points on Cycle 1, 
Day 1, a single trough level on Cycle 1 Day 2, at multiple time points on Cycle 1 Day 15, Cycle 
2 Day 1 and Cycle 3 Day 1. Additional serum and blood samples for translational research may 
be drawn at the discretion of the investigator. 
 
  
Sampling Strategy 
 
On Day 1 of Cycle 1, serial blood samples for PK, whole blood phosphoflow, and PIA will be 
drawn for translational research at the following time points: pre dose and at 30 (± 10), 60 (± 15), 
120 (± 15) minutes, 4 (±1) hours, and 8 (±2) hours after crenolanib administration (Appendix 
VIII forms).  
 
On Day 2 of Cycle 1 (24 (±6) hours), blood samples for Pk and PIA only will be drawn at a 
single time-point: pre first dose to obtain the trough levels of crenolanib. (Appendix VIII). 
 
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. 
 
On Day 15 of cycle 1, samples for Pk, whole blood phosphoflow, and PIA will be drawn at the 
following time points: pre dose prior to ANY study drug ingestion for the day, then 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 time point is obtained on day 15. 
(Appendix IX forms). 
 
On Day 1 of Cycle 2, and Day 1 of Cycle 3, samples for PK, whole blood phosphoflow, and PIA 
will be drawn at the following time points: pre dose prior to ANY study drug ingestion for the 
day, and 4 (±1) hours after administration of first crenolanib dose. Do not administer 
subsequent doses of crenolanib until after 4 hour time point is obtained. (Appendix X 
forms). 
 
For dose escalations, repeat the Day 1 of Cycle 1 and Day 15 of Cycle 1 instructions.   
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 X forms).  
Optional bone marrow biopsy samples and concurrent whole blood samples may be collected at 
any time while the patient is on treatment, at the discretion of the investigator (Appendix X).    
 
Sample Processing Instructions  
See lab manual. Other Correlative Studies 
 
Tissue cells 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. But the 
total blood drawn for these studies will be less than 400ml in any month. 


 
Protocol:
9.1 Resp
Response
are relap
CRi, or P
leukemia
 
1. C
2. C
3. P
 
4. M
 
5. H
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: ARO-004  
ponse Crit
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Complete rem
a. Periph
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b. Bone 
i. 
ii. 
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Partial remis
a. All CR
b. 50 %
c. Marro
Morphologic 
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a CR, 
ologic 
nes. 
109/L 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
10. Statistical Considerations 
10.1 Determination of Sample Size 
The FLT3-3 D835 AML activating mutations have been refractory to currently available TKIs. 
An upper one-sided 75% confidence bound on the fraction of such patients who might respond to 
no treatment or ineffective therapy is 10%.   
Therefore we will treat 15% response rate as our null hypothesis and submit 14 patients to this 
phase II trial. If at least 2 patients respond to treatment, the null hypothesis will be rejected. If the 
true response rate is 30%, this design will have 85.07% power and 8.61% type I error.  
 
10.2 Toxicity Evaluation 
Crenolanib has been well tolerated in studies including over 100 patients and toxicity patterns are 
relatively well understood.  
 
10.3 Statistical and Analytical Plans 
The primary end-point is overall response rate.  We will use tests of the binomial proportion for 
both response and toxicity (Section 11).  Descriptive statistics will be used for progression free 
survival and exploratory endpoints.  Duration of response and PFS will be listed and additionally 
summarized using Kaplan-Meier methodology. 
 
10.3.1 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. 
 
10.3.2 Patient Disposition 
A detailed description of patient disposition, broken by cohort, will be provided.  It will include: 
 Summary of patients entered  


 
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 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 
 
10.3.3 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 
 Prior therapies 
Other patient characteristics will be summarized as deemed appropriate. 
 
10.3.4 Concomitant Therapy 
Concomitant medication will be reported overall as well as summarized in a frequency table 
using the terms recorded on the CRF.  If warranted, an attempt may be made to determine how 
concomitant medications are related to observed study outcomes. 
 
10.3.5 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 
 
10.3.6 Primary Outcome and Methodology 
Response criteria will be adapted from the International Working Group for AML, as stated in 
section 9.1. 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
10.3.7 Efficacy Analysis  
The primary end-point is overall response rate (detailed in section 9.1).  Descriptive statistics 
will be presented for all categories of each best response category.  Duration of response and 
PFS will be listed and additionally summarized using Kaplan-Meier methodology. In addition, if 
at any time unacceptable toxicity is encountered in more than 33% of patients the accrual will 
stop and lower doses may be investigated. 
 
10.3.9 Safety Analyses 
All patients will be evaluable for safety. Adverse events that occur after a patient is entered 
(signs informed consent), but before the patient receives study drug, will not be recorded on the 
CRF unless the investigator believes that the events may have been caused by a protocol 
procedure. Safety analyses will include summaries of the incidence of adverse events by 
maximum CTCAE grade (version 4.03; NCI 2010) that occur during the study treatment period 
or within 30 days of the last dose of study treatment, regardless of causality or relatedness to 
study drug. The safety-related outcomes that will be summarized include: 
 Adverse events, 
 TEAEs, 
 SAEs, 
 Deaths, 
 Discontinuations due to adverse events, 
 Extent of exposure to study drug treatment, 
 Hospitalizations, 
 Use of key concomitant medications (for example, antipruritus medication). 
 
Analyses for data with discrete dates (for example, deaths and concomitant medications) will be 
performed through 30 days after the patient has been discontinued from study treatment. Adverse 
events will also be analyzed in this time frame. After 30-day post-discontinuation follow-up, 
only those SAEs that are thought to be related to study treatment or protocol procedure should be 
reported immediately to AROG or its designee. For these events, the patient must be followed 
until the event has resolved or stabilized. 
 
10.3.10 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 postlock data will eventually be combined with the locked database 
and stored in a data library separate from the locked database. 
 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
11. Safety Evaluations and Appropriateness of Measurements 
11.1 Safety Evaluations 
 
11.1.1 Adverse Event Definition 
An adverse event is defined as any condition which appears or worsens after participation in the 
study.  All adverse events will be captured on the Adverse Event Case Report Form, whether or 
not it is felt to be related to the trial activities. 
 
11.1.2 Serious Adverse Event Definition 
ICH Guideline E6 defines serious adverse events as those events which meets any of the 
following criteria (Appendix VII): 
 Fatal 
 Immediately life-threatening 
 Results in inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Results in a congenital anomaly/birth defect 
 
Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations; for example, important medical events may not be 
immediately life-threatening or result in death or hospitalization, but may jeopardize the patient 
or may require intervention to prevent one of the outcomes listed in the definition above. Any 
adverse event is considered a serious adverse event if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. 
 
Hospitalizations that do not meet these criteria are: 
 surgery or procedure planned prior to entry into the trial  
 social reason in the absence of an adverse event  
 
Study-specific clinical outcomes of death from PD should be reported as an SAE only if the 
investigator deems them related to use of the study drug. 
 
11.1.3 Unexpected Adverse Events Definition 
Any event occurring in one or more subjects participating in this research protocol in which the 
nature, severity, or frequency is not consistent with either: 
 
 The known or foreseeable risk of adverse events associated with the procedures involved in 
the research that are described (a) in the protocol-related documents, such as this protocol 
and the informed consent document, and (b) other relevant sources of information, such as 
product labeling and package inserts; or 


 
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 The expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for 
the adverse event. 
11.1.4 Attribution 
For reporting purposes, attribution is the assessment of the likelihood that an adverse event is 
caused by the research agent or protocol intervention. The attribution is assigned by the principal 
investigator after considering the clinical information, the medical history of the subject, and past 
experience with the research agent/intervention. This is recorded using one of the following three 
categories:  
 Likely Related 
 Possibly Related 
 Not Related 
 
Likely related means that the adverse event was most certainly caused by the procedures 
involved in the research. 
 
Possibly related means that there is reasonable possibility that the adverse events may have been 
caused by the procedures involved in the research. 
 
Not related means that the adverse event was due to an underlying disease, disorder, or condition 
of the subject, or may have been caused by other circumstances unrelated to either the research 
or any underlying disease, disorder, or condition of the subject. 
 
11.1.5 Adverse Event Reporting 
AROG has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent.  Lack of drug effect is not an AE in clinical 
trials, because the purpose of the clinical trial is to establish drug effect. 
 
Cases of pregnancy that occur during maternal or paternal exposures to study drug or drug 
delivery system should be reported.  Data on fetal outcome and breast-feeding are collected for 
regulatory reporting and drug safety evaluation. 
 
Study site personnel will record the occurrence and nature of each patient’s pre-existing 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.  During the study, site personnel will record any change in the condition(s) and the 
occurrence and nature of any adverse events. 
After the Informed Consent Document (ICD) is signed, site personnel will record any change in 
the condition(s) and the occurrence and nature of any AEs. All AEs related to protocol 
procedures are reported to AROG or designee. 
 
All AEs occurring after the patient receives the first dose of study drug must be reported to 
AROG or its designee via CRF.  Investigators will be instructed to report to AROG or its 
designee their assessment of the potential relatedness of each AE to protocol procedure, studied 
disease state, study drug, and/or drug delivery system via CRF. 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 
Study site personnel will record any daily dosage that exceeds the maximum dosage in the 
protocol or in the relevant reference safety document (for example, clinical dosage section for 
humans in the Investigator Brochure), whichever is greater, via CRF. 
 
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to AROG or its designee via CRF the circumstances and data 
leading to any such dosage reduction or discontinuation of treatment. 
 
Events leading to the clinical outcome of death due to disease progression will be included as 
part of the safety and efficacy analyses for this study and will not be reported to AROG or its 
designee as AEs via CRF, unless the investigator believes the event may have been caused by the 
study drug.  In this case the death should be reported to the sponsor as a Serious Adverse Event 
and appropriate guidelines followed for SAE reporting. 
 
Any clinically significant findings from labs, vital sign measurements, other procedures, etc. that 
result in a diagnosis should be reported to AROG or its designee. 
 
11.1.6 Serious Adverse Event Reporting 
Table 11.1 outlines adverse event and serious adverse event (SAE) assessment and follow–up 
guidelines. 
 
Table 11.1. Adverse Events/Serious Adverse Events Assessment Guide 
Time 
After 
ICD/Before 
Drug 
During Therapy
30-day Post-
discontinuation 
follow-up 
period 
Long-term 
follow-up 
period 
Events to collect AE/SAEs 
New/ongoing AE/SAEs 
New/ongoing 
SAEs 
Related to 
procedures 
Regardless of relatedness to study 
treatment or procedures 
Related to study 
treatment or 
procedures 
 
Serious adverse event collection begins after the patient has signed informed consent and has 
received a tablet or more of study drug.  If a patient experiences an SAE after signing informed 
consent, but prior to receiving study drug, the event will NOT be collected unless the 
investigator feels the event may have been caused by a protocol procedure. 
 
Study site personnel must alert AROG or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  Alerts issued 
via telephone are to be immediately followed with official notification on study-specific SAE 
forms.  All cases are recorded on the CRF and copy of an SAE report is provided to AROG by 
the site. 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events 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. 
 
Study-specific clinical outcomes of death from PD should be reported as an SAE only if the 
investigator deems them related to use of the study drug. 
 
Any event deemed serious within the 30-day post discontinuation follow-up period, regardless of 
relatedness to study drug or protocol procedure, must be reported immediately to AROG or its 
designee. 
 
AROG or its designee will be alerted to SAEs occurring after a patient’s 30-day post 
discontinuation follow-up only if the investigator believes that the event may have been caused 
by the study drug. 
 
SAEs occurring after a patient has taken the last dose of study drug will be collected for 30 days 
after the last dose of study drug, regardless of the investigator’s opinion of causation.  Thereafter, 
serious adverse events are not required to be reported unless the investigator feels the events 
were related to either study drug or a protocol procedure. 
 
All serious adverse events (SAE) will be reported to the study coordinator within 24 hours of the 
investigational staff’s knowledge. This includes any event that occurs during the participation of 
the trial regardless of associated participation, severity or relationship. 
 
11.1.7 Follow-up 
All adverse events will be followed up according to Good Clinical Practice. 
During Treatment:  During study, site personnel will record any change in the condition(s) and 
the occurrence and nature of any AEs.  A CTCAE rating will be assigned before each visit for 
any adverse events experienced during the previous visit period. 
 
30-Day Post-discontinuation Period:  Each patient will have a 30-day post-discontinuation 
follow-up evaluation after 30 days ± 5 days following the discontinuation of study treatment.  
Patients should be closely followed for AEs in order to detect delayed toxicity. A toxicity 
questionnaire will be completed by the patient, the patient’s physician, or the patient’s family 
member at the follow-up evaluation.  
 
Long-Term Follow-Up Period (after the 30-day post-discontinuation period):  Only new and 
ongoing serious adverse events (SAEs) thought to be related to study treatment or protocol 
procedures should be documented on the CRF and immediately reported to AROG or its 
designee via the designated transmission method. If drug-related toxicity is present beyond 
30 days post-discontinuation, patients must be followed every 30 days until the toxicity resolves. 
 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
In cases where the investigator notices an unanticipated benefit to the patient, study site 
personnel should enter “unexpected benefit” with the actual event term (for example, the 
complete actual term would be “unexpected benefit-sleeping longer”) to AROG or its designee 
via CRF.  
 
Serious Adverse Event Follow Up 
Serious adverse event collection begins after the patient has signed informed consent and has 
received study drug.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving study drug, the event will NOT be collected unless the investigator feels the event may 
have been caused by a protocol procedure 
 
Study site personnel must alert AROG or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  Alerts issued 
via telephone are to be immediately followed with official notification on study-specific SAE 
forms.  An SAE is any adverse event from this study that results in one of the following 
outcomes (Appendix VII): 
 Death (see exception noted below) 
 Initial or prolonged inpatient hospitalization 
 A life-threatening experience (that is, immediate risk of dying) 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 Considered significant by the investigator for any other reason. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events 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.  Study-specific 
clinical outcomes of death from PD should be reported as an SAE only if the investigator deems 
them related to use of the study drug. 
 
SAEs occurring after a patient has taken the last dose of study drug will be collected for 30 days 
after the last dose of study drug, regardless of the investigator’s opinion of causation.  Thereafter, 
serious adverse events are not required to be reported unless the investigator feels the events 
were related to either study drug or a protocol procedure. 
 
Any event deemed serious within the 30-day follow-up period, regardless of relatedness to study 
drug or protocol procedure, must be reported immediately to AROG or its designee. 
 
AROG or its designee will be alerted to SAEs occurring after a patient’s 30-day post 
discontinuation follow-up only if the investigator believes that the event may have been caused 
by the study drug. 
 
11.1.8 Other Safety Measures 
The schedule for laboratory testing is noted in Appendix IV, and the required tests are listed in 
Appendix V. While there are a number of blood tests, blood work being done is considered part 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
of routine care for patients undergoing therapy for relapsed AML.  Some blood work may be 
viewed as being done more often than might be required in usual care but this is to ensure equal 
probability of ascertaining side effects in all patients. 
 
11.2 Appropriateness of Measurements 
All efficacy and safety assessments used in this study are appropriate for an oncology study (US 
FDA Guidance, May 2007).  Overall response rate response is an appropriate primary endpoint 
for measuring initial activity of crenolanib in the targeted patient population (Crowley and 
Ankerst, 2006).  Duration of response is an important endpoint to judge the quality of the 
response.  In addition, progression free survival is an accepted endpoint in AML. 
 
The Common Terminology Criteria for Adverse Events (CTCAE, version 4.03; NCI 2010) is an 
acknowledged scale used to evaluate adverse events in oncology trials. 
 
 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
12. Data Quality Assurance 
To ensure accurate, complete, and reliable data, AROG or its representatives will do the 
following: 
 Provide instructional material to the study site, as appropriate. 
 Sponsor a start-up training session to instruct the investigators and study 
coordinators.  This session will give instruction on the protocol, the 
completion of the CRFs, and study procedures. 
 Make periodic visits to the study site. 
 Be available for consultation and stay in contact with the study site 
personnel by mail, telephone, and/or fax. 
 Review and evaluate CRF data and use standard computer edits to detect 
errors in data collection. 
 Conduct a quality review of the database. 
 
In addition, AROG or its representatives may periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by AROG or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs. 
 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable ethical 
review boards (ERBs) with direct access to original source documents. 
 
12.1 Data Capture System 
A paper data capture system will be used in this trial. Case report form (CRF) data will be 
encoded and stored in a clinical trial database. Any data that will serve as the source document 
will be identified and documented in the site’s study file.  Any data for which the CRF, or other 
paper documentation provided by the subject, will serve as the source document will be 
identified and documented in the study file. 
 
 
 


 
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13. Informed Consent, Ethical Review, and Regulatory 
Considerations 
13.1 Informed Consent 
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial. 
 
The informed consent document (ICD) will be used to explain the potential risks and benefits of 
study participation to the patient in simple terms before the patient is entered into the study, and 
to document that the patient is satisfied with his or her understanding of the risks and benefits of 
participating in the study and desires to participate in the study. 
 
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICD 
prior to the performance of any protocol procedures and prior to the administration of study drug. 
 
13.2 Ethical Review 
AROG must agree with all ICDs before they are submitted to the ethical review board (ERB) and 
are used at investigative site(s).  All informed consent documents must be compliant with the 
International Conference on Harmonization (ICH) guideline on good clinical practice (GCP).  
Informed consent obtained under special circumstances may occur only if allowed by local laws 
and regulations and performed in accordance with a written process approved by AROG. 
 
Documentation of ERB approval of the protocol and the ICD must be provided to AROG.  The 
ERB(s) will review the protocol as required. 
 
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol. 
 
As well as required documentation required by the study site’s ERB(s), the following will be 
provided:   
 Current Study Protocol 
 The current Investigator’s Brochure or package labeling and updates during the 
course of the study 
 Informed consent document 
 
13.3 Regulatory Considerations 
 
13.3.1 Investigator Information 
Physicians with a specialty in oncology will participate as investigators in this clinical trial. 


 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 
13.3.2 Protocol Signatures 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to an AROG representative. 
 
13.3.3 Final Report Signature 
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.  
 
The investigator with the most analyzable patients will serve as the clinical study report 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by AROG to serve as the clinical study report coordinating 
investigator. 
 
The sponsor’s responsible medical officer will sign the final clinical study report for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study. 
 
 
 


 
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14. References 
1. 
Mandelli F, Vignetti M, Suciu S, et al. Daunorubicin versus mitoxantrone versus 
idarubicin as induction and consolidation chemotherapy for adults with acute myeloid 
leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol 
2009;27:5397-403. 
2. 
Burnett AK, Milligan D, Goldstone A, et al. The impact of dose escalation and resistance 
modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic 
syndrome: the results of the LRF AML14 trial. Br J Haematol 2009;145:318-32. 
3. 
Small D. FLT3 Mutations: Biology and Treatment. Hematology 2006;2006:178-84. 
4. 
O'Donnell MR, Abboud CN, Altman J, et al. Acute myeloid leukemia. J Natl Compr 
Canc Netw 2011;9:280-317. 
5. 
Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging 
after all these years. Blood 2010;116:5089-102. 
6. 
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. 
7. 
Takahashi S. Downstream molecular pathways of FLT3 in the pathogenesis of acute 
myeloid leukemia: biology and therapeutic implications. J Hematol Oncol 2011;4:13. 
8. 
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. 
9. 
Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in 
cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358:1909-18. 
10. 
Fischer T. Rethinking bioactivity of FLT3 inhibitors. Blood 2011;117:3247-8. 
11. 
Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage 
chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first 
relapse. Blood 2011;117:3294-301. 
12. 
Marcucci G, Haferlach T, Dohner H. Molecular genetics of adult acute myeloid 
leukemia: prognostic and therapeutic implications. J Clin Oncol 2011;29:475-86. 
13. 
Sato T, Yang X, Knapper S, et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in 
vitro and in vivo. Blood 2011;117:3286-93. 
14. 
Zarrinkar PP, Gunawardane RN, Cramer MD, et al. AC220 is a uniquely potent and 
selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 
2009;114:2984-92. 
15. 
Lowenberg B, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older 
patients with acute myeloid leukemia. N Engl J Med 2009;361:1235-48. 
16. 
Whitman SP, Ruppert AS, Radmacher MD, et al. FLT3 D835/I836 mutations are 
associated with poor disease-free survival and a distinct gene-expression signature among 
younger adults with de novo cytogenetically normal acute myeloid leukemia lacking 
FLT3 internal tandem duplications. Blood 2008;111:1552-9. 
17. 
Arog-Pharmaceuticals. http://arogpharma.com/index%205-1.html. wwwarogpharmacom 
2011. 
18. 
CAS.org. http://www.cas.org/expertise/cascontent/registry/regsys/670220-93-6.html. 
CAS Registry Numbers. 
19. 
Davis MI, Hunt JP, Herrgard S, et al. Comprehensive analysis of kinase inhibitor 
selectivity. Nat Biotechnol 2011;29:1046-51. 


 
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20. 
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. 
21. 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. Journal of Clinical Oncology 2003;21:4642-9. 
22. 
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. 
23. 
Galanis A, Rajkhowa T, Muralidhara C., et al. Crenolainb: A next generation FLT3 
inhibitor.  AACR 2012. Abstract #3660. 
 
 
 


 
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Appendix I. Inclusion/Exclusion Criteria Checklist 
All subjects enrolled must meet eligibility criteria based on the inclusion/exclusion criteria 
detailed in the application and approved by the IRB. 
I. Study Information 
Protocol Title: 
A Phase II Study of Crenolanib Besylate in Subjects with 
Relapsed or Refractory Acute Myeloid Leukemia with FLT3-
D835 Activating Mutations 
Protocol Number: 
ARO-004 
 
II. Subject Information 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
 
 
III. Inclusion/Exclusion Criteria 
Inclusion Criteria-all must be YES 
(From IRB approved protocol) 
Yes 
No 
N/A 
Supporting 
Documentation* 
1. Relapsed 
primary 
or 
AML 
secondary 
to 
 
antecedent 
hematological disorder  with an 
expected survival of 3 months or 
greater 
 
 
 
 
2. Presence 
of 
FLT3 
activating 
mutation as tested within 60 days of 
enrollment. 
 
 
 
 
3. Age ≥18 years 
 
 
 
 
4. ECOG Performance Status 0 - 2 
 
 
 
 
5. Liver function: 
Transaminases ≤ 3x ULN  
Bilirubin ≤ 1.5x ULN  
 
 
 
 
6. Renal function: 
Total creatinine ≤ 1.5x ULN 
 
 
 
 
7. Recovery from toxicities of prior 
therapy (including HSCT) to no 
more than grade 1 (except alopecia) 
 
 
 
 


 
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8. In the absence of rapidly progressing 
leukemia, 
subjects 
should 
have 
received no antileukemic therapy 
(except hydroxyurea) for 14 days 
(for classical cytotoxic agents) and 
for five times the half life of FLT3 
inhibitors and antineoplastic agents 
that are neither cytotoxic nor FLT 3 
inhibitors prior to the first dose of 
crenolanib. 
 
 
 
 
9. Negative pregnancy test for women 
of childbearing potential 
 
 
 
 
10. Able and willing to provide written 
informed consent 
 
 
 
 
11. Subjects who received crenolanib 
prior to and are within 30-90 days of 
receipt of a HSCT and have either no 
active GVHD  where therapy has 
been initiated or GVHD where 
therapy has not been escalated 
within 14 days prior to start of study 
drug. 
 
 
 
 
Exclusion Criteria-All must be NO 
(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 
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. Inability to swallow pills.  
 
 
 
 
6. HIV infection or active hepatitis B 
or C  
 
 
 
 


 
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7. Subjects who have had HSCT and 
are within 29 days of an allogeneic 
transplant, and/or have clinically 
significant graft-versus-host disease 
requiring systemic treatment or did 
not take crenolanib prior to HSCT. 
 
 
 
 
8. Unwillingness or inability to comply 
with protocol 
 
 
 
 
9. Major surgical procedure within 14 
days of Cycle 1 of crenolanib 
 
 
 
 
10. Evidence of lack of engraftment if 
post HSCT 
 
 
 
 
 
*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: 
 
 


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


 
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Appendix III. Patient Diaries: Crenolanib 


 
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Appendix IV. Study Schedule 
 
screeni
ng 
Therapy 
End 
of 
Stud
y 
visit 
Follo
w‐up 
visit 
Cycle No.  
 
1 
2 
3 
n 
Duration 
28d 
28d 
28
d 
28
d 
Relative day 
within cycle 
(‐)28 
1 
2 
8 
1
5 
2
2 
1
1
5 
1 
1 
 
 
Baseline 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
  
 
  
  
  
  
  
  
 
  
  
Inclusion/Exclusion 
X 
  
 
  
  
  
  
  
  
 
  
  
Demography, 
Relevant medical 
history, current 
medical conditions 
including AML‐
specific history 
X 
 
 
  
  
  
  
  
  
 
  
  
Evaluation of FLT3‐
D835, FLT3‐ITD, 
and other 
mutational status 
X 
 
 
 
 
 
 
 
 
 
 
 
Routine 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
medications, 
significant non‐
drug therapies 
X 
X 
 
 
 
 
X
 
X 
X 
X 
X 
Physical 
examinationa 
X 
X 
 
 
 
 
X
 
 
X 
X 
X 
EKGb 
X 
X 
 
 
 
 
 
 
 
 
 
 
Vitals, ECOG 
Performance 
Status, Weight 
X 
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 
  
  
 
  
  
  
  
  
  
 
  
  
Hematologyc 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X
 
X 
 
X 
 
X 
X 
X 
Serum 
Chemistriesd 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X
 
X 
 
X 
 
X 
X 
X 
HIV, HepB/C 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine or serum 
Pregnancy test 
X 
 
 
  
  
  
  
  
  
 
X 
  
Peripheral blood 
for PK analysise 
  
X 
X 
  
X 
  
X
  
X  
 
  
  
Peripheral blood 
for correlative 
 
X 
X 
  
X 
  
X
  
X 
 
  
  


 
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analysisf 
Disease 
assessment 
  
  
 
  
  
  
  
  
  
 
  
  
Bone marrow 
aspirations (x2)g 
X 
X 
 
  
  
  
X
  
X 
X 
  
  
 
 
 
a Physical exam can be done within ±4 days of  start of cycle 1 and cycle 2 then every 2 cycles 
b EKG measurements to be obtained at 1 hour (± 30 mins) post first or second dose, in accordance to the visit.  If 
new drugs with known effect on QTc are to be co-administered with crenolanib, EKGs including a baseline prior to 
start of the new agent and 2-3 days after starting patient on combination of drugs is recommended. Weekly EKG x3 
is also recommended for follow up and as needed for assessment based on patient’s clinical condition.  EKG can 
then be resumed per study schedule 
 
c,d CBC includes platelet count, differential (differential may be omitted if WBC is <0.5 x109/L) and  Chemistry 
panel including creatinie, AST, ALT, and total bilirubin to be drawn 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). 
 
Labs obtained with the local physician can be used for monitoring; PI or designee 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. 
 
e,f Peripheral 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, and Day 
1 of Cycle 2 and Cycle 3.  Additional samples may be drawn at the discretion of the investigator.  
g Two bone marrow aspirations will be collected on day 1  (+4 days) of the second cycle, day 1  (±4 days) of the 
third cycle, then every 3 cycles (+/- 1 cycle) for as long as CR is maintained. At loss of CR, bone-marrow biopsy 
will be performed only as clinically indicated to exclude toxicity issues. 
 
 
 
 


 
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Appendix V.  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  
 
Eosinophils  
Alanine aminotransaminase (ALT/SGPT) 
Basophils  
Platelets 
Aspartate aminotransferase (AST/SGOT) 
 
 
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 Can be 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. 
 
 
 


 
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Appendix VI. Common Terminology Criteria for Adverse Events 
(CTCAE); Version 4.03 
 


 
 
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Appendix VII. 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? 
・ De-challenge experience: Did the adverse event resolve or improve on stopping or 
reducing the dose of the suspect drug? 


 
 
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・ 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix VIII-A. ARO-004 C1D1 Pharmacokinetics Data 
Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA:   
Total daily 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) 
 
 
 


 
 
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Appendix VIII-B. ARO-004 C1D1 Plasma Inhibitory Assay Data 
Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA:   
Total daily 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 plasma inhibitory assay 
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) 
 
 
 


 
 
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Appendix VIII-C. ARO-004 C1D1 Whole Blood Phospho-Flow Data 
Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA:   
Total Daily 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. List the scheduled and actual times of the collected 
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 
 
 
 


 
 
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Appendix IX-A. ARO-004 C1D15 Pharmacokinetics Data Collection 
Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA 
Total daily 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 (pre PK 
sample) 
 
 
 
30 (±10) minutes after dose (PK sample) 
 
 
 
4 (± 1) hours after dose (PK sample) 
 
 
 


 
 
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Appendix IX-B. ARO-004 C1D15 Plasma Inhibitory Assay (PIA) 
Data Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA  
Total daily 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 collected 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 (pre PIA 
sample) 
 
 
 
30 (±10) minutes after dose (PIA sample) 
 
 
 
46 (± 1) hours after dose (PIA sample) 
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
 
Appendix IX-C. ARO-004 C1D15 Whole Blood Phospho-Flow Data 
Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA 
Total Daily 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 collected 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  
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix X-A. ARO-004 C_D_ Pharmacokinetics Data Collection 
Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA 
Total daily 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 (pre PK sample) 
 
 
 
4 (± 1) hours after dose (PK sample) 
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix X-B. ARO-004 C_D_ Plasma Inhibitory Assay Data 
Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA 
Total daily 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 collected 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  
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix X-C. ARO-004 C_D_ Whole Blood Phospho-Flow Data 
Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA 
Total Daily 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 collected 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  
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix XI. C_D_ Bone Marrow Aspiration: Data Collection 
Form 
Study Acc #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
BSA:   
Total daily Crenolanib 
Dose(mg):   
Crenolanib Dosage (mg/m2):   
Today’s Date:     
 
 
 
Please fill in crenolanib dose date, time, and tolerance in the spaces below.  List sample volume 
or estimated mass, and note any collection issues in the chart below.  Use an additional sheet if 
necessary.     
Date of Dose: _______________________________________________________________    
Dose Administration Time: _____________________________________________________ 
Describe Dose Tolerance:  ______________________________________________________ 
 
  
 
 
 
 
 
 
Name of person completing form: ____________________________________ 
Phone Number: __________________________________________________ 
Email: _________________________________________________________ 
Date: __________________________________________________________ 
 
 
 
 
Bone Marrow Aspiration 
 
Sample Volume 
or Estimated 
Mass 
Note any  
collection issues 
Sample – 1 
 
 
Sample – 2 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix XII. 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. Whole-blood Phosho-flow Cytometry 
Alexander Perl, MD 
Abramson Cancer Center 
Perelman Center for Advanced Medicine, West Pavilion, 2nd Floor 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
(215) 573-8478   
Alexander.Perl@uphs.upenn.edu 
 
C. 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 
 
D. Bone Marrow Aspirate samples 
ProPath 
1355 River Bend Drive 
Dallas TX 75247 
Attn: Debra Cohen, Cytogenetics and Molecular Laboratory Manager 
214.237.1739 
www.ProPath.com 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix XIII. 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 
 
 
 
 
 
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix XIV. 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 
 
John Huang or Justin Rains 
AROG Pharmaceuticals, LLC 
E: lab@arogpharma.com 
O: +1 214.593.0500  
M: +1 817.849.0175 
F: +1 214.594.0002 
 
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix XV. Dosing Instructions for Relapsed/Refractory 
AML Patients  
 
To be filled out by SITE: 
Study ID:   
ARO-004 
Today’s Date:     
 
Time form faxed from site: 
 
Race:   
 
Sex: 
 
Date of Birth: 
 
Height (cm): 
 
Weight (kg): 
 
 
 
BSA Calculation Method: 
 
BSA:   
 
Date/Time Confirmation received from site: 
 
 
To be filled out by SPONSOR: See protocol section 8 for instructions on dose modification and 
application of appropriate dose levels. 
Starting Dose Crenolanib (CP-868,596) 
Dose level 0 (mg/m2): 200 mg/m2/day 
 
Calculated Crenolanib (CP-868,596) 
Total daily Dosage (mg) and instructions for 
divided dosing 
First dose reduction: 180 mg/m2/day 
 
 
 
 
Second dose reduction: 160 mg/m2/day 
 
 
 
Dose escalation: 220 mg/m2/day 
 
 
 
Time form faxed from Arog: 
 
 
 
 
Confirmation received from site: 
 
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix XVI. Dosing Instructions for Patients post HSCT 
To be filled out by SITE: 
Study ID:   
ARO-004 
Today’s Date:     
 
Time form faxed from site: 
 
Race:   
 
Sex: 
 
Date of Birth: 
 
Height (cm): 
 
Weight (kg): 
 
 
 
BSA Calculation Method: 
 
BSA:   
 
Date/Time Confirmation received from site: 
 
 
To be filled out by SPONSOR: See protocol section 8 for instructions on dose modification and 
application of appropriate dose levels. 
Starting Dose Crenolanib (CP-868,596) 
Dose level 0 (mg/m2):  
 
Calculated Crenolanib (CP-868,596) 
Total daily Dosage (mg) and instructions for 
divided dosing:  
 
 
 
First dose reduction:  
 
 
 
 
 
 
Second dose reduction:  
 
 
 
 
 
Dose escalation:  
 
 
 
 
Time form faxed from Arog: 
 
 
Confirmation received from site: 
 
 
 
 


 
 
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Protocol: ARO-004                       Confidential                  Version – 4.0 (09 SEPTEMBER 2013) 
Appendix XVII. 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 
KW-2449* 
KW-2449 
6.6 hours 
33 hours 
2 
Lestaurtinib 
CEP-701 
9.2 hours 
46 hours 
2 
R406* 
R406 
15 hours 
75 hours 
3 
PLX3397* 
PLX3397 
20 hours 
100 hours 
4 
Dovitinib 
TKI258 
24 hours 
120 hours 
5 
Sorafenib 
BAY-43-9006 
27 hours 
135 hours 
6 
Tandutinib 
MLN518 
33 hours 
165 hours 
7 
Quizartinib 
AC220 
67.2 hours 
336 hours 
14 
Sunitinib 
SU11248 
86 hours 
430 hours 
18 
Midostaurin 
PKC412 
96 hours 
480 hours 
20 
 
*No trade name is currently available