A Phase 1b/2 Study of TP-0903 in Patients With Acute Myeloid Leukemia and FLT3 Mutations
Phase: EARLY_PHASE1
Conditions: Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Therapy-Related Acute Myeloid Leukemia
Sponsor: Uma Borate

IRB Protocol Number: 
2020C0078 
IRB Approval date:  03/11/2021 
Version:  03/03/2021 
 
 
 
 
A Phase 1b/2 Study of TP-0903 in Patients with Acute Myeloid Leukemia and 
FLT3 mutations 
 
 
Principal investigator (PI):  
Uma Borate, MD 
1800 Cannon Drive 
Lincoln Tower 1120E  
Columbus, OH 43210 
Phone: 614-293-3316 
Fax: 614-293-6050 
 
Sponsor: The Ohio State University  
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No 
Yes 
AlloHSCT 
(TP-0903 to be discontinued 
one week prior to admission) 
TP-0903 maintenance 
(Continue until loss of 
response/clinical benefit) 
Transplant Eligible? 
(for patients achieving CR/CRh/MLFS) 
Synopsis 
We propose a phase 1b/2 study of TP-0903 in AML patients with FLT3 mutations. The study will include 
non-intensive therapy, using TP-0903 monotherapy for relapsed/refractory patients. 
TREATMENT PLAN 
 
TP-0903 MONOTHERAPY FOR AML PATIENTS WITH FLT3 MUTATIONS AND RELAPSED/REFRACTORY 
DISEASE 
AML patients with FLT3 mutations and relapsed/refractory disease are eligible to receive TP-0903, at a 
starting dose of 50 mg daily as a single agent for days 1-21 of a 28-day cycle. If the 50 mg dose does not 
meet the tolerability criteria, a lower dose level of 37 mg daily as a single agent for days 1-21 of a 28-day 
cycle will be considered. 
Dose Level 
TP-0903 (D1-21) 
(mg/day PO) 
-1 
25 
0 
37 
1 
50 
Patients may continue treatment indefinitely for as long as clinical benefit is achieved per the 
investigator’s judgment. Bone marrow examinations for disease response assessment will be mandated 
after the first cycle and at the end of treatment. Subsequent bone marrow examinations may be 
completed at the discretion of the treating physician. 
Schema: 
 
 
 
 
 
Clinical or hematologic response 
No clinical or hematologic response 
 
 
 
Off Treatment 
TP-0903 days 1-21 
of 28 day cycle 
(up to 4 cycles) 
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Study Objectives 
Primary Objectives 
• 
To determine a tolerable dose of TP-0903 monotherapy for relapsed/refractory patients 
with FLT3 AML. 
• 
To determine the complete remission (CR) or complete remission with partial 
hematologic recovery (CRh) rate following induction therapy with TP-0903 in 
relapsed/refractory patients with FLT3 AML. 
Secondary Objectives 
• 
To determine the toxicity profile of TP-0903 monotherapy. 
• 
To determine disease-free survival for patients achieving CR/CRh. 
• 
To determine overall survival for patients. 
• 
To determine the proportion of patients who go to transplant. 
Exploratory Objectives 
• 
To conduct pharmacokinetic studies of TP-0903 monotherapy. 
• 
To 
examine 
changes 
in 
circulating 
AXL, 
Gas6, 
FLT3 
ligand, 
and 
other 
cytokines/chemokines by TP-0903. 
• 
To determine the impact of TP-0903 on the inhibition of kinase signaling (AXL, FLT3, 
STAT5, AURKA), and metabolomics in AML cells. 
• 
To determine differentially expressed genes in bone marrow stromal cells and AML cells 
upon TP-0903 treatment. 
• 
To examine sensitivity and resistance patterns associated with TP-0903 by genomic, 
epigenomic, and transcriptomic profiling. 
Abbreviations: AlloHSCT, allogeneic hematopoietic stem cell transplant; CR, complete remission; CRh, 
complete remission with incomplete count recovery; MLFS, morphologic leukemia free state 
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Abbreviations 
 
Acronym 
Definition 
AE 
adverse event 
AST 
aspartate aminotransferase 
BM 
Bone marrow 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
ECG 
FLT3 
Electrocardiogram 
Fms-like tyrosine kinase 3 
G-CSF 
granulocyte-colony stimulation factor 
GI 
gastrointestinal 
IND 
Investigational New Drug [Application] 
IV 
JAK2 
intravenous 
Janus kinase 2 
kD 
kilodalton (molecular weight) 
MR 
minimal response 
MTD 
maximum tolerated dose 
NS 
not specified 
ORR 
overall response rate 
OS 
overall survival 
p21 
cyclin dependent kinase (CDK4) inhibitor protein of 21K molecular 
weight 
P2RD 
phase 2 recommended dose 
p53 
tumor suppressor gene/protein of 53K molecular weight, TP53 
PBMCs 
peripheral blood mononuclear cells 
PD 
progressive disease 
PDn 
pharmacodynamics 
PI3K 
phosphoinositol triphosphate kinase 
PK 
pharmacokinetics 
PO 
per os (oral) 
PR 
partial response 
QOD 
every other day dosing 
QODx3 
every other day dosing for 3 doses (over 5 days) 
QT interval 
the interval between Q and T waves of the electrocardiogram 
QTc interval 
corrected QT interval 
RBC 
red blood cell 
SAE 
serious adverse event 
SD 
stable disease 
TIW 
three times weekly 
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Table of Contents
Synopsis ...................................................................................................................................................... 2 
Study Objectives ......................................................................................................................................... 3 
Abbreviations ............................................................................................................................................. 4 
1. Background and Rationale ...................................................................................................................... 8 
1.1 AML ............................................................................................................................................................ 8 
1.2 FLT3 mutations and targeted therapies in AML ......................................................................................... 8 
1.3 Mechanisms of resistance to FLT3 inhibitors ............................................................................................. 9 
1.4 Co-occurring baseline and acquired somatic mutations with FLT3-ITD during TKI therapy ...................... 9 
1.5 Axl and Gas6 in AML biology and TKI resistance ...................................................................................... 10 
1.6 FLT3-ITD+ AML cell metabolic adaptations to FLT3 inhibition ................................................................. 11 
1.7 Summary of TP-0903 preclinical studies .................................................................................................. 11 
1.8 Summary of clinical studies ...................................................................................................................... 18 
1.9. Rationale and Hypothesis ........................................................................................................................ 19 
2. Patient Selection ................................................................................................................................... 20 
2.1. Eligibility Criteria ..................................................................................................................................... 20 
2.2. Exclusion Criteria ..................................................................................................................................... 21 
2.3. Inclusion of Women and Minorities ........................................................................................................ 21 
3. Treatment Plan .................................................................................................................................... 22 
3.1. Duration of Follow-up ............................................................................................................................. 23 
3.2. Recommended supportive care treatment and special considerations……………………………………………….23 
3.2.1 Nausea……….……………………………………………………………………………………………………………….…………….23 
3.2.2 Diarrhea……….…………………………………………………………………………………………………………….…………….23 
4. Definition of Dose Limiting Toxicity (DLT)/Dosing Delays and Treatment Modifications ......................... 23 
4.1. Definition of Dose Limiting Toxicity (DLT) ............................................................................................... 23 
4.2. Dosing Delays/Dose Modifications .......................................................................................................... 24 
4.2.1 Dose Delays/ Dose Modifications for DLTs ............................................................................................ 24 
4.2.1.1 Non-hematologic DLT ......................................................................................................................... 24 
4.2.1.2 Hematologic DLT  ................................................................................................................................ 25 
4.2.2 Dose Delays/ Dose Modifications for Non-DLTs  ................................................................................... 25 
4.2.2.1 Induction ............................................................................................................................................. 25 
4.2.2.2 Maintenance  ...................................................................................................................................... 25 
4.3 General Administration Guidelines .......................................................................................................... 26 
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4.3.1 Missed or Vomited Doses ................................................................................................................. 26 
5. Safety and Reporting Requirements ..................................................................................................... 26 
5.1. Assessment of Safety ............................................................................................................................... 26 
5.2. Definitions ............................................................................................................................................... 26 
5.2.1. Adverse Events (AE) ......................................................................................................................... 26 
5.2.2. Serious Adverse Event ...................................................................................................................... 27 
5.2.3. Severity ............................................................................................................................................ 28 
5.2.4. Suspected Adverse Reaction ............................................................................................................ 28 
5.2.5. Unexpected ...................................................................................................................................... 29 
5.3. Documenting and Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) .................... 28 
5.3.1. Adverse Event Reporting Period ...................................................................................................... 28 
5.3.2. Assessment of Adverse Events ......................................................................................................... 29 
5.4. Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ....................................... 30 
5.5. Expedited Reporting Requirements for Serious Adverse Events ............................................................ 30 
5.6. Routine Adverse Event Reporting ........................................................................................................... 31 
5.7. Type and Duration of Follow-up of Patients after Adverse Events ......................................................... 31 
5.8. Data Safety Monitoring Plan (DSMP) ...................................................................................................... 31 
6. Pharmaceutical Information .................................................................................................................. 32 
6.1 Drug information ...................................................................................................................................... 32 
6.1.1 Drug substance and description ........................................................................................................ 32 
6.1.2 Preclinical absorption, distribution, metabolism, and excretion ...................................................... 32 
6.1.2.1 Drug transporter effects ................................................................................................................ 32 
6.1.2.2 CYP450 effects ............................................................................................................................... 33 
6.1.2.3 Liver microsome stability ............................................................................................................... 33 
6.1.2.4 Serum albumin binding .................................................................................................................. 33 
6.1.2.5 pKa of TP0903 ................................................................................................................................ 33 
6.1.2.6 pH-dependent solubility of TP0903 ............................................................................................... 33 
6.2 Potential drug-drug interactions and concomitant medications ........................................................ 33 
6.3 Prohibited therapies ............................................................................................................................. 34 
6.4 Study Drug Management .......................................................................................................................... 34 
6.4.1    TP-0903 Drug Product ................................................................................................................... 34 
6.4.2 
Study Drug Dispensing and Accountability ................................................................................... 34 
6.4.3      Storage at Study Center ................................................................................................................ 34 
6.4.4 
Accountability and Destruction of Investigational Medicinal Product ............................................... 34 
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6.4.5 
Drug Administration ........................................................................................................................... 35 
7 
Measurement of Effect ................................................................................................................................ 35 
7.1. Response Criteria ..................................................................................................................................... 35 
8 
Correlative Studies ...................................................................................................................................... 38 
9 
Study Calendars ........................................................................................................................................... 41 
TP-0903 monotherapy, (Cycle 1 only) ............................................................................................................ 41 
TP-0903 monotherapy (Cycles 2-4 and maintenance) ................................................................................... 43 
10 Statistical Considerations .................................................................................................................... 45 
11 Ethics and Regulatory Requirements ................................................................................................... 47 
11.1. Patient Protection ................................................................................................................................. 47 
11.2. Patient Information ............................................................................................................................... 47 
11.3. Informed Consent ................................................................................................................................. 47 
11.4. Ethics Board Approval ........................................................................................................................... 48 
12 Documentation, Record Access and Maintenance of Study Records .................................................... 48 
12.1. Documentation of Patient’s Participation ............................................................................................. 48 
12.2. Source Documentation.......................................................................................................................... 48 
12.3. Regulatory Requirements ...................................................................................................................... 48 
12.4. Patient Confidentiality and Access to Source Data/Documents ........................................................... 48 
12.4.1. Patient Identification ..................................................................................................................... 48 
12.5. Confidentiality of the Study ................................................................................................................... 49 
12.6. Registration of Clinical Trial ................................................................................................................... 49 
12.7. Maintenance of Study Records ............................................................................................................. 49 
13 Administrative Procedures .................................................................................................................. 50 
13.1. Protocol Deviations and Violations ....................................................................................................... 50 
13.2. Premature Discontinuation of the Study .............................................................................................. 50 
14 References .......................................................................................................................................... 50 
Appendix A. Cytochrome P450 Drug Interaction Table ............................................................................... 54 
 
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1. Background and Rationale 
1.1 AML 
 
Acute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by genetic and epigenetic 
alterations that lead to a block in granulocyte differentiation and accumulation of leukemic blasts in blood 
and bone marrow (BM). Nonrandom chromosomal abnormalities (e.g., deletions, translocations) are 
identified in approximately 55% of all adult primary AML patients and are thought to provide the most 
significant information regarding prognosis and responsiveness to intensive therapy as well as to direct 
initial treatment strategies, including allogeneic transplantation in first CR[2]; however, approximately 
half of AML diagnoses are associated with a normal karyotype and highly variable disease outcomes[2, 3]. 
Over the past two decades, advances in molecular diagnostics have improved our understanding of AML 
biology and has contributed remarkably to refining overall prognosis, particularly in patients with 
cytogenetically normal AML (CN-AML) [4]. 
 
With current treatment strategies, approximately 40% of AML patients achieve long-term remission. Of 
those patients who relapse, only a fraction successfully undergo salvage treatment followed by allogeneic 
stem cell transplant with curative intent. For older adults (>65 years), the prognosis is even more dismal 
as patients in this age group often have poor-risk disease that is associated with adverse or complex 
karyotypes. Furthermore, the presence of comorbid conditions and lack of suitable donors render these 
patients ineligible for aggressive treatment (i.e., allogeneic stem cell transplant). Even with adaptation of 
cytogenetically risk-stratified therapies, 20% to 30% of AML patients never achieve CR, and greater than 
50% of patients who achieve CR subsequently experience very early disease relapse. The lack of significant 
advances in the treatment of AML in adults highlights the need for development of novel therapeutic 
strategies, particularly those directed against molecular targets that are known to be involved in disease 
pathogenesis. 
1.2 FLT3 mutations and targeted therapies in AML 
 
Mutations in the fms-like tyrosine kinase 3 (FLT3) gene were one of the first molecular abnormalities to 
be described in AML. FLT3 is a type 3 receptor tyrosine kinase expressed on normal bone marrow 
progenitor cells; its expression is normally lost with maturation of these progenitors[5]. Binding of FLT3 
ligand to FLT3 activates the FLT3 signal transduction pathway, which works in concert with other signaling 
pathways (including STAT, MAPK and PI3K) to regulate hematopoietic cell maturation and growth[5, 6]. 
FLT3 is expressed on AML cells in at least seventy-percent of cases, and approximately one third of AML 
patients harbor activating mutations of FLT3, including internal tandem duplications (ITDs) in 25% and 
tyrosine kinase domain (TKD) point mutations in 5% [5, 7, 8], resulting in constitutive activation of FLT3 
signaling. 
 
The presence of the FLT3-ITD mutation has a well-recognized adverse prognostic impact on disease 
outcomes, with short disease-free survival following standard AML chemotherapy [9-11]. As such, 
molecularly targeted therapies directed at inhibiting FLT3 signaling are an attractive treatment option to 
improve disease outcomes in this ill-fated subset of patients. 
A number of FLT3 tyrosine kinase inhibitors (TKIs) have been evaluated, initially as single agents, then in 
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combination with chemotherapy, to assess AML response and impact on outcomes in AML patients who 
carry FLT3 mutations. Phase I/II trials of single-agent lestaurtinib (CEP 701), midostaurin (PKC 412) and 
sorafenib, demonstrated that these agents were generally well tolerated and upward of seventy-percent 
of patients achieved some degree of hematologic improvement, as evidenced by reduction in blood 
and/or bone marrow blasts [12-15]. However, with single-agent therapy these responses were incomplete 
and transient, leading to evaluation of these agents in combination with standard chemotherapy 
regimens. A phase III trial of midostaurin in combination with chemotherapy for FLT3-ITD+ AML was 
completed and showed prolonged overall and event-free survival, which led to FDA approval in this 
disease [16]. These “first-generation” FLT3 inhibitors may not be optimal due to high plasma protein 
binding, [17] significant toxicities, and lack of potent FLT3 inhibition [18-22]. “Second- generation” FLT3 
inhibitors with more selective and potent FLT3 inhibition, including quizartinib, crenolanib and gilteritinib 
are in phase II and III clinical evaluation alone and in combination with chemotherapy in FLT3-ITD+ 
AML[23]. 
1.3 Mechanisms of resistance to FLT3 inhibitors 
 
One of the most well described mechanisms of acquired resistance to FLT3 TKIs is the development of 
secondary FLT3 TKD mutations, primarily at residues D835 and F691. TKD point mutations alters the 
conformation of the kinase which deters proper binding of the inhibitors. Docking models suggest that 
TKIs bind to the ATP-binding pocket and DFG residues in a region of the activation loop in the kinase 
domains. Substitution of amino acid residues within the activation loop shift the orientation of DFG residues 
to a “DFG-out” motif. Binding of TKIs with type II properties are perturbed by this substitution mutation, 
whereas TKIs with type I or type II properties have altered binding to FLT3 mutations at the gatekeeper 
residue, F691, in the ATP-binding pocket [24]. Currently, sorafenib and quizartinib are type II FLT3 TKIs 
used clinically in AML that have been shown to be susceptible to resistance conferring TKD mutations [24-
26]. While FLT3 D835 mutations have not been shown to emerge during gilteritinib and crenolanib 
treatment (type I TKIs), clinical studies have shown patients develop F691 gatekeeper mutations that 
confer drug resistance [27, 28]. Pharmacokinetic studies have revealed that some FLT3 TKIs have 
suboptimal properties such as high plasma protein binding and/or a short half-life, which can be 
associated with subtherapeutic plasma concentrations and insufficient cytotoxic effects. For example, the 
FLT3 TKI crenolanib must be administered three times daily to remediate such shortcomings[29]. The lack 
of patient medication adherence to strict drug regimens can become an added hurdle to achieve adequate 
drug response. Nonetheless, FLT3 inhibition remains an important therapeutic target that is the subject of 
ongoing studies. 
1.4 Co-occurring baseline and acquired somatic mutations with FLT3-ITD during TKI therapy 
 
Recent studies have reported the co-occurrence of mutations with FLT3-ITD, such as NPM1, DNMT3A, 
WT1, IDH1/2, and TET2, that likely impact prognosis and clinical outcomes.[30, 31] Using a targeted gene 
panel, WES, and deep amplicon sequencing of FLT3 TKD1 (exon 17) and TKD1 (exon 20), we determined the 
mutations that co-occurred with FLT3-ITD in patients prior to receiving crenolanib as a single agent, and 
compared the gene profiles between different crenolanib response groups. Higher frequencies of IDH1/2 
and TET2 mutations, among others, were present in poor responders versus crenolanib good responders. 
We did not observe an association of FLT3 mutation status (ITD, TKD or both) with crenolanib response, 
although 1 patient harboring a baseline FLT3 F691L mutation was a poor responder. Paired samples (pre-
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TKI/during ≥ 28 days of TKI) from 14 patients were profiled for FLT3 mutations. FLT3 F691L mutations 
arose in 2 patients. Further profiling revealed that TET2, IDH1/2, and NRAS mutations were not cleared 
during treatment, and new mutations in IDH1 and NRAS emerged in several patients during crenolanib 
treatment. A recent analysis by next generation sequencing of paired samples (pre-TKI/TKI progression) 
from 16 patients receiving gilteritinib (type I TKI) treatment revealed the emergence of new mutations 
including FLT3 F691L (N=3) and mutations in IDH2 (N=1) and NRAS (N=4).[32] These data highlight the 
genomic complexity of FLT3-ITD+ AML and the potential role that baseline and/or acquired co-occurring 
somatic mutations contribute to FLT3 TKI resistance. 
 
1.5 Axl and Gas6 in AML biology and TKI resistance 
 
The receptor tyrosine kinase Axl was first discovered 20 years ago and subsequently identified to be 
involved in the pathogenesis of various cancers. Axl, along with Tyro-3 and Mer, are receptor tyrosine 
kinase that belong to the TAM family of kinases. TAM kinases are involved in a variety of cellular processes 
including cell proliferation and survival, and cell adhesion and migration. The prognostic implications of 
Axl in AML was initially illustrated in the 1990s and has been reported to be associated with AML 
leukemogenesis [33]. Several literature reports have indicated that Gas6 (growth arrest specific 6), an Axl 
ligand, has prognostic implications. In 270 adults with de novo cytogenetically normal AML, patients 
expressing Gas6 more often failed to achieve a remission and had shorter overall survival and disease- 
free survival. Recently, the role of Axl in FLT3-ITD+ AML biology and as a potential therapeutic target has 
been described [34-36]. Axl and FLT3-ITD interaction was first proposed by Park et al., where 
phosphorylation of FLT3-ITD was disrupted by Axl-Fc (soluble Axl chimeric protein that binds to Axl ligand 
abrogating Axl activation) or siRNA targeting of Axl[35]. Axl inhibition by Axl-Fc led to a decrease in 
proliferation of FLT3-ITD+ AML cells and patient primary blasts due to cell cycle arrest and apoptosis. 
Further in vivo effects of Axl inhibition by Axl-Fc was demonstrated in a primary human FLT3-ITD+ AML 
xenograft in SCID mice, where there was less human CD45+ cells detected in the Axl-Fc treatment group 
compared to the control-Fc group. 
 
Another group evaluated Axl in the context of AML in the tumor microenvironment [36]. They 
demonstrated that AML cells stimulate bone marrow stromal cells to upregulate Gas6. Upregulation of 
Gas6 fostered AML cell growth and cytarabine drug resistance through Axl signaling, whereas silencing Axl 
in Gas6-negative AML cells in the absence of stromal cells did not produce significant effects [36]. 
 
The same group further determined the effects of Axl inhibition in FLT-ITD+ AML in combination with 
chemotherapy. Inhibition of Axl by BGB324, an Axl TKI undergoing clinical development, or Axl shRNA with 
concomitant administration with cytarabine or doxorubicin led to additive in vitro anti-leukemic effects. 
Upon silencing Axl, FLT3-ITD+ MV4-11 cells became more sensitive to doxorubicin compared to control 
group. Conversely, overexpression of Axl led to increased chemo resistance against doxorubicin. When 
primary AML cells were treated concurrently with BGB324 and cytarabine, the combination exerted 
additive effects compared to either drug alone. Considering that combination chemotherapy is utilized as 
the standard of care in managing AML, additive or synergistic effects upon concomitant inhibition of Axl 
with AML gold standard chemotherapeutic agents provides justification that Axl inhibitors in combination 
regimens could potentially be used as a therapeutic approach in treating patients with FLT3-ITD. 
More specifically, later published work by Park et al identified Axl as a key component of resistance to the 
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FLT3 TKIs, midostaurin and quizartinib[35]. Axl phosphorylation was increased in FLT3- ITD+ AML cells 
exposed to midostaurin and quizartinib, and inhibition of Axl by TP-0903, the Axl-Fc chimeric protein or 
lentiviral encoding shRNA targeting Axl in midostaurin-resistant MOLM13 cells, sensitivity to midostaurin 
and quizartinib was restored. While phospho-Axl was detected in FLT3-ITD+ primary blast samples with 
midostaurin resistance ex vivo, it was not detected in blasts that were sensitive to midostaurin therapy. 
Similar findings were observed in in vivo in a midostaurin-resistant MOLM13 cell line xenograft model. 
Mice were treated with either vehicle control, midostaurin alone, TP-0903 alone, or the combination of 
midostaurin and TP-0903. Combination therapy prolonged survival in mice compared to either TKI alone. 
As midostaurin received Breakthrough Therapy status from the FDA, identification of resistance 
mechanisms to midostaurin may have serious therapeutic implications for patients receiving this agent, 
and therapeutic strategies to circumvent resistance will be needed. Collectively, these findings indicate 
that upregulation of Axl is involved in resistance to several FLT3 TKIs, and inhibition of Axl is a potential 
approach to counteract FLT3 TKI resistance. 
 
1.6 FLT3-ITD+ AML cell metabolic adaptations to FLT3 inhibition 
 
Previous studies have demonstrated that FLT3-ITD+ AML cells display increased glycolysis and central 
carbon metabolism compared to FLT3 wild type cells, supported by analysis of clinical gene expression 
datasets showing signatures of upregulated glucose metabolism and TCA cycle.[37, 38] Two recent studies 
have highlighted the role of metabolic adaptations in response to FLT3 TKI treatment. One group showed 
that FLT3 inhibition with quizartinib impaired glycolysis in MOLM13 and MV411 AML cell lines.[38] By 
performing cellular uptake studies with glucose and glutamine, metabolic flux analysis using U-13C6-
glucose, and gene expression profiling, they showed that quizartinib blocked glucose uptake, but not 
glutamine, reduced glucose labeling of glycolytic intermediates, and downregulated glycolytic enzyme 
gene expression. They concluded that FLT3-ITD inhibition impairs glycolysis without affecting glutamine 
metabolism. Another group demonstrated that quizartinib impairs glutamine metabolism in MOLM13 
cells through metabolic flux analysis using 13C,15N-labeled glutamine; quizartinib decreased intracellular 
labeled glutamine and downstream metabolites (glutamate, α-ketoglutarate)[39]. These studies suggest 
AML cells undergo metabolic changes during FLT3 inhibitor treatment, which we will evaluate in response 
to TP-0903 treatment in primary patient AML samples. 
 
1.7 Summary of TP-0903 preclinical studies 
 
TP-0903 is an orally bioavailable inhibitor of Axl. The chemical name of TP-0903 is 2-{[5-chloro-2- ({4-[{4-
methylpiperazin-1-yl)methyl]phenyl}amino)pyrimidin-4-yl]amino}-N,N-dimethylbenzene 
-1- 
sulfonamide mono-tartrate salt. Based on previous reports that Axl is an important mechanism of 
resistance to FLT3 TKIs and AML-directed chemotherapy, we were interested in evaluating TKIs that target 
Axl as a possible therapy against de novo and drug resistant FLT3-ITD+ AML. Previously, in a screen 
consisting of 40 kinases, TP-0903 (200 nM) was shown to inhibit (>50%) eleven kinases[40]. We evaluated 
the inhibition of these kinases, as well as Axl, by TP-0903 in a binding assay with the resultant Kd values: 
Axl (8.2 nM), MER (4.4 nM), TYRO3 (970 nM), AURKA (0.99 nM), CHEK1 (24 nM), JAK2 (0.2 nM), ABL1 (1.2 
nM), IGF1R (56 nM), CSF1R (16 nM), PDGFRB (80 nM), and VEGFR2 (110 nM). In a kinase assay, TP-0903 
inhibited Axl with an IC50 value of 4.9 nM. It has been reported that other AXL inhibitors in development 
also target FLT3[41]. Therefore, we profiled the activity of TP-0903 against FLT3 and ITD/TKD mutants. TP- 
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0903 had potent binding affinities against wild type FLT3 (FLT3-WT) (Kd = 0.93 nM), FLT3-ITD (Kd = 5.6 
nM),      FLT3      TKD    D835 
mutants (Kd = 0.79 - 2.1 
nM), 
and 
the 
double 
ITD/TKD F691L gatekeeper 
mutant (Kd = 1.9 nM) (Table 
1). For comparison, binding 
affinities clinical candidate 
FLT3 inhibitors including 
gilteritinib, 
a 
FLT3/Axl 
inhibitor,    are    shown    in 
Table 1. In a kinase assay, TP-0903 inhibited FLT3-ITD and the D835Y mutant with IC50s of 3.9 and 0.12 
nM, respectively.  The observation that TP-0903 has greater potency against FLT3 activation loop D835 
mutations suggests that TP-0903 has type I kinase inhibitor properties. These findings provide the 
rationale for further evaluation of TP-0903 in de novo and TKI resistant FLT3-ITD+ AML. 
We compared the activity of TP-0903 and a series of clinical candidate FLT3 TKIs in Ba/F3 cells 
expressing FLT-ITD and TKD mutants, which many groups including our lab have used to understand the 
impact of different FLT3 mutations on TKI sensitivity [25, 42-44]. While sorafenib and quizartinib, were 
resistant to TKD mutations, TP-0903 showed activity against all FLT3 TKD mutations. The latter included 
the  gatekeeper  F691L  mutation,  which  gilteritinib,  crenolanib,  and  midostaurin  showed  reduced 
sensitivity by 36-, 32-, 
and 
4.8-fold, 
respectively, compared 
to cells expressing FLT3- 
ITD (Figure 1A and 1C). 
In Ba/F3 cells expressing 
FLT3-ITD and TKD single 
and double mutations, 
TP-0903 inhibited the 
phosphorylation of FLT3 
and downstream STAT5 
in a dose-dependent 
manner 
starting 
at 
10nM, as assessed by 
western blot (Figure 1B). 
Development of TKD      
mutations      are 
major obstacles to FLT3 TKI therapy presented in real clinical settings [24, 25, 42, 45, 46]. Here, in vitro 
sensitivity testing suggests that TP-0903 could overcome drug resistance from acquired TKD mutations. 
Additionally, TP-0903 has the most potent activity against the gatekeeper F691L mutation, which current 
FLT3 inhibitors succumb to. TP-0903 was originally designed on an Axl scaffold that does not clash with 
the Axl gatekeeper residue, Leu620. Given its initial drug design, TP-0903 may bind to F691 substitution 
mutation to leucine in similar manner as it does to L620 in Axl. Based on these data, TP-0903 can be used 
as a strategy to overcome clinically relevant FLT3 TKD mutations reported to date. 
 
 
 
 
 
 
 
 
 
Table 1. Inhibition of FLT3-ITD and TKD mutants by TP-0903 and other FLT3 TKIs in a 
binding assay. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Effect of TP-0903 and other TKIs in Ba/F3 cells transfected with FLT3 mutants. (A) 
Cell viability curve. (B) FLT3 signaling assessed by western blot after 4h of treatment with 
designated concentrations. (C) FLT3 TKI IC50 values (MTT assay, 72h, N=18). 
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We further evaluated the in 
vitro potency of TP-0903 in the FLT-ITD+ 
AML cell lines MOLM13, MOLM13-Res, 
and MV4-11 in a cell viability assay. 
MOLM13-Res cells are a FLT3 TKI 
resistant progeny of MOLM13 cells that 
harbor a dual ITD/D835Y mutation, that 
were generated in our lab [43]. TP-0903 
had potent anti-leukemic activity in all 
AML 
cell 
lines 
(Figure 
2). 
For 
comparison, IC50 values for other FLT3 
TKIs are shown in Figure 2B. Collectively, our preliminary data indicate that TP-0903 has therapeutic 
potential in both de novo and TKI resistant FLT3-ITD+ AML, by targeting FLT3-ITD, FLT3 TKD mutations, Axl 
and potentially other kinase targets. 
To determine if TP-0903 induces cytotoxicity in FLT3-ITD+ AML cell lines, we performed apoptosis 
and cell cycle assays by annexin-V/DAPI staining and flow cytometry. TP-0903 20nM induced significant 
apoptosis at 24 and 48h of treatment (Figure 3A and 3B), and a G2-M cell cycle arrest at 6h and 12 h 
(Figure 3 C). Consistent with cells undergoing apoptosis, an increase in a sub-G1 peak was observe at 24 
h (Figure 3D). The observed G2-M arrest is likely related to AURKA inhibition, which is a unique feature of 
TP-0903 relative to other clinical candidate FLT3 TKIs. 
 
There are literature reports in FLT3-ITD+ patients where FLT3 TKIs induced terminal myeloid 
Figure 2. Effect of TP-0903 and 
other FLT3 TKIs on cell viability in 
FLT3-ITD+ AML cell lines. (A) Cell 
viability curve (data are mean ± 
SEM). (B) FLT3 TKI IC50 values 
(MTT assay; 72h; N=18) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. TP-0903 induces apoptosis and a G2-M cell cycle arrest in AML cell lines. (A) Representative flow 
cytometry measurement of apoptosis using annexin-V and DAPI staining at 48h of treatment. (B) Quantification 
of annexin-V positive cells at designated treatment times (N=3). (C) Representative cell histograms after 12h of 
treatment. (D) Quantification of each cell cycle phase is shown at designated treatment time (N=3). 
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differentiation in leukemic blasts. Patients with minimal change in ITD allelic ratios post-quizartinib 
treatment displayed predominantly mature neutrophils with very little wild-type FLT3 allele [47]. This was 
also observed in sorafenib treated patients where blast-free bone marrow with normocellular or 
hypercellular marrows had readily detectable FLT3-ITD. This was further confirmed by in vivo 
transplantation in which sorafenib differentiated FLT3-ITD+ myeloblasts [45]. With induction of 
differentiation in blasts as another potential mechanism of action in FLT3 TKIs, we also examined if TP- 
0903 differentiates FLT3-ITD+ AML cells to mature myeloid cells. We first measured CD11b expression in 
AML cell lines via flow cytometry. TP-0903 increased CD11b expression to 3- to 30-fold at 48-72h 
compared to DMSO control (Figure 4A). In parallel, we measured expression of different genes that are 
expressed in more mature myeloid cells including the granulocyte colony stimulation factor receptor 
(GCSFR) and lysozyme gene using TaqMan Real-Time PCR (RT-PCR). In all FLT3-ITD+ AML cell lines, GCSFR 
and lysozyme gene expression was increased by up to 20-fold with TP-0903 treatment compared to DMSO 
control (Figure 4B). Ex vivo treatment of two FLT3-ITD+ primary patient blast samples with TP-0903 in a 
CFU assay, cells showed morphologic differentiation with multilobulated nuclei compared to DMSO 
control (Figure 4C). These data indicate that TP-0903 induces differentiation of FLT3-ITD+ leukemic blasts. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4. TP-0903 induces differentiation of FLT3-ITD+ AML cells. 
(A) Representative histogram of CD11b expression measured by 
flow cytometry shown at 72h (upper panel) and fold-change of 
CD11b expression compared to control at 48h and 72h (lower 
panel, n=3). (B) Increase in GCSFR and lysozyme gene expression at 
48h and 72h of TP-0903 treatment (RT-PCR, n=6). (C) Ex vivo 
treatment of two FLT3-ITD+ patient samples in a CFU assay (upper 
and lower panel) induced morphological differentiation. 
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We assessed the ex vivo activity of TP-0903 in human primary FLT3-ITD+ AML samples with co- 
occurring mutations including NRAS, IDH1/2, SMARCA2, NPM1, and among others. TP-0903 inhibited the 
viability of patient samples with IC50 values ranging from 26.6-67 nM; in comparison, gilteritinib was 3.5- 
to 35-fold less potent than TP-0903 with IC50 values ranging from 1.5 105 to 1300 nM (Figures 5A and 
5B). Other FLT3 TKIs showed much less potent activity in these samples compared to TP-0903. Although 
preliminary, these data suggest that TP-0903 may have activity against clinically relevant TKI-resistance 
conferring co-occurring mutations as described above. 
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With positive in vitro and ex vivo data demonstrating antileukemic activity in FLT3-ITD+ cells, we 
evaluated the in vivo therapeutic potential of TP-0903 in MOLM13-YFP/Luciferase (MOLM13-Luc+) and 
MOLM13-RES-Luc+ mouse xenograft models. We performed tolerability studies of TP-0903 in tumor- 
bearing 8- to 12-week old female NSG mice (1 million cells administered by tail vein injection) at doses 
ranging from 40-80 mg/kg administered once daily or daily x 5/week for 3 weeks and determined that 60 
mg/kg was the MTD on these schedules. PK studies performed in mice at TP-0903 60 mg/kg show that 
plasma exposure achieved is in the range observed in patients in the ongoing phase I clinical trial in solid 
tumors (data on file at Sumitomo Dainippon Pharma Oncology, Inc. (SDPO)). For efficacy studies, 
treatment was started on days 7 or 
13 in the MOLM13-Luc+ and MOLM13-RES- 
Luc+ xenografts, respectively, after a similar 
level of bone marrow engraftment was 
documented by bioluminescence imaging 
(Figure 6A). In both xenograft models, TP- 
0903 delayed the outgrowth of leukemia 
cells (P=0.0015 and 0.0007, respectively) 
(Figure 6A) and prolonged survival by 17 and 
9 days (P<0.0001 and P=0.002, respectively) 
compared to vehicle-treated mice (Figure 
6B). 
In the MOLM13-Res-Luc+ xenograft 
efficacy study, we collected bone marrow 
and blood samples when mice succumbed to 
leukemia. Bone marrow samples were 
enriched for MOLM13-RES cells by CD45 
selection, RNA was extracted and AXL gene 
expression was measured by RT-PCR. Plasma 
Gas6   was   measured   by   ELISA.   TP-0903 
significantly decreased AXL gene expression in leukemic cells (P=0.0009) (Figure 7A). High levels of 
circulating Gas6 was observed in vehicle-treated mice, which was significantly reduced in mice treated 
with TP-0903 (P=0.017) (Figure 7B). These preliminary data demonstrate that TP-0903 modulates AXL 
expression in leukemia cells and reduces circulating levels of its ligand Gas6 in the in vivo setting. These 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5. Effect of TP-0903 and other FLT3 TKIs on the viability of primary human FLT3-ITD+ AML samples with co- 
occurring mutations ex vivo. Cell viability curves in (A) patient blast samples and (B) TKI IC50 values (CellTIter-Glo assay, 72 
h, N=3-6). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 6. In vivo activity of TP-0903 in MOLM13-Luc+ and 
MOLM13-RES-Luc+ xenograft mouse models. (A) Bioluminescence 
imaging reported as average radiance. (B) Survival by Kaplan- 
meier analysis. Black bars depict treatment duration. 
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studies will be incorporated in the clinical pharmacodynamic studies outlined in Aim 2. Combined, our 
preclinical studies demonstrate that TP-0903 has activity in de novo and TKI-resistant FLT3-ITD+ AML and 
provide the scientific premise to conduct a phase 1b/2 trial of TP-0903 in patients with FLT3-ITD+ AML. It 
is anticipated that TP-0903 will have immediate clinical impact to circumvent and treat currently identified 
clinically relevant FLT3 TKI resistance mechanisms. 
Given the recent interest in the 
discovery and development of agents to 
target cancer metabolism, [48] these studies 
suggest the metabolic changes that occur 
during FLT3 TKI treatment can be exploited 
therapeutically. 
However, 
the 
exact 
mechanisms 
leading 
to 
metabolic 
reprogramming are not well described and it 
is unknown if different FLT3 TKIs induce 
distinct metabolic responses. To begin to 
address this, we performed gene expression 
analysis      (RNASeq)      of      bone   marrow 
MOLM13-RES AML cells obtained from mice treated with TP-0903 or vehicle (Figure 6) and determined 
the changes of genes involved in glutamine and glucose cellular transport and metabolism. TP-0903 
significantly downregulated genes involved in glutamine transport and metabolism (Figure 8A). Five of 7 
top downregulated genes in these pathways were: 1) three cell membrane glutamine transporters, 
SLC38A1 (SNAT1), SLC1A5 (ASCT2), and SLC7A5 (LAT1); 2) glutamic-pyruvic transaminase 2 (GPT2), a 
mitochondrial 
transaminase 
that 
converts glutamate→α- 
ketoglutarate; 
and 
3) 
asparagine 
synthetase 
(ASNS), an enzyme that 
converts 
aspartate 
→ 
asparagine coupled to 
the 
metabolism 
of 
glutamine → glutamate. 
Expression changes in 
these 
genes 
were 
validated 
by 
RT-PCR 
(Figure 8B). Expression 
changes in these genes 
were validated by RT-PCR 
(Fig 8B). We confirmed 
that TP-0903 inhibited 
the uptake of glutamine, 
which was not observed 
with gilteritinib (Fig 8C). 
Fig 8D illustrates a working model depicting the pathways involved in the inhibition of glutamine transport 
and metabolism by TP-0903. These data provide the scientific rationale to perform metabolomics and 
carbon flux studies in primary patient AML samples in response to TP-0903 treatment. 
Figure 8. TP-0903 impairs glutamine transport/metabolism in a MOLM13-RES-Luc+ 
xenograft model. (A) Volcano plot for gene expression changes by RNASeq in cells 
from mice treated with TP-0903 (N=5) or vehicle (N=10). (B) Validation of gene 
expression changes by RT-PCR. P values are from unpaired t-tests, two-sided. (C) 
TP-0903, but not gilteritinib, inhibits glutamine uptake in HeLa cells. (C) Model 
depicting pathways involved in impaired glutamine transport/metabolism by TP-0903. 
 
 
 
 
 
 
 
 
 
 
Figure 7. Effect of TP-0903 treatment on (A) AXL gene expression 
in bone marrow AML cells (by RT-PCR) and (B) circulating plasma 
Gas6 (by ELISA) in a MOLM13-RES-Luc+ xenograft mouse model. 
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1.8 Summary of clinical studies 
The first-in-human phase 1a/1b study with TP-0903, TP-0903-101 (Clinicaltrials.gov identifier: 
NCT02729298) is ongoing in patients with refractory solid tumors. The Phase 1a study is designed to 
identify the maximum tolerated dose (MTD) and to identify the safety profile and recommended phase 2 
dose of TP-0903. Once the MTD has been established, 5 additional cohorts of up to 20 patients each with 
specific tumor type will be enrolled at the MTD in the phase 1b study. TP-0903 is administered once daily 
for 21 days followed by a 7-day drug-free period for one cycle. Patients are allowed to continue on TP- 
0903 if it shows benefit and is reasonably well tolerated. As of August 2018, adverse events observed in 
patients treated at the first 7 dose levels are shown in Table 2. Patients are consistently presenting with 
nausea/vomiting, diarrhea, and anorexia and no DLTs have been observed. Thus far, TP-0903 has been 
well tolerated with no patients coming off study due to drug-related toxicity. As of March 2019, a flat dose 
of 50 mg daily on days 1-21 of a 28 day cycle is the dose that will be used for future phase 1b expansion 
cohorts. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2. Treatment-emergent adverse events by body system and preferred term by dosing cohort (safety population 
and overall). 
 
 
 
1.9. Rationale and Hypothesis 
In biochemical and cellular assays, we showed that TP-0903 can overcome drug resistance from acquired 
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FLT3 TKD mutations, including the gatekeeper F691L mutation, which current clinical candidate FLT3 
inhibitors are susceptible to. In ex vivo testing of primary FLT3-ITD+ leukemia samples, including those 
harboring a TKI-resistance conferring FLT3-ITD/IDH2 mutation, TP-0903 was more potent than other FLT3 
TKIs. In vivo, TP-0903 delayed the outgrowth of leukemia and prolonged survival in xenograft models of 
FLT3-ITD+ AML. Collectively, our preclinical data demonstrate that TP-0903 has activity in de novo and 
TKI-resistant FLT3-ITD+ AML with the potential to be a best-in-class FLT3 TKI, and provide strong 
scientific premise to conduct a phase 1b/2 trial of TP-0903 in patients with FLT3-ITD+ AML. Previous 
studies have shown that responses with single-agent FLT3 TKI therapy are generally short-lived, which has 
led to the evaluation of several TKIs in combination with chemotherapy in phase II/III trials [15, 18, 21, 49, 
50]. Therefore, we propose to evaluate TP-0903 as monotherapy for FLT3-ITD+ AML patients with relapsed 
or refractory disease. We hypothesize that TP-0903 will have immediate clinical impact in FLT3-ITD+ 
AML. 
 
 
2. Patient Selection 
 
2.1. Eligibility Criteria 
 
 
2.1.1. Patients age ≥18 with relapsed/refractory AML and the presence of FLT3-ITD mutation. 
2.1.2. Patients with secondary AML or therapy related disease (t-AML) are eligible. 
2.1.3. If the patient has co-morbid medical illness, life expectancy attributed to this must be 
greater than 6 months. 
2.1.4. ECOG performance status ≤2 
2.1.5. Patients must have adequate organ function as defined below: 
• 
Total bilirubin <2.0mg/dL unless due to Gilbert’s disease 
• 
AST (SGOT)/ALT (SGPT) <2.5 X institutional upper limit of normal 
• 
Cr clearance >50mL/min by Cockcroft-Gault calculation 
• 
NYHA CHF Class II or better 
• 
Cardiac ejection fraction ≥40% 
 
2.1.6. Female patients of child-bearing potential must agree to use dual methods of contraception 
and have a negative serum pregnancy test at screening, and male patients must use an effective 
barrier method of contraception if sexually active with a female of child-bearing potential. 
Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or 
injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal 
gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female 
patients, effective methods of contraception must be used throughout the study and for three 
months following the last dose. 
2.1.7. Ability to understand and willingness to sign the written informed consent document. 
2.1.8. HIV infection without history of AIDS and sufficiently high CD4 cells (>400/mm3) and low 
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HIV viral loads (<30,000 copies/ml plasma) not requiring anti-HIV therapy are eligible. 
 
2.2. Exclusion Criteria 
 
2.2.1. Patients with acute promyelocytic leukemia. 
2.2.2. Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study. Treatment with hydoxyurea is permitted 
during cycle 1 to maintain WBC< 40,000/uL. 
2.2.3. Patients receiving any other investigational agents or patients that have received other 
investigational agents within 14 days of enrollment. 
2.2.4. Patients with active CNS malignancy. 
2.2.5. Major surgery within 2 weeks before Day 1. 
2.2.6. Uncontrolled active infection. Patients with infection requiring parenteral antibiotics are 
eligible if the infection is controlled. 
2.2.7. Patients with significantly diseased or obstructed gastrointestinal tract. 
2.2.8. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive 
heart failure (New York Heart Association (NYHA) Class III or IV), unstable angina pectoris, 
myocardial infarction within 6 months prior to enrollment, severe uncontrolled ventricular 
arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities. Prior to study entry, any ECG abnormality at screening has to be documented by 
the investigator as not medically relevant. 
2.2.9. Patients with serious medical or psychiatric illness likely to interfere with participation in 
this clinical study. 
2.2.10. Pregnant women or women who are breastfeeding are excluded from this study. 
Confirmation that the subject is not pregnant must be established by a negative serum β-human 
chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy 
testing is not required for post-menopausal or surgically sterilized women. 
2.2.11. Patients with advanced malignant solid tumors. 
2.2.12. Patients who are not able to swallow capsules or tablets. 
2.3. Inclusion of Women and Minorities 
 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
 
 
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No 
Yes 
AlloHSCT 
(TP-0903 to be discontinued 
one week prior to admission) 
TP-0903 maintenance 
(Continue until loss of 
response/clinical benefit) 
Transplant Eligible? 
(for patients achieving CR/CRh/MLFS) 
3. Treatment Plan 
 
TP-0903   MONOTHERAPY FOR AML PATIENTS WITH FLT3 MUTATIONS AND RELAPSED/REFRACTORY 
DISEASE 
AML patients with FLT3 mutations and relapsed/refractory disease are eligible to receive TP-0903, at a 
starting dose of 50 mg daily as a single agent for days 1-21 of a 28-day cycle. If the 50 mg dose does not 
meet the tolerability criteria, a lower dose level of 37 mg daily as a single agent for days 1-21 of a 28-day 
cycle will be considered. 
 
 
 
Dose Level 
TP-0903 (D1-21) 
(mg/day PO) 
-1 
25 
0 
37 
1 
50 
 
Patients may continue treatment indefinitely for as long as clinical benefit is achieved per the 
investigator’s judgment. Bone marrow examinations for disease response assessment will be mandated 
after the first cycle and at the end of treatment. Subsequent bone marrow examinations may be 
completed at the discretion of the treating physician. 
 
Schema: 
 
 
 
 
 
Clinical or hematologic response 
No clinical or hematologic response
Abbreviations: AlloHSCT, allogeneic hematopoietic stem cell transplant; CR, complete remission; 
CRh, complete remission with incomplete count recovery; MLFS, morphologic leukemia free state 
TP-0903 days 1-21 
of 28 day cycle 
(up to 4 cycles) 
Off Treatment 
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3.1. Duration of Follow-up 
 
Patients will be followed monthly for treatment failure until the time of transplant or maintenance 
therapy, at which time they will go to clinical follow-up, followed every 3 months for up to 2 years from 
registration and then every 6 months for up to 5 years from registration until relapse or death. Patients 
who end treatment for reasons other than relapse or a subsequent AML treatment (excluding 
transplant) will follow the same clinical follow-up schedule. Patients who relapse or receive a 
subsequent AML therapy (excluding transplant) will go to survival follow-up, followed every 6 months 
for 5 years from registration until death or the completion of the study. A survival follow-up visit can be 
conducted by phone or electronic contact with the patient or authorized representative. Please see the 
study calendar in Section 9 for details. 
 
3.2. Recommended supportive care treatment and special considerations 
 
3.2.1. Nausea 
 
Patients experiencing Grade ≤ 2 nausea or vomiting on any dose level should be instructed to take 
prochlorperazine by mouth 10 mg every 6 hours as needed.  Patients experiencing Grade 3 nausea on 
any dose level should be instructed to take 10 mg of prochlorperazine by mouth 30 minutes before 
their scheduled dose of TP-0903.  Additional doses of prochlorperazine may be given on an as needed 
basis (10 mg every 6 hours).  If this is ineffective, patients may receive ondansetron 4 mg as an 
alternative, but will need an EKG checked prior to starting given the risk for increasing QTc interval. 
 
3.2.2 Diarrhea  
 
Patients experiencing Grade ≤ 3 diarrhea should be instructed to take loperamide following each loose 
bowel movement (4 mg initial dose, followed by 2 mg after every loose bowel movement; maximum 
dose is 16 mg daily).  
 
 
4. Definition of Dose Limiting Toxicity (DLT)/Dosing Delays and Treatment Modifications 
4.1. Definition of Dose Limiting Toxicity (DLT) 
Drug-related toxicity in this population may be difficult to ascertain, given the aggressive nature of the 
underlying hematologic disease. Investigators will attempt to assign attribution of toxicities to each drug 
if possible. Toxicity attributed to any of the agents will be considered dose limiting. DLT will be assigned 
only to adverse events occurring with cycle 1 of therapy. 
Patients who experience dose limiting toxicity may continue on trial provided that the toxicity has resolved 
to at least Grade 2. The National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 (http://ctep.cancer.gov) will be used to characterize toxicities.  However, any adverse 
reaction that leads to dose reduction or withdrawal will be considered a DLT. 
Non Hematologic: 
Any ≥ Grade 4 non-hematologic toxicity will be considered a DLT.   
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Any non-Hy's law ≥ Grade 3 liver abnormality is a DLT unless it resolves within 72 hours.   
Any ≥ Grade 3 infection lasting more than 7 days in the absence of active AML is considered a DLT. 
Any ≥ Grade 3 bleeding with thrombocytopenia in the absence of active AML is considered a DLT.  
Any ≥ grade 3 non-hematologic toxicity not resulting directly from active leukemia is a DLT, with the 
exceptions of: 
• 
Alopecia 
• 
Line associated venous thrombosis 
• 
Grade 3 fatigue, anorexia, constipation 
• 
Grade 3 or 4 electrolyte disturbance that resolves within 24 hours with electrolyte correction and 
is not clinically significant, 
• 
Grade 3 nausea or vomiting that does not require hospitalization or support with total parenteral 
nutrition and resolves to < grade 2 within 72 hours 
 
The DLT observation period is defined as cycle 1 day 1 until completion of cycle 1 and will require that in 
the absence of DLT, patients receive at least 14 of the 21 planned doses of TP-0903 during cycle 1 to be 
considered evaluable for the tolerability check of the phase 1b. In other words, a patient will be considered 
unevaluable for the tolerability check and phase 1b component if a patient does not complete the DLT 
observation period due to reasons other than toxicity (e.g. progression). These patients will still be 
considered evaluable and included in the denominator when analyzing efficacy endpoints. 
 
Hematologic toxicity: 
Any ≥ Grade 4 neutropenia lasting more than 14 days past the end of the cycle (by day 42) in the absence 
of active AML should be considered DLT.  For patients with > 5% blasts, myelodysplastic changes, or 
evidence of disease by flow cytometry/cytogenetics, failure to recover normal neutrophil count will not 
be considered DLT as this could be the result of persistent disease. Any patients who stop treatment prior 
to completing evaluation for the DLT observation period due to disease progression or refusal for further 
participation for reasons other than toxicity will be replaced for the purposes of dose- finding and safety 
evaluations. 
Other events may occur which do not meet the definition of a DLT but are concerning to the investigators 
and sponsor and may be then considered to be DLTs. Any other toxicities occurring during subsequent 
cycles after cycle 1 will lead to dose modifications as specified below. The National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (http://ctep.cancer.gov) will be 
used to characterize toxicities. 
 
4.2. 
Dosing Delays/Dose Modifications 
4.2.1 
Dosing Delays/Dose Modifications for DLTs: 
4.2.1.1 Non-hematologic DLT: 
Study treatment will be held for any patients experiencing a DLT. 
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Patients experiencing Grade ≥ 3 non-hematologic toxicity will have study treatment held until the toxicity resolves 
to NCI CTCAE  ≤ grade 1 or to the patient’s baseline values.  Patients may restart TP-0903 at the next lower dose 
level when the adverse event recovers to CTCAE ≤ grade 1. If study treatment is restarted and another non-
hematologic DLT (Grade ≥ 3) is encountered at the lower dose, the patient must be removed from the study. If the 
non- hematologic toxicity does not recur on re-challenge, the dose level may be re-escalated at the initiation of 
next cycle at the discretion of the investigator.  Study treatment will be discontinued permanently for any grade 4 
non-hematologic DLT. 
4.2.1.2 Hematologic DLT: 
After the 42 day period and confirmed hematologic DLT: If peripheral blasts are absent AND bone marrow 
blasts are less than 5%, then the patient may restart study treatment on cycle 2 at the next lower dose 
level. 
After achieving CR, the dose level may be re-escalated at the initiation of next cycle at the discretion of 
the investigator. 
4.2.2 
Dose Delays/Dose Modifications for Non-DLTs 
4.2.2.1 Induction 
Patients experiencing non-DLT toxicities during induction related believed to be due to TP-0903 therapy 
that present a challenge to medical management (i.e. grade 2 chronic nausea, myalgia, or fatigue) should 
have their dose held until it falls to a level of grade 1 or < and then re-start at a -1 dose reduction in 
therapy. If this recurs at the lower dose, the patient will discontinue TP-0903 and be followed on the 
treatment regimen.  
4.2.2.2 Maintenance 
Non-hematologic toxicities 
Dose modifications due to TP-0903: Patients experiencing grade 3 non-hematologic toxicities believed to 
be related to TP-0903 therapy (excluding correctable electrolyte abnormalities), select grade 2 toxicities 
(neurologic), or chronic grade 2 toxicity that presents a challenge to medical management (i.e. grade 2 
chronic nausea, myalgia, or fatigue) should have their TP-0903 dose held until this resolves to grade 1 or 
< and then it may be initiated at a dose level below the treating dose. If this recurs at the lower dose, the 
patient will discontinue TP-0903 and be followed on the treatment regimen. Patients experiencing any 
grade 4 non-hematologic toxicities will have treatment discontinued permanently.  
Hematologic toxicities 
TP0903 dose reductions in subsequent cycles after CR/CRi is achieved (i.e., Subsequent cycles after being 
in CR/CRi for at least 1 cycle) will depend on the counts prior to starting the preceding cycle. 
a) If prior to the previous cycle (for e.g., patient is starting C5, check the counts prior to starting 
C4) if the counts were: WBC ≥ 3.0 x109/L, ANC ≥ 1.5 x109/L, and platelets ≥ 75.0 x109/L (all 
three must apply), adjust the dose as follows, based on nadir counts of the prior cycle (per 
the e.g. above the prior cycle will be C4): 
 
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Nadir Counts 
% Dose TP- 0903 in the 
Next Course 
ANC (x109/L)* 
Platelets (x109/L)* 
50% 
<0.5 
<25.0 
* Dose reductions applies when either ANC OR Platelets are at these values 
 
4.3 General Administration Guidelines 
 
 
4.3.1 Missed or Vomited Doses 
Missed or vomited doses will not be made up.  The patient will follow regular schedule starting the next study 
dosing day. All missed doses should be documented in the patient diary. If a dose is vomited within one hour of 
ingestion, it will be considered a missed dose and recorded as such on the patient diary.  If vomiting occurs more 
than 1 hour after dosing, it will still be considered a complete dose. 
 
 
 
5. Safety and Reporting Requirements 
5.1. Assessment of Safety 
Safety assessments will consist of monitoring and recording adverse events (and serious adverse events); 
measurements of protocol-specified hematology, clinical chemistry, and other laboratory variables; 
measurement of protocol-specified vital signs; and other protocol-specified tests that are deemed critical 
to the safety evaluation of the study drug and should be consistent with institutional standards and Good 
Clinical Practice. 
5.2. Definitions 
 
 
5.2.1. Adverse Events (AE) 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of 
an investigational (medicinal) product or other protocol-imposed intervention, regardless of attribution. 
For the purposes of this clinical study, adverse events include only treatment-emergent events which are 
either new or represent detectable exacerbations of pre-existing conditions. 
This includes the following: 
• Subjective or objective symptoms spontaneously offered by the subject and/or observed by the 
investigator or study staff including laboratory abnormalities of clinical significance. 
• Any adverse events experienced by the subject through the completion of final study procedures. 
• AEs not previously observed in the subject that emerge during the protocol-specified AE reporting 
period, including signs or symptoms associated with MCL that were not present before the AE reporting 
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period 
• Complications that occur as a result of protocol-mandated interventions (eg, invasive procedures such 
as biopsies) 
The following are NOT considered an adverse event: 
• Pre-existing condition: A pre-existing condition (documented on the medical history CRF) is not 
considered an AE unless the severity, frequency, or character of the event worsens during the study 
period. 
• Preplanned hospitalization: A hospitalization planned before signing the informed consent form is not 
considered an SAE, but rather a therapeutic intervention. However, if during the pre-planned 
hospitalization an event occurs, which prolongs the hospitalization or meets any other SAE criteria, the 
event will be considered an SAE. Surgeries or interventions that were under consideration but not 
performed before enrollment in the study will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level. Hospitalizations for 
social reasons or due to long travel distances are also not SAEs. 
• Diagnostic Testing and Procedures: Testing and procedures should not to be reported as adverse events 
or serious adverse events, but rather the cause for the test or procedure should be reported. 
 
5.2.2. Serious Adverse Event 
The terms “severe” and “serious” are not synonymous. Severity (or intensity) refers to the grade of an AE 
(see below). “Serious” is a regulatory definition and is based on patient or event outcome or action criteria 
usually associated with events that pose a threat to a patient’s life or functioning. Seriousness (not 
severity) serves as the guide for defining regulatory reporting obligations to applicable regulatory 
authorities. 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life-threatening (with regards to determining if an AE is serious, “life-threatening” is defined as an 
AE in which the subject was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death if it were more severe. If either the investigator or the Sponsor 
believes that an AE meets the definition of life-threatening, it will be considered life-threatening.). 
• It requires or prolongs in-patient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of 
the patient’s ability to conduct normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational product. 
• It is considered a significant medical event by the investigator based on medical judgment (e.g., may 
jeopardize the patient or may require medical/surgical intervention to prevent 1 of the outcomes listed 
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above). 
5.2.3. Severity 
Definitions found in the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) will be 
used for grading the severity (intensity) of AEs. The CTCAE v5.0 displays Grades 1 through 5 with unique 
clinical descriptions of severity for each referenced AE. Should a patient experience any AE not listed in 
the CTCAE v5.0, the following grading system should be used to assess severity: 
• Grade 1 (Mild AE) – experiences which are usually transient, requiring no special treatment, and not 
interfering with the patient’s daily activities 
• Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or concern to the 
patient, and which may interfere with daily activities, but are usually ameliorated by simple therapeutic 
measures 
• Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly interrupt the 
patient’s usual daily activity, and require systemic drug therapy or other treatment 
• Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in imminent 
danger of death 
• Grade 5 (Death related to AE) – experiences which result in patient death 
 
 
5.2.4. Suspected Adverse Reaction 
 
• A Suspected Adverse Reaction is any adverse event for which there is a “reasonable possibility” that the 
drug caused the adverse event. 
• “Reasonable Possibility”, for the purposes of safety reporting, means there is evidence to suggest a 
causal relationship between the drug and the adverse event. Examples of evidence that would suggest a 
causal relationship between the drug and the adverse event are: 
• A single occurrence of an event that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, blood dyscrasias, rhabdomyolysis, hepatic injury, anaphylaxis, and Stevens- 
Johnson Syndrome). 
• One or more occurrences of an event that is not commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the drug (e.g., include tendon rupture or heart valve 
lesions in young adults, or intussusception in healthy infants). If the event occurs in association with other 
factors strongly suggesting causation (e.g., strong temporal association, event recurs on rechallenge), a 
single case may be sufficiently persuasive; but often, more than one occurrence (from one or multiple 
studies) would be needed before the sponsor could make a determination of whether the drug caused 
the event. 
• An aggregate analysis of specific events that can be anticipated to occur in the study population 
independent of drug exposure. Such events include known consequences of the underlying disease or 
condition under investigation (e.g., symptoms or disease progression), or events unlikely to be related to 
the underlying disease or condition under investigation, but commonly occur in the study population 
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independent of drug therapy (e.g., cardiovascular events in an elderly population). An aggregate analysis 
(across studies) will identify those events that occur more frequently in the drug treatment group than in 
a concurrent or historical control group. 
5.2.5. Unexpected 
An “unexpected” AE is an AE that is not listed in the Investigator Brochure or is not listed at the specificity 
or severity that has been observed. For example, hepatic necrosis would be “unexpected” (by virtue of 
greater severity) if the Investigator Brochure referred only to elevated hepatic enzymes or hepatitis. 
"Unexpected" also refers to AEs that are mentioned in the Investigator Brochure as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the study drug under investigation. 
5.3. Documenting and Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) 
 
The Sponsor-investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in the prior sections, are recorded on the case report form (CRF). All SAEs 
also must be reported according to the OSU IRB guidelines. 
5.3.1. Adverse Event Reporting Period 
The AE reporting period for this study begins after first dose of study drug administration until 30 days 
after discontinuation of the study drug. All AEs and SAEs that are encountered during the protocol 
specified AE reporting period should be followed to resolution or until the investigator assesses the 
patient as stable, a new anti-cancer therapy is initiated, or the patient is lost to follow up or withdrawals 
consent Resolution/stable means the subject has returned to baseline state of health or the Investigator 
does not expect any further improvement or worsening of the event. 
5.3.2. Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all patient evaluation time points during the 
study. All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, clinically significant laboratory test, or other 
means will be recorded in the patient’s medical record and on the AE CRF and, when applicable, on an 
SAE/Event reporting form. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, regulatory 
seriousness criteria, if applicable, suspected relationship to the investigational product (see following 
guidance), and any actions taken. 
All deaths should be reported with the primary cause of death as the AE term, as death is typically the 
outcome of the event, not the event itself. The primary cause of death on the autopsy report should be 
the term reported. 
An SAE will qualify for expedited reporting to regulatory authorities if the SAE is considered a Suspected 
Adverse Reaction and is not listed in the current Investigator’s Brochure (i.e., an unexpected event). To 
ensure consistency of AE and SAE causality assessments, investigators should apply the following general 
guideline: 
Fatal 
Adverse event resulted in death. 
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Unrelated 
Another cause of the adverse event is more plausible; a temporal 
sequence cannot be established with the onset of the adverse event 
and administration of the investigational   product; or, a causal 
relationship is considered biologically implausible. 
Possibly 
Related 
There is a clinically plausible time sequence between onset of the 
adverse event and administration of the investigational product, but 
the adverse event could also be attributed to concurrent or underlying 
disease, or the use of other drugs or procedures. Possibly related 
should be used when the investigational product is one of several 
biologically plausible adverse event causes. 
Definitely 
Related  
The adverse event is clearly related to use of the investigational 
product. 
 
 
5.4. Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy (See 
Section 4.2.4). Report any pregnancy that occurs in a patient or patient’s partner from the time of consent 
to 30 days after the last dose of study drug. Record any occurrence of pregnancy in the patient’s medical 
records and notify the treating physician within 24 hours of learning of the event. Abortion, whether 
therapeutic, elective or spontaneous, will be reported as an SAE. 
A patient must immediately inform the investigator if the patient or patient’s partner becomes pregnant 
from the time of consent to 30 days after the last dose of study drug. Any female patients receiving TP- 
0903 PO who become pregnant must immediately discontinue the drug. The investigator should counsel 
the patient, discussing any risks of continuing the pregnancy and any possible effects on the fetus. 
Although pregnancy itself is not regarded as an AE, the outcome will need to be documented. Report any 
pregnancy that occurs in a subject or subject’s partner from the time of consent to 30 days after the last 
dose of study drug. Record any occurrence of pregnancy on appropriate case report form and send it to 
Sumitomo Dainippon Pharma Oncology, Inc. (SDPO), or designee, within 24 hours of learning of the event. 
The pregnant female will be followed for outcome, which is defined as elective termination of the 
pregnancy, miscarriage, or delivery of the fetus. For pregnancies with an outcome of live birth, the 
newborn infant will be followed until 30 days old by completing the Pregnancy Report Form Part II. Any 
congenital anomaly/birth defect noted in the infant must be reported as an SAE. 
5.5. Expedited Reporting Requirements for Serious Adverse Events 
Institution/IND-Sponsor (OSU) of studies conducted under an IND must comply with the following safety 
reporting requirements. The Institution/IND-Sponsor (OSU) must submit each IND safety report in a 
narrative format or on FDA Form 3500A or in an electronic format that FDA can process, review and 
archive. A copy of this IND safety report must also be sent to Sumitomo Dainippon Pharma Oncology, Inc. 
(SDPO) within 24 hours. The Institution/IND-Sponsor (OSU) must notify FDA and Sumitomo Dainippon 
Pharma Oncology, Inc. (SDPO) of any serious, unexpected, suspected adverse reaction observed during 
the conduct of the study as soon as possible but in no case later than 15 calendar days after becoming 
aware of the occurrence. The Institution/IND- Sponsor (OSU) must notify FDA and Sumitomo Dainippon 
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Pharma Oncology, Inc. (SDPO) of any unexpected fatal or life-threatening suspected adverse reaction as 
soon as possible, but no later than 7 calendar days after the Institution/IND- Sponsor’s (OSU) receipt of 
the information. Upon request from the FDA or Sumitomo Dainippon Pharma Oncology, Inc. (SDPO) 
additional data or information that the agency or Sumitomo Dainippon Pharma Oncology, Inc. (SDPO) 
deems necessary, must be reported as soon as possible but no later than 15 calendar days. 
All SAEs (initial and follow-up information) will be reported on an Event Reporting form and submitted to 
the OSU IRB within 24 hours of the discovery of the event or information. All deaths should be reported 
with the primary cause of death as the AE term, as death is typically the outcome of the event, not the 
event itself. The primary cause of death on the autopsy report should be the term reported. If study drug 
is discontinued because of an SAE, this information must be included in the SAE report. 
As noted above, in addition to reporting to the FDA, OSU will forward completed SAE and pregnancy forms 
to representatives of Sumitomo Dainippon Pharma Oncology, Inc. (SDPO). 
Address and phone number of person/sponsor responsible for SAE management at Sumitomo Dainippon 
Pharma Oncology, Inc. (SDPO). 
 
SDPO Pharmacovigilance: BBISafety@bostonbiomedical.com 
 
 
5.6. Routine Adverse Event Reporting 
Adverse events which do not meet the definition of an SAE also require timely reporting dependent upon 
the grade of adverse event using CTCAE criteria, as defined by the protocol, attribution, and whether the 
event is expected or unexpected. All expedited adverse event reports must be reported to the CTO and 
OSU IRB, in accordance with the IRB reporting guidelines. These reports must be included in the in routine 
study data submission for the data safety monitoring report. 
5.7. Type and Duration of Follow-up of Patients after Adverse Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period should be 
followed to resolution, or until the investigator assesses the patient as stable, a new anticancer therapy 
is initiated, or the patient is lost to follow-up or withdraws consent. 
5.8. Data Safety Monitoring Plan (DSMP) 
The data and safety monitoring plan for this phase 2 trial will involve the continuous evaluation of safety, 
data quality and data timeliness. Investigators will conduct continuous review of data completeness and 
patient safety at the AML program meetings (twice monthly) and at the Phase 1/ 2 weekly meeting of 
phase I investigators and staff. This review of the trials includes discussion of ‘milestone’ events including 
encounters of DLT or SAEs. All discussions will be documented in the minutes. The PI of the trial will review 
toxicities and responses of the trial, where applicable, at these disease center meetings and determine if 
the risk/benefit ratio of the trial changes. Frequency and severity of adverse events will be reviewed by 
the PI and compared to what is known about the agent/device from other sources; including published 
literature, scientific meetings and discussions with the sponsors, to determine if the trial should be 
terminated before completion. Serious adverse events will also be reviewed monthly and overall summary 
reports submitted by the PI to the OSU-CCC Data and Safety Monitoring Committee (DSMC) quarterly. 
 
 
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6. Pharmaceutical Information 
6.1 Drug information 
 
6.1.1 Drug substance and description 
 
Generic name 
TP-0903 
Chemical name 
2-{[5-chloro-2-({4-[{4-methylpiperazin-1-yl)methyl]phenyl}amino) 
pyrimidin-4-yl]amino}-N,Ndimethylbenzene-1-sulfonamide mono-tartrate 
salt 
Other names 
TP-0903, TP-0903 tartrate, HCL-2084, CCS-1589/STG-08 
Chemical formula 
C28H36ClN7O8S 
Molecular weight 
666.15 Daltons 
Structure 
 
 
 
The drug substance is a white crystalline solid with a melting point around 296°C. The tartrate salt is soluble 
in water in a pH dependent manner; solubility increases with decreasing pH. In simulated gastric fluid (SGF) 
the solubility is 3.64 mg/mL. In pH 6.5 USP buffer solubility was poor, at 0.013 mg/mL. The drug is also 
soluble in various commonly used and pharmaceutically acceptable organic solvents. 
 
TP-0903 forms a stable polymorph that can be consistently prepared. The compound is hygroscopic, and 
will pick up as much as 12% of its weight in water, with about 3% observed in the drug substance at the 6-
month retest. Adding and subsequently removing water does not alter the polymorph form or have an 
impact on compound stability. 
 
Drug is supplied in 4 mg, 25 mg, and 100 mg dosage strengths in hard gelatin capsules (size #3). 
 
6.1.2 Preclinical absorption, distribution, metabolism, and excretion 
 
6.1.2.1 Drug transporter effects 
 
TP-0903 was tested in a bidirectional cell permeability assay using confluent monolayer of Caco- 2 cells in 
a 96-well based format. Fenoterol, propranolol and digoxin were used as controls. The efflux ratio (mean 
Papp A to B / mean Papp B to A) for TP-0903 was determined to be 1.49. Although mass recovery was low, 
this data suggests that TP-0903 is not a substrate for P-glycoprotein and is a compound of moderate 
permeability. 
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6.1.2.2 CYP450 effects 
TP-0903 was evaluated for the inhibition of human cytochrome P450 isozymes using human liver 
microsomes in the presence of NADPH. At 10 μM, TP-0903 inhibited the activity of only isoform 2C19 by 
more than 50% out of the isozymes selected for testing. The IC50 values were determined against all the 
CYP isozymes used in the panel and, consistent with the percent inhibition data, only 2C19 was inhibited 
at a concentration lower than 10 μM (IC50 4.4 μM). 
 
6.1.2.3 Liver microsome stability 
 
The stability of TP-0903 in the presence of isolated microsomes from three species (human, rat and dog) 
were determined. The concentration of TP-0903 was measured by liquid chromatography- tandem mass 
spectrometry (LC-MS/MS) with reference to a standard curve. The half-life of TP-0903 ranged from 4.3 
minutes in humans to 7.2 minutes in dogs. 
 
6.1.2.4 Serum albumin binding 
 
The serum albumin binding levels for TP-0903 were determined using human plasma in a dialysis plate-
based assay. The free fraction of TP-0903 was measured by LC-MS/MS, by reference to a standard curve, 
and warfarin was used as a control. Data showed that TP-0903 has moderate human serum albumin binding 
(7% unbound). Recovery of protein bound drug (80.3 %) indicated the binding was reversible. 
 
6.1.2.5 pKa of TP0903 
 
The pKa values for TP-0903 were determined by titration using ultraviolet metric detection. The pKa was 
determined in aqueous buffer and separately in the presence of two co-solvents (80% MeOH and 60% 
DMSO). The final pKa values were calculated as an average of the three values obtained under different 
solvent conditions with the exception of pKa 3, for which the pKa value determined in DMSO was 
excluded. The final pKa values for pKa1, pKa2, and pKa3 were 3.02, 3.96, and 7.81, respectively. 
 
6.1.2.6 pH-dependent solubility of TP0903 
 
The equilibrium solubility of TP-0903 tartrate was determined in the following media: pH 3.5, 4.5, 5.5, 6.5 
USP buffers, 0.1N HCl, simulated gastric fluid (SGF), fasted state simulated intestinal fluid, and fed state 
simulated intestinal fluid. As expected, based on the pKa determination, TP-0903 showed greatest 
solubility in acidic media. 
 
6.2 Potential drug-drug interactions and concomitant medications 
 
Clinicians should be aware of the possibility of drug interactions when TP-0903 is co-administered with 
drugs that are inhibitors or inducers of CYP2C19. Clinicians should refer to the products label and to the 
drug interaction website (http://medicine.iupui.edu/clinpharm/ddis/main-table). The website listing 
Cytochrome P450 inhibitors and inducers is updated on an ongoing basis and can be found at Appendix 
A. 
 
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6.3 Prohibited therapies 
 
CYP2C19 substrates: Patients receiving CYP2C19 substrates prior to study treatment should be monitored 
closely. If possible, the investigator should cease patient’s treatment with a CYP2C19 substrate prior to first 
dose, or at a minimum, switch to an alternative, but equivalent treatment that is not a CYP2C19 substrate. 
If a patient must remain on a CYP2C19 substrate, treatment with TP-0903 should proceed cautiously and 
the patient observed closely throughout the duration of the study. (See Appendix A) 
Patients must not be taking H2-receptor antagonists such as cimetidine, ranitidine, and famotidine, or any 
proton pump inhibitors such as omeprazole, lansoprazole, esomeprazole and pantoprazole. Patients must 
stop these medications within 7 days prior to starting treatment. Antacids such as calcium carbonate, 
aluminum hydroxide, sodium bicarbonate should be avoided just prior to administration of TP-0903. 
 
6.4. Study Drug Management 
 
6.4.1. TP-0903 Drug Product 
The study drug, oral TP-0903, is supplied by Sumitomo Dainippon Pharma Oncology, Inc. (SDPO) as a 
powder in hard gelatin capsules (size #3) and is manufactured under current Good Manufacturing 
Practices (cGMP) for investigational use. 
TP-0903 capsules are formulated in 4-mg, 25-mg and 100-mg strengths. Further information is available 
in the 2019 DSUR, Regional Appendix 5, (page 64). 
 
6.4.2 Study Drug Dispensing and Accountability 
TP-0903 will be provided by the Sponsor to study centers as an investigational drug. The label and package 
for the drug product will be prepared in accordance with current regulatory requirements. The 
Investigator or designee will inventory and acknowledge receipt of all shipments of study drugs. The study 
drugs must be kept in a locked area with access restricted to designated study personnel. 
 
An accurate and current accounting of the dispensing of the study drugs for each patient will be 
maintained on an ongoing basis by a member of the study site staff in a drug accountability log or 
equivalent document and will be verified by the sponsor's study monitor. All drug supplies, including 
unused study drug, must be accounted for. A final inventory of the total amount of drug received at each 
study site against the amount used and returned must be recorded in the study drug accountability log or 
an equivalent document. Inventory and dispense records must be readily available for inspection by the 
study monitor and/or auditor, and open to government inspection at any time. Study drug destruction 
will be handled by the sites of open/used vials. Unopened study drug vials should be returned to the 
Sponsor or CRO at the end of the study after full drug accountability has been completed by the study 
monitor. 
6.4.3. Storage at Study Center 
 
Study drug should be stored at room temperature. Protection from light is not necessary. 
 
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6.4.4. Accountability and Destruction of Investigational Medicinal Product 
 
The Principal Investigator (or an authorized designee) at each participating institution must maintain a 
careful record of the inventory of the Investigational medicinal product received using the Drug 
Accountability Form. The study drug will be destroyed as per site’s destruction policies and documentation 
of study drug destruction will be provided to the sponsor. Both used and unused study drug may be 
returned to Sumitomo Dainippon Pharma Oncology, Inc. (SDPO) if requested. 
 
6.4.5. Drug Administration 
 
TP-0903 will be provided by Sumitomo Dainippon Pharma Oncology, Inc. (SDPO). OSU must request study 
drug by submitting an order form directly to the drug depot in order for the study drug to be shipped to 
the site pharmacy. The Investigator (or designee) will verify and acknowledge receipt of all study drug 
shipments by signing and returning all required forms. 
 
Study drug accountability records will be maintained at the site pharmacy and will be available for review 
by the study monitor during each monitoring visit and at the close out visit. 
 
All medication must be stored in a secure area under the proper storage requirements with access 
restricted to the site staff pharmacist or designee(s). 
 
The Investigational medicinal product should not be used for any purpose outside the scope of this 
protocol, nor can Investigational medicinal product be transferred or licensed to any party not 
participating in the clinical study. Sumitomo Dainippon Pharma Oncology, Inc.’s (SDPO) data for 
Investigational medicinal product are confidential and proprietary and shall be maintained as such by the 
Investigators. 
 
7. Measurement of Effect 
 
7.1. Response Criteria 
Assessment of clinical response will be made according to 2017 ELN AML Recommendation [1]. The major 
criteria for judging response will include physical examination and examination of blood and bone 
marrow. All laboratory studies that are abnormal prior to study will be repeated to document the degree 
of maximal response. 
Complete Remission without minimal residual disease (CRMRD-) 
• 
If studied pre-treatment, CR with negativity for a genetic marker by realtime quantitative 
polymerase chain reaction (RT-qPCR), or CR with negativity by multi-color flow cytometry 
[Sensitivities vary by marker tested, and by method used; therefore, test used and sensitivity of 
the assay should be reported; analyses should be done in experienced laboratories (centralized 
diagnostics) 
Complete Remission (CR)* 
CR requires all of the following: 
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• 
Bone marrow blasts <5% 
• 
Absence of circulating blasts and blasts with Auer rods. 
• 
Absence of extramedullary disease 
• 
Absolute neutrophil count ≥1.0 x 109/L (1,000/μL). 
• 
Platelet count ≥100 x 109/L (100,000/μL). 
**MRD positive or unknown 
Complete Remission with hematologic improvement (CRh)** 
CRh meets all Criteria for CR except for residual thrombocytopenia and/or neutropenia defined as: 
• 
Bone marrow blasts <5% 
• 
Absence of circulating blasts on differential from peripheral blood (as determined by flow 
cytometry or blasts with morphologic Auer rods) 
• 
Absence of extramedullary disease (disease outside of bone marrow not including findings on 
CT scan or other organ sites that have not been biopsied to confirm leukemia) 
• 
Absolute neutrophil count > 0.5 x 109/L (500/μL) 
• 
Platelet count > 50 x 109/L (50,000/μL) 
Complete Remission with incomplete blood count recovery (CRi)** 
CRi meets all CR criteria except for Residual neutropenia or thrombocytopenia: 
• 
Bone marrow blasts <5% 
• 
Absence of circulating blasts and blasts with Auer rods. 
• 
Absence of extramedullary disease 
• 
Residual neutropenia <1.0 x 109/L (1,000/μL) or 
• 
Residual Thrombocytopenia <100 x 109/L (100,000/μL) 
**If patients meet criteria for both CRh and CRi, they should be classified as CRh 
Morphologic leukemia free state (MLFS)*** 
• 
Bone marrow blasts <5% 
• 
Absence of blasts with Auer rods. 
• 
Absence of extramedullary disease 
• 
No hematologic recovery required 
*** Marrow should not merely be “aplastic”; at least 200 cells should be enumerated or cellularity should 
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be at least 10% 
Partial Remission (PR) 
PR meets all hematologic criteria of CR: 
• 
Absolute neutrophil count ≥1.0 x 109/L (1,000/μL). 
• 
Platelet count ≥100 x 109/L (100,000/μL). 
  
 
 
 
And 
• 
Decrease of bone marrow blast percentage to 5% to 25% 
• 
Decrease of pretreatment bone marrow blast percentage by at least 50% 
Stable Disease: 
• 
Absence of CRMRD-, CR, CRh, CRi, PR, MLFS; and criteria for PD not met. 
Progressive Disease (PD): 
Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts in the 
blood: 
• 
>50% increase in marrow blasts over baseline (a minimum 15% point increase is required 
in cases with <30% blasts at baseline; or 
• 
Persistent marrow blast percentage of >70% over at least 3 months; without at least a 
100% improvement in absolute neutrophil count (ANC) to an absolute level [>0.5 x 109/L 
(500/μL), and/or platelet count to >50 x 109/L (50,000/μL) non-transfused]; or 
• 
>50% increase in peripheral blasts (WBC x % blasts) to >25 x 109/L (>25,000/μl) (in the 
absence of differentiation syndrome)****; or 
• 
New extramedullary disease 
**** Certain targeted therapies, for example, those inhibiting mutant IDH proteins, other kinases or other 
targets may cause a differentiation syndrome, i.e., a transient increase in the percentage of bone marrow 
blasts and an absolute increase in blood blasts; in the setting of therapy with such compounds, an increase 
in blasts may not necessarily indicate progressive disease. When this happens, it will be discussed with 
Beat AML Chief Medical Officer (CMO) on a case by case bases. 
Treatment Failure 
Treatment failure will be classified as one of the following: 
• 
Primary refractory disease: No CRMRD-, CR, CRh, CRi and MLFS after defined period of 
time; excluding patients with death in aplasia or death due to indeterminate cause 
• 
Death in aplasia: Deaths occurring ≥7 days following completion of initial treatment while 
cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 days of death, 
without evidence of persistent leukemia 
• 
Death from indeterminate cause: Deaths occurring before completion of therapy, or <7 
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days following its completion; or deaths occurring ≥7 days following completion of initial 
therapy with no blasts in the blood, but no bone marrow examination available. 
Recurrence 
Recurrence on this study is defined below. 
Recurrence for patients with prior morphological CRMRD-, CR, CRh, CRi or MLFS which is defined as: 
• 
Evidence of morphologic relapse with the reappearance of leukemic blasts in the 
peripheral blood or ≥ 5% blasts in the bone marrow not attributable to any other cause. 
In the setting of recent treatment, if there are no circulating blasts and the bone marrow 
contains 5-20% blasts, a bone marrow biopsy should be repeated within 1 week to 
distinguish relapse from bone marrow regeneration. 
• 
The reappearance of cytologically proven extramedullary disease also indicates relapse. 
• 
New CNS disease or other new sites of extramedullary involvement. 
It should be noted that reappearance of a cytogenetic or molecular abnormality would be considered a 
cytogenetic or molecular relapse. In the absence of morphologic relapse, this would not be considered a 
relapse. 
 
 
 
 
 
8. Correlative Studies 
 
8.1. Collection of specimens. 
See section 9 for time points for blood and/or marrow sampling for pharmacokinetic (PK) and 
pharmacodynamics (PD studies). At each time point, peripheral blood and bone marrow aspirate for PD 
studies will be collected. The samples will be processed at The OSUCCC Clinical Trials Processing Lab (CTPL) 
or the Leukemia Tissue Bank (LTB) Shared Resources. 
 
 
8.2. Pharmacokinetic and pharmacodynamic studies in blood and marrow. 
For standard techniques, only a brief summary is provided. For non-standard methods, additional 
information is provided on the technique to be utilized unless the method has been published. Blood 
samples for plasma PK will be transferred to the Pharmacoanalytical Shared Resource for bioanalytical 
analysis and estimation of pharmacokinetic parameters by Dr. Mitch Phelps and Dr. Sharyn Baker. Plasma, 
peripheral blood or bone marrow specimens for correlative PD studies will be transferred to Dr. Sharyn 
Baker’s lab for processing of cells for single cell RNA-seq analysis of AML cells and bone marrow stromal 
cell in the Genomics Shared Resource (GSR), and multicolor flow cytometry and Fluorescence Activated 
Cell Sorting of AML cells b in the Analytical Cytometry Shared Resource (ACSR).  
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8.2.2 Sampling for Plasma Pharmacokinetic and Pharmacodynamic studies 
All samples will be collected in green top (heparin) tubes. An intensive PK sampling scheme will be 
performed during course 1 in the patients enrolled during the phase I dose escalation phase. A limited 
sampling strategy will then be developed by Dr. Mitch Phelps for subsequent patients enrolled to the 
phase 2 portion of the trial. 
Sampling for TP-0903 plasma pharmacokinetic assessments will occur at the following times (cycle 1 
only): 
Day 1 and 5: just before dosing and at 0.5, 1, 2, 4, 8, and 24 hours after drug administration. The 24-hour 
post-dose blood sample must be collected prior to the patient receiving TP-0903 on Day 2. 
Day 12: just before dosing and at 0.5, 1, 2, 4, 8, and 24 hours after drug administration (prior to the next 
dose). 
Plasma samples will be quantitated by a validated LC-MS/MS assay and pharmacokinetic parameters will 
be estimated using the software program Phoenix WinNonlin. 
Sampling for TP-0903 plasma pharmacodynamics assessments for Axl, Gas6, FLT3 ligand and other 
cytokines/chemokines will occur at the following times: 
Day 1: Pre-dose then 2 and 24 hours after drug administration (prior to the next dose) 
Day 5 and 12: Pre-dose 
On the first day (pre-dose) prior to each subsequent dose 
Axl, Gas6, and FLT3 ligand will be determine by ELISA and other cytokines/chemokines will be determined 
using a multiplexed Luminex assay. 
 
 
8.2.3. Sampling for Blood and Bone Marrow Pharmacodynamic Studies 
All patients will have serial peripheral blood sampling where cells are isolated at screening, day 5, at count 
recovery, at day 28 of each subsequent cycle (when available) and at time of relapse (in responding 
patients). Samples will be collected in green top (heparin tubes). 
Patients will also have serial bone marrow sampling at screening, day 5, the time of remission marrow, 
and at time of relapse. 
In these samples we will assess the following*: 
• 
In baseline samples and paired baseline/relapse samples, patterns of sensitivity and resistance 
patterns will be assessed by genomic, epigenomic, and transcriptomic profiling. 
• 
In paired baseline and day 5 samples, differentially expressed genes in bone marrow stromal cells 
and AML cells will be assessed by single-cell RNA-eq. 
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• 
In paired baseline and day 5 samples, changes in pAXL, pFLT3, pSTAT5, pAURKA, cell cycle 
distribution, apoptosis will be assessed by multicolor flow cytometry. 
• 
In paired baseline and day 5 samples, changes in metabolites and the flux of carbon derived from 
either isotopically labeled glutamine (13C,15N-Gln), glucose (13C6-Glc) or other substrates (e.g. palmitate, 
pyruvate, aspartate), will be determined using UPLC-MS/MS analysis 
* Correlatives studies will be prioritized as above, depending on the amount of sample that is available 
for analysis. 
** If a significant potential somatic, acquired mutation is identified patients will not be returned these 
results. However, if in the future it is decided that a germline analysis should be done, we will amend the 
protocol as appropriate and patients will be given the option to have these germline mutation results 
returned and undergo CLIA-certified germline testing for the potential pathogenic mutation.
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9. Study Calendars 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. Labs must be done prior to treatment on day 1 and 
maybe used for screening purposes as well. Scans and X-rays must be done <4 weeks prior to the start of therapy. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
TP-0903 monotherapy, (Cycle 1 only) 
 
 
 
Screening* 
Induction             
  
  
  
 
  
 
  
 
  
  
  
  
End-of 
Treatment10 
Follow-
up11 
 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10  
D11 
D12 
D13 
D14 
D15 
D16 
D18 
D21 
D28 
  
 
Medical History  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Complete 
Physical 
exam and ECOG PS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Weight and BSA 
 
x 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
 
Symptom 
directed 
physical evaluation 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
Vitals signs1 
x 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
12-Lead 
Electrocardiogram 
(ECG)2 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Serum pregnancy test3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x **if fertile 
female only 
 
CBC4 
x 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
Complete 
Serum 
chemistry5 
 
 
x 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
Coagulation tests (PT 
and PTT ) 
 
 
x 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
TP-0903 
dosing 
in 
Clinic/Home/Inpatient6 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Bone 
Marrow 
(BM) 
aspiration and biopsy7 
 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
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* *Treatment may begin on the same day as screening. 
1  Vital signs including blood pressure [BP], heart rate [HR], respiratory rate [RR], temperature [T] pulse oximetry (POX) and weight will be assessed prior to 
administration of TP-0903.    
2  ECGs: to be performed in the supine position at screening and day 1 of the first cycle. 
3 Applies to women of childbearing potential (WOCP) only.  WOCP must have a negative pregnancy test within 2 weeks prior to the initiation of therapy. 
4 Complete Blood count with differential will be performed about twice weekly during induction and then as clinically indicated. 
5 Complete serum chemistries includes: Sodium, Potassium, Chloride, Bicarbonate, Creatinine, BUN, Glucose,  Phosphorus,  Albumin, Total bilirubin, SGOT 
(AST), SGPT (ALT), Alkaline phosphatase and  LDH Women of childbearing potential must have a negative pregnancy test within 2 weeks prior to the initiation 
of therapy. 
6 TP-0903 will be administered per section 3. 
7 Bone marrow (BM) core biopsy and aspiration which will include cytogenetics, flow cytometry, targeted mutational analyses and morphologic assessment.  
Aspirate (10ml) only is required on day 5 of cycle 1 for correlative studies.  Cycle 1, day 28 BM examination will require 10 ml aspirate to be collected for 
correlative studies.  All the specimens for correlative studies will be processed at the OSU Leukemia Tissue Bank. Aspiration only may be acceptable for 
patients with BM biopsy that falls out of the window, provided AML diagnosis is unequivocal. 
8Logistical issues that preclude patient visit on days noted will be allowed under special circumstances but must be discussed with the PI. Should such 
occasions arise, evaluations should be done as soon as feasible, preferably within 24-48hours 
9 Correlatives studies to be performed per section 8.2 (+/- 1 day). All patients will have serial peripheral blood sampling where cells are isolated at screening, 
day 5, day 12, at count recovery, at day 28 of each subsequent cycle (when available) and at time of relapse (in responding patients). Samples will be collected 
in green top (heparin tubes). 
10 End of Treatment visit, if applicable, is to be performed 30+7 days following patient last drug administration.  
11Patients will be followed monthly for treatment failure until the time of transplant or maintenance therapy, at which time they will go to clinical follow-up, 
followed every 3 months for up to 2 years from registration and then every 6 months for up to 5 years from registration until relapse or death. Patients who 
end treatment for reasons other than relapse or a subsequent AML treatment (excluding transplant) will follow the same clinical follow-up schedule. Patients 
who relapse or receive a subsequent AML therapy (excluding transplant) will go to survival follow-up, followed every 6 months for 5 years from registration 
until death or the completion of the study.  A survival follow-up visit can be conducted by phone or electronic contact with the patient or authorized 
representative. 
Adverse 
event 
and 
Toxicity evaluation8 
x 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
 
Correlative Studies9 
x 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
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TP-0903 monotherapy (Cycles 2-4 and maintenance) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 ECGs to be completed on day 1 of cycles 2, 3 and 4 only.  Subsequent ECGs for cycle 5 and later may be completed based on clinical judgment. 
2 TP-0903 will be administered per section 3. 
3 Bone marrow (BM) core biopsy and aspiration which will include cytogenetics, flow cytometry, targeted mutational analyses and morphologic 
assessment is required only on Cycle 4, day 28.   BM examination on cycle 4, day 28 will require 10 ml aspirate to be collected for correlative 
studies.  However, if the patient has persistent cytopenias or if there is concern for relapse, BM examination can be completed sooner based on 
clinical judgment.  All the specimens for correlative studies will be processed at the OSU Leukemia Tissue Bank. Aspiration only may be acceptable 
for patients with BM biopsy that falls out of the window, provided AML diagnosis is unequivocal. 
4Logistical issues that preclude patient visit on days noted will be allowed under special circumstances but must be discussed with the PI. Should 
 
Cycles 2-4 and maintenance 
  
  
  
 
  
 
  
 
  
  
  
  
End 
of 
Treatment6 
Follow-
up7 
 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10  
D11 
D12 
D13 
D14 
D15 
D16 
D18 
D21 
D28 
  
 
Weight and BSA 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
 Physical examination 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Vitals signs 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
12-Lead 
Electrocardiogram 
(ECG)1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
CBC 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
Complete 
Serum 
chemistry 
x 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
Coagulation tests (PT 
and PTT ) 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
TP-0903 
dosing 
in 
Clinic/Home/Inpatient2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Bone 
Marrow 
(BM) 
aspiration and biopsy3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Adverse 
event 
and 
Toxicity evaluation4 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
Correlative Studies5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
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such occasions arise, evaluations should be done as soon as feasible, preferably within 24-48hours.  Toxicity assessments on day 12 are only 
required for cycles 2-4.  Cycles 5 and beyond require toxicity assessment only on days 1 and 2. 
5 If applicable, peripheral blood will be collected for correlative studies at day 28 of each subsequent cycle (when available) and at time of relapse 
(in responding patients). Samples will be collected in green top (heparin tubes). 
6 End of Treatment visit, if applicable, is to be performed 30+7 days following patient last drug administration. 
7Patients will be followed monthly for treatment failure until the time of transplant or maintenance therapy, at which time they will go to clinical 
follow-up, followed every 3 months for up to 2 years from registration and then every 6 months for up to 5 years from registration until relapse 
or death. Patients who end treatment for reasons other than relapse or a subsequent AML treatment (excluding transplant) will follow the same 
clinical follow-up schedule. Patients who relapse or receive a subsequent AML therapy (excluding transplant) will go to survival follow-up, followed 
every 6 months for 5 years from registration until death or the completion of the study.  A survival follow-up visit can be conducted by phone or 
electronic contact with the patient or authorized representative. 
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10. Statistical Considerations 
Overview 
 
This phase 1b/2 study will be conducted in adult relapsed/refractory AML patients with FLT3 mutations 
 treated with TP-0903 monotherapy.  
 
The study will open to accrual initially to confirm tolerability of TP-0903 monotherapy using 50 mg daily. 
If in the first 6 patients treated, tolerability is not confirmed, then an additional 6 patients will be treated 
using 37 mg daily. Once a tolerable dose level of TP-0903 monotherapy is confirmed, full accrual to the 
phase 2 portion of the trial will continue. Design details described below assume that TP- 0903 
monotherapy of 50 mg daily will be found tolerable.  
Confirmation of Tolerability 
 
TP-0903 monotherapy has been evaluated in solid tumors and found to be safe at a dose level of 50 mg 
daily. Although we do not anticipate any safety challenges in patients with AML at this dose level, an early 
tolerability assessment will be included for the first 6 patients enrolled based on a standard Rolling 6 
design. If at most one in 6 patients has a DLT (See Section 4), then TP-0903 monotherapy at 50 mg daily 
will be considered safe and we will proceed with full accrual of the phase 2 study. If however TP-0903 
monotherapy at 50 mg daily does not have acceptable toxicity in the first 6 patients, then an additional 6 
patients will be treated at a lower dose level of TP-0903 at 37 mg daily, and the same rule will be used to 
confirm tolerability. Once a tolerable dose level is confirmed, enrollment can continue to the phase 2 
component at that dose level. 
Phase 2 
 
At the confirmed tolerable dose level, TP-0903 monotherapy will be assessed for efficacy in a phase 2 
component. Efficacy data from patients treated at the confirmed tolerable dose level during the 
tolerability check will be utilized in the phase 2 portion of the trial. Efficacy will be assessed using 
Simon’s optimal two-stage phase 2 clinical trial design constraining type I and II errors to 10%. 
 
The primary endpoint is the composite CR rate (CR/CRh), defined according to the 2017 ELN AML 
Recommendation. All eligible patients who start therapy will be considered evaluable for the primary 
endpoint and included in the denominator when calculating the composite CR rate. In relapsed/refractory 
adult patients with AML and FLT3 mutations, the ADMIRAL phase 3 study reported a composite CR rate 
of 34% with the FLT3 inhibitor gilteritinib, which led to improved overall survival (REF). We will therefore 
test the null hypothesis that the composite CR rate with TP-0903 is 30% versus the alternative hypothesis 
that it is 55%. By design, if 13 or more of 31 evaluable patients achieve CR/CRh, then there will be sufficient 
evidence to warrant further study of TP-0903 in this patient population. An interim analysis will occur 
after 13 patients have response determined. If 4 or fewer of 13 evaluable patients achieve CR/CRh, then 
the study will be terminated early. If 5 or more of 13 evaluable patients achieve CR/CRh then enrollment 
will continue as planned for all 31 evaluable patients. The probability of early termination under the null 
hypothesis is 0.65. 
Toxicity will continue to be monitored throughout the phase 2 component, and a rule for excessive 
toxicity will be continuously applied. The monitoring rule will be evaluated during the first cycle of 
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therapy and will be based on the number of patients with a DLT out of the total number of patients 
treated (See Table Below). The number of patients with a DLT that would warrant accrual suspension 
corresponds to a high posterior probability that the true DLT probability is greater than an acceptable 
level (i.e., Pr(pi > 0.25 | data) > 0.95), where the posterior probability is determined from a Beta- 
Binomial distribution with Beta (1, 1) as the prior on pi. For example, if 9 patients have been treated in 
the phase 2 study, and 5 or more patients have a DLT, then this is sufficient evidence of excessive 
toxicity and accrual will be suspended while data are reviewed more closely, and a decision will be made 
to modify or close the study. 
Table: Excessive Toxicity Rule, following the Confirmation of Tolerability in the First 6 Patients 
 
Number of 
Patients 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Number with 
DLT 
4 
4 
5 
5 
6 
6 
6 
7 
7 
7 
Number of 
Patients 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
Number with 
DLT 
8 
8 
8 
9 
9 
9 
10 
10 
10 
11 
Number of 
Patients 
27 
28 
29 
30 
31 
Number with 
DLT 
11 
11 
12 
12 
12 
 
 
Accrual 
 
In the phase 1b component, we expect 6 patients and a maximum of 12 patients. In the phase 2 
component, we will over-accrue by roughly 10% and target an accrual of 34 patients. Overall, we plan to 
accrue 40-46 patients. Based on past accrual of FLT3-mutated AML patients at OSU, we would anticipate 
accruing 1-2 patients per month, with accrual completed in 2-3 years.  
Analysis of Secondary Endpoints 
 
The degree of response will be summarized. Among eligible patients who achieve CR/CRh, disease-free 
survival (DFS) will be calculated. DFS is defined from the date of first CR/CRh until the first date of 
relapse/progression or death from any cause. Any patient without progression or death will be censored 
at the last date of clinical assessment. Further, patients who go to transplant prior to a progression will be 
censored at that time. The number and proportion of patients going to transplant prior to progression will 
be provided. Overall survival (OS) will be calculated for all eligible patients who start therapy. OS will be 
defined from the treatment start date until the date of death from any cause or date last known alive. Both 
time-to-event endpoints will be summarized by the Kaplan-Meier method. Associations between baseline 
variables and clinical outcome will be descriptive in nature due to the small sample sizes, primarily using 
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graphical displays to identify patterns and trends. 
 
The maximum grade of each type of adverse event will be recorded for each patient and summarized. 
Treatment-related adverse events, defined as possibly, probably or definitely related to study treatment 
per NCI CTCAE v5.0 will be summarized separately. In addition, reasons for treatment discontinuation and 
number of TP-0903 cycles received will be summarized and used to assess tolerability. All patients who have 
received at least one dose of study drug will be evaluable for safety and tolerability assessments. 
Initial analysis of plasma PK data will include standard compartmental and non-compartmental methods 
using Phoenix WinNonlin version 6.3 to generate estimates for relevant parameters (CL/F, V/F, Cmax, t1/2, 
AUC, etc.). Descriptive statistics will include means, standard deviations, and frequencies will be 
computed for all variables. Relationships between continuous variables will be performed using standard 
linear correlation and linear regression. Relationships between PK parameters such as Cmax and AUC with 
response will be performed using standard t-tests or Wilcoxon rank sum tests and illustrated using 
boxplots or other graphical displays. Differences in cytokines/chemokines, kinase signaling, and gene 
expression between days 1 and 5 will be evaluated using paired t-tests or Wilcoxon signed rank tests. 
Values will be log transformed as appropriate to reflect biologic plausibility. Patterns of sensitivity and 
resistance will be purely descriptive. 
 
11. Ethics and Regulatory Requirements 
 
 
11.1. Patient Protection 
This study will be conducted according to the principles outlined by the Declaration of Helsinki and all 
applicable amendments; the International Conference of Harmonization 29 Version 05/21/2013 (ICH) 
Guidelines for Good Clinical Practice; the U.S. Food and Drug Administration (FDA) regulations regarding 
the conduct of clinical trials and the protection of human subjects; the Institutional Review Board (IRB), 
any applicable local health authority, and the Ethics Committee requirements. 
 
11.2. Patient Information 
Before entry into the trial all eligible patients will receive written patient information describing the aim 
of the study, as well as probable and possible side effects and risks. Oral information from one of the 
investigators or a delegated person at the institution will also be given, and the patient must have the 
opportunity to ask questions, and to consider participation together with his/her family members if 
applicable. It will be emphasized that the participation is voluntary and that it is the right of the patient to 
refuse further participation in the study whenever he/she wants and that this will not influence his/her 
subsequent care. 
11.3. Informed Consent 
Patient / Legally acceptable representative (LAR) (as applicable) written consent must be obtained 
according to local Institutional and/or University Human Experimentation Committee requirements and 
must conform to the ICH guidelines for Good Clinical Practice, prior to any study-specific screening 
procedures and trial entry. The written informed consent form should be signed and personally dated by 
the patient or by the patient’s legally acceptable representative. A copy of the signed informed consent 
will be given to the patient or patient’s legally authorized representative. The original signed consent must 
be maintained by the investigator at OSU available for inspection by the sponsor, or regulatory authority 
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at any time. The IRB will review the consent form for approval. 
11.4. Ethics Board Approval 
This study must obtain the approval of the protocol, the informed consent document and any other 
material used to inform the patient about the nature of the trial by a properly constituted IRB. The trial 
should not start until a copy of this written approval has been received by the Investigator. The 
Investigator will supply with a copy of the IRB approval letter stating that the study protocol and any 
subsequent amendments and informed consent have been reviewed and approved. The investigator or 
designee will be responsible for obtaining annual IRB re-approval throughout the duration of the study 
including at completion or termination. 
Any changes to this protocol made by the Investigator must be in the form of a written amendment and 
the amendment will be appended to the protocol. Approval of amendments by the IRB is required prior 
to their implementation, unless there are overriding safety reasons. 
Upon completion of the trial, the Investigator must provide the IRB and sponsor with a summary of the 
trial’s outcome. 
Annual Report: The PI will submit annual reports to the sponsor and FDA. 
 
12. Documentation, Record Access and Maintenance of Study Records 
 
 
12.1. Documentation of Patient’s Participation 
A statement acknowledging the participation of a patient in this clinical trial must be documented in the 
patient's medical records along with the signed ICF. 
12.2. Source Documentation 
Source records are original documents, data, and records (e.g., medical records, raw data collection forms, 
pharmacy dispensing records, recorded data from automated instruments, laboratory data) that are 
relevant to the clinical trial. The Investigator will prepare and maintain adequate and accurate source 
documents. These documents are designed to record all observations and other pertinent data for each 
patient enrolled in this clinical trial. Source records must be adequate to reconstruct all data transcribed 
onto the Case Report Forms (CRFs). 
12.3. Regulatory Requirements 
Before the investigational drug is shipped to the Investigator, the Investigator will provide to the sponsor 
with a copy of the IRB approval letter stating that the study protocol and any subsequent amendments 
and informed consent form have been reviewed and approved. 
12.4. Patient Confidentiality and Access to Source Data/Documents 
 
 
12.4.1. Patient Identification 
A sequential unique identification number will be attributed to each patient registered in the trial. This 
number will identify the patient and must be included on all case report forms. A patient will not be 
identified by name, only by his/her initials. The patient’s name or any identifying information will not 
appear in any reports published as a result of this study. In order to avoid identification errors, patient’s 
initials and date of birth (as permitted by the ethics board) will also be reported on the study forms. Any 
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research information obtained about the patient in this study will be kept confidential. However, 
information obtained from individual patient’s participation in the study may be disclosed with his/her 
consent to the health care providers for the purpose of obtaining appropriate medical care. The patient’s 
medical records/charts, tests will be made available to the sponsor Sumitomo Dainippon Pharma 
Oncology, Inc. (SDPO), the US FDA, and the IRB and any other regulatory authorities. This is for the purpose 
of verifying information obtained for this study. Confidentiality will be maintained throughout the study 
within the limits of the law. 
A patient’s name will not be given to anyone except the researchers conducting the study, who have 
pledged an oath of confidentiality. All identifying information will be kept behind locked doors, under the 
supervision of the study Principal Investigator and will not be transferred outside of the hospital. 
A patient may take away his/her permission to collect, use and share information about him/her at any 
time. If this situation occurs, the patient will not be able to remain in the study. No new information that 
identifies the patient will be gathered after that date. However, the information about the patient that 
has already been gathered and transferred may still be used and given to others as described above in 
order to preserve the scientific integrity and quality of the study. 
12.5. Confidentiality of the Study 
Data generated as a result of this study are to be available for inspection on request by local health 
authority auditors, the Sponsor’s Study Monitors and other personnel (as appropriate) and by the IRB. 
The Investigator shall permit sponsor, authorized agents of the sponsor, and regulatory agency employees 
to enter and inspect any site where the drug or records pertaining to the drug are held, and to inspect all 
source documents. The protocol and other study documents contain confidential information and should 
not be shared or distributed without the prior written permission of sponsor. 
Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. 
 
12.6. Registration of Clinical Trial 
Prior to the first patient being registered/enrolled into this study, the Sponsor will be responsible for 
ensuring that the clinical trial is registered appropriately to remain eligible for publication in any major 
peer-reviewed journal, adhering to the guidelines put forth by the International Committee of Medical 
Journal Editors (ICMJE). 
 
12.7. Maintenance of Study Records 
To enable evaluations and/or audits from Regulatory Authorities, the Investigator agrees to keep records, 
including the identity of all participating patients (sufficient information to link records, CRFs and hospital 
records), all original signed informed consent forms, copies of all CRFs, source documents, and detailed 
records of treatment disposition. 
 
According to 21 CFR 312.62(c), the Investigators shall retain records required to be maintained under this 
part for a period of two years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated. If no application is to be filed or if the application is not 
approved for such indication, the Investigator shall retain these records until two years after the 
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IRB Approval date:  03/11/2021 
Version:  03/03/2021 
 
 
investigation is discontinued and the FDA is notified. The Investigator must retain protocols, amendments, 
IRB approvals, copies of the Form FDA 1572, signed and dated consent forms, medical records, case report 
forms, drug accountability records, all correspondence, and any other documents pertaining to the 
conduct of the study. 
If the investigator relocates, retires, or for any reason withdraws from the study, then the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such as 
another investigator, another institution, or to the Sponsor. The investigator must obtain the Sponsor’s 
written permission before disposing of any records. 
 
13. Administrative Procedures 
 
 
13.1. Protocol Deviations and Violations 
All violations or deviations are to be reported to the site’s IRB (as per the ethics board’s guidelines). All 
IRB correspondence is to be forwarded to the sponsor. The site must notify the sponsor immediately of 
any protocol violations. 
13.2. Premature Discontinuation of the Study 
The Sponsor reserves the right to discontinue the trial for any reason but intends only to exercise this right 
for valid scientific or administrative reasons. After such a decision, the Investigators must contact all 
participating patients immediately after notification. Standard therapy and follow-up for patients will be 
assured and, where required by the applicable regulatory requirement(s), the relevant regulatory 
authority(ies) will be informed. 
The IRB will be informed promptly and provided with a detailed written explanation for the termination 
or suspension. 
As directed by the Sponsor, all study materials must be collected and all CRFs completed to the greatest 
extent possible in the case of a premature discontinuation of study. 
 
 
14. References 
 
 
1. 
Dohner, H., et al., Diagnosis and management of AML in adults: 2017 ELN recommendations 
from an international expert panel. Blood, 2017. 129(4): p. 424-447. 
2. 
Byrd, J.C., et al., Pretreatment cytogenetic abnormalities are predictive of induction success, 
cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid 
leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood, 2002. 100(13): p. 
4325-36. 
3. 
Grimwade, D., et al., The importance of diagnostic cytogenetics on outcome in AML: analysis of 
1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and 
Children's Leukaemia Working Parties. Blood, 1998. 92(7): p. 2322-33. 
4. 
Schlenk, R.F., et al., Mutations and treatment outcome in cytogenetically normal acute myeloid 
leukemia. N Engl J Med, 2008. 358(18): p. 1909-18. 
5. 
Pemmaraju, N., et al., FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an 
era? Cancer, 2011. 117(15): p. 3293-304. 
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IRB Approval date:  03/11/2021 
Version:  03/03/2021 
 
 
6. 
Hart, S., et al., SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of 
myeloid and lymphoid malignancies. Leukemia, 2011. 25(11): p. 1751-9. 
7. 
Reindl, C., et al., Point mutations in the juxtamembrane domain of FLT3 define a new class of 
activating mutations in AML. Blood, 2006. 107(9): p. 3700-7. 
8. 
Thiede, C., et al., Analysis of FLT3-activating mutations in 979 patients with acute myelogenous 
leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. 
Blood, 2002. 99(12): p. 4326-35. 
9. 
Adolfsson, J., et al., Identification of Flt3+ lympho-myeloid stem cells lacking erythro- 
megakaryocytic potential a revised road map for adult blood lineage commitment. Cell, 2005. 
121(2): p. 295-306. 
10. 
Breccia, M., et al., Comorbidities and FLT3-ITD abnormalities as independent prognostic 
indicators of survival in elderly acute myeloid leukaemia patients. Hematol Oncol, 2009. 27(3): p. 
148-53. 
11. 
Whitman, S.P., et al., Absence of the wild-type allele predicts poor prognosis in adult de novo 
acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a 
cancer and leukemia group B study. Cancer Res, 2001. 61(19): p. 7233-9. 
12. 
Cortes, J.E., et al., Phase I study of quizartinib administered daily to patients with relapsed or 
refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem 
duplication status. J Clin Oncol, 2013. 31(29): p. 3681-7. 
13. 
Fischer, T., et al., Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 
receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and 
high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol, 2010. 
28(28): p. 4339-45. 
14. 
Stone, R.M., et al., Patients with acute myeloid leukemia and an activating mutation in FLT3 
respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood, 2005. 105(1): p. 54- 
60. 
15. 
Uy, G.L., et al., A phase 2 study incorporating sorafenib into the chemotherapy for older adults 
with FLT3-mutated acute myeloid leukemia: CALGB 11001. Blood Adv, 2017. 1(5): p. 331-340. 
16. 
Stone, R.M., et al., Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 
Mutation. N Engl J Med, 2017. 377(5): p. 454-464. 
17. 
Levis, M., et al., In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of 
administration is important to achieve synergistic cytotoxic effects. Blood, 2004. 104(4): p. 1145- 
50. 
18. 
Levis, M., et al., Results from a randomized trial of salvage chemotherapy followed by 
lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood, 2011. 117(12): p. 3294- 
301. 
19. 
Jain, P., et al., Mutated NPM1 in patients with acute myeloid leukemia in remission and relapse. 
Leuk Lymphoma, 2014. 55(6): p. 1337-44. 
20. 
Ravandi, F., et al., Phase I/II study of combination therapy with sorafenib, idarubicin, and 
cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol, 2010. 28(11): p. 1856- 
62. 
21. 
Serve, H., et al., Sorafenib in combination with intensive chemotherapy in elderly patients with 
acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol, 2013. 
31(25): p. 3110-8. 
22. 
Wander, S.A., M.J. Levis, and A.T. Fathi, The evolving role of FLT3 inhibitors in acute myeloid 
leukemia: quizartinib and beyond. Ther Adv Hematol, 2014. 5(3): p. 65-77. 
23. 
Larrosa-Garcia, M. and M.R. Baer, FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and 
Future Directions. Mol Cancer Ther, 2017. 16(6): p. 991-1001. 
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IRB Approval date:  03/11/2021 
Version:  03/03/2021 
 
 
24. 
Smith, C.C., et al., Characterizing and Overriding the Structural Mechanism of the Quizartinib- 
Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397. Cancer Discov, 2015. 5(6): p. 668- 
79. 
25. 
Baker, S.D., et al., Emergence of polyclonal FLT3 tyrosine kinase domain mutations during 
sequential therapy with sorafenib and sunitinib in FLT3-ITD-positive acute myeloid leukemia. Clin 
Cancer Res, 2013. 19(20): p. 5758-68. 
26. 
Kindler, T., D.B. Lipka, and T. Fischer, FLT3 as a therapeutic target in AML: still challenging after 
all these years. Blood, 2010. 116(24): p. 5089-102. 
27. 
McMahon, C.M., et al., Mechanisms of Acquired Resistance to Gilteritinib Therapy in Relapsed 
and Refractory FLT3 -Mutated Acute Myeloid Leukemia. Blood, 2017 ASH Abstract, 2017. 
130(295). 
28. 
Zhang, H., et al., Exome Sequencing Informs Mechanisms of Clinical Resistance to the FLT3-D835 
Inhibitor Crenolanib. Blood 2015 ASH Annual Meeting, 2015 126(2468). 
29. 
Panetta, J.C., et al., Population pharmacokinetics of crenolanib, a type I FLT3 inhibitor, in patients 
with relapsed/refractory AML. 2015, Blood. p. 3695. 
30. 
Patel, J.P., et al., Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. 
N Engl J Med, 2012. 366(12): p. 1079-89. 
31. 
Papaemmanuil, E., et al., Genomic Classification and Prognosis in Acute Myeloid Leukemia. N 
Engl J Med, 2016. 374(23): p. 2209-2221. 
32. 
McMahon, C.M., et al., Mechanisms of acquired resistance to gilteritinib therapy in relapsed and 
refractory FLT3-mutated acute myeloid leukemia. Blood, 2017. 130. 
33. 
Janning, M., I. Ben-Batalla, and S. Loges, Axl inhibition: a potential road to a novel acute myeloid 
leukemia therapy? Expert Rev Hematol, 2015. 8(2): p. 135-8. 
34. 
Park, I.K., et al., Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 
internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential 
therapeutic target. Blood, 2013. 121(11): p. 2064-73. 
35. 
Park, I.K., et al., Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3- 
targeted therapy in acute myeloid leukemia. Leukemia, 2015. 29(12): p. 2382-9. 
36. 
Ben-Batalla, I., et al., Axl, a prognostic and therapeutic target in acute myeloid leukemia 
mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood, 2013. 122(14): 
p. 2443-52. 
37. 
Ju, H.Q., et al., ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders 
therapeutic sensitivity to glycolytic inhibition. Leukemia, 2017. 31(10): p. 2143-2150. 
38. 
Gallipoli, P., et al., Glutaminolysis is a metabolic dependency in FLT3(ITD) acute myeloid leukemia 
unmasked by FLT3 tyrosine kinase inhibition. Blood, 2018. 131(15): p. 1639-1653. 
39. 
Gregory, M.A., et al., Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid 
leukemia. Exp Hematol, 2018. 58: p. 52-58. 
40. 
Mollard, A., et al., Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase 
Inhibitors. ACS Med Chem Lett, 2011. 2(12): p. 907-912. 
41. 
Myers, S.H., V.G. Brunton, and A. Unciti-Broceta, AXL Inhibitors in Cancer: A Medicinal Chemistry 
Perspective. J Med Chem, 2016. 59(8): p. 3593-608. 
42. 
Smith, C.C., et al., Validation of ITD mutations in FLT3 as a therapeutic target in human acute 
myeloid leukaemia. Nature, 2012. 485(7397): p. 260-3. 
43. 
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. 
44. 
Albers, C., et al., The secondary FLT3-ITD F691L mutation induces resistance to AC220 in FLT3- 
ITD+ AML but retains in vitro sensitivity to PKC412 and Sunitinib. Leukemia, 2013. 27(6): p. 1416- 
8. 
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45. 
Man, C.H., et al., Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial 
outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a 
D835 mutation. Blood, 2012. 119(22): p. 5133-43. 
46. 
Chu, S.H. and D. Small, Mechanisms of resistance to FLT3 inhibitors. Drug Resist Updat, 2009. 
12(1-2): p. 8-16. 
47. 
Sexauer, A., et al., Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in 
FLT3/ITD AML. Blood, 2012. 120(20): p. 4205-14. 
48. 
Vernieri, C., et al., Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions. 
Cancer Discov, 2016. 6(12): p. 1315-1333. 
49. 
Knapper, S., et al., A randomized assessment of adding the kinase inhibitor lestaurtinib to first- 
line chemotherapy for FLT3-mutated AML. Blood, 2017. 129(9): p. 1143-1154. 
50. 
Ravandi, F., et al., Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid 
leukemia and FLT-3 internal tandem duplication mutation. Blood, 2013. 121(23): p. 4655-62. 
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Appendix A. Cytochrome P450 Drug Interaction Table 
 
Physicians should be aware of the possibility of drug interactions when TP-0903 is co-administered with drugs that are inhibitors or inducers of CYP2C19. 
Physicians should refer to the products label and to the drug interaction website provided below. The website listing Cytochrome P450 inhibitors and 
inducers is updated on an ongoing basis and can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table. Below is a snapshot of the website as 
of August 2018. Attention should be focused on the 2C19 column. Please note that the website also lists substrates of CYP2C19. 
 
Cytochrome P450 Drug Interaction Table  
Substrates 
 
 
 
 
 
 
 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A 4,5,6 
amitriptyline  
caffeine2  
clomipramine  
clozapine  
cyclobenzaprine  
duloxetine  
estradiol  
fluvoxamine  
haloperidol  
imipramine N-DeMe  
mexiletine  
nabumetone  
naproxen  
olanzapine  
ondansetron  
phenacetin1→  
acetaminophen → 
NAPQI propranolol  
riluzole  
ropivacaine  
tacrine2  
artemisinin  
bupropion1  
cyclophosphamid
e  
efavirenz1  
ifosphamide  
ketamine  
meperidine  
methadone  
nevirapine  
propafol  
selegiline  
sorafenib  
 
amodiaquine  
cerivastatin  
paclitaxel  
repaglinide  
sorafenib  
torsemide  
 
 
NSAIDs:  
diclofenac  
ibuprofen  
lornoxicam  
meloxicam S-
naproxen→  
Norpiroxicam  
suprofen  
 
Oral 
Hypoglycemic 
Agents:  
tolbutamide  
glipizide  
 
Angiotensin II 
Blockers:  
losartan  
irbesartan  
 
Sulfonylureas:  
PPIs:  
esomeprazole  
lansoprazole  
omeprazole2  
pantoprazole  
 
Anti-epileptics:  
diazepam→ 
Nor phenytoin(O)  
S-mephenytoin1  
phenobarbitone  
 
amitriptyline  
carisoprodol  
citalopram  
chloramphenicol  
clomipramine  
clopidogrel  
cyclophosphamid
e  
hexobarbital  
tamoxifen  
 
Beta Blockers:  
carvedilol  
S-metoprolol  
propafenone  
timolol  
 
Antidepressants:  
amitriptyline  
clomipramine  
desipramine  
fluoxetine  
imipramine  
paroxetine  
venlafaxine  
 
Antipsychotics:  
haloperidol  
perphenazine  
risperidone→9-OH  
Anesthetics:  
enflurane  
halothane  
isoflurane  
methoxyflurane  
sevoflurane  
acetaminophen→ 
NAPQI  
aniline2  
benzene  
chlorzoxazone1  
ethanol  
N,N-
dimethylformamid
e  
theophylline→8-
OH  
 
Macrolide  
clarithromycin  
erythromycin2 
(not NOT 
telithromycin  
 
Anti-arrhythmics:  
quinidine→3-OH  
 
Benzodiazepines:  
alprazolam  
diazepam→3OH  
midazolam1 
triazolam2  
 
Immune:  
cyclosporine  
tacrolimus (FK506)  
 
HIV  
indinavir  
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theophylline2  
tizanidine  
triamterene  
verapamil  
(R)warfarin  
zileuton  
zolmitriptan  
 
glyburide  
glibenclamide  
glipizide  
glimepiride  
tolbutamide  
 
amitriptyline  
celecoxib  
fluoxetine  
fluvastatin  
glyburide  
nateglinide  
phenytoin-4-
OH2  
rosiglitazone  
tamoxifen  
torsemide  
valproic acid  
S-warfarin  
zakirlukast  
 
imipramine N-
DeME  
indomethacin  
labetalol R- 
mephobarbital  
moclobemide  
nelfinavir  
nilutamide  
primidone  
progesterone  
proguanil  
propranolol  
teniposide R- 
warfarin→8-OH  
voriconazole  
 
 
thioridazinezuclopenthix
ol alprenolol  
amphetamine  
aripiprazole  
atomoxetine  
bufuralol1  
chlorpheniramine  
chlorpromazine  
clonidine codeine (→O-
desMe)  
debrisoquine2  
dexfenfluramine  
dextromethorphan1  
donepezil  
duloxetine  
encainide  
flecainide  
fluvoxamine  
lidocaine  
metoclopramide  
methoxyamphetamine  
mexiletine  
minaprine  
nebivolol  
nortriptyline  
ondansetron  
oxycodone  
perhexiline  
phenacetin  
phenformin  
promethazine  
propafenone  
propranolol  
risperidone  
sparteine  
nelfinavir  
ritonavir  
saquinavir  
 
Prokinetic:  
cisapride  
 
Antihistamines: 
astemizole 
chlorpheniramine 
terfenadine2 
 
Calcium  
amlodipine  
diltiazem  
felodipine  
lercanidipine  
nifedipine2  
nisoldipine  
nitrendipine  
verapamil  
 
HMG:  
atorvastatin  
cerivastatin  
lovastatin  
NOT  
NOT  
simvastatin  
 
Steroid  
estradiol  
hydrocortisone  
progesterone  
testosterone1  
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tramadol  
 
Miscellaneous:  
alfentanil  
aprepitant  
aripiprazole  
boceprevir  
buspirone  
carbamazepine  
cafergot  
caffeine→TMU  
cilostazol cocaine  
codeine-N- 
demethylation  
dapsone  
dexamethasone  
dextromethorphan
2  
docetaxel  
domperidone  
eplerenone  
fentanyl 
finasteride  
gleevec  
haloperidol  
irinotecan  
LAAM  
lidocaine  
methadone  
nateglinide  
nevirapine  
ondansetron  
pimozide  
propranolol  
quetiapine  
quinine  
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risperidone  
romidepsin  
salmeterol  
sildenafil  
sirolimus  
sorafenib  
sunitinib  
tamoxifen  
taxol  
telaprevir  
terfenadine  
torisel  
trazodone  
vemurafenib  
vincristine  
zaleplon  
ziprasidone  
zolpidem  
Inhibitors 
 
 
 
 
 
 
 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A 4, 5, 6 
fluvoxamine  
ciprofloxacin  
cimetidine  
amiodarone  
efavirenz  
fluoroquinolones  
fluvoxamine  
furafylline1  
interferon  
methoxsalen  
mibefradil  
ticlopidine  
 
clopidogrel  
thiotepa  
ticlopidine  
voriconazole  
gemfibrozil2  
trimethoprim
2  
glitazones  
montelukast1  
quercetin1  
 
fluconazole2  
amiodarone  
efavirenz  
fenofibrate  
fluconazole  
fluvastatin  
fluvoxamine2  
isoniazid  
lovastatin  
metronidazole  
paroxetine  
phenylbutazone  
probenicid  
sertraline  
PPIs:  
esomeprazole  
lansoprazole  
omeprazole2  
pantoprazole  
 
Other:  
chloramphenicol  
cimetidine  
felbamate  
fluoxetine  
fluvoxamine  
indomethacin  
isoniazid  
ketoconazole  
bupropion  
cinacalcet  
fluoxetine  
paroxetine  
quinidine1  
duloxetine  
sertraline  
terbinafine  
amiodarone  
cimetidine  
celecoxib  
chlorpheniramine  
chlorpromazine  
citalopram  
clemastine  
diethyl-
dithiocarbamate2 
disulfiram  
 
HIV Antivirals:  
indinavir  
nelfinavir ritonavir  
clarithromycin  
itraconazole1  
ketoconazole  
nefazodone  
saquinavir  
suboxone  
telithromycin  
aprepitant  
erythromycin  
fluconazole  
grapefruit juice  
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sulfamethoxazol
e  
sulfaphenazole1  
teniposide  
voriconazole  
zafirlukast  
 
 
modafinil  
 
Oral 
contraceptives:  
oxcarbazepine  
probenicid  
ticlopidine2  
topiramate  
voriconazole  
clomipramine  
cocaine  
diphenhydramine  
doxepin  
doxorubicin  
escitalopram  
halofantrine  
haloperidol  
histamine H1 receptor 
antagonists  
hydroxyzine  
levomepromazine  
methadone  
metoclopramide  
mibefradil  
midodrine  
moclobemide  
perphenazine  
promethazine  
ranitidine  
reduced-haloperidol  
ritonavir  
ticlopidine  
tripelennamine  
 
verapamil2 
diltiazem  
cimetidine  
amiodarone  
chloramphenicol  
boceprevir  
ciprofloxacin  
delaviridine 
diethyl- 
dithiocarbamate  
fluvoxamine  
gestodene  
imatinib  
mibefradil  
mifepristone  
norfloxacin  
norfluoxetine  
starfruit  
telaprevir  
voriconazole  
 
Inducers 
 
 
 
 
 
 
 
1A2 
2B6 
2C8 
2C9 
2C19 
2D6 
2E1 
3A 4, 5, 6 
broccoli  
brussel sprouts  
carbamazepine  
char-grilled meat  
insulin 
methylcholanthrene
1  
modafinil  
artemisinin  
carbamazepine  
efavirenz  
nevirapine  
phenobarbital  
phenytoin  
rifampin  
 
rifampin 
carbamazepine 
enzalutamide  
nevirapine 
phenobarbital 
rifampin 
secobarbital  
St. John's Wort  
 
carbamazepine 
efavirenz 
enzalutamide 
norethindrone 
NOT 
pentobarbital 
prednisone 
rifampicin  
dexamethasone  
rifampin  
 
Ethanol 
isoniazid  
 
HIV Antivirals: 
efavirenz  
nevirapine  
barbiturates 
carbamazepine  
enzalutamide 
glucocorticoids 
modafinil 
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nafcillin  
beta-
naphthoflavone1  
omeprazole1  
rifampin  
tobacco  
 
 
ritonavir  
St. John's Wort  
  
 
oxcarbazepine 
phenobarbital2 
phenytoin2 
pioglitazone  
rifabutin  
rifampin  
St. John's Wort  
troglitazone  
 
 
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