Clinical trial NCT02400255
Conditions: Acute Myeloid Leukemia
Sponsor: Arog Pharmaceuticals, Inc.
Start date: 2015-09-01; Completion date: 2022-05-01
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm, Phase II study of crenolanib as maintenance in AML patients with FLT3 mutations who have achieved complete remission (CR) after allogeneic stem cell transplantation. Oral crenolanib will be administered daily post-transplant for up to two years.

Detailed description:
There are two patient subgroups: 1) those who were in complete remission (CR) at the time of transplant, and 2) those who were not in complete remission (NCR) at the time of transplant. Start of crenolanib therapy at 100 mg TID is intended at the earliest time no sooner than 42 days but no later than 90 days after allogeneic stem cell transplantation. Patients may take crenolanib continuously for up to 728 days or until one of the criteria for study discontinuation is fulfilled.

Arms: arm 1: Cohort A will include patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) while in first or second complete remission with count recovery. Crenolanib besylate maintenance therapy will start at the earliest time no sooner than 42 days but no later than 90 days after allogeneic HSCT. arm 2: Cohort B will include patients who underwent HSCT with incomplete count recovery although they had ≤%10 bone marrow blasts at the time of HSCT. Crenolanib besylate maintenance therapy will start at the earliest time no sooner than 42 days but no later than 90 days after allogeneic HSCT.
Interventions: intervention 1: Crenolanib besylate
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol ARO-009 version 3.0 
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Arog Pharmaceuticals, Inc.                 Confidential                    
 
 
 
 
Protocol ARO-009 
 
 Phase II Study of Crenolanib Besylate Maintenance following Allogeneic Stem Cell 
Transplantation in Patients with FLT3-positive Acute Myelogenous Leukemia  
 
 
 
 
IND Number: 118143 
 
 
 
 
 
 
Version Number: 3.0 
Version Date: November 6, 2018 
 
 
 
 
 
 
 
 
 
AROG Pharmaceuticals, Inc. 
5420 LBJ Freeway, Suite 410 
Dallas, TX 75240 
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of AROG Pharmaceuticals, Inc., or its subsidiaries 
and should not be copied by or distributed to persons not involved in the clinical 
investigation of crenolanib (CP-868,596), unless such persons are bound by a 
confidentiality agreement with AROG Pharmaceuticals, Inc., or its subsidiaries. 


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TITLE:   
Phase II Study of Crenolanib Besylate Maintenance following Allogeneic Stem Cell 
Transplantation in Patients with FLT3-positive Acute Myelogenous Leukemia   
 
Sponsor:   
Arog Pharmaceuticals, Inc. 
5420 LBJ Freeway, Suite 410 
Dallas, TX 75240 
Phone: (214) 593-0500 
Fax: (214) 594-0002 
Email: info@arogpharma.com 
 
Principal Investigators:  
Richard Champlin, M.D. 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd,  
Houston, TX 77030 
Phone: 713-792-3618 
E-mail: rchampli@mdanderson.org  
 
Betul Oran, M.D., M.S. 
The University of Texas M. D. Anderson Cancer Center 
1515 Holcombe Blvd,  
Houston, TX 77030 
Phone: 713-745-2820 
E-mail: boran@mdanderson.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1.  SYNOPSIS ................................................................................................................................. 1 
2.  BACKGROUND AND STUDY RATIONALE ....................................................................... 5 
2.1  Introduction .......................................................................................................................... 5 
2.2  Crenolanib inhibits wild-type FLT3 and constitutively active mutations ........................... 5 
2.3  Clinical Studies of Crenolanib in AML ............................................................................... 7 
2.4  Rationale for Baseline Dose Selection ................................................................................. 9 
3.  STUDY OBJECTIVES ............................................................................................................ 10 
4.  STUDY DESIGN..................................................................................................................... 10 
5.  PATIENT SELECTION .......................................................................................................... 11 
5.1  Inclusion Criteria ............................................................................................................... 11 
5.2  Exclusion Criteria .............................................................................................................. 12 
6.  TREATMENT PLAN .............................................................................................................. 12 
6.1  Evaluation during Treatment ............................................................................................. 13 
6.2  Evaluation during Follow-up ............................................................................................. 14 
6.3  Crenolanib Maintenance Therapy ...................................................................................... 14 
6.4  Duration of Therapy ........................................................................................................... 15 
7.  DOSING AND DOSE MODIFICATIONS OF CRENOLANIB ............................................ 16 
7.1  Dose Reductions of Crenolanib for Non-hematologic Toxicities...................................... 16 
7.2  Dose Reductions of Crenolanib for Hematologic Toxicities ............................................. 16 
7.3  Dose Level Schedule .......................................................................................................... 17 
7.4  Cycle Delays ...................................................................................................................... 17 
7.5  Concomitant Medications .................................................................................................. 18 
8.  AGENT FORMULATION AND PROCUREMENT ............................................................. 18 
9.  CORRELATIVE STUDIES .................................................................................................... 18 
9.1  Pharmacokinetic Assay ...................................................................................................... 18 
9.2  Bone Marrow Samples ....................................................................................................... 19 
9.3  Other tissue samples .......................................................................................................... 19 
10.  CRITERIA FOR RESPONSE MAINTENANCE ................................................................. 20 
11.  ADVERSE EVENT REPORTING........................................................................................ 21 
11.1  Adverse Event .................................................................................................................. 21 
11.2  Serious Adverse Event Reporting .................................................................................... 22 
11.3  Reporting of a Serious Adverse Event to FDA ................................................................ 23 
12.  STATISTICAL CONSIDERATIONS................................................................................... 23 
12.1  Preliminaries .................................................................................................................... 23 
12.2  Futility Monitoring........................................................................................................... 23 
12.3  Secondary outcomes and data analyses ........................................................................... 25 
12.4  Subject Disposition .......................................................................................................... 25 
12.5  Subject Characteristics ..................................................................................................... 25 
12.6  Concomitant Therapy....................................................................................................... 25 
12.7  Response Outcome and Methodology ............................................................................. 25 
12.8  Safety Analyses ................................................................................................................ 26 
12.9  Criteria for End of Study .................................................................................................. 26 
13. DATA QUALITY MANAGEMENT ..................................................................................... 26 
13.1. Data Safety Monitoring Plan ........................................................................................... 26 


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14.  PROTOCOL ADMINISTRATION ....................................................................................... 27 
15.  REFERENCES ...................................................................................................................... 28 
Appendix I. Administrative Procedures ........................................................................................ 29 
Appendix II. Inclusion/Exclusion Criteria Checklist .................................................................... 32 
Appendix III. Patient Diaries: Crenolanib .................................................................................... 36 
Appendix IV. Study Calendar ....................................................................................................... 40 
Appendix V. Definition of a Serious Adverse Event (SAE) ........................................................ 41 
Appendix VI. Laboratory manual ................................................................................................. 43 
FORM 1 ARO-009 C1D1Pharmacokinetics Data Collection Form......................................... 46 
FORM 2 ARO-009 C_D_  Pharmacokinetics Data Collection Form....................................... 46 
FORM 3 ARO-009 Whole Blood Collection Form .................................................................. 50 
FORM 4  ARO-009 Bone Marrow Aspiration C_ D_  Data Collection Form ......................... 51 
Appendix VII. Contact Information AROG Pharmaceuticals ...................................................... 52 
Appendix VIII. Shipping Addresses for Serum and Tissue Samples ........................................... 53 
Appendix IX. CYP3A4 drugs potentially affecting crenolanib pharmacokinetics ....................... 54 
 
 
 


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1.  SYNOPSIS 
Name of Investigational Product 
Crenolanib besylate (AR-868,596-26) 
Title of Study 
Phase II Study of Crenolanib Besylate Maintenance following Allogeneic Stem Cell 
Transplantation in Patients with FLT3-positive Acute Myelogenous Leukemia 
Number of Planned Patients   
48 patients 
Length of Study  
 2 years 
Primary Objective 
• To assess progression-free survival (PFS) time, defined as the time to disease 
progression or death, whichever occurs first, starting when crenolanib administration is 
begun. 
 
Secondary Objectives 
• To assess disease-free survival (DFS) time, overall survival (OS) time, graft-versus-host 
disease, and 100-day transplant-related mortality. 
Study Rationale 
 
The treatment of FLT3-mutant AML is complicated by the poor outcome with standard 
induction and consolidation therapy.  To date the use of allogeneic transplant in first 
remission is of limited effectiveness to improving outcomes due to persistent relapse risks.  
Crenolanib is a FLT3 targeted TKI that has preliminary clinical activity as a salvage therapy 
in a heavily pretreated AML population with FLT3 ITD, FLT3 D835, and compound FLT3 
ITD/D835 mutations including those with resistance after prior TKI therapy.  Given the 
favorable safety profile of crenolanib and promising clinical benefit in AML patients, a trial 
examining the role of crenolanib as maintenance in the post-transplant setting is warranted.  
 
Crenolanib besylate is an orally bioavailable benzimidazole that was designed to be a 
selective and potent inhibitor of the class III receptor kinase FLT3. Molecular binding data 
support that crenolanib is a type I kinase inhibitor that binds preferentially to the active 
kinase conformation of FLT3. As a result of this property, crenolanib potently inhibits both 
wild type and constitutively active mutant FLT3 kinase. Specifically, in 51 patients with 
relapsed/refractory FLT3 ITD and/or TKD mutant AML including relapse following 
multiple lines of therapy including prior TKIs, crenolanib was well tolerated and 
demonstrated an overall clinical benefit of 55% including complete remission (CR), 
incomplete hematological recovery (CRi), and partial remission (PR).  Six of 51 patients of 
this heavily pretreated group were bridged to transplant.   
 
Study Design   
This is a study of crenolanib as maintenance in the post-HSCT setting in AML patients with 
FLT3 mutations.  
 


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Forty-eight patients who have undergone first allogeneic transplant eligible to receive oral 
crenolanib besylate will be enrolled.  There will be two cohorts in the study. Cohort A will 
include patients who underwent allogeneic SCT while in first or second complete 
remission with count recovery. Cohort B will include patients who underwent HSCT with 
incomplete count recovery although they had ≤%10 bone marrow blasts at the time of 
HSCT. 
 
Start of maintenance crenolanib therapy is intended at the earliest time no sooner than 42 
days but no later than 90 days after allogeneic HSCT.  
 
Maintenance therapy with crenolanib will be given at a dose of 100 mg BID. Patients 
considered at high risk of relapse, i.e. patients in second remission after prior relapsed or 
refractory disease, patients with measurable residual disease, or patients who received a 
haploidentical HSCT may receive 100 mg TID.    
 
Crenolanib should be taken at least 30 minutes prior to or following a meal. Patients will 
complete a daily diary for 728 days to record the date, time, and amount (number of tablets) 
of crenolanib taken and relation to eating schedule (Appendix III). 
 
Patients may take crenolanib continuously for up to 728 days or until one of the criteria for 
study discontinuation is fulfilled. Cycles of therapy will be repeated every 28 days, and 
therapy will be continued until clinically significant disease progression or documentation 
of unacceptable toxicity as determined by the investigator or 728 days of therapy are 
reached.  If the drug is discontinued for toxicity, patient should be reassessed until toxicity 
has resolved.   
 
Patients who have discontinued study drug for reasons other than toxicity will be followed 
for 30 days post last dose or until the commencement of new therapy, whichever occurs 
earlier. 
Inclusion Criteria 
1. History of AML according to WHO classification  
2. First allogeneic HSCT using MAC, NMA or RIC preparative regimens. 
3. FLT3-ITD or FLT3-D835 positive disease at any time during disease course. 
4. Hematopoietic stem cell source is either with peripheral blood, bone marrow or 
cord blood. 
5. Donor source is matched related, unrelated, haploidentical donor or cord blood.  
6. At the time of allogeneic HSCT: 
a. 
No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus 
for unrelated donor with peripheral blood and bone marrow as the 
hematopoietic stem cell source; and 
b. 
Bone marrow blast ≤ 10%  
7. No sooner than 42 days but no later than 90 days after allogeneic HSCT. 
8. Post-transplant bone marrow blast count ≤ 5% confirmed within 21 days (+4 days)  
prior to starting study therapy 
9. Evidence of donor engraftment as defined by institutional standard T cell 
chimerism> 50%. 


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10. Adequate engraftment within 7 days prior to starting study therapy: ANC ≥ 1.0 x 
109/L without daily use of myeloid growth factor; and platelet ≥ 25 x 109/L without 
platelet transfusion within 1 week 
11. Non-hematological toxicities ≤  Grade 2  
12. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50mL/min/1.73 m2 for 
subjects with creatinine levels above institutional normal 
13. Adequate liver function within 24 hours of start of crenolanib administration: 
o with serum AST ≤ 2 x ULN and ALT ≤ 2 x ULN  
o and bilirubin within the normal range  
14. Acute GVHD ≤ Grade 1, either no signs of chronic GVHD or mild chronic GVHD 
graded as limited disease  
15. ECOG performance status of  0-2 
16. Age ≥ 18 years with the capacity to give written informed consent  
17. Non-pregnant and non-nursing women of childbearing potential must have a 
negative serum or urine pregnancy test (“Women of childbearing potential” is 
defined as a sexually active mature woman who has not undergone a hysterectomy 
or who has had menses at any time in the preceding 24 consecutive months) 
18. Women of childbearing potential and men must agree to use adequate contraception 
prior to study entry, for the duration of study participation and for 90 days following 
completion of therapy   
 
Exclusion Criteria 
 
1. Bone marrow blast >5% within 21 days (+ 4 days) of start of study drug 
2. Active GVHD grade ≥2   
3. Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg 
4. Active and/or untreated central nervous system (CNS) leukemia  
5. Concomitant therapies for treatment or control of leukemia  
6. Use of any of the following after transplantation and prior to starting study 
therapy: 
a. 
Chemotherapeutic agents for therapy of AML (note that prophylactic use of 
these agents is allowed in this study, e.g., methotrexate for GVHD) 
b. 
Investigational agents/therapies 
c. 
Azacitidine, decitabine or other demethylating agents 
d. 
Lenalidomide, thalidomide and pomalidomide 
7. Uncontrolled infection 
8. Known positive for HIV; active HBV or HCV infection 
9. Significant cardiac disease (New York Heart Association classes III or IV) or 
unstable angina despite medication 
10. Pregnant or breast-feeding 
11. Major surgery within 4 weeks of starting study drug 
12. Receipt of investigational agents within 5 half-lives of last dose of investigational 
agent 
13. Prior treatment with crenolanib with progression on treatment 
 
Statistical Methods   


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Preliminaries 
This is a single-arm, Phase II study of crenolanib in allogeneic stem cell transplant in 
patients with acute myeloid leukemia (AML) in CR after allogeneic stem cell 
transplantation. Administration of crenolanib is oral, and will be started at some time 
between 42 and 90 days post-transplant, and then given every day for up to two years.  There 
are two patient subgroups: 1) those that were in complete remission (CR) at the time of 
transplant, and 2) those that were not in complete remission (NCR) at the time of transplant.  
The primary outcome is progression-free survival (PFS) time, defined as the time to disease 
progression or death, whichever occurs first, starting when crenolanib administration is 
begun.  A maximum of 24 patients will be enrolled in each subgroup. 
 
Futility Monitoring 
PFS time will be monitored separately within each of the two subgroups, using the Bayesian 
method of Thall et al. [1].  Denote standard therapy by S and the experimental crenolanib 
therapy by E.  Assume that TS = PFS time with S follows an exponential distribution with 
median mS and that TE = PFS time with E in the each subgroup follows an exponential 
distribution with median mE.  Denote the median PFS times for the standard and 
experimental therapies by mS and mE, respectively.  Under a Bayesian model, both mS and 
mE are assumed to follow Inverse Gamma(a, b) priors. 
 
Secondary outcomes and data analyses. 
Secondary outcomes will include disease-free survival (DFS) time, overall survival (OS) 
time, graft-versus-host disease, and 100-day transplant-related mortality.  Within each 
subgroup, CR and no CR, these events will be tabulated and the distributions of DFS and 
OS time estimated using the method of Kaplan and Meier [2]. 
 


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2.  BACKGROUND AND STUDY RATIONALE 
2.1  Introduction 
 
Allogeneic hematopoietic stem cell transplantation (HSCT) is offered to eligible patients with 
suitable donor to increase long term survival in patients with FLT3 positive acute myelogenous 
leukemia (AML). However, disease relapse due to presence of minimal residual disease (MRD) 
remains a key reason of treatment failure in post-transplant patients [1]. Furthermore, a recent 
study showed that the presence of internal tandem duplication of FLT3 gene (FLT3-ITD) 
correlated with a higher risk of relapse and lower leukemia free survival  (LFS) after allogeneic 
HSCT performed in first CR (Figure 1.1).  
 
Figure 2.1 FLT3-ITD – A Negative Prognostic Marker After Allogeneic HSCT in 1st CR [2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Presence and absence of FLT3-ITD is denoted by dashed line and solid line, respectively.  
(A) Estimated probability of 2 years of cumulative incidence of relapse; (B) leukemia-free 
survival after transplantation at 2 years. 
 
The majority of relapses occur within 8 months after transplant [3] and most patients who relapse 
after allogeneic HSCT do not achieve long-term survival with available salvage treatment 
modalities including second HSCT. Prophylactic donor lymphocyte infusion (DLI) has been 
used to prevent relapse of AML in the post-transplant setting; however, it is often associated with 
life-threatening GVHD [4]. Therefore, it is critical to develop a novel agent which can be given 
when minimal MRD is present, is tolerable, has activity against the disease, and can be given 
early after transplant.  
2.2  Crenolanib inhibits wild-type FLT3 and constitutively active mutations 
 
Crenolanib, a FMS like tyrosine kinase inhibitor (TKI), is well tolerated in relapsed/refractory 
FLT3 mutant positive AML patients after allogeneic HSCT and may present a novel pathway to 
prevent relapse.  
 


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Crenolanib besylate (also known as CP-868,596-26) is an orally bioavailable class III RTK 
inhibitor that potently targets FLT3. Crenolanib inhibits wild-type FLT3 and its constitutively 
active mutations at clinically achievable concentrations.[5, 6]  
 
Crenolanib has heightened binding affinity against the FLT3-ITD mutation (the most frequent 
FLT3 aberration in AML) and TKD point mutations FLT3 (D835H), FLT3 (D835Y) and FLT3 
(D835V). Crenolanib binds to FLT3-ITD and FT3-TKD D835H with Kd values of 0.43 and 0.4 
nM, respectively. Similarly, crenolanib also binds to FLT3-TKD D835Y with a Kd of 0.18 nM. A 
saturation mutagenesis screen of FLT3 ITD showed that crenolanib is a “pan-FLT3 inhibitor” that 
has the ability to successfully suppress all resistance-conferring TKD mutants[5]. Crenolanib 
inhibitory activity has been verified in human AML cell lines. [5] 
 
Table 2.1 Dissociation constants of crenolanib with constitutively active FLT3 mutations 
Gene Symbol 
Crenolanib Kd  
(nM) 
FLT3(ITD) 
0.43 
FLT3(D835H) 
0.4 
FLT3(D835Y) 
0.18 
FLT3 (D835V) 
0.048 
 
Crenolanib is a type 1 tyrosine kinase inhibitor that is active against FLT3 regardless of 
conformation status.  
 
Figure 2.2 Schematic of inactive and active FLT3 with most common resistance mutations 
in AML.[7]  
 
Crenolanib has reduced activity against KIT 
Crenolanib has been found to be approximately 100-fold more selective for FLT3 than for KIT 
and is therefore highly selective toward FLT3 relative to KIT [8] and elicits cytotoxicity in FLT3–
mutant AML while largely sparing KIT inhibition (100-fold offset in both viability and 


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biochemical assays) with limited activity against other kinases. As a result, crenolanib may be 
associated with less myelosuppression than the other FLT3 TKIs.   
2.3 Clinical Studies of Crenolanib in AML 
 
2.3.1 Clinical Summary of Crenolanib in Relapsed/Refractory FLT3 mutated AML 
Crenolanib has been studied in relapsed/refractory FLT3 mutant AML (NCT01522469, 
NCT01657682). As of July 30, 2014, a total of 51 AML patients have been treated with single-
agent crenolanib. Patients had received a median number of 3 prior therapies for AML (range 1-
7) including prior transplant and TKI therapy.  
 
Of the 51 AML patients (FLT3 ITD, or FLT3 D835, or FLT3 ITD/D835) treated with crenolanib, 
49 patients were eligible for efficacy evaluation. Crenolanib has demonstrated clinical activity in 
this heavily treated population. Several patients showed peripheral blast clearance after crenolanib 
therapy (Figure 5.5). Twenty-seven (27) patients have demonstrated response, including 1 
complete remission (CR) with full count recovery, 8 CR with incomplete hematological recovery 
(CRi), 7 partial remissions (PR) and 11 blast responses. Clinical benefit rate was 55 %. Five (11 
%) of these heavily pre-treated patients were bridged to transplant. Of the 25 patients with FLT3-
D835 AMl, 14 patients have gained clinical benefit (56 %): 6 CR/CRi (24%), 4 PR (16 %), and 4 
blast response (16 %) [9, 10].  
 
Figure 2.3 Peripheral blast clearance in FLT3 mutant AML patients treated with crenolanib. 
  
 
Toxicity data from 38 patients is available. Overall, crenolanib was well-tolerated. Commonly 
observed side effects included nausea (76 %), vomiting (52 %), diarrhea (47%), and transaminase 
*No peripheral blasts 
at study entry 
 * * *  * * 


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elevations (8-11 %). Two patients went off study due to toxicities, one due to nausea/ vomiting 
and one due to fatigue. Dose reduction occurred in 2 patients, one due to nausea and another due 
to transaminitis, respectively.  
 
As of yet, QT prolongation has not been reported in the 51 patients with AML treated with 
crenolanib. Most patients had received concomitant medication including antifungal medicine 
throughout crenolanib therapy; nonetheless no QT prolongation has been observed. 
 
In conclusion, crenolanib is a FLT3 TKI that has showing preliminary clinical activity in a heavily 
pretreated AML population with FLT3-ITD, FLT3-D835, and compound FLT3-ITD/D835 mutant 
disease. Importantly, crenolanib is the first agent to demonstrate clinical activity in patients with 
FLT3-D835 activating mutations. 
 
2.3.2 Tolerability of Crenolanib in AML Patients Who Have Undergone Prior Allogeneic 
Bone Marrow Transplant 
 
Within the 51 AML patients treated with single agent crenolanib, a total of thirteen patients (6M, 
7F) had undergone prior allogeneic stem cell transplants.   Seven patients received crenolanib at 
a dose of 100 mg TID (total daily dose of 300 mg). Six patients received a higher total daily dose 
of 200mg/m2/day given in three divided doses. 
 
The median age of these patients was of 55 years (37-76). The median duration between 
allogeneic HSCT and initiation of crenolanib therapy was 249 days (34-1313).  Nine patients had 
progressed after prior FLT3 TKI exposure (7 patients had had prior treatment with sorafenib, 4 
with midostaurin, 3 with quizartinib, and one with PLX3397).   
 
Overall, a similar rate and spectrum of toxicities were observed when crenolanib was 
administered at either dose level to these 13 previously transplanted patients as compared to the 
non-transplanted patients with relapsed AML. The most common adverse events were 
gastrointestinal (nausea (31%), vomiting (31%), diarrhea (23%), and constipation (23%)), and 
infections (pneumonia (23%), mucositis oral (21%), and fever (15%)). 
 
Three of the six patients who received the higher total dose of 200mg/m2/day of crenolanib 
required dose reduction due to toxicities:  one patient for periorbital edema, one patient for 
neutropenia, and another patient for elevated bilirubin. This latter patient was found to have 
reactivation of GVHD on liver biopsy as major causative factor causing elevated bilirubin. The 
patient with neutropenia recovered his neutrophil counts after stopping valganciclovir. The 
patient with periorbital edema was able to resume crenolanib without recurrence of the edema. 
All seven patients treated with the 100 mg TID dose of crenolanib tolerated drug well without 
needing a dose reduction. None of these 7 patients was discontinued for toxicities.  Therefore, it 
appears crenolanib at 100 mg TID should be reasonably tolerated in this patient population.  
 
 
 
2.3.3 Long-term Safety Data of Crenolanib  


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Crenolanib has been given to patients with relapsed FLT3(+) AML for up to five months without 
any cumulative toxicities.   In a Phase I pediatric glioma study conducted at the St. Jude 
Children's Research Hospital, 6 children received crenolanib for at least 12 months and two 
children stayed on study drug for 24 months.  Long-term exposure to crenolanib seems to be 
tolerable and safe.     
2.4  Rationale for Baseline Dose Selection  
 
Day 1 pharmacokinetics data is shown in Figure 5.7 for 7 post-HSCT patients receiving a 100 
mg TID dose of crenolanib.  The crenolanib pharmacokinetics did not appear to be altered in 
patients who had had prior HSCT (as compared to the other AML patients). However, due to the 
vulnerability of this patient population, out of abundant caution, crenolanib will be administered 
at a dose of 100 mg BID. Patients considered at high risk of relapse, i.e. patients in second 
remission after prior relapsed or refractory disease, patients with measurable residual disease, or 
patients who received a haploidentical HSCT may receive 100 mg TID.   
 
Figure 2.4  Crenolanib pharmacokinetics in AML patients with a prior history of HSCT 
(dose 100mg TID)  
 
 
 
 
Patients with post-allo BMT receive immunosuppressive agents including tacrolimus. These 
agents are typically tapered off by Day 100 post-transplant. A number of other anti-microbial 
agents are also gradually tapered off post 100 days of allogeneic transplant. As this protocol 
allows patients to start as early as Day 42, patients earlier in the transplant course will be started 
at 60mg BID. Dose will be escalated no sooner than at 1 month intervals to 80 mg BID, then to 
80 mg TID. That dose will then be maintained for a maximum of 2 years maintenance.  
 
Rationale for this trial 
The treatment of FLT3-mutant AML is complicated by the poor outcomes with standard induction 
and consolidation therapy.  To date the use of allogeneic stem cell transplantation in first remission 
is of limited effectiveness to improving outcomes due to persistent relapse risks.  Crenolanib is a 
FLT3 targeted TKI that has  preliminary clinical activity as a salvage therapy in a heavily 
1
10
100
1000
10000
0.00
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10.00
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pretreated AML population with FLT3 ITD, FLT3 D835, and compound FLT3 ITD/D835 
mutations including those with resistance after prior TKI therapy.  Given the favorable safety 
profile of crenolanib and promising clinical benefit in AML patients, a trial examining the role of 
crenolanib as maintenance in the post-transplant setting is warranted.  
 
 
3.  STUDY OBJECTIVES 
Primary Objective 
• To assess progression-free survival (PFS) time, defined as the time to disease progression or 
death, whichever occurs first, starting when crenolanib administration is begun. 
 
Secondary Objectives 
• To assess disease-free survival (DFS) time, overall survival (OS) time, graft-versus-host 
disease, and 100-day transplant-related mortality. 
 
4.  STUDY DESIGN 
This is a phase II study of crenolanib as maintenance in the post-HSCT setting in AML patients 
with FLT3 mutations.  
 
Forty-eight patients who have undergone first allogeneic transplant eligible to receive oral 
crenolanib besylate will be enrolled.  There will be two cohorts in the study. Cohort A will include 
patients who underwent allogeneic SCT while in first or second complete remission with count 
recovery. Cohort B will include patients who underwent HSCT with incomplete count recovery 
although they had ≤%10 bone marrow blasts at the time of HSCT. 
Start of maintenance crenolanib therapy is intended at the earliest time no sooner than 42 days but 
no later than 90 days after allogeneic HSCT.  
 
Maintenance therapy with crenolanib will be given at a dose of 100 mg BID. Patients considered 
at high risk of relapse, i.e. patients in second remission after prior relapsed or refractory disease, 
patients with measurable residual disease, or patients who received a haploidentical HSCT may 
receive 100 mg TID.   
 
Crenolanib should be taken at least 30 minutes prior to or following a meal. Patients will complete 
a daily diary to record the date, time, and amount (number of tablets) of crenolanib taken and 
relation to eating schedule (Appendix III). 
 
Patients may take crenolanib continuously for up to 728 days or until one of the criteria for study 
discontinuation is fulfilled. Cycles of therapy will be repeated every 28 days, and therapy will be 
continued until clinically significant disease progression or documentation of unacceptable 
toxicity as determined by the investigator or 728 days of therapy is reached.  If the drug is 
discontinued for toxicity, patient should be reassessed until toxicity has resolved.   
 
Patients who have discontinued study drug for reasons other than toxicity will be followed for 30 
days post last dose or until the commencement of new therapy, whichever occurs earlier.   


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5.  PATIENT SELECTION 
Patients must have baseline evaluations performed within 7 days (except otherwise specified) prior 
to the first dose of study drug and must meet all inclusion and exclusion criteria. Results of all 
baseline evaluations must be reviewed by the Principal Investigator or his/her designee prior to 
enrollment of that patient. In addition, the patient must be thoroughly informed about all aspects 
of the study, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The written informed consent must be obtained from the 
patient prior to initiating treatment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
5.1 Inclusion Criteria 
 
1. History of AML according to World Health Organization (WHO) classification  
2. First allogeneic hematopoietic stem cell transplantation (HSCT) using myeloablative 
conditioning (MAC), non-myeloablative (NMA), or reduced-intensity conditioning (RIC) 
preparative regimens. 
3. FLT3-ITD or FLT3-D835 positive disease at any time during disease course. 
4. Hematopoietic stem cell source is either with peripheral blood, bone marrow or cord 
blood. 
5. Donor source is matched related, unrelated, haploidentical donor or cord blood.  
6. At the time of allogeneic HSCT: 
a. No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for 
unrelated donor with peripheral blood and bone marrow as the hematopoietic stem 
cell source; and 
b. Bone marrow blast ≤ 10%  
7. No sooner than 42 days but no later than 90 days after allogeneic HSCT. 
8. Post-transplant bone marrow blast count ≤ 5% confirmed within 21 days (+4 days) prior to 
starting study therapy 
9. Evidence of donor engraftment as defined by institutional standard T cell chimerism > 
50%. 
10. Adequate engraftment within 7 days prior to starting study therapy: ANC ≥ 1.0 x 109/L 
without daily use of myeloid growth factor; and platelet ≥ 25 x 109/L without platelet 
transfusion within 1 week 
11. Non-hematological toxicities ≤  Grade 2  
12. Serum creatinine ≤ 1.5 × ULN OR creatinine clearance ≥ 50mL/min/1.73 m2 for subjects 
with creatinine levels above institutional normal 
13. Adequate liver function within 24 hours of start of crenolanib administration: 
a. with serum AST ≤ 2 x ULN and ALT ≤ 2 x ULN 
b. and bilirubin within the normal range  
14. Acute graft-versus-host disease (GVHD) ≤ Grade 1, either no signs of chronic GVHD or 
mild chronic GVHD graded as limited disease  
15. Eastern Cooperative Oncology Group (ECOG) performance status of  0-2 
16. Age ≥ 18 years with the capacity to give written informed consent  
17. Non-pregnant and non-nursing women of childbearing potential must have a negative 
serum or urine pregnancy test (“Women of childbearing potential” is defined as a 


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sexually active mature woman who has not undergone a hysterectomy or who has had 
menses at any time in the preceding 24 consecutive months) 
18. Women of childbearing potential and men must agree to use adequate contraception prior 
to study entry, for the duration of study participation and for 90 days following completion 
of therapy   
 
5.2 Exclusion Criteria 
 
1. Bone marrow blast > 5% within 21 days (+4 days) of start of study drug 
2. Active GVHD grade ≥ 2   
3. Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg 
4. Active and/or untreated central nervous system (CNS) leukemia  
5. Concomitant therapies for treatment or control of leukemia.  
6. Use of any of the following after transplantation and prior to starting study therapy: 
a. Chemotherapeutic agents for therapy of AML (note that prophylactic use of these 
agents is allowed in this study, e.g., methotrexate for GVHD) 
b. Investigational agents/therapies 
c. Azacitidine, decitabine or other demethylating agents 
d. Lenalidomide, thalidomide and pomalidomide 
7. Uncontrolled infection 
8. Known positive for human immunodeficiency virus (HIV); active hepatitis B (HBV) or 
hepatitis C (HCV) infection 
9. Significant cardiac disease (New York Heart Association classes III or IV) or unstable 
angina despite medication 
10. Pregnant or breast-feeding 
11. Major surgery within 4 weeks of starting drug 
12. Receipt of investigational agents within 5 half-lives of last dose of investigational agent 
13. Prior treatment with crenolanib with progression on treatment 
 
6.  TREATMENT PLAN 
After providing informed consent, subjects fulfilling the eligibility criteria will be enrolled in the 
study. The Sponsor should be provided the complete “Enrollment Checklist” indicating the request 
to enroll the patient to the trial.  After review, the Sponsor will provide the site a “Confirmation of 
Enrollment” signifying enrollment of the patient to the trial and formal verification of the study 
unique patient identifier number (UPIN).  
 
Baseline Screening 
 
The following assessments will be performed after completion of the informed consent and within 
7 days of start of study drug except as otherwise specified (Appendix IV): 
1. Medical history, Demographics and physical exam  
2. Height, weight, and vital signs 
3. ECOG Performance Status  
4. Serum or urine pregnancy test for women of child bearing capacity 


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5. CBC, platelet count, and differential  
6. Chemistry panel* including creatinine, total bilirubin, ALT, and AST  
7. HIV, hepatitis B, and hepatitis C screening (unless previously tested for prior to HSCT) 
8. Concomitant medications review 
9. Evaluation of baseline adverse events 
* Liver function tests including ALT, AST, and bilirubin need to be re-checked within 24 hours at 
the commencement of crenolanib. ALT and AST must be ≤ 2 x ULN and bilirubin must be normal.  
 
The following assessments will be performed within 21 days (+4 days) of start of study drug except 
as otherwise specified: 
1. Bone marrow aspirate (BMA) to assess remission status, FLT3 testing and a portion for 
correlative testing (see Section 9.0).  
2. Evaluation of FLT3-D835, FLT3-ITD and other mutational status at the time of HSCT.  
 
6.1 Evaluation during Treatment  
 
During crenolanib maintenance, the following will be evaluated (Appendix IV): 
(“Cycle” will be defined as 28 consecutive days regardless of whether crenolanib is ingested or 
not.  Assessments should be done approximately 28 days apart).   
 
Protocol assessments start as of Day 1 (D1) of cycle 1.  D1 correlates with start of study drug. 
As specified, on-therapy laboratory assessments may be done with a local non-1572 MD with 
results available for PI but patient must be evaluated at the study center at least once weekly until 
three months following transplant, and once per return visit to the study site/institution following 
this. Return visits to the study site/institution will be at least once a month for the first 6 months 
and then every 3 months for the rest of the maintenance therapy.   
 
The investigator is responsible for ensuring that all information required per protocol has been 
obtained, reviewed, and recorded on CRFs per study protocol. 
 
1. ECOG, vital signs, and weight q28days (± 7 days).  ECOG assessment by phone interview 
is allowable after the first six cycles; during the last 18 cycles, VS and weight may be taken 
by local non-1572 physician and data provided to study center for investigator review per 
protocol stipulated timeframes. 
2. CBC with platelet count and differential must be obtained  D1 (+ 2 days) and D14 (±7 
days) during the first 14 days of maintenance then q28days (± 7 days).  CBC per local non-
1572 physician is allowed to be used for this assessment but must be reviewed by the study 
investigator within the protocol specified timeframe.  Results are to be recorded in the CRF.  
CBC at the study site to be done no less than every 3 cycles. 
3. Chemistry panel including creatinine, total bilirubin, ALT, AST must be obtained  D1 (+ 2 
days) and D14 (±7 days) then q28days (± 7 days).  Labs per local non 1572 physician are 
allowed to be used for this assessment but must be reviewed by the study investigator 
within the protocol specified timeframe.  Results are to be recorded in the CRF.  Chemistry 
panel at the study site to be done no less than every 3 cycles.   


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4. Bone marrow at loss of CR or if at any time during therapy a bone-marrow sample is 
obtained for clinical purposes, a portion of the sample is requested to also be sent to Propath 
(Appendix XI).  
5. Serum or urine pregnancy test for women of child bearing capacity should be done every 
3 cycles while on study.  
6. Peripheral blood for correlative studies as per Study Calendar (Appendix IV) *  
7. Concomitant medications are to be reviewed at each study visit during the first two cycles 
and thereafter per cycle ± 7 days.  An interview by telephone is allowed to obtain this 
information.  Data are to be recorded in study CRFs 
8. Adverse event evaluation weekly during first 14 days then q28days ±7 days.  Telephone 
interview assessment to obtain information is allowed but must be done within protocol 
specified timeframe. Data is to be recorded in study CRFs.   Patient should be assessed at 
the study site for adverse events considered of significance or possibly study drug related.   
9. Patient will have contact information of their treating physician and PIs of the study to 
reach them anytime while they are treated by their local non-1572 MD.  
*Every effort will be made to collect correlative studies at defined time points for all patients; 
however, missing collection in one or more of these time points in occasional patients will not be 
considered a protocol deviation/violation. 
6.2 Evaluation during Follow-up  
All patients who do not discontinue study drug for toxicity will need to be followed for 30 days 
post-discontinuation to address any late developing toxicities which may occur.  This follow up 
will cease when patients start a new therapy if prior to the 30-day follow up interval. 
  
To assess secondary end points of PFS and overall survival, all patients will need to be followed 
till relapse, progression and death.   
 
STUDY THERAPY 
6.3 Crenolanib Maintenance Therapy 
  
Generally, patients will be treated according to the following:  
• Maintenance therapy with crenolanib is intended in all patients in CR/CRi after allogeneic 
HSCT. 
• Start of maintenance crenolanib therapy is intended at the earliest time no sooner than 42 days 
but no later than 90 days after allogeneic HSCT.  
• Prerequisites for start of maintenance are hematological recovery with  neutrophils >1.0 x 
109/L, all non-hematological toxicities have to be below CTCAE grade 2, GVHD ≤ Grade 1, 
either no signs of chronic GVHD or mild chronic GVHD graded as limited disease.  
• Maintenance therapy will be given for up to 728 days. (up to 26 cycles where 1 cycle of therapy 
is defined as 28 consecutive days regardless of whether study drug is taken or not) after 
recovery from allogeneic HSCT as long as the patient does not develop disease progression 
while on crenolanib therapy. 
• Patients should take their doses at approximately the same time each day, and approximately 
8 hours should elapse between doses. Each dose should be given at least 30 minutes prior to 


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or 30 minutes after food with a glass of water (no juice) (~240 ml).  Patients should be 
instructed to swallow the tablets whole and not to chew them.  
• Maintenance therapy with crenolanib will be given at a dose of 100 mg BID. Patients 
considered at high risk of relapse, i.e. patients in second remission after prior relapsed or 
refractory disease, patients with measurable residual disease, or patients who received a 
haploidentical HSCT may receive 100 mg TID.   
• Dose reduction guidelines for adverse events are listed in Table 7.1 and 7.2 in Section 7.1.  
Dose reductions beyond those mentioned in these tables or different than those specified, 
should be discussed with the Sponsor and documentation of the justification recorded. 
• Antiemetics per ASCO guidelines for moderately emetogenic therapy should be instituted. 
Reduction in antiemetic support can be individualized as appropriate. 
• If a dose is missed or vomited, it should not be taken again.  The next dose should not be 
increased to account for missing a dose.  The patient should note the missed dose in the patient 
diary and take the next regular dose at the regularly scheduled time.  
• Subsequent cycles may be delayed for recovery of toxicity.  Delays in start of subsequent 
cycles greater than 8 weeks will be acceptable only after determination of the principal 
investigator of potential risk/benefit ratio.  
• For patients who discontinue therapy, the reason for treatment discontinuation will be captured.  
6.4 Duration of Therapy 
Treatment may continue for 728 days until one of the following criteria applies: 
 
1. progressive disease defined as: 
1.1 Death due to any cause  
1.2 Start of any non-protocol therapy directed toward AML 
1.3 Relapse defined as detection of leukemia blasts in the peripheral blood OR >5% blasts in 
marrow not attributed to another cause.   
2. Intercurrent illness that in the opinion of the investigator prevents further administration of 
treatment, or 
3. Patient request, or 
4. General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator, or 
5. Unacceptable toxicity that in the opinion of the investigator makes it unsafe to continue 
therapy, or 
 
It is planned that up to a total of 728 days of therapy will be administered for patients deriving 
benefit from this regimen.  
 
A minimum of 1 full course (defined as the administration of crenolanib for 28 days) will be 
required for a patient to be considered as having received an adequate trial to evaluate efficacy. 
Only those patients who failed to complete at least one cycle (28 consecutive days) of crenolanib 
therapy, unless they progressed or dropped out due to toxicity will be replaced. All patients 
receiving at least one dose of study drug will be considered evaluable for toxicity.   
 
 


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7.  DOSING AND DOSE MODIFICATIONS OF CRENOLANIB 
Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 4.03. 
 
7.1 Dose Reductions of Crenolanib for Non-hematologic Toxicities  
Dose reductions for non-hematologic toxicities due to crenolanib, will be done according to the 
schema outlined in Table 7.1 and 7.2.  Dose levels are outlined in Table 7.3. 
 
Table 7.1 Crenolanib dose reduction for all toxicities (except GI (nausea, vomiting and diarrhea)) 
related to study drug 
 
 
Table 7.2 Crenolanib dose reduction GI toxicity related to study drug 
 
7.2 Dose Reductions of Crenolanib for Hematologic Toxicities 
It is expected that some patients who commence maintenance crenolanib will have abnormal 
baseline blood counts.   
 
Patients who develop hematologic toxicities while on maintenance crenolanib should follow the 
dose modifications as outlined below:   
Toxicity  
(NCI Criteria) 
Dose Modification 
Grade 1 or 2 
 
No dose modification 
Clinically significant 
persistent grade 2 
despite optimal therapy 
Hold drug until toxicity resolves to grade 1 or less. Restart drug at 
same dose level (Table 7.3). 
Grade 3 or 4 
Hold drug until toxicity resolves to grade 1 or less. Restart drug at 
next lower dose level (Table 7.3). 
Toxicity  
(NCI Criteria) 
Dose Modification 
Grade 1 or 2 
 
No dose modification 
Clinically significant 
persistent grade 2 or 3 
despite optimal therapy 
Hold drug until toxicity resolves to grade 1 or less. Restart drug at 
same dose level (Table 7.3). 
Grade 4 
Hold drug until toxicity resolves to grade 1 or less. Restart drug at 
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• Patients with counts of neutrophils >1x109/L and platelets >100 x109/L should not have any 
dose modification. 
• 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. 
7.3 Dose Modifications of Crenolanib due to Toxicities   
 
Dose Modifications of Crenolanib due to Toxicities  
One dose reduction to 80 mg BID is allowed in a single subject for toxicity management 
regardless of the attribution. Reductions below 80 mg BID are not planned. Dose reductions 
beyond 80 mg BID or different form the dose specified below should be discussed with and 
approved by the sponsor or its designees. Any dose modification, including dose hold and dose 
delay, must be documented and justified in the eCRF. Dose re-escalation is in general not 
allowed on this study. Any exception must be approved by the sponsor in writing. 
 
Table 7.3 Crenolanib dose reduction schedule  
Dose level  
Crenolanib dosing 
0 
100 mg BID 
-1 
80 mg BID 
 
Patients considered at high risk of relapse, i.e. patients in second remission after prior relapsed or 
refractory disease, patients with measurable residual disease, or patients who received a 
haploidentical HSCT may receive 100 mg TID. 
 
If more than 20% (more than 1 patient of the first 5 patients enrolled; more than 2 patients of the 
first 10 patients enrolled; or more than 3 patients of the first 15 patients enrolled)  of the subjects 
require crenolanib dose reduction during the first 2 cycles of therapy, then the study will be paused 
for protocol re-evaluation. These data will be presented to the Sponsor’s safety monitoring team 
to determine whether the crenolanib dose should be modified for all future patients. 
7.4 Cycle Delays 
• A cycle of therapy may be delayed to allow recovery from toxicities.  
• Delays in start of subsequent cycles greater than 8 weeks will be acceptable only after 
determination of the principal investigator of the potential risk/benefit ratio.  


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7.5 Concomitant Medications 
In general, the use of any concomitant medication/therapies deemed necessary for patient 
supportive care and safety are permitted. Other anticancer agents including systemic 
chemotherapy, radiation therapy, or biologic response modifiers are not permitted during the study.  
 
Antiemetics per ASCO guidelines for moderately emetogenic therapy should be instituted. 
Reduction in antiemetic support can be individualized as appropriate. 
 
No other investigational drugs are allowed during the study without consent of the medical 
monitor.  
 
8.  AGENT FORMULATION AND PROCUREMENT 
Crenolanib is supplied as 20 mg tablets for oral dosing, in 30-count bottles. Crenolanib tablets 
should be refrigerated at a temperature between 2C and 8C (35.6F and 46.4F).  Standard 
household refrigeration is considered adequate for drug storage. Crenolanib should be stored in 
the vials provided by the pharmacy and kept out of the reach of children. 
 
Used bottles and unused tablets and bottles should be returned by the patient to the treating 
physician before starting a new therapeutic cycle to assess treatment compliance. Study drug will 
be supplied by AROG Pharmaceuticals, Inc.  Study drug may be packaged by a third party.  
Clinical trial materials will be labeled according to regulatory and institutional requirements. 
 
9.  CORRELATIVE STUDIES 
9.1 Pharmacokinetic Assay 
Sample Collection 
 
Samples collected during study of crenolanib therapy will be collected into no additives added (red 
top) vacutainers and will be transported to the laboratory. 
 
Sampling Strategy 
 
Peripheral blood for pharmacokinetic studies will be drawn pre- and post-administration of 
crenolanib dose at the following time points:  
Cycle 1 Day 1: 120 (±15) minutes, 4 (±1) hours, 8 (±2) hours after crenolanib administration.  
Cycle 2 Day 1: pre-dose and at 3 (±1) hours after crenolanib administration. 
Cycle 3 Day 1: pre-dose and at 3 (±1) hours after crenolanib administration. 
 
These samples should be labeled with time of sample relative to last dose of drug ingested. 
 
Sampling Processing Instructions  
 


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The date and time of sample collection, crenolanib dose, and date and time of the last crenolanib 
dose should be recorded on the appropriate Pharmacokinetics Data Collection Form (Appendix 
VII-A, VIII-A and IX-A). 
 
Sampling Handling and Shipping Instructions 
 
In preparation of shipping samples, contact AROG Pharmaceuticals (refer to appendix XV) and 
MicroConstants (Appendix XI) to notify of sample shipment and to provide FedEx tracking 
number.  Samples should be shipped within 60 days of the last sample collection. Specimens 
collected should be shipped via FedEx Priority Overnight shipping for delivery Tuesday through 
Thursday. Weekend and holiday deliveries should be avoided.  Ship all pharmacokinetic samples 
on dry ice, along with a completed Pharmacokinetics Data Collection Forms.  
 
9.2 Bone Marrow Samples  
Sampling collection schedule: 
During screening procedures (after obtaining informed consent), a portion of the enrollment 
(baseline) sample of bone marrow or peripheral blood containing blasts should be obtained. A 
sample of this marrow should also be shipped on same day as collection as per instructions 
below.  
 
Samples from additional bone marrow aspirations obtained while the patient is on study should be 
submitted in a similar fashion. 
 
Sampling Collection: 
Bone marrow aspiration will be done as per institutional protocol which will be on day 100 ±10, 
6th month ± 1 month, 1st year ±1 month and 2 years ±2 months after allogeneic stem cell 
transplantation. Patients may have repeat bone marrow evaluation any time when deemed 
necessary by the treating physician. 
 
Shipping of bone marrow samples: 
Bone marrow aspirates should be shipped to the laboratory promptly on the day of collection on 
wet ice along with a completed Data Collection Form (Appendix X) by overnight courier (FedEx). 
 
In preparation of marrow sample shipment, contact AROG Pharmaceuticals and ProPath 
(Appendix XI) to notify of sample shipment and provide the FedEX tracking number.   
 
9.3 Other tissue samples 
Tissue cells and blood samples may be requested for assessment in other tests which assess study 
drug activity and 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.   
 


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10.  CRITERIA FOR RESPONSE MAINTENANCE 
Response criteria will be modified from the International Working Group for AML (34). Patients 
on this trial should be in CR, CRi, or PR following allogeneic SCT with evidence of donor 
engraftment documented per institutional standard.  Briefly, CR criteria and definition of 
progression are as follows: 
 
Complete Remission (CR): 
• Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count ≥1.0 x109/L 
 
 
Platelet count ≥100 x109/L 
 
• Bone marrow aspirate and biopsy: 
 
≤5% blasts 
 
No Auer rods 
 
No extramedullary leukemia 
 
Complete Remission with Incomplete Blood Count Recovery (CRi): 
• Peripheral blood counts: 
 
No circulating blasts 
 
Neutrophil count <1.0 x109/L, or 
 
Platelet count <100 x109/L 
 
• Bone marrow aspirate and biopsy: 
 
≤ 5% blasts 
 
No Auer rods 
 
No extramedullary leukemia 
 
Partial Remission (PR):  
• All CR criteria if abnormal before treatment  except: 
50 % reduction in bone marrow blast but still >5% or 
 
Marrow blasts <5% with persistent Auer rods 
 
Progressive Disease: 
• death due to any cause 
• start of non-protocol therapy directed for AML 
• relapse as defined as  
o circulating blasts in peripheral blood 
o >5% blasts in marrow not attributable to any other cause 
 
Progression Free Survival will be assessed in two ways: Time to disease progression or death, 
whichever occurs first, starting when crenolanib administration is begun and when stem cell 
infusion was performed (Day 0).  BMA will be scheduled at the following time points: On day 100 
± 10, 6th month ± 1 month, 1st year ± 1 month and 2 years ± 2 months after allogeneic stem cell 


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transplantation. Patients may have repeat bone marrow evaluation any time when deemed 
necessary by the treating physician. 
 
11.  ADVERSE EVENT REPORTING 
11.1 Adverse Event 
An adverse event is any untoward medical occurrence that may present during treatment with a 
pharmaceutical product but which does not necessarily have a causal relationship with study 
treatment.  
 
Adverse drug reaction is a response to a drug which is noxious and unintended and which occurs 
at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the 
modification of physiologic function.  
 
Assessing causal connections between agents and disease is fundamental to the understanding of 
adverse drug reactions. In general, a drug may be considered a contributory cause of an adverse 
event if, had the drug not been administered, 1) the event would not have happened at all, 2) the 
event would have occurred later than it actually did, or 3) the event would have been less severe. 
 
Adverse Events (AEs) will be evaluated according to the NCI CTCAE version 4.03 and 
documented in the case report form (CRF). After the Informed Consent Form is signed, study 
site personnel will record the occurrence and nature of each patient’s pre-existing conditions, 
including clinically significant signs and symptoms of the disease. During the study, site 
personnel will record any change in the pre-existing condition(s) and the occurrence and nature 
of any new adverse events. All adverse events of grade 3, grade 4, or grade 5, regardless of the 
relationship to the study drug, either expected or unexpected, must be recorded, graded, and 
reported to the Sponsor.  
 
Expected events post-transplant are:    
 
1) Febrile or infection episodes not requiring management in the intensive care unit 
2) Preexisting side effects related to prior disease specific therapy including GVHD related 
symptoms  (Sinusoidal Obstruction Syndrome (SOS), rash etc.) or ongoing medications 
for management of non-leukemia conditions (Diarrhea, mucositis etc.)  
3) Myelosuppresion and myelosuppression-related events  
4) Bone, joint, or muscle pain 
5) Fatigue/malaise 
6) Weakness 
7) Alopecia 
General Therapy Related Events: 
 
1). Catheter related events (thrombosis, bleeding, infection) 
2). Rash related to antibiotic use or GVHD 
3). Hospitalization for the management of any of the above expected events 
 


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Reporting Hematology and Blood Chemistry Results: 
 
• Data captured in addition to the protocol specified scheduled visit is to be reported on 
CRFs; this includes grade 3 and grade 4 laboratory abnormalities, independent of impact 
on dosing or associated signs and symptoms 
• Transfusion information is to be captured throughout the study. 
 
Adverse Event Reporting in 30-day Follow-up Period: 
• Adverse events will be captured from the time the patient signs consent until 30 days 
after the last dose of study drug or until start of new study drug.  
• If the patient with active AE goes on to another clinical study or standard therapy within 
the 30 day post-discontinuation follow up, active adverse events should continue to be 
captured until resolution for minimum of 30 days, if possible.  Data should include name 
of new therapy.  
• Patients who do not have progressive disease but stop crenolanib for toxicity should be 
followed until resolution of toxicity. 
• Patients who have progressive disease and do not receive further therapy do not need to 
be followed, unless there is toxicity related to study drug which is unresolved at the time 
patient is taken off study 
11.2 Serious Adverse Event Reporting 
A serious adverse event (SAE) is any adverse drug experience occurring at any dose that results 
in any of the following outcomes:  
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity – a substantial disruption of a person’s ability 
to conduct normal life functions. 
• A pregnancy or congenital anomaly/birth defect. 
• Important medical events that do not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
Any important medical event may be reported as an SAE if deemed appropriate by the Principal 
Investigator and the IND Sponsor.    
 


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All serious adverse events occurring during the conduct of a protocol will be reported (either via 
expedited report or log) to the IRB in accordance with the timeframes and procedures.    
 
All serious adverse events will be recorded in the case report form.  
 
Hospitalizations for the management of any expected adverse events (previously described) 
will not have an expedited report but it will be included in the annual report via the SAE log. 
 
• All life-threatening or fatal events, expected or unexpected, and regardless of attribution to the 
study drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to AROG.   
• The institution’s Internal SAE Report Form for Prompt Reporting will be used for reporting to 
AROG.  
• Serious adverse events will be captured from the time the patient signs consent until 30 days 
after the last dose of drug. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day post-discontinuation time 
period that is related to the study treatment must be reported to IRB and to AROG. This may 
include the development of a secondary malignancy. 
11.3 Reporting of a Serious Adverse Event to FDA 
Serious adverse events will be forwarded to FDA by the IND Sponsor (AROG) according to 21 
CFR 312.32. 
 
It is the responsibility of the PI and the research teams to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, 
the sponsor’s guidelines, and Institutional Review Board policy. 
 
12.  STATISTICAL CONSIDERATIONS 
12.1 Preliminaries 
This is a single-arm, Phase II study of crenolanib in allogeneic stem cell transplant in patients with 
acute myeloid leukemia (AML) in CR after allogeneic stem cell transplantation. Administration 
of crenolanib is oral, and will be started at some time between 42 and 90 days post-transplant, and 
then given every day for up to two years.  There are two patient subgroups: 1) those that were in 
complete remission (CR) at the time of transplant, and 2) those that were not in complete remission 
(NCR) at the time of transplant.  The primary outcome is progression-free survival (PFS) time, 
defined as the time to disease progression or death, whichever occurs first, starting when 
crenolanib administration is begun.  A maximum of 24 patients will be enrolled in each subgroup. 
12.2 Futility Monitoring 
PFS time will be monitored separately within each of the two subgroups, using the Bayesian 
method of Thall et al. [1].  Denote standard therapy by S and the experimental crenolanib therapy 
by E.  Assume that TS = PFS time with S follows an exponential distribution with median mS and 


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that TE = PFS time with E in the each subgroup follows an exponential distribution with median 
mE.  Denote the median PFS times for the standard and experimental therapies by mS and mE, 
respectively.  Under a Bayesian model, both mS and mE are assumed to follow Inverse Gamma(a, 
b) priors.   
 
12.2.1 Futility Monitoring for the CR Subgroup 
From historical experience, it will be assumed that Prob(TS > 12 months) = 0.67, which implies 
that the median PFS is 20.77 months. Assume that mS follows an Inverse Gamma (28.96,  
580.77) prior, which has a mean of 20.77 and a variance of 16, and that mE follows an Inverse 
Gamma (3, 41.54) prior, which has the same mean of 20.77 months but a much higher variance 
of 431.5.  The possibly right-censored times TE will be monitored continuously throughout the 
trial.   Accrual into the CR subgroup will be terminated due to futility at any time if  Prob (mS < 
mE | data) < 0.0785.  The operating characteristics of this monitoring rule were developed using 
the program TTEDesigner version 1.2.2, available from the MDACC Department of 
Biostatistics, assuming an accrual rate of 1 patient per month.  The operating characteristics 
(OCs) OCs for the CR subgroup rule are summarized in the Table 1.   
 
Table 1.  Operating characteristics of the design for the CR subgroup, assuming an accrual 
rate of 1 patient per month, with maximum sample size 24.  
True Median PFS 
(months) 
Pr (Stop Early) 
Mean Sample 
Size 
 
 
 
12 
0.62 
17.4 
16 
0.31 
20.8 
20.77 
0.12 
22.5 
28 
0.05 
23.4 
36 
0.02 
23.8 
 
12.2.2 Futility Monitoring for the no CR Subgroup 
For the NCR subgroup, under the Bayesian model, mS and mE follow Inverse Gamma(a, b) 
priors.  From historical experience, it is assumed that Prob(TS > 12 months) = 0.21, which 
implies that the median is 5.33 months.  Assume that mS follows an Inverse Gamma (14.63, 
72.63) prior, which has a mean of 5.33 and a variance of 2.25, and that mE follows an Inverse 
Gamma (3, 10.66) prior, which has the same mean of 5.33 months but a much higher variance of 
28.4 months. Possibly right-censored TE will be monitored continuously throughout the trial. 
Accrual into the NCR subgroup will be terminated is at any time if Prob(mS < mE | data) < 
0.0795.  The OCs of this monitoring rule were developed using the program TTEDesigner v. 
1.2.2, available from the MDACC Department of Biostatistics, assuming an accrual rate of 1 
patient per month.  These OCs for the NCR subgroup rule are summarized in Table 2. 
 
 
Table 2.  Operating characteristics of the design for the NCR subgroup, assuming an accrual rate 
of 1 patient per month, with maximum sample size 24.  
 


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True Median PFS 
(months) 
Pr (Stop Early) 
Mean Sample 
Size 
 
 
 
2 
0.99 
8.3 
4 
0.32 
19.9 
5.33 
0.10 
22.5 
8 
0.02 
23.8 
10 
0.005 
23.9 
 
Both monitoring rules will be applied by use of the MDACC Department of Biostatistics Clinical 
Trial Conduct website, https://biostatistics.mdanderson.org/ClinicalTrialConduct/. The study 
biostatisticians, Peter Thall and Roland Bassett should be consulted as necessary. 
12.3 Secondary outcomes and data analyses  
Secondary outcomes will include disease-free survival (DFS) time, overall survival (OS) time, 
graft-versus-host disease, and 100-day transplant-related mortality.  Within each subgroup, CR 
and no CR, these events will be tabulated and the distributions of DFS and OS time estimated 
using the method of Kaplan and Meier [2]. 
12.4 Subject Disposition 
A summary of patient disposition will be provided for each cohort and will include the following: 
• Number of patients enrolled 
• Number of patients who participate in each study phase (induction, consolidation, 
maintenance) 
• Reasons for discontinuation from study treatment and follow-up 
• Summary of major protocol violations 
12.5 Subject Characteristics 
Patient characteristics will be reported for each cohort, and will include a summary of the 
following: 
• Demographics 
• Baseline disease characteristics 
• Pre-existing conditions 
Other characteristics will be summarized as deemed appropriate. 
12.6 Concomitant Therapy 
Concomitant medication will be reported overall as well as summarized in a frequency table using 
the terms recorded on the CRF. If warranted, an attempt may be made to determine how 
concomitant medications are related to observed study outcomes. 
12.7 Response Outcome and Methodology 
Response criteria will be adapted from the International Working Group for AML, as stated in 
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12.8 Safety Analyses 
All subjects will be evaluable for safety. Adverse events that occur after a subject is entered (signs 
informed consent), but before the patient receives study drug, will not be recorded on the CRF 
unless the investigator believes that the events may have been caused by a protocol procedure. 
Safety analyses will include summaries of the incidence of adverse events by maximum CTCAE 
grade (version 4.03; NCI 2010) that occur during the study treatment period or within 30 days of 
the last dose of study treatment or until alternate therapy is started, regardless of causality or 
relatedness to study drug. The safety-related outcomes that will be summarized include: 
• Adverse events, 
• TEAEs, 
• SAEs, 
• Deaths, 
• Discontinuations due to adverse events, 
• Extent of exposure to study drug treatment, 
• Hospitalizations, 
• Use of key concomitant medications. 
 
Analyses for data with discrete dates (for example, death date and start/stop dates of concomitant 
medications) will be performed through 30 days after the patient has been discontinued from study 
treatment or until alternate therapy is started. Adverse events will also be analyzed in this time 
frame. After 30-day post-discontinuation follow-up, only those SAEs that are thought to be related 
to study treatment or protocol procedure should be reported immediately to AROG or its designee. 
For these events, the patient must be followed until the event has resolved or stabilized. 
12.9 Criteria for End of Study 
This study will be considered complete following the data cut-off date for the final analysis.  
Documentation of the data cut-off will be included in the master study file. 
 
After the final analysis, if subjects are continuing to benefit from study treatment, they may be 
allowed to continue receiving study treatment for up to additional one year as part of planned 
maintenance.  
 
Patient is considered “off therapy” when study drug stops for any reason and crenolanib therapy 
is not continued.  
 
Patient is considered “off study” after completion of the 30 day safety follow up or upon death or 
upon start of a new therapy, whichever comes first. 
 
13. DATA QUALITY MANAGEMENT 
13.1. Data Safety Monitoring Plan 
Adverse events will be monitored during the treatment and post-treatment follow-up periods. 
Adverse events will be monitored on a continuous basis by the Sponsor. The Sponsor will conduct 
a biweekly teleconference with the study site to review safety data from this trial. A more frequent 
evaluation will be performed if accrual is rapid. The Sponsor and its medical consultants will 


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convene to analyze the safety data at least every 3 months or when more than 20% (more than 1 
patient of the first 5 patients enrolled, more than 2 patients of the first 10 patients enrolled, or more 
than 3 patients of the first 15 patients enrolled) of the subjects require crenolanib dose reduction 
during the first 2 cycles of therapy. The study will be halted, and these data will be presented to 
the Sponsor’s safety monitoring team to decide whether the crenolanib dose should be modified 
for all future patients. Enrollment will be halted if an apparent increase is observed in the 
occurrence of one or more of the following outcomes: 
 
• Early mortality due to any cause  
• Expected, non-hematologic, crenolanib-related toxicity (CTCAE Grade 4) 
• Unexpected, non-hematologic, crenolanib-related toxicity (CTCAE Grade 4) 
 
14.  PROTOCOL ADMINISTRATION 
Protocol amendments 
 
Changes to the protocol will be made only when protocol amendments have been signed by the 
principal investigator and approved by the sponsor and the IRB of the study center. 
 
Archival of data 
 
All patient data (including source data) generated in connection with this study will be kept in the 
archives of each respective institution per policy or for at least 2 years after the approval of 
crenolanib. All data will be available for inspection by company representatives of the Medical 
Department and by regulatory authorities. 
 


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15.  REFERENCES 
 
1. 
Bacher, U., J.A. Talano, and M.R. Bishop, Monitoring and prevention of relapse after 
allogeneic hematopoietic cell transplantation for myeloid malignancies. Biol Blood 
Marrow Transplant, 2012. 18(1 Suppl): p. S62-73. 
2. 
Brunet, S., et al., Impact of FLT3 internal tandem duplication on the outcome of related 
and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first 
remission: a retrospective analysis. J Clin Oncol, 2012. 30(7): p. 735-41. 
3. 
Champlin Richard Treatment of Relapse of Acute Leukemia Post-Transplant: Still Hope 
for Patients With Chemosensitive Disease. The ASCO post, 2013. 4. 
4. 
Platzbecker, U., et al., Azacitidine for treatment of imminent relapse in MDS or AML 
patients after allogeneic HSCT: results of the RELAZA trial. Leukemia, 2012. 26(3): p. 
381-9. 
5. 
Smith, C.C., et al., Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad 
Sci U S A, 2014. 111(14): p. 5319-24. 
6. 
Zimmerman, E.I., et al., Crenolanib is active against models of drug-resistant FLT3-ITD-
positive acute myeloid leukemia. Blood, 2013. 122(22): p. 3607-15. 
7. 
Fathi, A.T., Emergence of crenolanib for FLT3-mutant AML. Blood, 2013. 122(22): p. 
3547-8. 
8. 
Muralidhara, C., A. Ramachandran, and V. Jain. Crenolanib, a novel Type I, mutant-
specific inhibitor of Class III receptor tyrosine kinases, preferentially binds to 
phosphorylated kinases. in American Association of Cancer Research. 2012. 
9. 
Collins et al., C.R.e., Clinical activity of Crenolanib in patients with D835 mutant FLT3-
positive relapsed/refractory acute myeloid leukemia (AML). J Clin Oncol, 2014. 32(5s). 
10. 
Randhawa, J.K., et al., Results of a Phase II Study of Crenolanib in Relapsed/Refractory 
Acute Myeloid Leukemia Patients (Pts) with Activating FLT3 Mutations. 2014: ASH 
Annual Meeting Abstracts. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


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


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


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Appendix II. Inclusion/Exclusion Criteria Checklist 
All subjects enrolled must meet eligibility criteria based on the Inclusion/Exclusion criteria 
detailed in the application and approved by the IRB.  Alternatively the study site/institution 
internal form can be used. 
 
I. Study Information 
 
Protocol Title: 
Phase II Study of Crenolanib Besylate Maintenance following 
Allogeneic Stem Cell Transplantation in Patients with FLT3-
positive Acute Myelogenous Leukemia 
Protocol Number: 
ARO-009 
 
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. History of AML according to World 
Health Organization (WHO) 
classification  
 
 
 
 
2. First allogeneic hematopoietic stem 
cell transplantation (HSCT) using 
myeloablative conditioning (MAC), 
non-myeloablative (NMA), or 
reduced-intensity conditioning (RIC) 
preparative regimens. 
 
 
 
 
3. FLT3-ITD or FLT3-D835 positive 
disease at any time during disease 
course. 
 
 
 
 
4. Hematopoietic stem cell source is 
either with peripheral blood, bone 
marrow or cord blood. 
 
 
 
 
5. Donor source is matched related, 
unrelated, haploidentical donor or 
cord blood.  
 
 
 
 


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6. At the time of allogeneic HSCT: 
a. No more than 1 antigen mismatch 
at HLA-A, -B, -C, -DRB1 or -
DQB1 locus for unrelated donor 
with peripheral blood and bone 
marrow as the hematopoietic stem 
cell source; and 
b. Bone marrow blast ≤ 10%  
 
 
 
 
7. No sooner than 42 days but no later 
than 90 days after allogeneic HSCT. 
 
 
 
 
 
8. Post-transplant bone marrow blast 
count ≤ 5% confirmed within 21 days 
(+4 days) prior to starting study 
therapy 
 
 
 
 
9. Evidence of donor engraftment as 
defined by institutional standard T cell 
chimerism > 50%. 
 
 
 
 
10. Adequate engraftment within 7 days 
prior to starting study therapy: ANC ≥ 
1.0 x 109/L without daily use of 
myeloid growth factor; and platelet ≥ 
25 x 109/L without platelet transfusion 
within 1 week 
 
 
 
 
11. Non-hematological toxicities ≤  Grade 
2  
 
 
 
 
12. Serum creatinine ≤ 1.5 × ULN OR 
creatinine clearance ≥ 50mL/min/1.73 
m2 for subjects with creatinine levels 
above institutional normal 
 
 
 
 
13. Adequate liver function within 24 
hours of start of crenolanib 
administration: 
a. with serum AST ≤ 2 x ULN 
and ALT ≤ 2 x ULN 
b. and bilirubin within the 
normal range  
 
 
 
 
14. Acute 
graft-versus-host 
disease 
(GVHD) ≤ Grade 1, either no signs of 
chronic GVHD or mild chronic 
GVHD graded as limited disease  
 
 
 
 
15. Eastern Cooperative Oncology Group 
(ECOG) performance status of  0-2 
 
 
 
 
16. Age ≥ 18 years with the capacity to 
give written informed consent  
 
 
 
 


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17. Non-pregnant and non-nursing 
women of childbearing potential must 
have a negative serum or urine 
pregnancy test (“Women of 
childbearing potential” is defined as a 
sexually active mature woman who 
has not undergone a hysterectomy or 
who has had menses at any time in 
the preceding 24 consecutive months) 
 
 
 
 
18. Women of childbearing potential and 
men must agree to use adequate 
contraception prior to study entry, for 
the duration of study participation and 
for 90 days following completion of 
therapy   
 
 
 
 
Exclusion Criteria (all must be NO) 
(From IRB approved protocol) 
Yes 
No 
 
Supporting 
Documentation* 
1. Bone marrow blast > 5% within 21 
days (+ 4 days) of start of study drug 
 
 
 
 
2. Active GVHD grade ≥ 2   
 
 
 
 
3. Concurrent use of corticosteroids 
equivalent of prednisone at a dose > 
0.5 mg/kg 
 
 
 
 
 
4. Active and/or untreated central 
nervous system (CNS) leukemia 
 
 
 
 
5. Concomitant therapies for treatment 
or control of leukemia.  
 
 
 
 
6. Use of any of the following after 
transplantation and prior to starting 
study therapy: 
a. Chemotherapeutic agents for 
therapy of AML (note that 
prophylactic use of these agents is 
allowed in this study, e.g., 
methotrexate for GVHD) 
b. Investigational agents/therapies 
c. Azacitidine, decitabine or other 
demethylating agents 
d. Lenalidomide, thalidomide and 
pomalidomide 
 
 
 
 
 


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7. Uncontrolled infection 
 
 
 
 
8. Known positive for human 
immunodeficiency virus (HIV); 
active hepatitis B (HBV) or hepatitis 
C (HCV) infection 
 
 
 
 
9. Significant cardiac disease (New 
York Heart Association classes III or 
IV) or unstable angina despite 
medication 
 
 
 
 
10. Pregnant or breast-feeding 
 
 
 
 
11. Major surgery within 4 weeks of 
starting drug 
 
 
 
 
12. Receipt of investigational agents 
within 5 half-lives of last dose of 
investigational agent 
 
 
 
 
13. Prior treatment with crenolanib with 
progression on treatment 
 
 
 
 
*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 III. Patient Diaries: Crenolanib 
 
 
Protocol ID: ARO-009 


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Protocol ID: ARO-009 


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Protocol ID: ARO-009 


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Protocol ID: ARO-009 


Protocol ARO-009 version 2.0 
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Appendix IV. Study Calendar 
Cycle No.  
Screening 
C1 
C2 
CN 
Follow 
up 
Relative day within each cycle 
(-) D-7 
D1 
D14 
DN 
DN 
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
Relevant Medical history, 
Demographics and Physical 
Exam 
X 
 
 
 
 
 
FLT3 mutationsa 
X 
 
 
 
 
 
HIV, HepB, HepCa 
X 
 
 
 
 
 
Serum or urine Pregnancy test 
X 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
 
Vitals, ECOG, Weight 
X 
X 
 
X 
X 
 
Hematologyb 
X 
X 
 
X 
X 
X 
 
Blood Chemistryb 
X 
X 
X 
X 
 
X 
 
Peripheral blood for PK 
analysisc 
 
X 
 
X 
X* 
 
Peripheral blood for 
correlative analysisd 
 
X 
 
 
 
 
Bone marrow aspirationse 
X 
 
 
 
X 
 
Adverse Event 
X 
X 
X 
X 
X 
X 
 
a Unless previously drawn or tested prior to HSCT 
 
b CBC and chemistry panel must be obtained within 24 hours prior to the first dose of crenolanib and on 
D1 (+ 2 days) and D14 (±7 days) during the first 14 days of maintenance then q28days (± 7 days).  CBC 
and chemistry panels per local non-1572 physician is allowed to be used for this assessment but must be 
reviewed by the study investigator within the protocol specified timeframe.  Results are to be recorded in 
the CRF.  CBC and chemistry panel at the study site to be done no less than every 3 cycles. 
 
c, d Peripheral blood for correlative analysis including Pharmacokinetics Assay will be obtained at multiple 
time points: C1D1 at 120 (± 15) minutes, 4 (±1) hours, and 8 (±2) hours after crenolanib administration, 
C2D1 at pre dose and at 3 (± 1) hours after crenolanib administration and finally on *C3D1 at pre dose 
and 3 (± 1) hours after crenolanib administration. 
Further collections may be as requested by sponsor.  Additional samples may be drawn at the discretion 
of the investigator.  
 
eBaseline bone marrow aspirations should be collected within 21 days (+ 4 days) prior to start of 
crenolanib therapy.  Bone marrow aspiration will be done as per institutional protocol during maintenance 
as long as criteria for CR are maintained. At loss of CR, if bone-marrow sample is obtained for clinical 
purposes to exclude toxicity issues (such as persistent pancytopenia due to study drug vs from progressive 
AML.), a sample is requested to also be sent to Propath (see Appendix XIII). Aspiration samples for 


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study purposes may also be submitted for subjects not in CR if a marrow will be done for clinical 
purposes. 
Appendix V. 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 


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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? 
 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 VI. Laboratory manual 
 
Pharmacokinetic Assay 
 
ONLY FOR SELECTED SITES. The participating institution will request a Pharmacokinetics 
(PK) Kit from AROG Pharmaceuticals to perform PK on each patient enrolled on the study. Site 
should contact Arog Pharmaceuticals at info@arogpharma.com or 1 214.593.0515 to request a 
Pharmacokinetics Kit.  
 
Sampling Strategy:  USE THE PK KIT PROVIDED BY THE SPONSOR 
Peripheral blood for pharmacokinetic studies will be drawn at the following points:  
 
Day 1 of Cycle 1 (first day of crenolanib treatment) 
a. 
post-dose 120 minutes (± 15 minutes)   
b. 
post-dose 4 hours (± 30 minutes)  
c. 
post-dose 8 hours (± 2 h)  
 
Day 1 of Cycle 2 
a.      pre-dose 
b.      post-dose 3 hours (± 60 minutes)   
 
Day 1 of Cycle 3 
a.       pre-dose 
b.       post-dose 3 hours (± 60 minutes)   
 
Sampling Collection and Processing Instructions  
 
• At the sampling time point, collect 10 mL of whole blood for each time point in an 
appropriately labeled red/orange-top tube containing thrombin and completely cover with 
aluminum foil to protect from light.  
• The whole blood will remain at room temperature until clotted (approximately 5 
minutes). 
• The serum will be separated from whole blood by centrifugation at 1500xG for 10 
minutes. Minimize light exposure during this process. 
• Prepare screw-capped  polypropylene collection tubes labeled with UPIN, date and time 
of collection.  
• The serum will be transferred to the appropriate tubes and covered with aluminum foil if 
not immediately frozen. Store at -80oC within 1 hour of collection.  
• Samples from each individual patient will be stored and batched for that patient. The date 
and time of sample collection, crenolanib dose, and date and time of the last crenolanib 
dose should be recorded on the appropriate Pharmacokinetics Data Collection Form 
(Forms 1, 2, 3 and 4). 
 
 
 


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Sampling Handling and Shipping Instructions 
 
• Samples should be shipped within 30 days of the last sample collection, whenever 
feasible. Specimens collected should be shipped via FedEx Priority Overnight shipping 
for delivery Tuesday through Thursday. Weekend and holiday deliveries should be 
avoided.  
• In preparation of shipping samples, contact AROG Pharmaceuticals at 
info@arogpharma.com and Cynthia Gomez at CGomez@microconstants.com to notify of 
sample shipment and to provide the FedEx tracking number. AROG will provide a 
confirmation regarding receipt of email concerning the shipment to the site. 
• Ship all pharmacokinetic samples on dry ice, along with a completed Pharmacokinetics 
Data Collection Form to: 
Cynthia Gomez 
Senior Project Coordinator 
MicroConstants, Inc. 
9050 Camino Santa Fe 
San Diego, CA 92121 
P 858.652.4600 . F 858.652.4699 
E CGomez@microconstants.com 
www.microconstants.com 
 
Additional Information 
 
If any additional information is needed for pharmacokinetic sampling, storage or shipment, 
please contact AROG Pharmaceuticals. 
AROG Pharmaceuticals, LLC 
E: info@arogpharma.com  
O: +1 214.593.0500  
F: +1 214.594.0002 
 


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Figure 1: Sampling collection and processing instructions for Pharmacokinetic Assay 
 
 
PROTECT 
SPECIMEN 
FROM LIGHT.  
Allow the 
whole blood to 
remain at room 
temperature 
for 
approximately 
30 minutes to 
clot 
Centrifuge the 
clotted blood at 
1500xG for 10 
minutes 
Transfer the 
serum layer to the 
appropriately 
labeled tubes. 
PROTECT FROM 
LIGHT IF NOT 
IMMEDIATELY 
STORING IN 
FREEZER.  
Store the serum 
samples at -80
oC 
within 1 hour of 
collection  


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FORM 1 ARO-009 C1D1Pharmacokinetics Data Collection Form 
 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
 
Total daily Crenolanib Dose (mg):   
Today’s Date:     
 
 
Fill in crenolanib dose date, time, and tolerance in the spaces below.  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: _________________________________________________________________ 
 
FORM 2 ARO-009 C_D_  Pharmacokinetics Data Collection Form 
 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
 
Total daily Crenolanib Dose (mg):   
Today’s Date:     
Please mark cycle above 
 
Fill in crenolanib dose date, time, and tolerance in the spaces below.  Do not take second dose 
of crenolanib until 3h PK time point has been drawn. List the scheduled and actual times of 
Course 1 Day 1 
Date 
Scheduled Time 
Actual Time 
post crenolanib 120 minutes (±15 minutes)  
 
 
 
post crenolanib 4 hours (±30 minutes) 
 
 
 
post crenolanib 8 hours (±2 h) 
 
 
 


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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: _________________________________________________________________ 
 
 
Bone Marrow Aspiration and Whole Blood Collection 
 
Sampling Schedule for Bone Marrow Aspirates 
Bone marrow aspirates for research purposes will be collected at the time of routine marrow 
sampling with 1 additional aspiration of about 5 ml drawn for study purposes and placed in 
heparinized cell preparation tubes. The following are suggested time points, and after the first 
induction, bone marrow should be performed at the discretion of the treating physician.  
• Screening 
• Maintenance: as per the institutional standard of care 
• When patient is determined to have progressive disease by the treating physician (loss of 
CR/CRi). 
 
Sampling Schedule for whole blood 
One sample of 10 mL of whole blood for each time point is drawn and placed in heparinized cell 
preparation tubes for other correlative science research studies. See FORMS 5 or 6. Sample should 
be drawn at the following two time points: 
• Pre administration of first dose of crenolanib. 
• When patient is determined to have progressive disease by the treating physician. 
 
Sampling collection and processing  
C_D_ 
Date 
Scheduled Time 
Actual Time 
Prior to crenolanib dose (pre) 
 
 
 
post crenolanib 3 hours (±60 minutes) 
 
 
 


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• BMA/Blood will be done as per institutional bone marrow aspiration protocol. Sampling will 
consist of up to 5 mL of aspirated BMA sample or 10 ml of whole blood placed in 
heparinized cell preparation tubes. 
• After collection of bone marrow or whole blood, store tube upright at room temperature until 
centrifugation. BMA/Blood samples should be centrifuged within one hours of blood 
collection for best results. 
• NOTE: Remix the BMA/blood sample immediately prior to centrifugation by gently 
inverting the tube 8 to 10 times. Also, check to see that the tube is in the proper centrifuge 
carrier/adapter.  
• Centrifuge marrow/blood sample at room temperature (18-25ºC) in a horizontal rotor (swing-
out head) for a minimum of 20 minutes at 1500 to 1800 RCF (Relative Centrifugal Force). 
• After centrifugation, mononuclear cells and platelets will be in a whitish layer just under the 
plasma layer (see Figure 2 below). Aspirate approximately half of the plasma without 
disturbing the cell layer.  
• Collect cell layer with a Pasteur pipette (provided by AROG) and transfer to 3 
cryopreservation tubes (provided by AROG) and centrifuge at 3000 rpm for 5 min. Remove 
all liquid and either snap freeze cell pellet in liquid nitrogen or dry ice and  then store -80ºC 
immediately. 
• Samples from each individual patient will be stored and batched for that patient. Please 
complete appropriate Data Collection Form (FORMS 5 or 6). 
 
 
 
 
 
Figure 2 Layering of formed elements in the cell preparation tubes 
 
Shipping of Samples 
• In preparation of sample shipping, contact AROG Pharmaceuticals at 
svali@arogpharma.comand site at debra.cohen@propath.com to notify of sample shipment 
and to provide the FedEx tracking number. AROG Pharmaceuticals will provide a 
confirmation regarding receipt of email concerning shipment to the site. 
• Samples can be shipped at intermediate times along with Data Collection Form to: 
Collect Mononuclear Cells  


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Debra Cohen 
Cytogenetics and Molecular Laboratory Manager 
ProPath 
1355 River Bend Drive 
Dallas TX 75247 
214.237.1739 
debra.cohen@propath.com  
www.ProPath.com 
 
Contact Information for notification of bone marrow aspiration samples: 
AROG Pharmaceuticals, LLC 
E: svali@arogpharma.com 
O: +1 214.593.0519 (Sheetal Vali)  
F: +1 214.594.0002 
 
 


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FORM 3 ARO-009 Whole Blood Collection Form 
Study Accession #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
 
Crenolanib Dose (mg) and time of ingestion:   
Today’s Date:     
Please indicate phase of therapy:  
Screening 
Follow up 
 
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 and Time 
Administered  
Crenolanib Dose 
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.  
 
Name of person completing form:  __________________________________________ 
Phone Number:  ________________________________________________________ 
Email: ________________________________________________________________ 
Date: _________________________________________________________________ 
Date: _________________________________________________________________ 
Samples 
Date 
Scheduled Time 
Actual Time 
 
 
 
 
 
 
 
 


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FORM 4 ARO-009 Bone Marrow Aspiration C_ D_  Data Collection Form 
Study Acc #: 
Study ID:   
Race:   
Sex: 
Date of Birth: 
Height (cm): 
Weight (kg): 
 
Total daily Crenolanib Dose(mg):   
Crenolanib Dosage 
(mg/m2):   
Today’s Date:     
Please indicate phase of therapy: 
Induction 
 
Consolidation 
 
Maintenance 
 
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 
Date 
Sample – 1 
 
 
 
Sample – 2 
 
 
 


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Appendix VII. Contact Information AROG Pharmaceuticals 
 
Contact Information of Medical Monitor 
 
James Strauss, M.D. 
AROG Pharmaceuticals, Inc. 
Email: jstrauss@arogpharma.com  
Phone (O): (214) 593-0525 
           (M): (214) 536-6861 
Fax: 214.594.0002 
 
Contact Information of Director of Clinical Operations 
 
Abhijit Ramachandran 
AROG Pharmaceuticals, Inc. 
Email: aramachandran@arogpharma.com  
Office: 214.593.0515  
Mobil: 817.849.0175 
Fax: 214.594.0002 
 
Contact Information of Study Monitors 
 
Vinoo Urity 
AROG Pharmaceuticals, Inc. 
Email: vurity@arogpharma.com 
  
Phone: 214.593.0521 
 
Contact Information for notification of shipment of correlative studies samples 
 
AROG Pharmaceuticals, Inc. 
Email: info@arogpharma.com 
Office: +1 214.593.0500  
Fax: +1 214.594.0002 
 
 
 
 
 
 
 
 
 
 
 


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