Clinical trial NCT02272998
Conditions: Malignant Neoplasm
Keywords: FGFR, RET, KIT
Sponsor: Sameek Roychowdhury
Start date: 2015-02-24; Completion date: 2022-11-17
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well ponatinib hydrochloride works in treating patients with cancer that has spread to other parts of the body (metastatic), has failed previous treatment (refractory), and has one of several alterations, or mutations, in its deoxyribonucleic acid (DNA) sequence. Ponatinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether a patient's genetic alterations may affect how well ponatinib hydrochloride works.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the response of ponatinib (ponatinib hydrochloride) in patients with fibroblast growth factor receptor (FGFR) altered cancers.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of ponatinib in advanced solid tumors with genomic FGFR alterations.

II. To assess progression free survival (PFS) and overall survival (OS) with ponatinib.

III. To determine candidate genomic and proteomic biomarkers of sensitivity and resistance to ponatinib using unbiased high throughput approaches (exome, transcriptome, reverse phase protein array \[RPPA\]).

IV. To assess response of ponatinib in advanced cancers with subsets of genomic FGFR alterations (fusions vs. amplifications vs. mutations).

OUTLINE:

Patients receive ponatinib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 52 weeks.

Arms: arm 1: Patients receive ponatinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: ponatinib hydrochloride intervention 2: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
Version: 03/23/2020 
OSU IRB Approved:  5/22/2020 
1 
 
OSU Protocol # 14078: 
 
 
TITLE: Phase II study of ponatinib for advanced cancers with genomic alterations in 
fibroblastic growth factor receptor (FGFR) and other genomic targets (KIT, PDGFRα, RET 
FLT3, ABL1) 
 
Coordinating Center: 
 
 
The Ohio State University – Wexner Medical Center 
 
*Principal Investigator: 
Sameek Roychowdhury, MD, PhD 
 
460 W 12th Ave, 508 Biomedical Research Tower,  
 
Columbus, OH-43210-1267 
 
Phone: (614) 685-5841 
 
Fax: (614) 292-6356 
 
sameek.roychowdhury@osumc.edu  
 
 
Statistician: 
Susan Geyer, PhD 
 
University of South Florida 
 
Susan.geyer@epi.usf.edu 
 
CTO Multi-Center Trial Program: 
Phone: (614) 366-5642 
Fax: (614) 366-6652 
OSUCCC-CTO-MCTP@osumc.edu 
 
 
 
Participating Centers:   
 
University of Michigan 
 
 
IND #  122943   
 


Version: 03/23/2020 
OSU IRB Approved:  5/22/2020 
1 
SCHEMA 
 
Figure 1: Trial outline is shown 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
TABLE OF CONTENTS 
 
1. 
OBJECTIVES ......................................................................................................................4 
1.1 
Primary Objectives ...................................................................................................4 
1.2 
Secondary Objectives ...............................................................................................4 
2. 
BACKGROUND .................................................................................................................4 
2.1 
Study Disease(s).......................................................................................................4 
2.2 
Investigational New Drug ........................................................................................6 
2.3 
Rationale ................................................................................................................26 
3. 
PATIENT SELECTION ....................................................................................................27 
3.1 
Eligibility Criteria ..................................................................................................27 
3.2 
Exclusion Criteria ..................................................................................................29 
3.3 
Inclusion of Women and Minorities ......................................................................31 
4. 
REGISTRATION PROCEDURES ...................................................................................31 
4.1 
General Guidelines .................................................................................................31 
4.2 
External Participating Site Registration Process ....................................................32 
5. 
TREATMENT PLAN ........................................................................................................33 
5.1 
Agent Administration .............................................................................................33 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................33 
5.3 
Duration of Therapy ...............................................................................................34 
5.4 
Duration of Follow Up ...........................................................................................34 
5.5 
Criteria for Removal from Study ...........................................................................34 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................35 
6.1 
Dose Modifications for Ponatinib ..........................................................................35 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS:  LIST AND REPORTING 
REQUIREMENTS .............................................................................................................46 
7.1 
Definitions..............................................................................................................46 
7.2 
Adverse Reactions for Ponatinib ...........................................................................48 
Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities ........................52 
Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities ................52 
7.3 
Adverse Event Characteristics ...............................................................................53 
7.4 
Exchange of Safety Information ............................................................................53 
7.5 
Serious Adverse Event Reporting Procedures .......................................................55 
8. 
PHARMACEUTICAL AGENT INFORMATION ...........................................................59 
8.1 
Ponatinib ................................................................................................................59 
9. 
BIOMARKER AND CORRELATIVE STUDIES ............................................................60 
9.1 
Collection of Specimens ........................................................................................61 
9.2 
Laboratory Correlative Studies ..............................................................................63 
9.3 
Specimen Storage and Disposal .............................................................................65 


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9.4 
Sites Performing Correlative Studies .....................................................................65 
9.5 
Potential risks and procedures for minimizing risks ..............................................65 
10. 
STUDY CALENDAR .......................................................................................................69 
11. 
MEASUREMENT OF EFFECT........................................................................................70 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................70 
12. 
STATISTICAL CONSIDERATIONS...............................................................................77 
12.1 
Study Design/Endpoints.........................................................................................77 
12.2 
Analysis of Primary Objectives .............................................................................77 
12.3 
Sample Size/Accrual Rate ......................................................................................79 
12.4 
Analysis of Secondary Objectives .........................................................................79 
12.5 
Reporting and Exclusions ......................................................................................80 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................82 
APPENDIX B 
MEDICATION DIARY...............................................................................0 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS .....................0 
APPENDIX D             PONATINIB MEDICATION GUIDE........................................................2 
 
APPENDIX E  
COVID-19 PRECAUTIONS 
References ........................................................................................................................................8 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
To evaluate the response of ponatinib in solid tumor patients with FGFR alterations.  
 
1.2 
Secondary Objectives 
 
 To assess the safety and tolerability of ponatinib in advanced solid tumors with genomic 
FGFR alterations 
 To assess progression free survival (PFS) and overall survival (OS) with ponatinib 
 To determine candidate genomic and proteomic biomarkers of sensitivity and resistance 
to ponatinib using unbiased high throughput approaches (exome, transcriptome, RPPA) 
 To assess response of ponatinib in advanced cancers with subsets of genomic FGFR 
alterations (fusions vs. amplifications vs. mutations) 
 To assess response of ponatinib by tumor type 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Fibroblast growth factors (FGF) and their receptors (FGFRs) play essential roles in 
mediating cell proliferation, migration, angiogenesis, and survival.1 FGFR belongs to the 
receptor tyrosine kinase (RTK) receptor family of proteins that also includes epidermal growth 
factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) family. FGFR 
family has 5 members (FGFR1-4 and FGFRL1) and 18 known ligands. The ligand-receptor 
interaction is stabilized by the formation of a ternary complex involving heparan sulfate 
proteoglycans (HSPG) or Klotho proteins.2 Specificity in signaling is afforded based on tissue 
specific expression as well as interaction of FGFs, FGFRs, HSPGs, and Klotho proteins. FGFR 
activation leads to phosphorylation of FGFR substrate 2 (FRS2) and recruitment of growth 
factor-receptor bound 2 (GRB2) resulting in the activation of downstream mitogen activated 
protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/ Akt pathway. Additionally, 
activation of PKC is carried out independent of FRS2, through phospholipase C-γ (PLC-γ) 
mediated activation of phosphatidylinositol 3,4,5-triphosphate (PIP3) and diacylglycerol (DAG). 
 
Deregulation of FGF-FGFR signaling has been recognized in multiple solid tumors 
including breast, prostate, bladder, stomach, endometrial and lung cancers.1 Cancer genomic 
analyses have identified alterations in FGFR including point mutations, amplifications, and gene 
fusions. A list of common FGFR alterations in cancers is shown in Table-1. Mutations in FGFR2 
have been observed in about 10-15% of endometrial cancers and these have also shown 
sensitivity to FGFR inhibitors.1 FGFR3 mutations are reported in approximately 70% of low 
grade urothelial carcinomas.3 Mutations in FGFR4 are identified in 7 to 8% of 
rhabdomyosarcomas.4 Approximately, 10% of the patients with breast cancer harbor the 8p11-12 
amplicon leading to overexpression of FGFR15 in the highly proliferative luminal B breast 
cancers and has been shown to correlate with resistance to hormonal therapy leading to worse 
outcomes.6, 7 Amplification of FGFR2 has also been implicated in 4% of triple-negative breast 
cancers (TNBC)8, particularly in BRCA2 associated tumors.9 FGFR1 amplification has also been 


5 
reported in 22% of squamous lung carcinomas.10 Gene fusions involving FGFR1 have been 
reported in alveolar rhabdomyosarcomas, 8p11 myeloproliferative syndrome and 
glioblastomas.11, 12 FGFR3-MMSET fusion resulting from t(4:14) translocation, is seen in 15 to 
20% of patients with multiple myeloma and is associated with a worse prognosis.13 Recently, the 
Chinnaiyan Lab (Co-Investigator) at University at Michigan identified novel FGFR2 and 
FGFR3 fusions in diverse solid tumors including biliary, breast, and prostate cancers. They 
further demonstrated that the FGFR fusions result in constitutive activation of FGFR signaling, 
substantiating that FGFR fusions could potentially be a clinically important target.14 The 
widespread prevalence of FGFR activating alterations across multiple cancer subtypes provides 
an excellent opportunity to assess if FGFR inhibitors would lead to meaningful clinical responses 
among patients with activating alterations in FGFR.15-18 
 
 
 
 
FGFR Alteration 
Cancer 
Prevalence 
Amplifications 
FGFR1 
Squamous Lung Cancer18 
22% 
 
Breast Cancer (Estrogen Receptor-
Positive)19 
10% 
FGFR2 
Gastric Cancer20 
9% 
 
Breast Cancer (Triple Negative)8 
4% 
Mutations 
FGFR2 
Endometrial Cancer16 
10% 
 
Melanoma11 
10% 
FGFR3 
Bladder Cancer (Invasive)3 
15% 
 
Multiple Myeloma21 
1% 
FGFR4 
Rhabdomyosarcoma4 
8% 
Fusions/ Translocations 
FGFR1 
8p11 Myeloproliferative Syndrome22 
>90% 
 
Alveolar Rhabdomyosarcoma23 
80% 
 
Glioblastoma Multiforme12 
3% 
FGFR2 
Cholangiocarcinoma14 
Rare (<1%) 
 
Breast Cancer14 
Rare (<1%) 
 
Prostate Cancer14 
Rare (<1%) 
 
Thyroid cancer14 
Rare (<1%) 
FGFR3 
Multiple Myeloma13 
12% 
 
Peripheral T Cell Lymphoma24 
Rare (<1%) 
 
Glioblastoma Multiforme12 
3% 
 
Bladder Cancer14 
Rare (<1%) 
Table 1: Distribution and prevalence of FGFR genomic alterations 
 


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2.2 
Investigational New Drug 
 
2.2.1 Ponatinib (AP24534) 
 
Ponatinib (Takeda Pharmaceutical Company; Iclusig) is a FDA-approved oral drug for the 
treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, 
accelerated phase, or blast phase) or T315I-Philadelphia chromosome positive acute 
lymphoblastic leukemia (Ph+ ALL). It is also indicated in the treatment of adult patients with 
chronic phase, accelerated phase, or blast phase CML or Ph+ ALL for whom no other tyrosine 
kinase inhibitor (TKI) therapy is indicated.25 In addition to BCR-ABL, it has activity against 
FGFR, KIT, platelet-derived growth factor receptor (PDGFR), RET and FLT3 kinases.17, 26  
 
The following information is summarized from the Ponatinib Investigator’s Brochure (4.2014) 
and USPI (12.2013). 
 
Mechanism of Action 
 
 
AP24534 (international non-proprietary name [INN]: ponatinib) is a novel, orally-
available TKI. In addition to BCR-ABL, ponatinib is also a potent inhibitor of members of the 
FGFR family, which are implicated in a variety of solid tumors. Ponatinib also inhibits other 
kinases, including KIT, RET, VEGFR, PDGFRα, FMS-like tyrosine kinase 3 (FLT3) receptor 
tyrosine kinase expressed on vascular endothelium (TIE2), and tyrosine kinase homologous to 
the Rous sarcoma virus oncogene protein PP60 (SRC). Taken together, the kinase inhibition 
profile of ponatinib suggests the potential for clinical activity in other hematologic and non-
hematologic malignancies in addition to CML. 
 
Preclinical data: 
 
FGFR 
 
Ponatinib potently inhibited the in vitro kinase activity of all 4 FGFRs (IC50: 2 to 18 
nM). In Ba/F3 cells dependent on activated variants of native FGFR1-4 (via fusion to a TEL 
dimerization domain), ponatinib inhibited viability with IC50s of 14-47 nM. In Ba/F3 cells 
engineered to express activated FGFR1-4, ponatinib potently inhibited FGFR mediated signaling 
and viability with IC50s <40 nM, with substantial selectivity over parental Ba/F3 cells. Similar 
potency was observed in human embryonic kidney (HEK-293) cells transiently transfected to 
overexpress full-length FGFR1-3, as measured by inhibition of FGFR phosphorylation (IC50s 
15-35 nM). In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, 
gastric, breast, lung, and colon), and containing FGFRs dysregulated by a variety of mechanisms, 
ponatinib inhibited FGFR mediated signaling with IC50s <40 nM and inhibited viability with 
IC50 values of 7 to 181 nM.17 Ponatinib had substantially reduced activity (IC50s>300nM) 
against cells that did not contain a deregulated FGFR. Daily oral dosing of ponatinib (10 to 30 
mg/kg) to mice reduced tumor growth and inhibited signaling in all 3 FGFR-driven models 
examined. These results demonstrate that ponatinib is a potent inhibitor of all 4 FGFR family 
members with activity in multiple FGFR-driven cancer types. 
 


7 
The HEK cell system was used to further assess ponatinib’s ability to inhibit FGFR 
mutations. Of 12 FGFR2 mutants tested, ponatinib inhibited the activity of 10 with high potency 
and 2 with moderate potency. The 10 mutants inhibited most potently (IC50 < 45 nM) included 
the 2 that together account for over half of those observed in endometrial cancer (S252W and 
N550K). Also included were the mutants located in all 4 functional domains: the LB domain 
(S252W and P253R), the EC domain (Y376C and W290C), the TM domain (C383R), and the 
KD domain (I548V, N550K, G584W, K660N and R738K). The 2 FGFR2 mutants inhibited with 
moderate potency (IC50: 113 nM to 152 nM) were N550H and K660E. Ponatinib had moderate 
potency against the FGFR3-S249C EC domain mutant (IC50: 128 nM) commonly found in 
bladder cancer, and did not inhibit the less common K652E KD mutant. Ponatinib potently 
inhibited the FGFR1-N546K KD mutant found in glioblastoma multiforme (IC50: 18 nM). 
 
 
RET 
 
RET kinase is deregulated by activating mutations or fusion gene formation in 
multiple cancers. RET point mutations are found in 50-95% of medullary thyroid cancers (MTC) 
and translocations involving RET occur in papillary thyroid cancer.27 Recently, a novel 
translocation that results in formation of a KIF5B-RET fusion oncogene has been identified in 1-
2% of non-small cell lung cancers (NSCLC).28 Ponatinib inhibits the in vitro kinase activity of 
RET with an IC50 of 0.16 nM. In Ba/F3 cells dependent on activated RET (activated via fusion 
to the TEL dimerization domain) ponatinib potently inhibited viability with an IC50 of 8 nM. In 
Ba/F3 cells dependent on expression of the most common, naturally-occurring activated variants 
of RET found in MTC and NSCLC, ponatinib potently inhibits viability of RET C634R, RET 
M918T, and KIF5B-RET cells with IC50s of 2, 3, and 11 nM, respectively. Consistent with these 
effects being due to inhibition of RET, ponatinib inhibited RET phosphorylation with similar 
potency in each respective cell line (IC50s of 4, 2, and 9 nM).  
 
PDGFR and KIT 
 
In in vitro assays, ponatinib has been shown to inhibit the kinase activity of PDGFRα 
(1.1 nM IC50), as well as PDGFRβ. In Ba/F3 cells dependent on activated PDGFRα, ponatinib 
inhibited viability and PDGFRα phosphorylation with IC50s of 1 and 5 nM, respectively and in a 
cell line containing an activated PDGFRα (FIP1L1- PDGFRα fusion), ponatinib inhibited 
viability and PDGFRα phosphorylation with IC50s of 0.5 and 0.6 nM, respectively. Ponatinib 
also potently inhibited viability of Ba/F3 cells expressing activated PDGFRα containing the 
gatekeeper T674I mutation with an IC50 of 2 nM.29 
Ponatinib has been shown to inhibit the kinase activity of KIT (12.5 nM IC50). In 
cellular assays, ponatinib also inhibited activated variants of KIT and variants with secondary 
mutations that confer clinical resistance to other KIT inhibitors approved for the treatment of 
gastrointestinal stromal tumors (GIST), imatinib and sunitinib. Ponatinib potently inhibited 
viability of Ba/F3 cells expressing activated KIT (exon 11 Δ557-8), activated KIT with a 
secondary T670I gatekeeper mutation, and activated KIT with the secondary activation loop (A-
loop) mutations D816H, D820A, N822K, and A829P (IC50s <15 nM for all mutants).29 
Ponatinib potency is slightly reduced versus the KIT exon 9 primary mutant (IC50 = 56 nM), or 
when V654A is present as a secondary mutation (IC50 = 59 nM).Takeda is supporting a separate 


8 
clinical trial investigating the benefit of ponatinib for the treatment of advanced gastrointestinal 
tumor (GIST) with KIT mutations refractory to two different tyrosine kinase inhibitors. 
 
FLT3 
 
Ponatinib inhibits the in vitro kinase activity of FLT3 with an IC50 of 12.6 nM. Studies 
conducted to examine the activity of ponatinib in models of FLT3-driven AML.30 Ponatinib 
potently inhibited phosphorylation of FLT3-ITD and viability of MV4-11 cells with IC50s ≤2 
nM. In contrast, ponatinib inhibited viability of RS4-11 cells, which express native FLT3, with 
an IC50 >100 nM. MV4-11 cells were used to test the antitumor activity of ponatinib in vivo. In 
a xenograft model, significant inhibition of tumor growth occurred with daily oral dosing of 
ponatinib at doses of 2.5 mg/kg and greater. After administration of a single dose of ponatinib, a 
dose-dependent inhibition of FLT3-ITD phosphorylation in the tumor was observed that was 
associated with the degree of antitumor activity. In an in vitro kinase assay, ponatinib did not 
potently inhibit FLT3 containing a D835Y activating mutation (IC50: 948 nM). 
 
Pharmacodynamics 
 
In a cell-based assay, ponatinib concentrations of 20 nM (10.65 ng/mL) were sufficient to 
suppress most BCR-ABL mutant clones. However, ponatinib concentrations of 40 nM (21.3 
ng/mL) were required to suppress T315I gatekeeper mutants. The median and range of steady-
state Cmax and trough (Cmin) concentrations of ponatinib following 29 days of once-daily 
dosing of 15 mg, 30 mg and 45 mg are listed below.  
 
           Median, Maximum, and Minimum Ponatinib Exposure at Steady-State by Dose 
Dose 
Median Cmax (Range) (nM) 
Median Cmin (Range) (nM) 
15 mg QD (n = 8) 
49 (23 – 105) 
28 (11 – 68) 
30 mg QD (n = 9) 
125 (67 – 178) 
54 (41 – 89) 
45 mg QD (n = 21) 
161 (64 – 336) 
67 (22 – 137) 
 
Pharmacokinetics 
 
Absorption 
 
The AP24534-07-101 Phase 1 study, evaluated the safety, tolerability, maximum 
tolerated dose (MTD) and biologic properties of ponatinib, using a sequential, dose escalation, 
3+3 design with expansion of some cohorts to provide additional safety data at each dose level 
(2, 4, 8, 15, 30, 45, or 60 mg/day).25 Dose escalation began at 2 mg and extended up to 60 mg 
once-daily oral dosing. The pharmacokinetic profiles of parent ponatinib and AP24567 (a 
CYP3A4/5-mediated desmethyl-ponatinib metabolite) were characterized on the first day of 
study treatment, Cycle 1 Day 1 (C1D1), and on Day 1 of Cycle 2 (C2D1). All patients in the 2, 4, 
8, 15, and 30 mg cohorts were given the capsule formulation. However, a total of 24 of 50 
patients in the combined 45 and 60 mg cohorts received a tablet formulation instead of the 
capsule. In the 45 mg and 60 mg cohorts, there was no evidence of statistically important 
differences between the tablet and capsule formulations based on either Cmax (p=0.53) or AUC0-
τ (p=0.64). Therefore, the capsule and tablet pharmacokinetic data were pooled together in 
summaries by dose in this analysis. As of 06 January 2014, 24 (29.6%) of the 81 enrolled 


9 
patients remained on therapy. Median patient age was 55 years; median time elapsed from 
original diagnosis to enrollment was 5.5 years. Prior therapies in CML and Ph+ ALL patients 
included imatinib (97%), dasatinib (89%), nilotinib (55%), and other standard and investigational 
therapies; 94% of patients experienced a failure of 2 or more prior TKIs, while 62% had 
experienced a failure of 3 or more TKIs. 
 
Ponatinib plasma level data indicated that Cmax occurred 4 to 6 hours after dosing, and 
steady-state t1/2 was between 20 and 29 hours for doses ≥15 mg. The median tmax in the 15 
through 60 mg cohorts was 4 hours. At 45 mg (the recommended therapeutic dose), steady-state 
geometric mean (GeoMean) Cmax and minimum plasma concentration (Cmin) (both ng/mL), AUC 
from time 0 to the end of the dosing period (eg, 24 hours; AUC0-τ; h.ng/mL), and t1/2 (hours) 
were 77.41 (145.3 nM; percent coefficient of variance [%CV] 49.9), 34.22 (64.3 nM; %CV 
45.4), 1296 (%CV 48.1), and 22 (%CV 55.5), respectively. The mean steady-state Cmax and AUC 
appeared to increase in a manner approximately proportional with increasing dose, particularly in 
the 15- to 60-mg dose range. Cmax of 25.82 ng/mL (48.48 nM) at the 15 mg dose, and steady-
state trough concentrations (Ctrough) of 29.85 ng/mL (56.05 nM) at the 30 mg dose exceeded the 
40 nM exceeded the concentration (40nM) required for suppression of BCR-ABL. Following 
ingestion of either a high-fat or low-fat meal by 22 healthy volunteers, plasma ponatinib 
exposures (AUC and Cmax) were not different when compared to fasting conditions. The aqueous 
solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility. Drugs that 
elevate the gastric pH may reduce ponatinib bioavailability. 
 
Distribution 
 
Ponatinib was very highly bound to plasma protein of mouse, rat, monkey and human 
(≥99.8%). The blood to plasma partition ratios for ponatinib was 1.20, 1.13, 1.11, and 0.96 
respectively, in mouse, rat, monkey, and human blood. The percent distribution into RBCs was 
49.2%, 48.8%, 48.5%, and 46.8%, respectively in mouse, rat, monkey, and human blood. These 
results show ponatinib is equally distributed into RBCs and plasma. The geometric mean (CV%) 
apparent steady state volume of distribution is 1223 liters (102%) following oral administration 
of ponatinib 45 mg once daily for 28 days in patients with cancer.  Ponatinib is a weak substrate 
for both P-gp and BCRP in vitro. Ponatinib is not a substrate for organic anion transporting 
polypeptides (OATP1B1, OATP1B3) and organic cation transporter 1 (OCT1) in vitro. In vitro, 
ponatinib bound to human plasma proteins (at 145 nM) was not displaced from the binding sites 
by other highly protein-bound drugs: ibuprofen, salicylic acid, propranolol, nifedipine, or 
warfarin. 
 
 
 
Metabolism 
 
Ponatinib was not extensively metabolized in rat and human microsomes, but was 
metabolized to a moderate extent in monkey liver microsomes. The rate of metabolism 
(pmol/min/mg of protein) was 38.7, 83.5, and 36.2, respectively, in rat, monkey, and human liver 
microsomes. Major biotransformation pathways in liver microsomes were the formation of N-
desmethyl ponatinib (AP24567), and ponatinib N-oxide (AP24734). Metabolite AP24600 was 
not observed in these in vitro systems. Ponatinib was not metabolized by rhCYPs (recombinant 
human CYPs) 1A2, 2C9, and 2E1.rhCYPs 3A5 and 2C19 metabolized ponatinib to AP24567 and 
AP24734, but only to a very low extent of 3% to 5%. At least 64% of a ponatinib dose undergoes 
phase I and phase II metabolism. Ponatinib was mainly metabolized by CYP3A4 (52%), to a 


10 
moderate extent by CYP2C8 (30.4%), and to lesser extent by CYP2D6 (14.4%).  Results from 
the CYP-inhibition studies, using isoform-specific chemical inhibitors and inhibitory monoclonal 
antibodies, show that ponatinib was mostly metabolized by CYP3A4, and to a lesser extent by 
CYP2D6, CYP2C8, and CYP3A5.Since ponatinib is mostly metabolized by CYP3A4/5, it is 
likely to have drug-drug interactions with co-administered CYP3A4/5 inhibitors. Ponatinib is an 
inhibitor of P-glycoprotein, BCRP, and bile salt export pump (BSEP). 
 
Elimination 
 
The excretion of [14C] ponatinib in humans was investigated following a single target 
oral dose of 45 mg/100 μCi. [14C] Ponatinib (drug powder in capsules) was administered orally 
to each of 6 subjects (age 19 to 45 years) as three 15-mg capsules (each containing ~36.7μCi) 
with 240 mL of non-carbonated water in the fasted state. Whole plasma, urine, feces, and toilet 
tissue wipes were collected up to the time of discharge (10 to 14 days post dose, different for 
each subject). The mean percentage radioactive dose recovered was 5.38 ± 0.93% and 86.63 ± 
2.37%, in urine and feces respectively. In human plasma following an oral dose of [14C] 
ponatinib, ponatinib and metabolite AP24600 were the 2 major radioactive components. The 
levels of AP24600 were 58.4% of ponatinib levels. Urinary metabolites were mostly AP24600 
and its glucuronides. In human feces, all of the metabolites were biotransformation products of 
intact ponatinib. Ponatinib accounted for 23.7% of the radioactivity in feces and there was 
extensive metabolism of ponatinib in feces. Other metabolites identified in feces were hydroxy 
ponatinib, N-desmethyl ponatinib, and several minor metabolites. The geometric mean (range) 
terminal elimination half-life of ponatinib was approximately 24 (12 to 66) hours following 
ponatinib 45 mg oral administration once daily for 28 days in patients with cancer.  
 
Drug Interactions 
 
Ponatinib is a reversible inhibitor of CYPs, with IC50 in the range of 5.2 to 13.6 μM. 
Ponatinib is unlikely to inhibit CYP-mediated metabolism of concomitant drugs at plasma 
concentrations of ≤ 260 nM. Ponatinib is not a metabolism- or time-dependent inhibitor. The 
major human plasma metabolite, AP24600, was not an inhibitor of CYPs. Ponatinib did not 
induce expression of CYP1A2, CYP2B6 or CYP3A4 in the primary human hepatocytes up to a 
concentration of 5 μM. 
 
 
Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent 
CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette 
G2 (ABCG2) [also known as BCRP], and BSEP transporter systems in vitro. In a drug 
interaction study in healthy volunteers, co-administration of ponatinib with ketoconazole 
increased plasma ponatinib AUC0-inf  and Cmax by 78% and 47%, respectively, while exposure to 
AP24567 decreased by approximately 70%. When administering ponatinib with strong CYP3A 
inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 
mg once daily. Patients taking concomitant strong inhibitors may be at increased risk for adverse 
reactions. 
 
 
The phase 1 rifampin study (AP24534-12-107) was conducted in healthy subjects to 


11 
evaluate the effect of multiple oral doses of 600 mg rifampin on the PK of a single oral 45-mg 
dose of ponatinib and its CYP3A4-mediated human metabolite of ponatinib, AP24567. Overall, 
the rifampin study demonstrated a statistically and clinically relevant effect of rifampin 
coadministration on relative ponatinib and AP24567 bioavailability. Estimated mean ratios of 
Cmax, AUC0-t , and AUC0-∞, indicated decreased exposure to ponatinib by approximately 42%, 
59%, and 62%, respectively. Time to achieve maximal plasma ponatinib and AP24567 
concentrations was not altered. Estimated mean ratios of Cmax, AUC0-t , and AUC0-∞, indicated 
increased exposure to AP24567 by 222%, 114%, and 93%, respectively. Mean t½ was lower for 
both ponatinib and AP24567. 
 
Co-administration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. 
John’s Wort) with ponatinib should be avoided unless the benefit outweighs the possible risk of 
ponatinib underexposure. Monitor patients for signs of reduced efficacy. 
 
 
Ponatinib displays pH-dependent aqueous solubility in vitro; as pH increases, 
ponatinib solubility decreases. These in vitro data suggest that concomitant administration of 
agents that alter gastric pH, including H2 antagonists and proton pump inhibitors, could affect 
ponatinib absorption and should be avoided unless the benefit outweighs the possible risk of 
ponatinib underexposure.  AP 24534-12-108 is a phase-1 study designed to evaluate the effects 
of concomitant multiple doses of lansoprazole on the PK profile of single dose ponatinib in 
healthy subjects.This study demonstrated a statistically significant effect of lansoprazole 
coadministration on ponatinib Cmax and Tmax. However, these changes in absorption-related 
parameters did not result in corresponding changes in overall plasma exposure to ponatinib 
across the 2 treatments or the elimination half-life. Similar observations were observed for the 
main metabolite, AP24600. Estimated mean ratios of ponatinib and AP24600 Cmax decreased by 
25%, and the 90% CIs did not fall within the 80% to 125% required for bioequivalence, 
suggesting the presence of a statistically significant DDI. Time to achieve maximal plasma 
ponatinib and AP24600 concentrations was slightly delayed by 1 and 2 hours, respectively; this 
is not thought to represent a clinically relevant difference. Plasma exposures of ponatinib and 
AP24600 in terms of AUC0-t and AUC0-∞ were equivalent after ponatinib dosing either alone 
or with lansoprazole (eg, within the bioequivalence criteria). Mean t½ was not altered for either 
ponatinib or AP24600. These minor reductions in plasma ponatinib Cmax, without corresponding 
decreases in overall plasma exposure, are not believed to be important clinical safety or efficacy 
findings. Ponatinib therefore may be administered concurrently with drugs that raise gastric pH, 
without the need for a ponatinib dose adjustment or separation of administration. 
 
 
In vitro studies demonstrate that ponatinib inhibits the P-gp and ABCG2 [BCRP] 
transporter systems. The effect of co-administration of ponatinib with sensitive substrates of the 
P-gp (e.g., aliskiren, colchicine, dabigatran, digoxin, everolimus, fexofenadine, lapatinib, 
maraviroc, posaconazole, ranolazine, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 
(e.g., methotrexate, mitoxantrone, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) 
transporter systems on exposure of these substrates has not been evaluated in clinical studies.
 
 
 
 
Safety Profile 


12 
 
As of 06 January 2014, 753 patients have received ponatinib therapy through clinical 
studies, and 1312 through global expanded access programs. Following approval of ponatinib in 
the US and in Europe, more than 900 patients have been treated with ponatinib commercially. 
Ponatinib has a FDA safety label for arterial thrombosis, heart failure and hepatotoxicity. It is 
likely that some of the adverse effects are specific to myeloproliferative disorders (e.g. 
thrombosis, neutropenia). A dose intensity safety analysis showed a significant increase in grade 
3 or higher adverse reactions (i.e., hypertension, thrombocytopenia, neutropenia, rash, ALT 
elevation, AST elevation, pancreatitis, and lipase elevation) with an increase in dose intensity. 
 
 
Phase -1 (AP24534-07-101) study  
 
In the AP24534-07-101 phase-1 study, all the 81% experienced at least 1 adverse event (AE) 
during the study. Patients in the phase 1 study received a median dose intensity of 30 mg of 
ponatinib daily.  The median dosing period was 308 days (3 to 1799 days). 
 
By System Organ Class (SOC), 50 or more patients experienced events in the following 
categories: 
 Gastrointestinal disorders (70 patients, 86.4%) 
 General disorders and administration site conditions (68, 84.0%) 
 Investigations (65, 80.2%) 
 Infections and infestations (64, 79.0%) 
 Nervous system disorders and Skin and subcutaneous tissue disorders (58, 71.6% each) 
 Metabolism and nutrition disorders and Musculoskeletal and connective tissue disorders 
 (57, 70.4% each) 
 Respiratory, thoracic, and mediastinal disorders (50, 61.7%) 
 
Treatment-emergent adverse events (TEAEs) reported in more than 25% of patients included: 
 rash (48.1% of patients) 
 nausea (45.7%) 
 abdominal pain and fatigue (44.4% each) 
 headache (42.0%) 
 constipation and arthralgia (39.5% each) 
 vomiting (38.3%) 
 hypertension (37.0%) 
 peripheral edema, pyrexia, and platelet count decreased (35.8% each) 
 diarrhea (29.6%) 
 dry skin (27.2%) 
 pain in extremity (25.9%) 
 
Sixty-nine (85.2%) patients had events considered by the investigator to be related to ponatinib. 
Treatment-related AEs (TRAEs) of any grade, by preferred term, that occurred in more than 10% 
of patients included: 
 rash (33.3% of patients) 


13 
 platelet count decreased (29.6%) 
 lipase increased (19.8%) 
 arthralgia, dry skin, and fatigue (17.3% each) 
 pancreatitis (14.8%) 
 nausea, dermatitis acneiform, and headache (13.6% each) 
 abdominal pain, neutrophil count decreased, myalgia, and hypertriglyceridemia (12.3% 
 each) 
 hypertension (11.1%) 
 
Serious AEs (SAEs) were reported for 63 patients. The most commonly reported (≥ 10% of 
patients) SAEs were: 
 febrile neutropenia (14.8% of patients) 
 pneumonia (13.6%) 
 pyrexia (12.3%) 
 pancreatitis (11.1%) 
 
Twenty-one patients had SAEs that were considered by the investigator to be related to 
treatment, including the following: 
 pancreatitis (9 patients, 11.1%) 
 myocardial infarction (MI) and peripheral arterial occlusive disease (2 patients each, 
 2.5%) 
 abdominal pain, accidental overdose, cardiac failure congestive, cardiomyopathy, 
cerebral infarction, cholecystitis acute, coronary artery disease, dehydration, ejection 
fraction decreased, electrocardiogram (ECG) QT prolonged, hypertension, interstitial 
lung disease, intestinal ischemia, LVD, peripheral ischemia, platelet count decreased, 
troponin increased, and visceral arterial ischemia (1 patient each, 1.2%) 
 
Twenty patients died within 30 days of their last ponatinib dose. Time on study for these patients 
ranged from 11 to 1496 days (4.1 years). One patient in the 8-mg cohort died 2 days after 
receiving the last ponatinib dose, from a possibly related case of acute ischemic bowel. The 
investigator considered the SAE of acute ischemia bowel to be fatal (Grade 5) in intensity 
(previously reported as life threatening) and possibly related to study drug. 
Since cardiac events have been reported following use of approved TKIs, patients were 
monitored for signs of QT prolongation. Non-corrected QT decreased in both the 30 mg and 60 
mg dose groups between baseline and end-of-study; patients in the 45 mg dose group 
experienced a mean increase of 3.3 milliseconds in non-corrected QT in the same period.  
Twenty-eight patients in the phase 1 study experienced 1 or more events with preferred terms 
that have been classified as vascular occlusive. Among these 28 patients, 7 experienced 14 
vascular occlusive events that were considered by the investigator to be possibly or probably 
related to ponatinib therapy. 
 
 
 
 
Phase -2 (AP24534-10-201) study  


14 
 
In the Phase 2 Study (AP24534-10-201), for patients who had refractory CML (any phase) or 
Ph+ ALL, and either were resistant to or intolerant of therapy with either dasatinib or nilotinib; 
or had developed the T315I mutation of BCR-ABL, as of 06 January 2014, 172 (38.3%) patients 
remained on treatment, while 277 (61.7%) had discontinued. Median duration of exposure was 
508 days (ranging from 1 to 1202 days), with an overall median dose intensity of 36.2 mg QD 
(ranging from 3 to 52 mg QD). The majority (291, 64.8%) of phase 2 patients had their dose 
reduced at some point during the study, and 310 (69.0%) had a dose interruption of at least 3 
days while on study. Eighty-nine (30.6%) of the patients with dose reductions had their 
doses later re-escalated, and all (100.0%) of the patients with dose interruptions of 3 or more 
days resumed ponatinib therapy . All but 1 patient (448, 99.8%) experienced at least 1 TEAE, 
419 (93.3%) experienced at least 1 TRAE, 277 (61.7%) experienced at least 1 SAE, and 137 
(30.5%) experienced at least 1 treatment-related SAE. 
 
Treatment-emergent AEs of any grade that occurred in ≥10% of patients overall included: 
 
 thrombocytopenia, anemia, neutropenia 
 constipation, abdominal pain (including abdominal pain upper), nausea, diarrhea, 
 vomiting 
 headache 
 dry skin, rash 
 fatigue 
 pyrexia 
 arthralgia, myalgia, pain (including pain in extremity, back pain, bone pain, muscle 
 spasms) 
 hypertension 
 lipase increased 
 peripheral edema 
 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased 
 cough, dyspnea, upper respiratory tract infection, nasopharyngitis 
 asthenia 
 decreased appetite 
 dizziness 
 insomnia 
 
TRAEs were reported for 419 (93.3%) patients. The most commonly reported TRAEs of any 
grade (≥ 20% of patients) included: 
 platelet count decreased (37.6%) 
 rash (35.4%) 
 dry skin (32.3%) 
 abdominal pain (23.4%) 
 
The most common SAEs, by preferred term, that were considered related to ponatinib include: 
abdominal pain, cardiac failure, cardiac failure congestive, diarrhea, dyspnea, lipase increased, 
neutrophil count decreased, pancreatitis, pancytopenia, pericardial effusion, peripheral arterial 


15 
occlusive disease, platelet count decreased, and pleural effusion. 
 
Serious Treatment-Emergent and Treatment-Related Adverse Events by Preferred Term 
and Maximum Severity, or of Any Grade in ≥ 1% of Patients (N = 449) 
 
Serious Treatment-Emergent 
Serious Treatment-Related 
Preferred Term 
Any grade 
n (%) 
Grade 3 and 4 
n (%) 
Any Grade 
n (%) 
Grade 3 and 4 
n (%) 
Neoplasm progression 
38 (8.5) 
5 (1.1) 
0 
0 
Pneumonia 
29 (6.5) 
23 (5.1) 
4 (0.9) 
2 (0.4) 
Pancreatitis 
25 (5.6) 
24 (5.3) 
24 (5.3) 
23 (5.1) 
Pyrexia 
19 (4.2) 
4 (0.9) 
6 (1.3) 
0 
Abdominal pain 
18 (4.0) 
11 (2.4) 
9 (2.0) 
6 (1.3) 
Myocardial infarctiona 
16 (3.6) 
13 (2.9) 
7 (1.6) 
6 (1.3) 
Atrial fibrillation 
15 (3.3) 
9 (2.0) 
5 (1.1) 
3 (0.7) 
Anaemia 
15 (3.3) 
11 (2.4) 
6 (1.3) 
5 (1.1) 
Platelet count decreased 
14 (3.1) 
14 (3.1) 
8 (1.8) 
8 (1.8) 
Febrile neutropenia 
13 (2.9) 
13 (2.9) 
5 (1.1) 
5 (1.1) 
Coronary artery disease 
9 (2.0) 
9 (2.0) 
4 (0.9) 
4 (0.9) 
Sepsis 
8 (1.8) 
5 (1.1) 
2 (0.4) 
2 (0.4) 
Angina pectoris 
6 (1.3) 
4 (0.9) 
2 (0.4) 
2 (0.4) 
Cardiac failure 
8 (1.8) 
7 (1.6) 
6 (1.3) 
6 (1.3) 
Cardiac failure congestive 
8 (1.8) 
6 (1.3) 
4 (0.9) 
3 (0.7) 
Cerebrovascular accident 
9 (2.0) 
1 (0.2) 
4 (0.9) 
1 (0.2) 
Hypertension 
9 (2.0) 
8 (1.8) 
4 (0.9) 
3 (0.7) 
Lipase increased 
8 (1.8) 
6 (1.3) 
8 (1.8) 
6 (1.3) 
Cellulitis 
6 (1.3) 
5 (1.1) 
1 (0.2) 
0 
Diarrhoea 
7 (1.6) 
5 (1.1) 
5 (1.1) 
3 (0.7) 
Peripheral arterial 
occlusive disease 
7 (1.6) 
6 (1.3) 
4 (0.9) 
3 (0.7) 
Dyspnoea 
7 (1.6) 
6 (1.3) 
5 (1.1) 
4 (0.9) 
Dehydration 
7 (1.6) 
5 (1.1) 
2 (0.4) 
2 (0.4) 
Pericardial effusion 
6 (1.3) 
4 (0.9) 
5 (1.1) 
3 (0.7) 
Pancytopenia 
6 (1.3) 
6 (1.3) 
5 (1.1) 
5 (1.1) 
Neutrophil count 
decreased 
6 (1.3) 
6 (1.3) 
5 (1.1) 
5 (1.1) 
Pleural effusion 
6 (1.3) 
3 (0.7) 
4 (0.9) 
1 (0.2) 
Clostridium difficile colitis 
5 (1.1) 
3 (0.7) 
0 
0 
Urinary tract infection 
6 (1.3) 
4 (0.9) 
1 (0.2) 
0 
Deep vein thrombosis 
5 (1.1) 
3 (0.7) 
1 (0.2) 
0 
Pulmonary embolism 
5 (1.1) 
4 (0.9) 
2 (0.4) 
2 (0.4) 
Renal failure acute 
6 (1.3) 
2 (0.4) 
1 (0.2) 
0 
Data cutoff: 06 January 2014 
 
Sixty-eight patients (46 CP-CML; 9 AP-CML; 11 BP-CML; 2 Ph+ ALL) discontinued 
participation in the phase 2 study due to a TEAE. Platelet count decreased was the most common 
TEAE leading to discontinuation (17 patients, 3.8%), and was also the most common TRAE 
leading to discontinuation (18 patients, 4.0%). Coronary artery disease, myelodysplastic 
syndrome, and sepsis led to discontinuation of 2 patients each. All other events leading to 
patients withdrawing from the study occurred in 1 patient each, and can generally be grouped 
into vascular occlusive events, other cardiac events, laboratory abnormalities, and general 
conditions (eg, asthenia, pain, headache). 


16 
 
Fifty-two of 449 phase 2 patients (11.6%) have died within 30 days of their last ponatinib dose or 
due to a treatment-related SAE. As of 06 January 2014, 5 of these deaths, described below, were 
considered treatment-related due to SAEs of pneumonia, acute myocardial infarction (AMI)/MI, 
pneumonia fungal, gastritis hemorrhagic, and cardiac arrest, respectively. 
 
Phase-2 study of ponatinib in GIST (AP24534-12-202). 
 
This study was intended to evaluate ponatinib therapy in patients with metastatic and/or 
unresectable GIST, following failure of prior treatment with 1 or more TKIs. In this study, 
median dose intensity was 45.0 mg QD, ranging from 23.4 to 45.0 mg QD. Twenty-six percent 
of patients required either a dose reduction or an interruption of treatment of 3 days or more. 
 
Rash was the most frequently reported TEAE (19 patients, 54.3% of patients overall), followed 
by: 
 myalgia and fatigue (16 patients each, 45.7%) 
 dry skin and headache (14, 40.0% each) 
 abdominal pain and constipation (12, 34.3% each) 
 blood alkaline phosphatase increased and hypertension (10 each, 28.6%) 
 peripheral edema (9, 25.7%) 
 decreased appetite (8, 22.9%) 
 nausea, pyrexia, AST increased, and cough (6, 17.1% each) 
 vomiting and ALT increased (5, 14.3% each) 
 dyspepsia, lipase increased, dysphonia, dyspnea, and insomnia (4, 11.4% each) 
 
TRAEs affecting 10 or more patients overall included: 
 rash (19, 54.3%) 
 myalgia (16, 45.7%) 
 dry skin and fatigue (14, 40.0% each) 
 headache (13, 37.1%) 
 constipation (11, 31.4%) 
  
All other TEAEs occurred in fewer than 10% of patients, and no events of pancreatitis were 
reported. There were no grade 4 events. One grade 5 event was reported (preferred term: 
pneumonia, reported as related to ponatinib treatment). Grade 3 TEAEs in more than 1 patient 
included:  abdominal pain and lipase increased (3 each) and anemia, nausea, vomiting, fatigue, 
and hypertension (2 each). 
 
Ten patients had at least 1 SAE. Gastrointestinal disorders (5 patients), and Cardiac disorders, 
General disorders and administration site conditions, and Infections and infestations (2 patients 
each) contributed the majority of SAEs. By preferred term, the most common SAEs were: 
 abdominal pain (4, 11.4%) 
 fatigue, nausea, and vomiting (2, 5.7% each) 
 intestinal abscess, duodenal stenosis, hypercalcemia, hypoxia, MI, pneumonia, and right 
ventricular dysfunction (each in single patients, 2.9% each) 


17 
 
Seven patients discontinued the GIST study due to development of AEs. Most patients had been 
receiving ponatinib for less than 2 weeks at the time of event onset; most events were considered 
at least possibly related to treatment. 
 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI Common 
Terminology Criteria for Adverse Events (CTCAE) terms is included in Section 7.1 of the 
protocol. 
 
Vascular Occlusion 
 
Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, 
stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the 
need for urgent revascularization procedures have occurred 
in at least 27% of ponatinib-treated patients from the phase 1 and phase 2 trials. Ponatinib can 
cause fatal and life-threatening vascular occlusion within 2 weeks of starting treatment. 
Ponatinib can also cause recurrent or multi-site vascular occlusion. The median time to onset of 
the first vascular occlusion event was 5 months. Ponatinib can cause fatal and life threatening 
vascular occlusion in patients treated at dose levels as low as 15 mg per day. Patients with and 
without cardiovascular risk factors, including patients age 50 years or younger, experienced these 
events. Vascular occlusion adverse events were more frequent with increasing age and in patients 
with prior history of ischemia, hypertension, diabetes, or hyperlipidemia 
 
Vascular Occlusion Incidence in Ponatinib-Treated Patients in Phase 2 Trial According to Risk 
Categories 
 
Prior history of ischemia, 
hypertension,diabetes, or 
hyperlipidemia 
No history of ischemia, 
hypertension, 
diabetes, or hyperlipidemia 
Age: 49 or younger 
18% 
(6/33) 
12% 
(13/112) 
Age: 50 to 74 years 
33% 
(50/152) 
18% 
(20/114) 
Age: 75 and older 
56% 
(14/25) 
46% 
(6/13) 
All age groups 
33% 
(70/210) 
16% 
(39/239) 
Total 
24% 
(109/449) 
 
 
 Arterial Thrombosis 
Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal MI and 
stroke have been observed in ponatinib-treated patients. Patients with cardiovascular risk factors 
are at increased risk for arterial thrombosis with ponatinib; therefore, these patients are 
excluded for this protocol. Monitor patients for arterial thrombotic events, and consider 
interrupting or stopping ponatinib if these events are suspected.  
 


18 
In AP24534-10-201 (phase-2 trial of ponatinib in refractory CML and ALL), 91/449 patients 
(20%) experienced at least 1 treatment-emergent ischemic vascular event: 55 (12%) had 
cardiovascular events, 27 (6%) had cerebrovascular events and 36 (8%) had peripheral vascular 
events.  
 
Overall, 53 patients (12%) experienced ischemic vascular SAEs: 28 (6%) had cardiovascular 
SAEs, 18 (4%) had cerebrovascular SAEs, and 16 (4%) had peripheral vascular SAEs. The most 
commonly reported SAEs were MI/AMI (14/449: 3%), CAD (10/449: 2%), and CVA (9/449: 
2%). Four fatalities were reported due to events in this MedDRA preferred-term search: AMI 
(considered by the investigator to be possibly related to ponatinib), CAD, cerebral ischemia, and 
hemorrhagic cerebral infarction. Of 22 patients with SAEs of MI/AMI or CAD, 14 developed 
CHF concurrent or subsequent to the myocardial ischemic event. Ten of the 18 patients with 
SAEs of cerebrovascular ischemic events developed stenosis of large arterial vessels of the brain 
(eg, carotid, vertebral, middle cerebral artery). Ponatinib was withdrawn for 7 patients due to 
AEs in this group of preferred terms: CAD, hemorrhagic cerebral infarction, cerebral infarction, 
cerebral infarction with cerebral artery stenosis, CAD and myocardial ischemia with peripheral 
arterial occlusive disease (PAOD), CVA, and peripheral ischemia. The hemorrhagic cerebral 
infarction (considered by the investigator not related) was fatal, and peripheral ischemia and 
CAD/PAOD (considered by the investigator possibly/probably related) were reported as not 
resolved. All other events were reported as resolved. Most other patients’ SAEs in this list of 
preferred terms also resolved, either with dose adjustments or no change to the dose. Almost all 
patients with ischemic vascular SAEs had at least 1 risk factor, and most had more than 1. 
 
Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-
threatening peripheral arterial disease, have occurred in ponatinib-treated patients. Patients have 
developed digital or distal extremity necrosis and have required amputations. Peripheral vascular 
SAEs were also reported in the AP24534-07-101 trial. Angina pectoris and MI were reported as 
treatment-related SAEs. One case of cerebral infarction in the expanded access program was 
considered by the investigator possibly related to ponatinib. 
 
 Venous Thromboembolism 
In AP24534-10-201, venous thromboembolic events were observed in 5% (23/449) of ponatinib-
treated patients, including deep venous thrombosis/venous embolism/venous thrombosis (11 
patients), pulmonary embolism (6 patients), superficial thrombophlebitis (3 patients), retinal vein 
thrombosis (2 patients) and 1 case each of portal vein thrombosis, and veno-occlusive liver 
disease. Consider dose interruption of ponatinib in patients who develop serious venous 
thromboembolism. 
 
Neuropathy 
Similar to vascular occlusion, a prospectively defined, MedDRA-based search strategy, 
containing nearly 300 preferred terms, was employed in the summarization of neuropathy events. 
Events were further classified as peripheral or cranial neuropathy. 
 
Peripheral and cranial neuropathy has occurred in ponatinib-treated patients. Monitor patients for 
symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning 
sensation, neuropathic pain or weakness. Consider interrupting ponatinib and evaluate if 


19 
suspected.  
 
In AP24534-10-201, neuropathy events were observed in 14% (65/449) of patients (cranial in 
1% (6/449) and peripheral in 13% (59/449). The most common events were peripheral 
neuropathy (4%), paresthesia (4%), hypoesthesia (2%), and hyperesthesia (1%). Of the patients 
who developed neuropathy, 31% (20/65) developed neuropathy during the first month of 
treatment. One patient discontinued therapy because of neuropathy events (IVth nerve paralysis). 
 
Hepatotoxicity 
Liver function test abnormalities are seen with ponatinib, and hepatic failure has been reported. 
Hepatotoxicity, most commonly manifested by reversible transaminase and alkaline phosphatase 
elevation and hyperbilirubinemia, has been observed in patients taking ponatinib. Fulminant 
hepatic failure leading to death occurred in a patient within one week of starting ponatinib. Two 
additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with 
blast phase CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts. 
 
Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, 
reduce or discontinue ponatinib as clinically indicated. 
 
The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation 
was 56% (all grades) and 8% (grade 3 or 4). Ponatinib treatment may result in elevation in ALT, 
AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of 
patients. Eight percent of patients had grade 3 or 4 elevation in ALT, 4% had grade 3 or 4 
elevation in AST and 2% had grade 3 or 4 elevation in alkaline phosphatase. Two patients whose 
laboratory values met Hy’s Law criteria for drug induced liver injury had other etiology to 
explain the laboratory results: one patient had liver failure due to disease progression and died 
due to progressive CML, and the second patient had underlying possible Gilbert’s syndrome.  
Acute hepatic failure leading to death was reported in 1 Ph+ ALL patient with decreased cardiac 
function (an ejection fraction decreased to 28% from 54% within the 5 months prior to first dose) 
within one week of starting ponatinib (Japan phase 1/2 trial: AP24534-11-106). One additional 
case of acute liver failure from the expanded access program was reported. The patient, with Ph+ 
ALL, had liver failure in conjunction with disease progression. 
 
Congestive Heart Failure (CHF) 
Severe congestive heart failure (CHF) and left ventricular (LV) dysfunction have been reported 
in patients taking ponatinib. Patients with cardiac disease or risk factors for cardiac disease 
should be monitored carefully and any patient with signs or symptoms consistent with cardiac 
failure should be evaluated and treated. Consider discontinuation of ponatinib in patients who 
develop serious CHF.  
 
As of 6 January 2014, 37 (8.2%) patients had events of cardiac failure; 23 (5.1%) of these were 
serious, with SAEs in 14 patients (3%) considered related to therapy, with 4 fatalities (cardiac 
failure congestive in 2, and cardiac failure and cardiopulmonary failure in 1 patient each. None 
of the deaths was considered related to ponatinib). Most patients had advanced CML, and almost 
all had at least 1 cardiac risk factor, with multiple cardiac risk factors in more than half the 
patients.  Twenty-four patients with cardiac failure events discontinued therapy: 6 did so due to 


20 
AEs, 7 because of progressive disease/lack of efficacy, 6 by either patient or investigator 
withdrawal or for other reasons, and 5 due to fatal events (4 were cardiac events, discussed 
above; 1 was due to pneumonia, which was considered not related to ponatinib). The majority of 
patients treated with ponatinib who have experienced cardiac failure AEs have also experienced 
vaso-occlusive AEs, either with a direct temporal relationship or, less frequently, with timing 
that makes a relationship less clear. Almost all patients who experienced cardiac failure events in 
the absence of vascular occlusive events had a strong history of heart failure, ischemic disease, 
or structural heart disease. 
 
Hypertension 
Patients receiving ponatinib have experienced hypertension and blood pressure should be 
monitored at each visit. In addition, a home blood pressure assessment will be performed twice 
per week for patients starting ponatinib, using blood pressure cuff supplied by the study sponsor, 
Takeda. Patients will be instructed to contact their study doctor and/or study coordinator in the 
event an at-home blood pressure reading reaches ≥ 160/90. Any hypertensive measurement will 
be confirmed by the study team in clinic. For patients who develop HTN or worsening HTN 
during study treatment, antihypertensive medication should be initiated or optimized to achieve 
target blood pressure before interruption or dose reduction of the study treatment at the discretion 
of the investigator.  If hypertension is persistent despite adequate anti-HTN therapy including 
titration of anti-HTN medication or introduction of additional anti-HTN medications, or if grade 
4 HTN develops, dose interruption, reduction or discontinuation is recommended. A 
measurement of ≥ 160/100 requires dose interruption. 
 
Treatment-emergent hypertension occurred in 67% of patients (300/449) treated with ponatinib. 
In AP24534-10-201, 9 (2%) patients treated with ponatinib experienced treatment-emergent 
hypertension as a serious adverse reaction and one patient (<1%) experienced treatment 
emergent hypertensive crisis as a serious adverse reaction, and required clinical intervention for 
hypertension associated with confusion, headache, chest pain, or shortness of breath.  
In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% 
(220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 
hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% 
developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm 
Hg). In 164 patients with Stage 1 hypertension at baseline, 64% (66/164) developed Stage 2 
hypertension.  No patients discontinued due to AEs of hypertension, although 6 (2.2%) patients 
had dose reductions or interruptions due to the event. None of the hypertension events were fatal. 
 
 
Ocular Toxicity  
Ocular toxicities have occurred in clinical trials of ponatinib. Serious ocular toxicities leading to 
blindness or blurred vision have occurred in ponatinib-treated patients. Conduct comprehensive 
eye exams at baseline and periodically during treatment. 
 
Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage have 
occurred in ponatinib-treated patients (3%). In AP24534-10-201, adverse events in the more-
general eye disorders SOC included dry eyes (7%), blurred vision (4%), conjunctivitis (3%), eye 
pain (3%), periorbital edema (2%), blepharitis (2%), and cataract (2%). Other ocular toxicities 


21 
were cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis.  
 
Pancreatitis 
Pancreatitis (symptomatic abdominal pain associated with pancreatic enzyme elevation) and/or 
elevations in lipase and amylase are known AEs associated with ponatinib.  Most cases of 
pancreatitis or elevated pancreatic enzymes occur within the first 2 months of treatment with 
ponatinib.  The events are generally uncomplicated and reversible and can be managed with a 
brief interruption of treatment and standard medical management.  Almost all patients are able to 
continue with ponatinib treatment at the same or a reduced dose once the event has improved to 
grade 1 or resolved.   
 
Patients with low-grade (1 or 2) elevation in amylase can be continued without dose reduction 
but should be monitored closely with serial enzyme level determinations.   
 
Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as 
clinically indicated. Consider additional serum lipase monitoring in patients with a history of 
pancreatitis or alcohol use. In patients with pancreatitis, do not consider restarting ponatinib until 
patients have complete resolution of symptoms and lipase levels are less than 1.5 × ULN. 
 In AP24534-10-201, treatment-emergent pancreatitis occurred in 7% (30/449) of patients (25; 
5.6% Grade 3). Pancreatitis resulted in treatment interruption or dose reduction in 6% of patients 
(26/449). One patient discontinued ponatinib permanently due to pancreatitis. Twenty-three of 
29 patients with pancreatitis had resolution of the events within 2 weeks with dose interruption 
or reduction or with no change in dose; 2 patients had resolution within 4 days with the dose 
unchanged. The incidence of treatment-emergent lipase elevation was 41% (grade 3 or 4: 18%). 
Pancreatitis was the DLT from AP24534-07-101and has been reported in the expanded access 
program. 
 
Hemorrhage 
Hemorrhagic events have been reported with ponatinib (mostly in leukemic patients with grade 4 
thrombocytopenia).   
 
Treatment-emergent hemorrhagic events occurred in 25.6% (115/449) of patients, the majority 
(87, 19.4%) of which were grade 1/2. The most common hemorrhagic events were epistaxis 
(7.1%), petechiae (3.1%), and ecchymosis (2.2%). 
 
In AP24534-10-201, serious bleeding events were observed in 5.8% (26/449) of patients treated 
with ponatinib, including 5 fatalities (1 event each of subdural hematoma, traumatic intracranial 
hemorrhage, hemorrhagic gastritis, intracranial hemorrhage, and hemorrhagic cerebral infarction. 
One fatality (hemorrhagic gastritis) was assessed by the investigator as possibly related to 
ponatinib. The incidence of serious bleeding events was higher in patients with accelerated 
phase-CML, blast phase-CML, and Ph+ALL. The most commonly reported serious bleeding 
events included: gastrointestinal hemorrhage, subdural hematoma (3 patients each, 0.7%); 
cerebral hemorrhage, hemorrhoidal hemorrhage, retroperitoneal hematoma, epistaxis, post-
procedural hemorrhage, traumatic intracranial hemorrhage, gastric hemorrhage (2 patients each, 
0.4%). Three patients had their doses reduced or interrupted due to single events each of ear 
hemorrhage, gingival bleeding, and subarachnoid hemorrhage. Two patients had study drug 


22 
discontinued following single events each of cerebral hemorrhage and intracranial hemorrhage. 
Interrupt ponatinib for serious or severe hemorrhage and evaluate 
 
Fluid Retention 
Ponatinib is associated with edema and occasionally serious fluid retention.  Patients should be 
weighed and monitored regularly for signs and symptoms of fluid retention.  An unexpected 
rapid weight gain should be carefully investigated and appropriate treatment provided.  Interrupt, 
reduce the dose of, or discontinue ponatinib according to the recommendations for non-
hematologic toxicity. 
 
One or more fluid retention AEs occurred in 125 (27.8%) patients in this study. The most 
common events were peripheral edema (16.7%), pleural effusion (7.6%), and pericardial effusion 
(3.8%). In AP24534-10-201, serious fluid retention events were observed in 4% (18/449) of 
patients treated with ponatinib. One instance of brain edema in a blast phase-CML patient with 
post-craniotomy was fatal. Serious fluid retention events in more than 1 patient included: pleural 
effusion (6/449), pericardial effusion (6/449, 1%), and ascites (2/449, <1%).  In most cases, 
patients were able to continue ponatinib therapy without dose reductions or interruptions. 
Ponatinib was discontinued for three patients, due to pericardial effusion in two, and pleural 
effusion in one. 
 
Cardiac Arrhythmias 
Supraventricular tachyarrhythmias have been reported in patients treated with ponatinib. 
Supraventricular tachyarrhythmias occurred in 5% (25/449) of ponatinib-treated patients. Atrial 
fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. 
All patients with serious atrial fibrillation had risk factors, confounding events, or both. The 
other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular 
tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to 
hospitalization. Three patients (0.4%) died due to cardiac arrest. One was assessed as related to 
ponatinib. This patient had a history of sinus bradycardia and left bundle branch block; the 
cardiac arrest followed a 2-day history of severe diarrhea and dehydration. The second patient 
had a past history of MI and died in the setting of an AMI and lobar pneumonia. The third patient 
had pleural effusions and pulmonary hypertension. One patient discontinued therapy due to 
grade 3 atrial fibrillation that was considered related to treatment. Advise patients to report signs 
and symptoms of rapid heart rate (palpitations, dizziness).  
 
Symptomatic bradyarrhythmias have also been reported.  Symptomatic bradyarrhythmias that led 
to a requirement for pacemaker implantation occurred in 1% (3/449) of ponatinib treated 
patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus 
syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and 
symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).  
 
In AP24534-07-101, SAEs of atrial fibrillation were reported in 7% of patients, with none 
considered treatment related. No cardiac arrest was reported in that trial. 
 
Prolonged QTcF 
A QT assessment was performed in 39 patients with cancer who received 30 mg, 45 mg, or 60 


23 
mg ponatinib once daily. No large changes in the mean QTc interval (i.e., > 20 ms) from baseline 
were detected in the study. However, a small increase in the mean QTc interval (i.e., < 10 ms) 
cannot be excluded because of study design limitations. If a prolongation of QTcF is observed, it 
is important to perform serum electrolyte analysis (including potassium, calcium, and 
magnesium) and correct any significant abnormalities with supplements if below normal limits.  
It is also necessary to review all concomitant medications and discontinue medications that are 
known or suspected to cause QT prolongation. 
 
If no contributing reason is identified and the reason for QTcF prolongation is believed to be due 
to ponatinib, dose interruption and reduction guidelines for general non-hematologic toxicities 
should be followed.  Additionally, weekly ECG monitoring is recommended for 4 weeks upon 
resumption of study drug, then monthly for 6 months, and then every 3 months for the remainder 
of the study, or more frequently as clinically indicated. Echocardiogram and ECG results for all 
sites will be reviewed by the lead investigator at The Ohio State University (OSU). 
 
Myelosuppression 
Neutropenia, anemia, and thrombocytopenia have all been commonly reported either together or 
individually in leukemia patients treated with ponatinib.  Ponatinib has not been studied in solid 
tumor patients and whether (or to what extent) myelosuppression will occur in these patients is 
unknown.  While myelosuppression can occur any time during treatment, its onset most 
commonly occurs within the first month on treatment. 
 
Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as 
clinically indicated, and adjust the dose as recommended.  
 
In AP24534-10-201, grade 3 or 4 myelosuppression, reported as an AE, occurred in 52% 
(262/449) of patients treated with ponatinib. The most commonly reported grade 3/4 
myelosuppression AEs were platelet count decrease (43.9%), neutrophil count decrease (24.9%), 
febrile neutropenia (5.1%) and anemia (22.3%). The incidence of these events was greater in 
patients with advanced disease than in patients with CP-CML and patients frequently 
experienced multiple occurrences of these events.. SAEs of myelosuppression events occurred in 
10% of patients, with febrile neutropenia and decreased platelet count the 2 most common SAEs, 
in 3% of patients each. In AP24534-10-201, decreased platelet count led to the discontinuation of 
17 patients, making it the most common AE leading to discontinuation. Most patients who 
experienced grade 3 or 4 decreased platelet count had their first occurrence within the first 3 
months of treatment. Most patients recovered from decreased platelet counts with dose 
interruptions or reductions or with no change to the regimen. 
 
In AP24534-07-101, the incidences of AEs of myelosuppression were similar overall, with 
incidences of SAEs of febrile neutropenia and decreased platelet count were slightly higher, in 
15% and 5% of patients, respectively. Myelosuppression events were reported as SAEs in the 
expanded access program. 
 
 
Compromised Wound Healing and Gastrointestinal Perforation 
Based on the mechanism of action, ponatinib could potentially compromise wound healing. 


24 
Interrupt ponatinib for at least 1 week prior to major surgery. The decision when to resume 
ponatinib after surgery should be based on clinical judgment of adequate wound healing. 
Serious GI perforation (fistula) was observed in one patient 38 days post-cholecystectomy in 
AP24534-10-201. No formal studies of the effect of ponatinib on wound healing have been 
conducted. 
 
Tumor Lysis Syndrome 
Two patients (<1%) treated with ponatinib in AP24534-10-201 developed serious tumor lysis 
syndrome (TLS). Both cases occurred in patients with advanced CML. Hyperuricemia occurred 
in 7% (304/449) of patients; the majority had CP CML (19 patients).TLS is likely specific to 
patients with CML and is unlikely in the solid tumor patients.  
 
Constitutional Symptoms/Joint Pain 
Certain constitutional symptoms such as myalgia, arthralgia, headache, weakness, fatigue, 
asthenia, and low grade fever have been commonly reported with ponatinib.  These symptoms 
have been reported mainly at the initiation of treatment, are typically short lived (<2 weeks), and 
are seldom, if ever, reported beyond the first month of treatment.  These AEs are most 
commonly low grade (grade 1 and 2) and are self-resolving without the need for dose 
interruption or dose reduction when they do occur.  Most patients can be maintained on the 
current dose of ponatinib, uninterrupted, and their symptoms can be managed with a short course 
of oral analagesics, corticosteroids, and/or anti-pyretics as clinically indicated.  If dose 
interruption is indicated, patients can resume the same dose of ponatinib typically without 
recurrence of symptoms once the original episode has improved or resolved. 
 
Embryo-Fetal Toxicity 
Although no studies have been conducted, ponatinib may cause fetal harm, and women who are 
pregnant should be prohibited from using ponatinib. Ponatinib showed embryo-fetal toxicity in 
rats at exposures lower than human exposures at the recommended human dose. Advise women 
to avoid becoming pregnant while taking ponatinib. 
 
Overdosage  
 
Overdoses with ponatinib were reported in clinical trials. One patient was accidentally 
administered the entire contents of a bottle of study medication via nasogastric tube. The 
investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, 
the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus 
rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the 
overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on 
cycle 1 day 2. The patient experienced fatigue and non-cardiac chest pain on day 3. Multiple 
doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory 
response, atrial fibrillation, and a moderate pericardial effusion. 
 
In the event of an overdose, stop ponatinib, observe the patient and provide appropriate 
supportive treatment. 
 
Ponatinib use in specific populations 


25 
 
Pregnancy 
Based on its mechanism of action and findings in animals, ponatinib can cause fetal harm when 
administered to a pregnant woman. Ponatinib was studied for effects on embryo-fetal 
development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. 
At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the 
recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased 
resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal 
alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day 
(approximately 24% the AUC in patients receiving the recommended dose) and involved 
multiple fetal soft tissue and skeletal alterations, including reduced ossification. There are no 
adequate and well-controlled studies with ponatinib in pregnant women. Advise women to avoid 
becoming pregnant while taking ponatinib. If this drug is used during pregnancy, or if the patient 
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to 
a fetus. 
 
Pediatric Use 
The safety and efficacy of ponatinib in patients less than 18 years of age have not been 
established. 
 
Nursing 
It is unknown whether ponatinib is excreted in human milk. Because of the potential for serious 
adverse reactions in nursing infants from ponatinib, a decision should be made whether to 
discontinue nursing or to discontinue ponatinib, taking into account the importance of the drug to 
the mother. 
 
Geriatric use 
One hundred and fifty-five of 449 patients (35%) in the CML clinical trial of ponatinib were 65 
years of age and over. Forty-six percent of patients ≥ 65 years had vascular occlusion events. 
Patients of age ≥ 65 years are more likely to experience adverse reactions including vascular 
occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, 
muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be 
cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of 
concomitant disease or other drug therapy. 
 
Hepatic Impairment 
The Mass-Balance study (AP24534-11-104) confirmed that ponatinib elimination in humans 
primarily occurs via the liver. AP24534-12-109, Phase-1 study compared the PK of 30-mg 
ponatinib in subjects with chronic hepatic impairment with those of matched healthy subjects. 
The study was designed as open-label, single-dose, parallel-group, and nonrandomized. Eighteen 
subjects with hepatic impairment (6 each in Child-Pugh categories A, B, and C, corresponding to 
mild, moderate, and severe impairment, respectively) were matched to 9 healthy subjects. The 
study demonstrated that ponatinib or metabolite AP24600 exposure appeared to be comparable, 
albeit slightly higher, in subjects with mild hepatic impairment (Child-Pugh A) compared to 
healthy subjects. In contrast, lower plasma exposures of ponatinib and AP24600 were observed 
in subjects with either moderate or severe hepatic impairment (Child-Pugh B and C, 


26 
respectively) relative to healthy control subjects.  PK data alone do not suggest the need for a 
starting dose adjustment for ponatinib in subjects with varying degrees of hepatic impairment. 
No clinically meaningful differences were observed in ponatinib PK in subjects with chronic 
hepatic impairment compared to matched healthy subjects. Ponatinib should be used with 
caution in patients with moderate or severe hepatic impairment. 
 
 
Renal Impairment 
Although renal excretion is not a major route of elimination, ponatinib has not been studied in 
patients with renal impairment. The potential for moderate or severe renal impairment to affect 
hepatic elimination has not been determined. 
 
 
2.3 
Rationale 
 
The FGF-FGFR signaling pathway plays a critical role in regulating physiologic 
processes such as embryogenesis, angiogenesis and cell survival. FGFR genes are proto-
oncogenes and their activation secondary to genomic alterations such as gene amplification, 
chromosomal translocation, and point mutation can mediate the development and growth of 
cancers.1 A rapidly expanding list of cancers with genomic FGFR alterations is provided in 
Table 1. Therefore, inhibition of the FGF-FGFR signaling pathway presents a viable therapeutic 
strategy for multiple malignancies. In addition to their role in inhibiting angiogenesis and 
tumorigenesis, FGFR inhibitors can also ameliorate resistance to other therapies. Inhibition of 
FGFR has been demonstrated to overcome resistance to endocrine therapy in patients with breast 
cancers.31 They have also been shown to enhance sensitivity of resistant tumors to 
chemotherapy.32 FGFR inhibitors are purported to be an effective therapeutic option for relapsed 
tumors that have been treated previously with EGFR or VEGFR inhibitors due to secondary 
FGFR activation.11  
Currently FGFR inhibitors, both selective and non-selective are being evaluated as cancer 
therapies. Several small molecule tyrosine kinase inhibitors (TKI) have been studied, and they 
share characteristics as ATP-competitive VEGFR2 inhibitors due to structural similarity of 
VEGFR and FGFR kinase domains. However, potential toxicities associated with pan-
FGFR/VEGFR inhibition have also led to monoclonal antibodies targeting specific FGFRs (e.g. 
IMC-A1 (Imclone), R3Mab (Genentech)).33, 34 Preclinical as well as early clinical studies have 
demonstrated that genomic FGFR alterations predict sensitivity and response to the use of FGFR 
inhibitors. Guagnano et al. have shown that genetic alterations in FGFR predict sensitivity to 
BGJ398 (Novartis), a selective pan-FGFR inhibitor.35  Currently, BGJ398 is being evaluated in a 
Phase 1 study for patients with advanced solid tumors harboring amplifications (FGFR1/2) or 
mutations (FGFR3).36 Dovitinib (TKI258, Novartis), a combined FGFR and VEGFR inhibitor, 
has recently been shown to be effective in patients with FGFR1 amplified advanced breast 
cancers.37 Similarly, FGFR2 amplification in gastric cancers predicted sensitivity to selective 
FGFR inhibitor AZD4547 (AstraZeneca) 38, and this agent is being investigated in a phase-2 trial 
in patients with advanced gastric adenocarcinoma with FGFR2 polysomy or amplification39, 40. 
We propose to evaluate ponatinib (Takeda), a pan-FGFR inhibitor, in patients with any 
cancer histology and molecular eligibility with defined genomic FGFR alterations. Ponatinib is 
FDA approved for the treatment of CML and Philadelphia chromosome positive ALL ) for 


27 
whom no other tyrosine kinase inhibitor (TKI) therapy is indicated .25 In addition to BCR-ABL, 
it is also a potent inhibitor of FGFR family members and other kinases including KIT, RET, 
PDGFRα, and FLT3 Gozgit et al. have shown ponatinib to be more potent (1 to 2 log scale) than 
previous FGFR inhibitors with activity across multiple FGFRs (FGFR 1-4) and types of genomic 
alterations.17 Also, ponatinib has been shown to have activity against secondary gatekeeper 
mutations that mediated resistance in tyrosine kinases (e.g. T315I in BCR-ABL; T670I in KIT).25 
We and others (Gozgit et al.) have shown that ponatinib produces a robust, dose-dependent, 
growth inhibition across multiple cancer cell lines harboring FGFR alterations, compared to wild 
type FGFR, supporting these findings. We hypothesize that activating genomic FGFR 
alterations predict response to ponatinib. In addition, we hypothesize that activating genomic 
alterations in KIT, RET, PDGFRα, ABL1, FLT3 will predict response to ponatinib given the 
activity of this drug in preclinical studies. 
To evaluate this, we propose a single arm phase-2 study of ponatinib in patients with any 
cancer histology and molecular eligibility with activating FGFR alterations (amplifications, 
mutations, translocations) as well as KIT, PDGFRα,  FLT3, RET, ABL1 alterations. While 
enrollment of multiple tumor subtypes facilitates accrual rate of patients with genetic FGFR 
alterations as these are rare, importantly, we can assess whether tumor subtypes with FGFR 
alterations would indeed respond to FGFR inhibition. For instance, BRAF mutant colon cancers 
did not show sensitivity to BRAF inhibition as melanomas with similar mutation.41 This was 
demonstrated to be due to EGFR-mediated reactivation of MAP kinase pathway, and combined 
EGFR and BRAF inhibition was able to improve response.42 As yet, no tumor specific context 
for FGFR response has been recognized and our trial could help ascertain if there is any. Further, 
we can compare primary non-responders versus responders to identify additional pathways that 
render patients resistant to FGFR inhibition despite the presence of an FGFR alteration. As stated 
previously, ponatinib has also been demonstrated to be a potent inhibitor of other kinases altered 
in cancers including PDGFRα, FLT3, RET, ABL1 and KIT.43, 44 Therefore, we plan to evaluate 
the activity of ponatinib in cancers that harbor genomic alterations in these kinases as a separate 
cohort.   
 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
3.1.1 Patients with histologically or cytologically confirmed diagnosis of refractory metastatic 
solid tumor for whom no other standard treatment options are available. 
 
3.1.2 Patients must have tumor suitable for biopsy (as assessed by trained specialists in 
interventional radiology) and medically fit to undergo a biopsy or surgical procedure; OR 
archival tumor specimen of biopsied tumor; OR if patients do not have a tumor suitable 
for biopsy but have another tissue (preferably progressive metastatic site) available for 
molecular evaluation (biopsy will be performed through OSU-13053 study or the UM 
Precision Cancer Study). 
 


28 
3.1.3 Patients must have activating genomic alterations in FGFR (mutations, fusions or 
amplifications (> 6 copies)) or activating genomic alterations in KIT, PDGFRα, RET, 
ABL1 and FLT3 by any validated CLIA-certified molecular testing (FISH, PCR or 
sequencing data are acceptable). CLIA validated results from other institutions; 
diagnostic labs (e.g. foundation medicine) are acceptable.  
 
3.1.4 Patients with solid tumors must have measurable disease (RECIST 1.1), defined as at 
least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm 
with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by 
clinical exam.  Note: This trial is open only to patients with solid tumors. 
 
3.1.5 Patients older than or equal to 18 years of age (The safety and efficacy of ponatinib in 
patients less than 18 years of age have not been tested). 
 
3.1.6 ECOG performance status ≤ 1 (Karnofsky ≥ 80%, see Appendix A). 
 
3.1.7 Life expectancy of greater than 3 months. 
 
3.1.8 Patients with multiple malignancies remain eligible. 
 
3.1.9 Patients with an inherited cancer syndrome or a medical history suggestive of an 
inherited cancer syndrome remain eligible. 
 
3.1.10 Patients must have controlled blood pressure with a systolic blood pressure < 140 mmHg 
and diastolic < 90 mmHg (for patients with an elevated initial BP reading (hypertensive 
range), a repeat measurement at least 2 minutes later should be performed, and the two 
readings should be averaged to obtain a BP reading). Any hypertensive at-home blood 
pressure reading will be confirmed in clinic. Patients on anti-hypertensive medications 
are eligible, if blood pressure is controlled. Study drug dosing will be interrupted for any 
reading ≥ 160/100, as outlined in management table in Section 6 of the protocol. 
 
3.1.11 Ponatinib can cause fetal harm when administered to a pregnant woman based on its 
mechanism of action and findings in animals. For this reason women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and through 4 months after the end of 
treatment.  For females of childbearing potential, a negative pregnancy test must be 
documented prior to registration.  
 
3.1.12 Patients must have normal organ and marrow function as defined below: 
 
Absolute neutrophil count 
≥1,500/mcL 
 
Platelets 
≥75,000/mcL 
 
Total bilirubin 
≤1.5 × upper limit of normal (ULN), unless due to            
 
 
  
 
Gilbert’s syndrome (<5 if liver involvement  with 
                
              
                             primary tumor) 
 
Serum lipase and amylase  
≤1.5 × ULN 


29 
 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
 
LVEF ≥ 50% by ECHO or MUGA 
 
Serum creatinine ≤1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault 
formula) ≥60 mL/min OR 24-hour urine creatinine clearance ≥60 mL/min 
 
3.1.13 Patient has the ability to swallow oral medication and keep a pill diary 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients with hematological malignancies. 
 
3.2.2 Patients who have not received any prior treatment. 
 
3.2.3 Patients with known ponatinib-resistant gene alterations 
 PDGFRA D842V mutation 
 cKIT D816V mutation 
 FLT3 D835V/Y/H/F or Y842C mutations 
 FGFR3 K652E mutation 
 
3.2.4 Major surgery (e.g. thoracic, abdominal, vascular, neurosurgery) within 28 days prior to 
registration on study. 
 
3.2.5 History of acute pancreatitis within one year of study entry or history of chronic 
pancreatitis. 
 
3.2.6 History of alcohol abuse 
 
3.2.7 Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL). 
 
3.2.8 Patients who are receiving any other investigational agents. 
 
 
3.2.9 Patients with history of clinically significant bleeding disorder. 
 
3.2.10 Pregnant women are excluded from this study because ponatinib can affect embryo-fetal 
development. Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with ponatinib breastfeeding must 
be discontinued.   
 
3.2.11 Patients who are incarcerated are not eligible. 
 


30 
3.2.12 Patients with any history of arterial thromboembolic disease. Any patient with a history of 
MI, stroke, TIA, unstable angina or peripheral vascular disease will not be eligible. 
 
3.2.13 Patients with history of recurrent venous thromboembolism (deep venous thrombosis or 
pulmonary embolism) or history of venous thromboembolism within 6 months prior to 
registration on study will not be eligible 
 
3.2.14 Patients with history of active hepatitis B or C infection or chronic hepatitis with Child 
Pugh B or C hepatic dysfunction. 
 
3.2.15 Patients with prolonged corrected QT interval, defined as QTc >450 msec 
 
3.2.16 Use of antiplatelet agents other than low-dose aspirin as described in the protocol. 
 
3.2.17 GI bleed within 30 days prior to registration on study . 
 
3.2.18 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ponatinib. 
 
3.2.19 Patients with history of atrial arrhythmia (requiring any anti-arrhythmic therapy) or 
patients with any history of ventricular arrhythmia are excluded 
 
3.2.20 Clinically significant, uncontrolled intercurrent illness including, but not limited to: 
- 
Symptomatic or active infection 
- 
Uncontrolled hypertension (Diastolic blood pressure > 90 mm Hg; Systolic >140 mm 
Hg). Patients with hypertension should be under treatment on study entry to effect 
blood pressure control. 
- 
Psychiatric illness/social situations that would limit compliance with study 
requirements.  
 
3.2.21 Patients with history of congestive heart failure are excluded.  
 
3.2.22 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with ponatinib. 
 
3.2.23 Patients on medications known to be associated with Torsades de Pointes 
 


31 
3.2.24 Patients who received the last administration of an anti-cancer therapy including, 
chemotherapy, immunotherapy/biologic therapy, targeted therapy or radiotherapy within 
4 weeks (6 weeks for nitrosoureas or mitomycin C) or within 5 half-lives, whichever is 
shorter, prior to entering the study. 
 
3.2.25 Patients who have not recovered (< CTCAE grade 1) from adverse events (with the 
exception of alopecia) due to agents administered more than 4 weeks earlier. 
 
3.2.26 Patients taking medications or herbal supplements that are known to be strong CYP3A4 
inhibitors within at least 14 days prior to registration are excluded 
 
3.2.27 Patients with symptomatic or progressive brain metastases are ineligible. Subjects with 
treated brain metastases are eligible if they have no radiographic or other signs of 
progression in the brain for ≥ 4 weeks after completion of local therapy. 
 
3.2.28 Patients with macular edema, retinal vein occlusion or retinal hemorrhage are excluded. 
 
3.2.29 Patients who have received prior FGFR targeted therapy. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. It is expected that 
the patients entering this study will reflect the demographics of our clinical population and 
geographic area.  We expect that some participants will be racial/ethnic minorities which reflects 
the catchment area.   
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at the The Ohio State University.  OSU 
patients will be registered by the OSU Clinical Research Specialist/Coordinator.  External 
participating site patients will be registered by the OSU Multi-Site Coordinator.  External sites 
should alert the Multi-Site Coordinator by e-mail or phone as soon as a potential patient is 
identified for screening.  The required registration forms can be found in the protocol 
Supplemental Forms packet. 
 
Following registration, patients should begin protocol treatment within 5 business days. Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  If a 
patient does not receive protocol therapy following registration, a written explanation 
documenting the reason for delay will be required before proceeding with therapy. The Multi-
Site Coordinator should be notified of any cancellations as soon as possible.  The patient’s 
registration may be cancelled, pending approval by the Principal Investigator who will determine 
whether the patient will be replaced. 
 


32 
4.2 
External Participating Site Registration Process 
 
External participating site patients will have eligibility verified and will be centrally registered at 
The Ohio State University by the OSU Multi-Site Coordinator. Participating sites should call or 
email the OSU Multi-Site Coordinator to verify enrollment availability prior to consenting 
patients. 
 
Following registration, patients should begin protocol treatment within 5 business days. Issues 
that may cause treatment delays should be discussed with the OSU Principal Investigator and 
OSU Multi-Site Coordinator as soon as possible. The OSU Multi-Site Coordinator must be 
notified immediately if a patient does not receive protocol therapy. 
 
Only patients deemed eligible by the participating site research team should be submitted for 
eligibility verification and registration by the OSU Multi-Site Coordinator.  
 
To request patient registration, the documents below must be completed by the participating site 
research team and faxed to the OSU Multi-Site Coordinator.  The OSU secure e-mail system 
may be used, if needed.  Contact the OSU Multi-Site Coordinator for more information.  Regular 
e-mail must not be used to send patient registration documents. 
 
Required documents for registration: 
 Enrollment Form (refer to Supplemental Forms packet) 
 Signed Eligibility Checklist (refer to Supplemental Forms packet) 
 Signed informed consent document (and HIPAA if separate form) 
 Documentation of consent process 
 Source documents verifying every inclusion & exclusion criteria 
 Source documents for every required screening item as listed in the Protocol 
Calendar. Screening tests must be within the specified window. 
 Other signed and dated documents used as source documentation 
 
 
The OSU Multi-Site Coordinator will confirm receipt of the registration documents with the 
participating site contact listed on the Enrollment Form.  If confirmation is not received within 2 
hours, it is strongly recommended that the participating site call the OSU Multi-Site Coordinator 
to confirm registration documents were received.   
 
Registration requests will be processed as soon as possible and no later than 1 business day after 
receipt of the registration documents, pending there is no additional information needed to 
complete eligibility verification.  Registration will occur upon OSU confirmation that the patient 
meets eligibility criteria.   
 
The Multi-Site Coordinator will securely email the participating site contact listed on the 
Enrollment Form with the registration confirmation and the patient’s assigned study number. 
 
 
 


33 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Ponatinib would be administered as a single agent at a starting dose of 45 mg oral once 
daily on an outpatient basis.  In clinical trials involving CML and ALL the starting dose 
of ponatinib was 45 mg administered orally once daily. However, 59% of the patients 
required dose reductions to 30 mg or 15 mg once daily during the course of therapy. The 
optimal dose of ponatinib in solid tumors has not been identified.  All subjects should 
receive a copy of the Ponatinib Medication Guide (Appendix D). 
 
Reported adverse events and potential risks are described in Section 7. Appropriate dose 
modifications are described in Section 6.  Details regarding administration of study 
drugs are detailed in Section 8. No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the 
patient's malignancy. The patient will be requested to maintain a medication diary of 
each dose of medication. The medication diary will be returned to clinic staff at the end 
of each course. 
 
Ponatinib at a dose of 45 mg should be taken orally once daily with or without food for a 
28 day cycle.  Tablets should be swallowed whole. Patients should not crush or dissolve 
the tablets. Continue treatment as long as the patient does not show evidence of disease 
progression or unacceptable toxicity (Section 5.3).    
 
 
Patients treated with ponatinib are recommended to have concomitant thrombo-
prophylaxis with ASA (81 or 325 mg daily), if tolerated. Patients with documented 
allergy to aspirin do not require an alternate agent and are still eligible. ASA should be 
held when platelets drop to 75000 or below. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
 Aspirin, at a dose of 81mg once daily, should be taken orally beginning on the first day of 
ponatinib administration as a prophylactic for hypertension. Aspirin should be 
discontinued when ponatinib is discontinued, unless a clinical indication suggests 
otherwise. 
 
 Nausea/Vomiting – prophylactic pre-medications are not planned as ponatinib is not 
highly emetogenic. However, if patients experience nausea during a treatment cycle, anti-
emetics may be used per institutional guidelines.  
 
 Cytopenias – prophylactic growth factors (e.g. G-CSF, erythropoietin) are not permitted, 
however, if patients require admission for fever and neutropenia and the treating 
physician feels that the administration of growth factors may be beneficial then they can 
be given according to ASCO guidelines. Use of recombinant erythropoietin is not 
allowed. Platelets and red cell transfusions can be given as necessitated.  


34 
 
 Short courses (up to a maximum of 3 weeks) of oral corticosteroids intended to treat 
study treatment related rash or diarrhea are allowed. Oral steroids should be used with 
caution and subjects monitored for steroid-induced hyperglycemia. 
 
 Loperamide or lomotil is recommended for supportive care of diarrhea.  
 
 The use of bisphosphonates for skeletal metastasis is permitted. 
 
Because there is a low potential for interaction with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies. 
The Principal Investigator should be alerted if the patient is taking any agent known to 
affect or with the potential to affect selected CYP450 iso-enzymes. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
 
Disease progression, 
 
 
Unacceptable adverse event(s)  
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.4 
Duration of Follow Up 
 
Patients will be followed every 3 months for 52 weeks after removal from study or until death, 
whichever occurs first, in order to document time of progression (if patient did not progress 
while on study), survival, and to document subsequent alternate therapy received.  Patients 
removed from study for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
Patients must be discontinued from the trial in the event of myocardial infarction, stroke, 


35 
development or progression of arterial disease necessitating revascularization, or other vascular 
occlusive events. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose Modifications for Ponatinib  
A maximum of two ponatinib dose level reductions are allowed.  If a third dose level reduction is 
required, treatment will be permanently discontinued. The starting dose for ponatinib is 45 mg 
oral daily.  
 
Patients who experience a vascular (arterial or venous) occlusive event should be immediately 
discontinued from the study and ponatinib should not be restarted. For serious reactions other 
than arterial or venous occlusion, do not restart until the serious event has resolved. 
 
Dose Modifications 
Dose Level 
Ponatinib Dose/Schedule 
0 
45 mg daily 
-1 
30 mg daily 
-2 
15 mg daily 
 
Dose Modification for Nausea 
Nausea and vomiting are reported with ponatinib.  The use of an antiemetic prophylactically is 
not recommended.  However, if a patient is symptomatic, appropriate antiemetic medications 
may be used as clinically indicated. 
 
 
CTCAE Grade 
Action and Dose Modification 
≤ Grade 1 
No change in dose 
Grade 2 
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 45 mg after recovery to ≤ Grade 1  
Occurrence at 30 mg:  
 Interrupt ponatinib and resume at 30 mg after recovery to ≤ Grade 1 
Occurrence at 15 mg:  
Discontinue ponatinib 
 
Grade 3 
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 30 mg after recovery to ≤ Grade 1  
Occurrence at 30 mg:  
 Interrupt ponatinib and resume at 15 mg after recovery to ≤ Grade 1 
Occurrence at 15 mg:  
Discontinue ponatinib 
 
Grade 4 
Off protocol therapy 
*Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: Anti-emetics. 
 


36 
 
 
Dose Modification for Vomiting  
CTCAE Grade 
Action and Dose Modification 
≤ Grade 1 
No change in dose 
Grade 2 
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 45 mg after recovery to ≤ Grade 1  
Occurrence at 30 mg:  
 Interrupt ponatinib and resume at 30 mg after recovery to ≤ Grade 1 
Occurrence at 15 mg:  
Discontinue ponatinib 
   
Grade 3 
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 30 mg after recovery to ≤ Grade 1  
Occurrence at 30 mg:  
 Interrupt ponatinib and resume at 15 mg after recovery to ≤ Grade 1 
Occurrence at 15 mg:  
Discontinue ponatinib 
 
Grade 4 
Off protocol therapy 
*Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: Anti-emetics. 
 
Dose Modification for Diarrhea 
Diarrhea is a common side effect of ponatinib.  The use of anti-diarrheal medications is 
permitted.  Patients who experience ≥ grade 2 diarrhea may begin loperamide (4 mg orally x 1, 
then 2 mg orally after each loose stool). 
 
CTCAE Grade 
Action and Dose Modification 
≤ Grade 1 
No change in dose 
Grade 2 
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 45 mg after recovery to ≤ Grade 1  
Occurrence at 30 mg:  
 Interrupt ponatinib and resume at 30 mg after recovery to ≤ Grade 1 
Occurrence at 15 mg:  
Discontinue ponatinib 
 
Grade 3 
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 30 mg after recovery to ≤ Grade 1  
Occurrence at 30 mg:  
 Interrupt ponatinib and resume at 15 mg after recovery to ≤ Grade 1 
Occurrence at 15 mg:  
Discontinue ponatinib 
 
Grade 4 
Off protocol therapy 


37 
CTCAE Grade 
Action and Dose Modification 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-
free for 12 hours. Adjunct antidiarrheal therapy is permitted and should be recorded when used. 
 
Dose Modifications for Hepatic Toxicity 
Hepatotoxicity, most commonly manifested by reversible transaminase and alkaline phosphatase 
elevation and hyperbilirubinemia, has been observed in patients taking ponatinib.  Monitoring of 
hepatic function is recommended and management of laboratory abnormalities should be 
managed with dose interruption and/or dose reduction according to the dose modification table. 
 
CTCAE Grade 
Action and Dose Modification 
Elevation of liver transaminases 
> 3 x ULN* or alkaline 
phosphatase > 2.5 x ULN 
(Grade 2 or higher; or alkaline 
phosphatase > 4x ULN if 
related to metastatic disease 
limited to liver [e.g. 
cholangiocarcinoma]) 
Occurrence at 45 mg: 
 
Interrupt ponatinib and monitor hepatic function  
 
Resume ponatinib at 30 mg after recovery to ≤ 
Grade 1 (< 3 × ULN) 
Occurrence at 30 mg: 
 
Interrupt ponatinib and resume at 15 mg after 
recovery to ≤ Grade 1 
Occurrence at 15 mg: 
 
Discontinue ponatinib  
Elevation of AST or ALT ≥ 3 x 
ULN concurrent with an 
elevation of bilirubin > 2 x 
ULN and alkaline phosphatase  
> 2 x ULN 
Discontinue ponatinib 
 
 
Dose Modifications for Myelosuppression 
 
While myelosuppression can occur any time during treatment, its onset most commonly occurs 
within the first month on treatment. Ponatinib has not been studied in solid tumor patients and 
whether (or to what extent) myelosuppression will occur in these patients is unknown. 
 
 
 
Action and Dose Modification 
Absolute Neutrophil Count 
(ANC)  < 1 x 109/L 
Or  
Platelets < 50 x 109/L 
First Occurrence 
 Interrupt ponatinib and resume initial dose after 
recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 
109/L 
Second Occurrence 
 Interrupt ponatinib and resume at 30 mg after recovery 


38 
 
Action and Dose Modification 
to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L 
Third Occurrence 
 Interrupt ponatinib and resume at 15 mg after recovery 
to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L 
 
 
Dose Modifications for Hemorrhage 
Concomitant use of ponatinib with anticlotting agents should be approached with caution in 
patients who may be at risk of bleeding events. Serious bleeding events, including fatalities have 
been reported in patients treated with ponatinib. Most hemorrhagic events, but not all, occurred 
in patients with grade 4 thrombocytopenia. Interrupt ponatinib for serious or severe hemorrhage 
and evaluate. 
 
CTCAE Grade 
Action and Dose Modification 
Grade 1  
No intervention 
Grade 2  
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 30 mg after recovery 
to ≤ Grade 1  
Occurrence at 30 mg:  
 Interrupt ponatinib and resume at 15 mg after recovery 
to ≤ Grade 1 
Occurrence at 15 mg:  
 Discontinue ponatinib 
Grade 3 or 4 
Permanently discontinue ponatinib 
 
Dose Modifications for Pancreatitis / Lipase Elevations 
Pancreatitis (symptomatic abdominal pain associated with pancreatic enzyme elevation) and/or 
elevations in lipase and amylase are known AEs associated with ponatinib.  Most cases of 
pancreatitis or elevated pancreatic enzymes occur within the first 2 months of treatment with 
ponatinib.  Patients with low-grade (1 or 2) elevation in enzymes can be continued without dose 
reduction but should be monitored closely with serial enzyme level determinations.  Patients can 
continue with ponatinib treatment at the same or a reduced dose once the event has improved to 
grade 1 or resolved. See below for dose-modification guidelines. 
 
 


39 
CTCAE Grade 
Action and Dose Modification 
Asymptomatic Grade 1 or 2 
elevation of serum lipase 
Consider interruption or dose reduction of ponatinib  
Asymptomatic Grade 3 or 4 
elevation of lipase (> 2 X 
ULN*) or asymptomatic 
radiologic pancreatitis (Grade 
2 pancreatitis) 
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 30 mg after recovery to 
≤ Grade 1 (< 1.5 x ULN)  
Occurrence at 30 mg:  
 Interrupt ponatinib and resume at 15 mg after recovery to 
≤ Grade 1 
Occurrence at 15 mg:  
 Discontinue ponatinib 
Symptomatic Grade 3 
pancreatitis  
Occurrence at 45 mg: 
 Interrupt ponatinib and resume at 30 mg after complete 
resolution of symptoms and after recovery of lipase 
elevation to ≤ Grade 1  
Occurrence at 30 mg: 
 Interrupt ponatinib and resume at 15 mg after complete 
resolution of symptoms and after recovery of lipase 
elevation to ≤ Grade 1  
Occurrence at 15 mg: 
 Discontinue ponatinib 
Grade 4 pancreatitis (> 5 X 
ULN of lipase) 
Discontinue ponatinib 
*ULN = Upper Limit of Normal for the lab 
 
Dose Modifications for Skin Rash 
Skin rashes have been commonly reported in patients taking ponatinib.  The vast majority of the 
skin events are nonserious, either self-limiting or manageable with antihistamines or topical 
steroids, and do not result in discontinuation.  In more severe cases, a short course of oral 
corticosteroids may be used until the rash has improved or resolved. In patients treated with 
ponatinib, the most common skin manifestations are a diffuse maculopapular rash that is non-
pruritic or an acneiform dermititis.  Occasionally, patients treated with ponatinib have been 
reported to have a dry, flaky or exfoliative type of rash or psoriasiform dermatitis.  Rarely, an 
erythema multiforme type of rash has been associated with ponatinib. 
 
CTCAE Grade 
Action and Dose Modification 
Grade 2 persistent* despite 
optimal symptomatic therapy, 
but not clinically significant 
No change, continue ponatinib therapy, continue monitor 
every 2 weeks. 


40 
CTCAE Grade 
Action and Dose Modification 
Grade 2 persistent* despite 
optimal symptomatic therapy, 
is clinically significant 
Hold ponatinib 
Resume at 45 mg after recovery to ≤ grade 1 
 
Recurrence at 45 mg: Hold ponatinib 
Resume at 30 mg after recovery to ≤ grade 1 
 
Recurrence at 30 mg: Hold ponatinib 
Resume at 15 mg after recovery to ≤ grade 1 
 
Recurrence at 15 mg: Discontinue ponatinib 
Grade 3 persistent* despite 
optimal symptomatic therapy, 
but not clinically significant  
No change, continue ponatinib therapy, continue monitor 
every 2 weeks. 
Grade 3 persistent* despite 
optimal symptomatic therapy, 
is clinically significant 
Hold ponatinib 
Resume at 30 mg after recovery to ≤ grade 1 
 
Recurrence at 30 mg: Hold ponatinib 
Resume at 15 mg after recovery to ≤ grade 1 
 
Recurrence at 15 mg: Discontinue ponatinib 
*Persistent rash is defined as 7 days. 
 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
Prevention/Prophylaxis 
 
 Avoid unnecessary exposure to sunlight. 
 Apply broad-spectrum sunscreen (containing titanium dioxide 
or zinc oxide) with a skin protection factor (SPF) ≥15 at least 
twice daily. 
 Use thick, alcohol-free emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least twice 
daily. 
Symptomatic Carea 
 
 Pruritic lesions:  Cool compresses and oral antihistamine 
therapies. 
 Fissuring lesions:  Monsel’s solution, silver nitrate, or zinc 
oxide cream. 
 Desquamation:  Thick emollients and mild soap. 
 Paronychia:  Antiseptic bath, local potent corticosteroids in 
addition to antibiotics; if no improvement, consult 
dermatologist or surgeon. 
 Infected lesions:  Appropriate bacterial/fungal culture-driven 
systemic or topical antibiotics. 


41 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
a Patients who develop rash/skin toxicities should be seen by a qualified physician and should 
receive evaluation for symptomatic/supportive care management. 
 
 
Dose Modifications for Hypertension 
 
Patients receiving ponatinib have experienced hypertension and blood pressure should be 
monitored at each visit. In subjects with an initial BP reading within the hypertensive range, a 
second reading should be taken at least 2 minutes later, with the two readings averaged to obtain 
a final BP measurement. The averaged value should be recorded in the eCRF. 
For patients who develop HTN or worsening HTN during study treatment, antihypertensive 
medication should be initiated or optimized to achieve target blood pressure before interruption 
or dose reduction of the study treatment at the discretion of the investigator.  If hypertension is 
persistent despite adequate anti-HTN therapy including titration of anti-HTN medication or 
introduction of additional anti-HTN medications, or if grade 4 HTN develops, dose interruption, 
reduction or discontinuation is recommended. Patients with prior history of hypertension (on 
anti-hypertensive agents) should monitor/record their BP at home while on ponatinib therapy. 
Patients will be provided with a diary to record their at-home assessments. 
 
Patients will obtain blood pressure assessments twice per week at home, using a blood pressure 
cuff supplied by Takedafor purposes of the research study.  Any reading within the hypertensive 
range will be confirmed in clinic.  
 
 
Event 
Management Guideline 
Dose Modification 
Definitions used in the table: 
- Persistent hypertension:  Hypertension detected in two separate readings during up to three 
subsequent visits. 
- Well-controlled hypertension:  Blood pressure of SBP ≤140 mmHg and DBP ≤90 mmHg in 
two separate readings during up to three subsequent visits. 
- Symptomatic hypertension:  Hypertension associated with symptoms (e.g., headache, light-
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is 
controlled within the normal range. 
- Asymptomatic hypertension: SBP >140 mmHg and/or DBP >90 mmHg in the absence of 
the above symptoms. 


42 
Event 
Management Guideline 
Dose Modification 
(Scenario A) 
 Asymptomatic and 
persistent SBP of ≥140 and 
<160 mmHg, or DBP ≥90 
and <100 mmHg,  
or 
Clinically significant increase 
in DBP of 20 mmHg (but still 
below 100 mmHg). 
 Adjust current or initiate new 
antihypertensive 
medication(s). 
 Titrate antihypertensive 
medication(s) during the next 
2 weeks to achieve well-
controlled BP.  If BP is not 
well-controlled within 2 
weeks, consider referral to a 
specialist and go to scenario 
(B). 
Continue ponatinib at the 
current dose. 
(Scenario B) 
 Asymptomatic SBP ≥160 
mmHg, or DBP 
≥100 mmHg,  
or 
Failure to achieve well-
controlled BP within 2 weeks 
in Scenario A. 
 Adjust current or initiate new 
antihypertensive 
medication(s). 
 Titrate antihypertensive 
medication(s) during the next 
2 weeks to achieve well-
controlled BP. 
 Interrupt ponatinib. 
 Once BP is well-controlled, 
restart ponatinib at a reduced 
dose. 
(Scenario C) 
 Symptomatic hypertension  
or 
Persistent SBP ≥160 mmHg, 
or DBP ≥100 mmHg, despite 
antihypertensive medication 
and dose reduction of study 
treatment 
 Adjust current or initiate new 
antihypertensive 
medication(s). 
 Titrate antihypertensive 
medication(s) during the next 
2 weeks to achieve well-
controlled BP. 
 Referral to a specialist for 
further evaluation and 
follow-up is recommended. 
 Interrupt ponatinib. 
 Once BP is well-controlled, 
restart ponatinib at a reduced 
dose. 
(Scenario D) 
Refractory hypertension 
unresponsive to above 
interventions or hypertensive 
crisis. 
Continue follow-up per 
protocol. 
Discontinue ponatinib. 
 
Dose Modifications for Ocular Toxicity 
Ocular toxicities have occurred in clinical trials of ponatinib. Serious ocular toxicities leading to 
blindness or blurred vision have occurred in ponatinib-treated patients. Patients are required to 
have a standard ophthalmic exam performed by an ophthalmologist at baseline and as clinically 
warranted. The exam will include indirect fundoscopic examination, visual acuity (corrected), 
visual field examination, tonometry, and direct fundoscopy.  
 
Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage have 
occurred in ponatinib-treated patients.  


43 
 
Grade  
Management Guideline 
Dose Modification 
Grade 1 
Asymptomatic or symptomatic but 
not limiting ADL; intervention not 
indicated. 
 
 Consult ophthalmologist within 7 
days of onset. 
 Exclude ME, RVO, or RH. 
 Consult retinal specialist if 
available in case of ME, RVO, or 
RH 
 Continue follow up examination(s) 
(by retinal specialist if available) 
for ME, RVO, or RH 
 
 
 Continue ponatinib at the same 
dose level until ophthalmologic 
examination can be conducted.* 
 If ophthalmologic examination 
cannot be performed within 7 days 
of onset, interrupt ponatinib until 
ME, RVO, or RH can be excluded 
and symptoms resolve. 
 If ME, RVO, or RH excluded 
restart ponatinib at same dose level. 
 If ME: Permanently discontinue 
ponatinib. 
 If RVO:  Permanently 
discontinue ponatinib. 
 If RH: Permanently discontinue 
ponatinib. 
Grade 2 and 3 
Grade 2 defined as:  Symptomatic 
with moderate decrease in visual 
acuity (20/40 or better; limiting 
instrumental ADL; local or non-
invasive intervention indicated.   
 
Grade 3 defined as:  Symptomatic 
with marked decrease in visual 
acuity or marked visual field defect 
(worse than 20/40 but better than 
20/200); severe pain or medically 
significant; operative intervention 
indicated. 
 
 Consult ophthalmologist 
immediately. 
 Exclude ME, RVO, or RH. 
 Consult retinal specialist in case of 
ME, RVO, or RH for follow-up 
exam. 
 Continue follow up examination(s) 
(by retinal specialist if available) 
for ME, RVO, or RH. 
 Interrupt ponatinib until signs and 
symptoms have resolved to 
baseline. 
 If ME, RVO, or RH excluded and 
symptoms resolved to baseline, 
restart ponatinib reduced by one 
dose level. 
 If ME: Permanently discontinue 
ponatinib. 
 If RVO:  Permanently 
discontinue ponatinib. 
 If RH: Permanently discontinue 
ponatinib. 
Grade 4 
Sight-threatening consequences; 
urgent intervention indicated; 
blindness (20/200 or worse). 
 Consult ophthalmologist 
immediately. 
 Exclude ME and RVO. 
 Continue follow up examination(s) 
(by retinal specialist if available) 
for ME and RVO. 
Permanently discontinue 
ponatinib. 
 
ME = macular edema; RVO = retinal vein occlusion; RH = retinal haemorrhage. SAE = serious adverse event 
* If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required. 
* If ocular toxicities do not resolve within 14 days, permanently discontinue ponatinib. 
 
 
Dose modification for neuropathy 


44 
CTCAE Grade 
Action and Dose Modification 
Grade 1 or transient  Grade 2 
No intervention 
Grade 2 lasting ≥7 days  
Hold ponatinib 
Resume at 45 mg after recovery to ≤ grade 1 
 
Recurrence at 45 mg: Hold ponatinib 
Resume at 30 mg after recovery to ≤ grade 1 
 
Recurrence at 30 mg: Hold ponatinib 
Resume at 15 mg after recovery to ≤ grade 1 
 
Recurrence at 15 mg: Discontinue ponatinib 
Grade 3 or 4 
Hold ponatinib 
Resume at 30 mg after recovery to ≤ grade 1 
 
Recurrence at 30 mg: Hold ponatinib 
Resume at 15 mg after recovery to ≤ grade 1 
 
Recurrence at 15 mg: Discontinue ponatinib 
 
Dose Modifications for reduced left ventricular ejection fraction (LVEF). 
Severe congestive heart failure (CHF) and left ventricular (LV) dysfunction have been reported 
in patients taking ponatinib. Patients should be monitored carefully for signs or symptoms 
consistent with cardiac failure. ECHOs must be performed at regular intervals as outlined in the 
Study Calendar.  The same procedure (either ECHO or MUGA, although ECHO is preferred) 
should be performed at baseline and at follow-up visit(s).  Consider discontinuation of ponatinib 
in patients who develop serious CHF. 
 
 


45 
Symptoms 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
Asymptomatic 
 
Absolute decrease of  >10% in 
LVEF compared to baseline and 
ejection fraction below the 
institution’s LLN. 
 Interrupt ponatinib and repeat 
ECHO within 4 weeks. 
 If the LVEF recovers within 4 
weeks (defined as LVEF ≥LLN 
and absolute decrease ≤10% 
compared to baseline): 
 Restart treatment with 
ponatinib at reduced dose by 
one dose level. 
 Repeat ECHO 4 and 12 
weeks after re-start; continue 
in intervals of 12 weeks 
thereafter. 
 If LVEF does not recover 
within 4 weeks: 
 Consult with cardiologist. 
 Permanently discontinue 
Ponatinib. 
 Repeat ECHO after 4, 8, 12 
weeks or until resolution. 
Symptomaticb 
 
 Grade 3:  resting LVEF 39-20% 
or >20% absolute reduction 
from baseline 
 Grade 4:  Resting LVEF ≤20%. 
 Permanently discontinue 
ponatinib. 
 Report as SAE. 
 Consult with cardiologist. 
 Repeat ECHO after 4, 8, and 
12weeks or until resolution. 
a Symptoms may include:  dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion 
and edema. 
 
Treatment delays at the start of treatment that are unrelated to drug will require restaging of the 
patient and re-initiating treatment. If at any time during the course of the trial, treatment is 
delayed over 3 weeks due to events unrelated to drug, treatment will resume as normal once the 
patient is deemed stable to continue. 
 
Dose Modifications for General Non-hematologic Toxicities 
CTCAE Grade 
Action and Dose Modification 


46 
Grade 1 or transient Grade 2 
No intervention 
Grade 2 lasting ≥7 days with 
optimal care 
Hold ponatinib 
Resume at 45 mg after recovery to ≤ grade 1 
 
Recurrence at 45 mg: Hold ponatinib 
Resume at 30 mg after recovery to ≤ grade 1 
 
Recurrence at 30 mg: Hold ponatinib 
Resume at 15 mg after recovery to ≤ grade 1 
 
Recurrence at 15 mg: Discontinue ponatinib 
Grade 3 or 4 
Hold ponatinib 
Resume at 30 mg after recovery to ≤ grade 1 
 
Recurrence at 30 mg: Hold ponatinib 
Resume at 15 mg after recovery to ≤ grade 1 
 
Recurrence at 15 mg: Discontinue ponatinib 
 
Dose Modification for concurrent strong CYP3A inhibitors 
 
The recommended dose should be reduced to 30 mg once daily when administering ponatinib 
with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, voriconazole).  Patients taking concomitant strong 
inhibitors may be at increased risk for adverse reactions.  
 
 
7. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS:  LIST AND REPORTING 
REQUIREMENTS  
 
Expected adverse events include the adverse reactions that have at least possible relationship to 
ponatinib and are considered expected in ponatinib clinical studies. To mitigate the inherent risks 
in clinical studies of ponatinib, patients should be monitored closely while receiving treatment. 
A list of AEs (Section 7.2) for ponatinib is listed. 
 
 
 
 
 
7.1 
Definitions 
 
7.1.1   Adverse Event 
 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 


47 
relationship with the treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product whether or not considered related to the medicinal product. Any worsening of 
a preexisting condition, which is temporally associated with the use of the study drug (ie, occurs 
after the first dose of study drug), is also an AE. 
 
AEs include: 
 
 Abnormal test findings 
 Changes in physical examination findings 
 Other untoward medical events, regardless of their relationship to the study drug, such as 
injury, events that require surgery, accidents, or apparently unrelated illnesses 
 Hypersensitivity 
 
Additionally, AEs may include signs or symptoms resulting from: 
 
 Drug overdose 
 Drug withdrawal 
 Drug abuse 
 Drug misuse 
 Drug interactions 
 Drug dependency 
 Exposure in utero 
 
7.1.2 Serious Adverse Event 
 
The Investigator will determine the seriousness of an AE based on the following. 
An AE is considered a SAE if at least one (1) of the following conditions applies: 
 
 Death: An AE that results in death is any patient death within 30 days of the last dose of 
study drug administration. The cause of death or AE that resulted in a fatal outcome is the 
SAE. 
 
 Life-threatening AE: An AE that places the patient, in the view of the Investigator or 
Takeda, at immediate risk of death from the event as it occurred (ie, this does not include 
an event that had it occurred in a more severe form, might have caused death). 
 
 Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions is defined as any substantial disruption of a person’s ability 
to conduct normal life functions. 
 
 Inpatient hospitalization or prolongation of existing hospitalization: Hospitalization 
refers to admission of a patient into a hospital for any length of time. 
 


48 
 A congenital anomaly/birth defect: A fixed, permanent impairment established at or 
before birth. 
 
 Overdose: Any AE associated with an overdose of study drug. An overdose of study drug 
is defined as an occurrence of administered dose exceeding that which is prescribed by 
the investigator per protocol. 
 
 Important medical event: Medical and scientific judgment should be exercised in 
determining whether an event is an important medical event. An important medical event 
may not result in death, be life-threatening, or require hospitalization. However, if it is 
determined that the event may jeopardize the patient and/or may require intervention to 
prevent one of the other outcomes listed in the definition above, the important medical 
events should be reported as serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization; or the development of drug dependency 
or drug abuse. 
 
AEs reported from clinical trials that require hospitalization or prolongation of hospitalization 
are considered serious. Any initial admission (even if less than 24 hours) to a health care facility 
meets these criteria. Adverse events that require emergency room care that do not result in 
hospital admission are not SAEs unless assessed by the investigator to be an important medical 
event. Hospitalization does not include the following: 
 Hospice facilities 
 Respite care 
 Skilled nursing facilities 
 Nursing homes 
 Routine emergency room admissions 
 Same day surgeries (as outpatient/same day/ambulatory procedure) 
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating AE is not in 
itself a SAE. Examples include: 
 Social admission (eg, patient has no place to sleep) 
 Protocol-specified admission during a clinical trial (eg, for a procedure required by the 
trial protocol) 
 Optional admission not associated with a precipitating AE (eg, for elective cosmetic 
surgery that was planned prior to study enrollment [appropriate documentation is 
required for these cases]) 
 
 
7.1.3 Abnormal Test Findings 
 
Test results meeting ≥ grade 3 CTCAE v4 criteria will be reported to the principal investigator 
and will be reported as adverse events.  
 
7.2 
Adverse Reactions for Ponatinib 
 


49 
The following adverse events and reactions described in this section can be found described in 
further detail in the prescribing information for ponatinib. 
 
 
Vascular Occlusion  
 
Heart Failure  
 
Hepatotoxicity 
 
Hypertension  
 
Pancreatitis  
 
Neuropathy  
 
Ocular Toxicity  
 
Hemorrhage  
 
Fluid Retention  
 
Cardiac Arrhythmias  
 
Myelosuppression  
The adverse events described in this section were identified in a single-arm, open-label, 
international, multicenter trial in 449 patients with CML or Ph+ALL who disease was 
considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy 
including those with the BCR-ABL T315I mutation.  All patients received a starting dose of 45 
mg ponatinib once daily.  At the time of analysis, the median duration of treatment with 
ponatinib was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days 
in patients with BP-CML, and 81 days in patients with Ph+ ALL.  The median dose intensity 
was 37 mg or 83% of the expected 45 mg dose. The events of arterial ischemia, cardiac failure, 
and peripheral neuropathy reported in the tables below include data from an additional 13 
months of follow-up (median duration of treatment CP-CML: 672 days, AP-CML: 590 days, 
BP-CML: 89 days, Ph+ ALL: 81 days). 
Adverse reactions reported in more than 10% of all patients treated with ponatinib in this trial are 
presented in the table below. Overall, the most common non-hematologic adverse reactions (≥ 
20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, 
arthralgia, nausea, and pyrexia. 
 
Adverse Reactions Occurring in >10% of Patients, Any Group  
CP-CML 
(N=270) 
AP-CML 
(N=85) 
BP-CML 
(N=62) 
Ph+ ALL 
(N=32) 
System Organ Class 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Cardiac or Vascular 
disorders 
Hypertension (a) 
68 
39 
71 
36 
65 
26 
53 
31 
Arterial ischemia (b)* 
20 
11 
19 
9 
10 
5 
3 
0 
Cardiac Failure (c)* 
7 
4 
6 
4 
15 
8 
6 
3 
Gastrointestinal disorders 
Abdominal pain (d) 
49 
10 
40 
8 
34 
6 
44 
6 
Constipation 
37 
2 
24 
2 
26 
0 
47 
3 
Nausea 
23 
1 
27 
0 
32 
2 
22 
0 
Diarrhea 
16 
1 
26 
0 
18 
3 
13 
3 
Vomiting 
13 
2 
24 
0 
23 
2 
22 
0 
Oral mucositis (e) 
10 
1 
15 
1 
23 
0 
9 
3 


50 
CP-CML 
(N=270) 
AP-CML 
(N=85) 
BP-CML 
(N=62) 
Ph+ ALL 
(N=32) 
System Organ Class 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
GI hemorrhage (f) 
2 
<1 
8 
1 
11 
5 
9 
6 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
1 
<1 
4 
4 
11 
11 
25 
25 
Infections and infestations 
Sepsis 
1 
1 
5 
5 
8 
8 
22 
22 
Pneumonia 
3 
2 
11 
9 
13 
11 
9 
3 
Urinary tract infection 
7 
1 
12 
1 
0 
0 
9 
0 
Upper respiratory tract 
infection 
11 
1 
8 
0 
11 
2 
0 
0 
Nasopharyngitis 
9 
0 
12 
0 
3 
0 
3 
0 
Cellulitis 
2 
1 
4 
2 
11 
3 
0 
0 
Nervous system disorders 
Headache 
39 
3 
28 
0 
31 
3 
25 
0 
Peripheral neuropathy (g)* 
16 
2 
11 
1 
8 
0 
6 
0 
Dizziness 
11 
0 
5 
0 
5 
0 
3 
0 
Respiratory, thoracic, and 
mediastinal disorders 
Pleural effusion 
3 
1 
11 
2 
13 
0 
19 
3 
Cough 
12 
0 
17 
0 
18 
0 
6 
0 
Dyspnea 
11 
2 
15 
2 
21 
7 
6 
0 
Skin and subcutaneous 
tissue disorders 
Rash and related conditions 
54 
5 
48 
8 
39 
5 
34 
6 
Dry skin 
39 
2 
27 
1 
24 
2 
25 
0 
Musculoskeletal and 
connective tissue disorders 
Arthralgia 
26 
2 
31 
1 
19 
0 
13 
0 
Myalgia 
22 
1 
20 
0 
16 
0 
6 
0 
Pain in extremity 
17 
2 
17 
0 
13 
0 
9 
0 
Back pain 
15 
1 
11 
2 
16 
2 
13 
0 
Muscle spasms 
12 
0 
5 
0 
5 
0 
13 
0 
Bone pain 
12 
<1 
12 
1 
11 
3 
9 
3 
General disorders and 
administration site 
conditions 
Fatigue or asthenia 
39 
3 
36 
6 
35 
5 
31 
3 
Pyrexia 
23 
1 
31 
5 
32 
3 
25 
0 
Edema, peripheral 
13 
<1 
19 
0 
13 
0 
22 
0 
CP-CML 
(N=270) 
AP-CML 
(N=85) 
BP-CML 
(N=62) 
Ph+ ALL 
(N=32) 
Pain 
8 
<1 
7 
0 
16 
3 
6 
3 
Chills 
7 
0 
11 
0 
13 
2 
9 
0 
Metabolism and nutrition 
disorders 
Decreased appetite 
8 
<1 
12 
1 
8 
0 
31 
0 
Investigations 
Weight decreased 
6 
<1 
7 
0 
5 
0 
13 
0 


51 
CP-CML 
(N=270) 
AP-CML 
(N=85) 
BP-CML 
(N=62) 
Ph+ ALL 
(N=32) 
System Organ Class 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Any 
Grade 
(%) 
CTCAE 
Grade 
3 / 4 
(%) 
Psychiatric disorders 
Insomnia 
7 
0 
12 
0 
8 
0 
9 
0 
Events) for assessment of toxicity. 
Treatment-emergent, all causality events 
(a) derived from blood pressure (BP) measurement recorded monthly while on trial 
(b) includes cardiovascular, cerebrovascular, and peripheral vascular ischemia 
(c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection 
fraction decreased, pulmonary edema, right ventricular failure 
(d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort 
(e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal 
pain, pharyngeal ulceration, stomatitis, tongue ulceration 
(f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, 
hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal 
hemorrhage, and upper gastrointestinal hemorrhage 
(g) includes burning sensation, skin burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy 
peripheral, paresthesia, peripheral sensorimotor neuropathy, peripheral motor neuropathy, peripheral sensory 
neuropathy, polyneuropathy 
* represents an additional 13 months of follow-up 
 
Serious Adverse Reactions 
N (%) 
Cardiovascular disorders 
Arterial ischemic event* 
53 (11.8%) 
Cardiovascular 
28 (6.2%) 
Cerebrovascular 
18 (4.0%) 
Peripheral vascular 
16 (3.6%) 
Hemorrhage 
22 (4.9%) 
CNS hemorrhage 
10 (2.2%) 
Gastrointestinal hemorrhage 
10 (2.2%) 
Cardiac failure* 
22 (4.9%) 
Effusions(a) 
13 (2.9%) 
Atrial fibrillation 
11 (2.4%) 
Venous thromboembolism 
10 (2.2%) 
Hypertension 
8 (1.8%) 
Gastrointestinal disorders 
Pancreatitis 
23 (5.1%) 
Abdominal pain 
17 (3.8%) 
Blood and lymphatic system disorders 
Febrile neutropenia 
13 (2.9%) 
Thrombocytopenia 
13 (2.9%) 
Anemia 
12 (2.7%) 
Infections 
Pneumonia 
24 (5.3%) 
Sepsis 
11 (2.4%) 
General 
Pyrexia 
14 (3.1%) 
(a) includes pericardial effusion, pleural effusion, and ascites 
* represents an additional 13 months of follow-up 
 
Laboratory Abnormalities 


52 
Myelosuppression was commonly reported in all patient populations. The frequency of grade 
3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-
CML, and Ph+ ALL than in patients with CP-CML (see Table below). 
Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities 
Laboratory Test 
CP-CML 
AP-CML 
BP-CML 
Ph+ ALL 
(N=270) 
(N=85) 
(N=62) 
(N=32) 
(%) 
(%) 
(%) 
(%) 
Hematology 
Thrombocytopenia (platelet count 
decreased) 
36 
47 
57 
47 
Neutropenia (ANC decreased) 
24 
51 
55 
63 
Leukopenia (WBC decreased) 
14 
35 
53 
63 
Anemia (Hgb decreased) 
9 
26 
55 
34 
Lymphopenia 
10 
26 
37 
22 
ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count 
*Reported using NCI-CTC-AE v 4.0 
 
Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities 
 
Laboratory Test 
Safety Population 
N=449 
Any Grade* 
(%) 
CTCAE Grade 3/4 
(%) 
Liver function tests 
ALT increased 
53 
8 
AST increased 
41 
4 
Alkaline phosphatase increased 
37 
2 
Albumin decreased 
28 
1 
Bilirubin increased 
19 
1 
Pancreatic enzymes 
Lipase increased 
41 
15 
Amylase increased 
3 
<1 
Chemistry 
Glucose increased 
58 
6 
Phosphorus decreased 
57 
8 
Calcium decreased 
52 
1 
Sodium decreased 
29 
5 
Glucose decreased 
24 
0 
Potassium decreased 
16 
2 
Potassium increased 
15 
2 
Sodium increased 
10 
<1 
Bicarbonate decreased 
11 
<1 
Creatinine increased 
7 
<1 
Calcium increased 
5 
0 
Triglycerides increased 
3 
<1 
ALT=alanine aminotransferase, AST=aspartate aminotransferase. 
*Graded using NCI-CTC-AE v 4.0 
 
 


53 
7.3 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
If the AE is not defined in the CTCAE, the Investigator will determine the severity of the 
AE based on the following definitions: 
 
Mild (Grade 1): The AE is noticeable to the patient, but does not interfere with routine 
activity. The AE does not require discontinuing administration or reducing the dose of the 
study drug. 
 
Moderate (Grade 2): The AE interferes with routine activity, but responds to 
symptomatic therapy or rest. The AE may require reducing the dose, but not 
discontinuing administration of the study drug. 
 
Severe (Grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy. In addition, the AE leads to discontinuing 
administration or reducing the dose of the study drug. 
 
Life Threatening (Grade 4): The AE requires discontinuing administration of the study 
drug. The patient is at immediate risk of death. 
 
Death (Grade 5): The patient dies as a direct result of the complication or condition 
induced by administration of the study drug. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
The Investigator must provide attribution for all AEs (serious and non-serious). In addition, if the 
investigator determines a Serious Adverse Event (SAE) is associated with trial procedures, the 
investigator must record this causal relationship in the source documents and on the SAE form, 
and report such an assessment in accordance with the SAE reporting requirements. 
 
7.4 
Exchange of Safety Information 
 
a) From The Ohio State University to Takeda: 
 
 Serious adverse events, as defined in FDA regulations 21 CFR 312.32 are to be reported 


54 
to Takeda or Takeda’s designee no later than at time of submission to the FDA per the 
time frames outlined in 21 CFR 312.32.  
 OSU will provide a copy of any aggregate safety reports which have been submitted by 
the institution to the appropriate regulatory authorities in accordance with Applicable 
law, within 7 calendar days. 
 Reports of pregnancies in female subjects and female partners of male subjects and 
pregnancy outcomes will be promptly provided to Takeda (no more than 10 calendar 
days after PI awareness). 
 Study institution will promptly respond to Takeda queries on SAE and make available 
Medical Records or Study Data as Takeda may deem necessary to investigate and/or 
report on an adverse event. 
 Reports of non-serious adverse events will be routinely collected during the course of the 
trial in an appropriately configured database and provided to Takeda with dedicated 
outputs. 
 Provide Takeda with a list of any / all events within a reasonable timeframe of Takeda’s 
request to support Takeda’s management of the product safety profile (e.g. investigation 
of a potential new signal). 
 Submit a final study report to Takeda, to include, when applicable, a list of all adverse 
events and special situation reports, when available, but within no more than 1 year of 
study completion. If study involves a publication, OSU will provide draft publication to 
Takeda at least 1 month prior to submission of final publication. 
 OSU will provide reports of all vascular occlusive events to Takeda or Takeda’s designee 
within 2 business days of awareness of the vascular occlusive event. OSU should expect 
follow-up queries from Takeda that will need a response. OSU will respond to Takeda 
queries as soon as possible after additional information is known at OSU, or made 
available by external participating sites.  
 
Adverse Events of Special Interest (AESIs)  
Vascular occlusive events have been identified as AESIs for ponatinib. These include arterial 
and venous thrombotic and occlusive adverse events that meet the criteria for SAEs (cross-
refer to the section where the serious criteria are described and defined) and those adverse 
events that do not meet the SAE criteria. AESIs require ongoing monitoring by investigators 
and rapid identification and communication by the investigator to the study sponsor. All 
AESIs, whether SAEs or not, must be reported within 2 business days of the study sponsor 
awareness to Takeda. Takeda has determined that the events listed below (whether considered 
serious or non-serious by investigators) should be considered AESIs:  
A. Myocardial infarction: Defined by the Third Universal Definition of Myocardial 
Infarction 
B. Angina (newly diagnosed or worsening of existing angina or unstable angina)  
C. Coronary artery disease (CAD) (newly diagnosed or worsening of existing CAD) or 
symptoms that may reflect cardiovascular disease  
D. Cerebrovascular ischemic disease including ischemic or hemorrhagic stroke, vascular 
stenosis, transient ischemic accident (TIA), cerebrovascular occlusive disease 
documented on diagnostic neuroimaging, or symptoms that may reflect cerebrovascular 
disease  


55 
E. New onset or worsening of peripheral artery occlusive disease (eg, renal artery, 
mesenteric artery, femoral artery) or symptoms that may reflect peripheral vascular 
disease  
F. Retinal vascular thrombosis, both venous and arterial  
G. Venous thromboembolism where significant compromise of organ function or other 
significant consequences could result (eg, pulmonary embolism, portal vein thrombosis, 
renal vein thrombosis) or symptoms that may reflect venous thrombosis  
 
Takeda may request additional information to the study sponsor on observed AESIs and this 
information should be provided in a timely fashion (ie, within 2 business days of the study 
sponsor awareness). All serious adverse events whether “reportable” as defined in this 
protocol or not, must be reported to Takeda. All expedited (7/15 day) reports will be sent to 
Takeda simultaneously or within 24 hours of study sponsor’s submission to the competent 
authorities. Non-expedited SAE reports (except for AESIs) can be batched by the study 
sponsor and sent to Takeda on a monthly basis. Also, any event of a vascular occlusive nature, 
either serious or non-serious, must be reported to Takeda within 2 business days of the study 
sponsor’s awareness.  
 
The study PI or designee is responsible forTakeda reporting SAE reports to Takeda: 
 
Toll-Free Fax #: 1-800-963-6290 
E-mail: takedaoncocases@cognizant.com 
 
b) From Takeda to The Ohio State University: 
 
 Investigator’s Brochures and other reference safety information 
 Takeda agrees to promptly notify Investigator in writing promptly of information that 
could affect the safety or medical care of current or former subjects, influence the 
conduct of the Study, or alter the IRB's approval.  
 
c) From The Ohio State University to External Participating Sites: 
 
 Investigator’s Brochures and other reference safety information (e.g. safety reports) 
 Serious adverse events 
 Other non-serious, but notable toxicities 
 
7.5 
Serious Adverse Event Reporting Procedures 
 
7.5.1 Serious Adverse Event Reporting Period 
 
The Ohio State University will be solely responsible for reporting serious adverse events to the 
OSU IRB, FDA, and Takeda. Participating sites are only permitted to report directly to OSU and 
must report serious adverse events to the OSU PI and Multi-Site Coordinator within 24 hours of 
knowledge of the event. Serious adverse events are to be reported to the OSU IRB (per policy), 
FDA (per 21CFR312.32), and Takeda Drug Safety and Pharmacovigilance or its designated 
representative beginning from the time the patient is first administered investigational product 


56 
through and including 30 days after permanent discontinuation of the investigational product. 
Any SAEs occurring any time after the reporting period must be promptly reported to the OSU 
IRB (per policy), FDA (per 21CFR312.32) and Takeda Drug Safety and Pharmacovigilance or 
its designated representative if a causal relationship to the investigational product is suspected. 
When expedited reporting applies, OSU will provide Takeda with the submitted report of any 
expedited report concurrent to agency submission (no more than 1 business day/3 calendar days 
after the submission). 
 
Patients must be followed for all AEs from the date the patient is first administered 
investigational product until at least 30 Days after the End of Treatment, and for all serious or 
study drug-related toxicities until the AEs are resolved or until patient contact discontinues. 
 
7.5.2 Immediate Reporting of Serious Adverse Events 
 
NOTE: External participating sites are NOT permitted to report directly to the FDA or 
The Ohio State University Office of Responsible Research Practices (ORRP [OSU IRB]). 
All reports must be sent to the OSU Principal Investigator and Multi-Site Coordinator for 
review and submission to the FDA and ORRP. Sites must also report to their IRB 
according to their institutional guidelines. 
 
The Investigator or designee must notify the OSU PI and Multi-Site Coordinator within 24 hours 
of knowledge of an SAE. OSU will then notify the OSU IRB (per policy), FDA (per 
21CFR312.31) and Takeda Drug Safety and Pharmacovigilance or its designated representative. 
A complete SAE report using the FDA MedWatch 3500A Mandatory Reporting Form must be 
submitted to OSU within 3 business days.  Additional or follow-up information on a SAE must 
also be reported immediately (ie, within 24 hours of new SAE information) and on the 
MedWatch 3500A form. Should the FDA, OSU IRB, or Takeda require additional data on the 
event, the Investigator will be asked to provide those data to OSU in a timely fashion. 
 
All SAEs should be reported to the OSU IRB using the most current version of the Event 
Reporting Form (available at http://go.osu.edu/Buck-IRB) and within time frames outlined in the 
IRB policy. SAEs reported from participating institutions will be reported to the IRB by the 
Multi-Site Coordinator. Participating institutions are responsible for reporting to their local IRB 
per their institutional guidelines. 
 
7.5.3 Information to be Provided by the Investigator for a Serious Adverse Event 
 
SAEs are to be reported using the FDA MedWatch 3500A Mandatory Reporting Form.  
Information about the SAE that must be provided includes (refer to the SAE Cover Sheet in the 
Supplemental Forms packet): 
 
 Investigator identification 
 Patient identification (eg, study assigned sequence ID) 
 Information on study drug and concomitant therapies (eg, start/stop date, dose and 
frequency of study drug) 
 Description of event 


57 
 Severity of the SAE 
 Relationship of the SAE to the study drug, the patient’s disease, or other contributing 
factors 
 Outcome of the SAE 
 
7.5.4 Follow-up information on a Serious Adverse Event 
 
Appropriate diagnostic tests should be performed and therapeutic measures, as medically 
indicated, should be instituted. Appropriate consultation and follow-up evaluations should be 
carried out until the event has resolved or is otherwise explained by the Investigator. For all 
SAEs, the investigator is obligated to pursue and provide information to the OSU PI. In addition, 
an investigator may be requested by the OSU PI to obtain specific information in an expedited 
manner. This information may be more detailed than that captured on the SAE form. In general, 
this will include a description of the AE in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality. Information on other 
possible causes such as concomitant medication and illnesses must be provided. 
 
7.5.5 Required Follow-up for Serious Adverse Events  
 
There should be routine follow-up for 30 days after permanent discontinuation of study drug in 
all patients in order to monitor for the occurrence of SAEs. If an SAE continues after the 30-day 
evaluation period, then the patient must be followed until the event resolves or stabilizes. The 
medical monitor may specify a longer period of time, if required to assure the safety of the 
patient. 
 
7.5.6 Takeda Responsibility for Expedited Safety Reports 
 
Takeda will notify investigators of all reportable SAEs. This notification will be in the form of 
an expedited safety report. The OSU Multi-Site Coordinator will distribute safety reports to the 
external participating sites.  Upon receiving such notices, the investigator must review and retain 
the notice with other study-related documentation. The OSU PI and Institutional Review Board 
(IRB) will determine if the informed consent requires revision. The investigator should also 
comply with the IRB procedures for reporting any other safety information. 
Suspected serious adverse reactions and other significant safety issues reported from the study 
shall be reported to the relevant competent health authorities in all concerned countries according 
to local regulations (either as expedited safety reports and/or in aggregate reports), by Takeda or 
its designated representative. 
 
7.5.7 Pregnancy and other safety issues 
 
Females of childbearing potential and fertile males will be informed as to the potential risk of 
conception while participating in this study and will be advised that they must use effective 
contraception during the dosing and for a period of at least 4 months thereafter. A pregnancy test 
will be performed on each pre-menopausal female of childbearing potential prior to the first dose 
of study drug. A negative pregnancy test must be documented prior to administration of study 
drug. 


58 
 
If a patient is confirmed pregnant during the trial, study drug administration must be 
discontinued immediately. Information regarding a pregnancy must be immediately forwarded to 
the OSU PI, who will report the information to Takeda Drug Safety and Pharmacovigilance or its 
designated representative. OSU will notify Takeda of any pregnancy (patient or partner) while on 
drug (no more than 10 calendar days after PI awareness). 
 
The Investigator must immediately report follow-up information to Takeda Drug Safety and 
Pharmacovigilance regarding the course of the pregnancy, including perinatal and neonatal 
outcome, regardless of whether the patient has discontinued participation in the study. If the 
pregnancy results in the birth of a child, additional follow-up information may be requested. If 
the pregnancy results in spontaneous abortion or stillbirth, the event should be reported as an 
SAE. Pregnancy outcomes must be collected for the female partners of any males who took 
study drug in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner. 
 
7.5.8 Adverse error monitoring and reporting  
 
Adverse effects related to ponatinib will be monitored using a custom database and aggregate 
reports of AE (including type, CTCAE grade, duration, attribution and outcome) will be reported 
to the OSU DSMC, per policy. 
 
OSU will notify Takeda of any safety findings that the PI determines may impact the 
risks/benefits of the drug (no more than 1 business day/3 calendar days after determination). 
 
7.5.9 Data safety monitoring plan 
 
Continuous evaluation of safety, data quality and data timeliness will be carried out. The PI will 
conduct continuous review of data and patient safety at their regular disease group meetings (at 
least monthly) and the discussion will be documented in the minutes. The PI of the trial will 
review toxicities and responses of the trial where applicable at these disease group 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 Takeda, to 
determine if the trial should be terminated before completion. 
 
Serious adverse events and responses will also be reviewed by the OSUCCC –James Data and 
Safety Monitoring Committee (DSMC). The PI will also submit a progress report (quarterly) that 
will be reviewed by the committee per the DSMC plan. All reportable serious adverse events will 
also be reported to the Institutional Review Board (IRB) of record as per the policies of the IRB. 
 
A mandatory monthly trial and safety review teleconference will be held for all participating 
sites. It will be expected that representatives from all participating sites be present for each call. 
Meeting minutes will document the attendance and discussions. Safety related information and 
data completion status will be minimally reviewed each month. 
 


59 
 
8. PHARMACEUTICAL AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent ponatinib 
administered in this study can be found in Section 7.1. 
 
8.1 
Ponatinib 
 
The drug substance AP24534 (ponatinib) HCl is the mono-hydrochloride salt of the active 
moiety AP24534 free base. 
 
Chemical name: 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1 
yl) methyl)-3-(trifluoromethyl)phenyl) benzamide, hydrochloride salt 
 
CAS Registry number: 1114544-31-8 (HCl salt) 
 
 
  943319-70-8 (free base) 
 
Molecular Formula: C29H28CIF3N6O  
 
 
M.W.: 569.02. 
 
Approximate Solubility: The free base of AP24534 has solubility in hydrochloric acid-
potassium chloride at pH 1.7 of 2.64 mg/mL. The free base of AP24534 has an aqueous 
solubility of less than 0.0001 mg/mL. 
 
Mode of Action: orally-available TKI that is a potent inhibitor of BCR-ABL along with FGFR 
family members and other kinases including KIT, RET, PDGFRα, ABL1 and FLT3. 
 
Description:  Ponatinib HCl is an off-white to yellow crystalline, anhydrous solid 
 
How Supplied: Ponatinib for investigational use is supplied as 15 mg and 45 mg round, white, 
film-coated tablets. Inactive ingredients in the capsule blend are colloidal silicon dioxide, lactose 
anhydrous, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 
capsule shell contains gelatin and titanium dioxide. The tablet formulation includes inactive 
ingredients lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal 
silicon dioxide, magnesium stearate, polyethylene glycol, talc, polyvinyl alcohol, and titanium 
dioxide. 
 
Storage and Handling: Ponatinib drug product is recommended for storage at controlled room 
temperature (20°C to 25°C [68°F to 77°F]). 
 
Route of Administration: Oral, with or without food. Tablets should be swallowed whole. 
Should not be crushed or dissolved. 
 
Potential Drug Interactions: Based on in vitro studies ponatinib is a substrate of CYP3A4/5 
and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), 


60 
ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) 
transporter systems in vitro. 
 
Availability: Ponatinib is an investigational agent supplied by Takeda  
 
 
 
9. BIOMARKER AND CORRELATIVE STUDIES 
 
Integral  
The primary hypothesis of the correlative component is that genomic alterations in 
FGFR (as well as KIT, RET, PDGFRα, ABL1 and FLT3) predict sensitivity and response to 
ponatinib. To corroborate the hypothesis, patients will have mandatory research biopsies and 
tumor sequencing to detect genomic alterations in these genes as well as the rest of the exome 
and transcriptome. Research biopsies and genomic sequencing are supervised and carried out in a 
companion tissue collection study, OSU precision study (OSU-13053/2013C0152), PI: 
Roychowdhury), or University of Michigan precision study (HUM00055952, Determining 
feasibility of dissemination of molecular profiling data to patients with cancer. IRB 
FWA00004969), PI: Dr. Arul Chinnaiyan. These IRB approved tissue collection and cancer 
profiling studies enroll eligible patients who have advanced or refractory metastatic cancer, to 
undergo mandatory tumor biopsy, integrated sequencing, bioinformatics analysis, and return of 
clinically significant sequence results to the treating oncologists and patients. An outline of the 
Precision Cancer Study process is shown in Figure 2. Importantly, the study includes CLIA-
certified gene testing for the top ~200 cancer genes so that these results can be utilized for 
clinical-decision making such as trial eligibility. Patients with targetable molecular alterations 
can subsequently be treated with agents that target the respective genomic alterations.  
The pilot version of the Precision Cancer Study opened at University of Michigan’s 
Comprehensive Cancer Center in April 2011, under the direction of Dr. Roychowdhury and Dr. 
Chinnaiyan, and has enrolled 200 adult patients with advanced cancer to date.45 The success rate 
for tumor biopsy was 89%, and there were no significant procedural complications (expected 
complication rate is <1 %).46, 47 Therefore, the Precision Cancer Study would screen and identify 
candidate patients with tumors that harbor activating genomic alterations in FGFR (mutations, 
amplifications, fusions) or other genomic alterations (KIT, RET, PDGFRα, ABL1 and FLT3) for 
the Phase 2 ponatinib therapeutic trial. OSU-13053 has been enrolling up to 4 metastatic cancer 
patients (any histology) every 2 weeks, scaling to 4 every week later this spring. To enable a 
clinically pertinent and feasible approach we use a CLIA-certified customized cancer gene panel 
(220 genes) that captures targetable genetic alterations such as point mutations (e.g. BRAF 
V600E mutation), copy number variations (e.g. ERBB2 amplification) and gene fusions (e.g. 
ALK). In addition, patients will also undergo parallel “research sequencing” that entails whole 
“exome” and “transcriptome” sequencing.   
A similar precision study is in place at University of Michigan (MI-ONCOSEQ/ 
HUM00067928; PI- Arul Chinnaiyan) that supervises research tumor biopsies, genomic 
sequencing strategies, and return of results.  This study would screen and identify patients with 
tumors that harbor activating genomic alterations in FGFR (mutations, amplifications, fusions) 
and other genomic alterations (KIT, RET, PDGFRα, ABL1 and FLT3), and is mandatory for 
enrollment into the trial at University of Michigan (sub-site).  


61 
 
Integrated  
Patients who have activating genomic alterations in FGFR, KIT, RET, PDGFRα, 
ABL1 or FLT3 would be treated with ponatinib until disease progression. Eligible patients can 
undergo repeat tumor biopsies at the time of disease progression, and their tumors would be 
subjected to genomic (exome and transcriptome) and proteomic (RPPA) analysis and compared 
with pre-treatment analyses to evaluate for candidate mechanisms of resistance. 
 
Figure-2: Precision cancer study process is shown. Patients with advanced or refractory metastatic 
cancer would undergo tumor biopsy and integrating sequencing. Patients with targetable alterations can 
subsequently be enrolled in trials that target the respective genomic alterations. 
 
 
9.1 
Collection of Specimens 
 
Biospecimens will be collected at the beginning of the study. Consent and tissue management is 
supervised by the OSU Precision Cancer Study (OSU-13053, PI: Roychowdhury). Biospecimens 
included in this protocol may be fresh, frozen or fixed. Biospecimens may be collected through 
The Ohio State University outpatient and inpatient facilities. Generally, most procedures will 
occur through the Department of Radiology (Interventional procedures). However, some 
procedures could occur through other areas such as dermatology (skin biopsy) or operating 
rooms (undergoing a standard of care procedure that is anticipated to yield excess tissue). 
Previously collected tissue blocks, can also be used for sequencing. For complete details, please 
refer to the Precision Cancer Study protocol (OSU-13053). The Precision Cancer Study uses a 
secure Custom Database/LIMS to catalog, store, and track specimens.  
 
9.1.1 
Blood and Tissue Procurement:  
 
A) Blood 


62 
Where possible, blood samples will be drawn from patients scheduled to have venipuncture for 
routine clinical purposes. When this is not possible, blood draws will occur at times other than 
those needed for routine clinical care. Generally, blood draws for research purposes will be 4 
tablespoons of blood (amounts to 4-5 10mL tubes). Exception includes patient with 
hematological malignancies who require leukapheresis procedure as part of their routine clinical 
care, the leftover leukapheresis product may be collected and banked for the study 
Blood Processing: Generally, the processing and storage of blood samples will involve the 
following: blood will be drawn into one or more tubes that contain EDTA, heparin or citrate for 
the collection and stored as serum, white blood cells or whole blood. To preserve patient and 
donor confidentiality, samples are given a specimen ID number. Serum and white blood cells 
will be separated from other cellular components by centrifugation, allocated into tubes, 
catalogued, and frozen at –80° C or viably in liquid nitrogen freezers. Samples may be processed 
for DNA, RNA, and/or protein. 
  
B) Buccal smear  
Buccal smears are a source of normal tissue for comparison to tumor samples. Three buccal 
smears will be obtained at the time of diagnosis or at routine follow-up evaluations. Samples are 
given a specimen ID number. 
Buccal Smear Processing: Swabs will be processed for nucleic acid and/or protein and stored at -
20° C or -80° C respectively. 
 
C) Previously collected and processed biospecimens  
Fixed or frozen specimens may also be obtained from participants. In some cases, patients 
referred to The Ohio State University clinics with a cancer diagnosis from outside hospitals will 
bring hematoxylin and eosin stained slides for routine review by pathologists. To preserve 
patient and donor confidentiality, samples are given a specimen identification number which will 
be entered into the sample database. Authorized study personnel will contact the institution 
where tissue was already obtained and request the appropriate sample. A copy of the informed 
consent will be provided to such institutions to allow release of the tissue or cut slides for 
research purposes. To preserve patient and donor confidentiality, samples are given a specimen 
ID (generated in Custom Database/LIMS) which will be entered into the sample database. 
 
D) Tumor tissue biopsy  
Tumor tissue or fluids will be collected from patients through the least invasive approach. 
Patients will receive informed consent detailing risks and benefits of the specific procedure. The 
list of possible procedures includes but is not limited to: percutaneous needle biopsy (liver, lung, 
breast, soft tissue mass), lymph node biopsy, bone marrow biopsy and aspirate, thoracentesis for 
pleural fluid and paracentesis for peritoneal fluid. When patients undergo tumor biopsy, they will 
receive a routine clinical consent as provided by the health care professional who performs the 
procedure. Generally, this will be staff from the Department of Radiology. This consent process 
will describe the procedure, risks, benefits, and alternatives. 
 
Tissue Biopsy Processing. Freshly excised tissue will be placed in OCT medium and frozen 
immediately at -80 C. An H&E slide will be prepared for review by an OSU pathologist. To 
preserve patient and donor confidentiality, samples are given a specimen ID number. Patients 
who have progression of their cancer may choose to be re-consented for additional tissue 


63 
procurement including tumor biopsy and other samples. This is subject to the same eligibility 
and consent requirements. 
 
Some clinical sites may not be completing pretreatment tumor biopsy due to resource limitations. 
These sites will provide the most recent archival tumor specimen available. 
 
9.2 
Laboratory Correlative Studies 
 
Genome and Transcriptome Sequencing 
 
Pretreatment tumor biopsy or archival specimen will undergo sequencing would as 
part of the OSU Precision Cancer Study (OSU-13053), a companion study to this trial. This 
study supervises collection of research tumor biopsies/archival specimens, germline tissue 
collection (blood, buccal swabs), genomic sequencing strategies, and return of results. This study 
shares data and samples for patients who subsequently participate in a therapeutic study such as 
this Phase 2 ponatinib trial. An integrative sequencing strategy, clinical and research would be 
utilized for this study. Clinical sequencing would be performed in CLIA-certified lab 
(Roychowdhury Lab) for a custom cancer panel of 220 genes. Research sequencing includes 
whole exome and transcriptome sequencing (RNASeq) of tumor to identify potentially 
informative mutations, amplifications, or gene fusions to evaluate for biomarkers of sensitivity 
and mechanisms of resistance. The custom cancer panel includes assessment of both DNA and 
RNA for 220 oncogenes (including FGFR1, FGFR2, FGFR3, and FGFR4) and tumor 
suppressors and is designed to detect point mutations, copy number changes, and gene fusions. 
The list of genes is shown in Figure 3. 
A similar study is in place at University of Michigan (MI-ONCOSEQ/ 
HUM00067928; PI- Arul Chinnaiyan) that supervises collection of research tumor 
biopsies/archival specimens, genomic sequencing strategies, and return of results.  This study 
would screen and identify patients with tumors that harbor activating genomic alterations in 
FGFR (mutations, amplifications, fusions) and other genomic alterations (KIT, RET, PDGFRα, 
ABL1 and FLT3) for enrollment at University of Michigan.  
 
CLIA Sequencing: Targeted gene sequencing is accomplished by solution-based 
hybridization capture with custom baits (Agilent) of both tumor (biopsy or archival specimen) 
and normal DNA (Blood). This is used to generate somatic point mutations and copy number 
changes using published tools (Varscan2, MuTect)45, 48. Targeted gene sequencing from RNAseq 
libraries is utilized to identify gene fusions involving FGFRs and analyzed using published 
fusion tools (Tophat2, Chimerscan)49, 50. All sample collection, processing, sequencing, and 
analysis will be completed in Dr. Roychowdhury’s CLIA-certified lab. 
 
 
Research Sequencing: For research sequencing, we would use Agilent’s SureSelect 
whole exome capture and Illumina’s TruSeqRNA protocols to prepare libraries for sequencing as 
previously described.45 Libraries will be submitted to a vendor for sequencing on an Illumina 
HiSeq2000 instrument (Beijing Genomics Institute). Bioinformatics analysis will be performed 
in the lab to derive annotated single nucleotide variation, copy number alterations, and gene 
expression using existing tools as previously described (Exome: BWA, Varscan2, MuTect; 
RNAseq: Tophat2, Cufflinks).45  
 


64 
Figure 3: Gene Panel List 
 
Reverse Phase Protein Assay (RPPA) 
 
In addition to genome and transcriptome sequencing we would also perform RPPA to assess 
protein expression and modifications that characterize canonical pathways in cancers. This assay 
will be run at MD Anderson Cancer Center RPPA-Functional Proteomics Core Facility. 
Sections of the OCT embedded core biopsies/archival tumor specimens will be evaluated by a 
pathologist to verify tumor content.  Tissue will then be cut out of the OCT and protein will be 
extracted using standard methods.  The protein will be denatured, diluted and arrayed on 
nitrocellulose coated slides.  The slides will be probed with a set of over 200 validated antibodies 
and spot density determined by MicroVigene software.  Samples will be normalized for protein 
loading and concentrations will be determined using the Super Curve Fitting program.  
Supervised and un-supervised hierarchical clustering analysis will then be performed.  Some of 
the proteins of interest that are included in this assay are; PI3KCA, total and phosphorylated 
forms of Akt, mTOR, Cyclin D1, ERK, MEK, p70-S6 kinase etc. RPPA data at the time of 


65 
disease progression to ponatinib would be compared with data prior to treatment with ponatinib 
to evaluate for putative mechanisms of resistance to FGFR targeting.  
 
Data Integration: Using the exome sequencing, transcriptome sequencing, and RPPA, we can 
systematically characterize candidate mechanisms of resistance in the FGFR pathway at the time 
of disease progression with ponatinib. Putative changes of interest would likely include splice 
variants in FGFR, increased FGFR gene expression, point mutations or copy number variation in 
FGFR signaling pathways (PI3-kinase or MAP kinase).  
 
 
9.3 
Specimen Storage and Disposal 
 
Specimens will be stored in designated and secure facilities at The Ohio State University. The 
Precision Cancer Study uses a secure Custom Database/LIMS to catalog, store, and track 
specimens. The Study stores specimens in monitored and locked freezers that are in a secure 
facility. 
Generally, frozen tissue will be stored in secured -80ºC freezers. Storage and retrieval of fixed 
and paraffin embedded specimens will be handled using routine procedures of the Pathology 
Department affiliated with the hospital at which the specimen was collected. Disposal of 
biospecimens will be considered under certain circumstances including but not limited to 
reduced specimen integrity, exhausted capacity or insufficient funds for long-term maintenance 
or storage of low priority biospecimens. Determination of the integrity and priority of 
biospecimens is at the discretion of study personnel. The discarding of research specimens is also 
subject to any institutional policy and the informed consent under which the specimen was 
obtained. 
 
 
9.4 
Sites Performing Correlative Studies 
 
 Integrated sequencing analysis (exome and transcriptome sequencing) would be performed at 
The Ohio State University (Dr.Roychowdhury Lab) and University of Michigan (Dr.Arul 
Chinnaiyan’s Lab). Methodologies for exome and transcriptome sequencing are identical. 
 
 The RPPA assay will be performed by MD Anderson Cancer Center RPPA-Functional 
Proteomics Core Facility. 
 
 
9.5 
Potential risks and procedures for minimizing risks 
 
9.5.1 Risks of blood draws 
 
 
All blood draws will be performed by trained personnel that use standard sterile 
techniques.  Infection is unlikely since stringent aseptic techniques are followed during all 
venipuncture procedures. 
 
9.5.2 Risks of biopsy  
 


66 
 
The risks of this study relate primarily to the risk of a biopsy. In general, these 
procedures are associated with a small risk of pain, bleeding, infection, and damage to adjacent 
organs.  The magnitude of this risk depends somewhat upon the site of the procedure.  Potential 
risks according to site are: 
 
Risks of core breast biopsy: 
 Likely: local discomfort and minor bleeding.  
 Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, pneumothorax, 
damage to adjacent organs. 
 
Risks of skin/chest wall punch biopsy: 
 Likely: local discomfort and minor bleeding.  
 Less likely: moderate or major bleeding, or infection 
 
Risks of lymph node or soft tissue core needle biopsy: 
 Likely: local discomfort and minor bleeding.  
 Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, pneumothorax, 
damage to adjacent organs. 
 Additional risks may be present if i.v. conscious sedation is required. 
 
Risks of liver core needle biopsy: 
 Likely: local discomfort and minor bleeding 
 Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, bowel 
perforation or damage to adjacent organs 
 Additional risks may be present if i.v. conscious sedation is required. 
 
Lung biopsy core needle biopsy: 
 Likely: local discomfort and minor bleeding 
 Less Likely: moderate or major bleeding, need for blood transfusion, lung 
collapse, hospitalization due to bleeding or other complications, infection, damage 
to nearby organs, allergic reaction to the numbing medicine 
 
Bone Marrow Biopsy: 
 Likely: local discomfort and minor bleeding 
 Less Likely: Nerve injury, blood collection at the site 
 
In order to minimize the risk of a biopsy, only qualified personnel will perform these procedures.  
Prior to the procedure, the physician performing the procedure will discuss the risks with each 
study participant, answer any questions, and obtain separate procedure consent.  For biopsies of 
lesions that are not superficial and clearly palpable, imaging studies such as CT, ultrasound, or 
MRI will be used to guide the biopsy in order to minimize the risk of damage to adjacent 
structures. After lymph node biopsies, patients will be observed for approximately 2 hours (range 
2-4 hours) after the procedure, or per institutional standard guidelines.  After liver biopsies, 


67 
patients will be observed for approximately 4 hours (range 4-6 hours) after the procedure, or per 
institutional standard guidelines.  Less than the goal quantity of tissue is acceptable for each type 
of biopsy, and will be left to the clinical judgment of the physician performing the procedure.   
 
All grade 3 or 4 events attributable to any of the study procedures will be reported to the 
Principal Investigator within 24 hours of occurrence.  Adverse events will be reported by the PI 
to the IRB consistent with standard procedures.   
 
9.5.3 Anesthesia Risk 
 
Risks of local anesthesia 
 
All biopsy procedures require local anesthesia using lidocaine, xylocaine, or related compounds.  
There is a small risk of an allergic reaction associated with these drugs. 
 
In order to minimize the risk of local anesthesia, only qualified personnel will perform the biopsy 
procedure.  Patients will be queried if they have had previous allergic reactions to local 
anesthetics.   
 
Risks of intravenous conscious sedation 
 
Certain biopsy procedures, such as lymph node or liver biopsies, may require intravenous 
conscious sedation (IVCS).  IVCS is a minimally depressed level of consciousness that retains 
the patient’s ability to maintain a patent airway independently and continuously and respond 
appropriately to physical stimulation and verbal commands. 
 
The risks of intravenous conscious sedation include: inhibition of the gag reflex and concomitant 
risk of aspiration, cardiopulmonary complications (myocardial infarction, cardiac arrhythmias, 
hypoxemia), and allergic reactions to the sedative or analgesic medications.  These risks are 
small but real; for example, in a prospective study of 14,149 patients undergoing IVCS during 
upper gastrointestinal endoscopies, the rate of immediate cardiopulmonary events was 2 in 1000. 
The 30-day mortality was 1 per 2,000 cases.  In this study, there was a strong association 
between lack of monitoring and use of high-dose benzodiazepines with adverse outcomes.  There 
was also an association between the use of local anesthetic sprays to the oropharynx and the 
development of pneumonia. 
 
In order to minimize the risk of intravenous conscious sedation, only qualified personnel will be 
responsible for conscious sedation as per institutional protocols.  A minimum of two individuals 
will be involved in the care of patients undergoing conscious sedation—the physician performing 
the biopsy procedure, and the individual (M.D. or R.N.) who monitors the patients and his/her 
response to both the sedation and the procedure, and who is capable of assisting with any 
supportive or resuscitative measures.  The room where the procedure utilizing IVCS takes place 
will have adequate equipment to provide supplemental oxygen, monitor vital signs, and maintain 
an airway should this be necessary.  An emergency cart will also be immediately accessible to 
the room where the procedure is to take place, and emergency support services will be available 
on page.  Patients will be screened and evaluated for their fitness to undergo conscious sedation 


68 
by a trained physician. Following the procedure, patients will be observed closely in the recovery 
room according to standard institutional guidelines.  
 
 
 
9.5.4 Risk of imaging studies 
 
Some biopsy procedures require imaging studies, either to plan or guide the procedure.  Imaging 
studies that may be used in obtaining tissue samples include CT scans and ultrasound.  CT scans 
will expose study participants to controlled amounts of radiation.  The total dose of radiation 
from these tests is not anticipated to cause any adverse effects.  There is also a risk of an allergic 
reaction to the intravenous contrast dye used during CT imaging, as well as a risk of 
experiencing feelings of anxiety or claustrophobia while undergoing a CT scan.  There are no 
anticipated risks with the use of ultrasound. 
In order to minimize these risks, patients will be queried, as per standard institutional practice, 
regarding their history of reactions to intravenous contrast dye.  If a patient has had such a 
reaction, she/he will be premedicated, or dye will not be used, as per standard institutional 
practice.  If a patient has previously experienced anxiety or claustrophobia while undergoing a 
CT scan, anxiolytics may be considered as indicated. 
 
 


69 
10. STUDY CALENDAR 
 
Baseline evaluation must be conducted within 2 weeks prior to start of ponatinib therapy. 
Imaging studies 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.  Appropriate delays in study treatment or 
procedures are allowed to adjust for holidays or weekends. Each cycle is 28 days. 
 
Study 
Assessment
s1 
Screen 
During Ponatinib Therapy  
Final Study 
Visit3 
Follow-Up9 
Informed 
Consent 
X 
 
 
 
Baseline 
Demographic
s 
X 
 
 
 
Ophthalmic 
Exam2 
X 
As clinically indicated 
 
 
Medical 
History / 
Interim 
History 
X 
Day 1 (± 3 days) of each cycle  
X 
 
Concomitant 
Medications 
X 
Continuous 
 
Physical 
Exam 
X 
Day 1 (± 3 days) of each cycle 
X 
 
ECOG 
Performance 
Status 
X 
Day 1 (± 3 days) of each cycle 
X 
 
Vital Signs 
(BP, 
HR,Temperat
ure, weight) 
X 
Day 1 (± 3 days) of each cycle 
X 
 
Blood 
Pressure (at 
home)4 
 
Twice per week during cycle  
 
 
Chemistry5 
X 
Day 1 (± 3 days) of each cycle 
X 
 
Triglycerides 
X 
 
 
 
CBC, Diff, Plt 
X 
Every 2 weeks for first 2 
cycles 
Day 1 (± 3 days) from 
cycle 3 
 
 
Liver Function 
Testing 
 
Cycle 1 Day 1 
Once per month, or more 
frequent if clinically 
indicated 
 
 
Serum 
Amylase, 
Serum Lipase 
X 
Every 2 weeks for first 2 
cycles 
Day 1 (± 3 days) from 
cycle 3 
 
 
Pregnancy 
Test6 
X 
 
 
 
12-Lead ECG 
X 
Repeated as Clinically Indicated 
 
 
LVEF 
(ECHO) 
X 
Repeated every 3 cycles ± 7 days or as Clinically Indicated 
 
Research 
Biopsy(s) 7 
Research 
biopsies 
on eligible 
Research biopsies will be attempted on all patients at 
time of progression  
 
 


70 
patients 
prior to the 
study  
Study Agents 
 
 Ponatinib will be administered daily  
 
Tumor 
measurement
s8  
X 
Staging will occur after every 2 cycles ± 7 days or as Clinically Indicated 
 
Adverse 
Events 
 
Continuous 
 
1. Assessments scheduled on days of dosing must be done prior to administration of study drug(s), 
unless otherwise specified. 
2. Ophthalmic exam will include indirect and direct fundoscopy, visual acuity, visual field examination, 
tonometry and color fundus photos.  Additional ophthalmic exams will be performed if 
symptomatically warranted. 
3. Final Study Visit must occur 21 days (7 days) after last dose of study drug. 
4. Blood pressure cuff will be provided by Takeda. Patients will record readings in diary (Appendix B) 
and bring with them to clinic visits. 
5. Including alkaline phosphatase, total bilirubin, albumin, creatinine, glucose, potassium, SGOT, 
SGPT, sodium, magnesium, chloride, bicarbonate, phosphate. 
6. Perform only in women of child-bearing potential.   
7. Research biopsies will be performed as part of the OSU Precision Cancer Trial (or through MI-
ONCOSEQ for study enrollment at University of Michigan). Blood, buccal samples must also be 
obtained per Section 9. 
8. Radiologic documentation must be provided for patients removed from the study due to progressive 
disease for solid tumors. CT chest/abdomen/pelvis is preferred. Bone scan, MRI or PET may be 
used at the discretion of treating physician. 
9. Patients discontinuing for toxicity are followed until resolution of the toxicity, as outlined in Section 
5.4. Patients who have discontinued protocol therapy will be followed every 3 months for 52 weeks 
or until death, whichever occurs first, in order to document time of progression (if patient did not 
progress while on study), survival, and to document subsequent alternate therapy received. For 
patients with resolution of toxicity to protocol therapy, telephone follow-up is permitted. 
 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 8 weeks following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with ponatinib 


71 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may be considered 
measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 


72 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 


73 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 


74 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1. Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 


75 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2. Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3. Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
No 
SD 
Documented at least once >4 


76 
PD/not 
evaluated 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 


77 
11.1.7 Response Review 
 
All responses will be reviewed by an expert(s) independent of the study at the study’s 
completion.  Simultaneous review of the patients’ files and radiological images will 
occur. 
 
 
 
 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
With the advent of genomic profiling and targeted therapies, focusing on patients with a specific 
target (or genomic alteration) of interest regardless of disease type or histology is a new 
paradigm that cancer research is beginning to adopt. This is a Phase-2, “basket” study for 
patients with advanced cancers (stage 4, any histology) who have disease progression with at 
least one prior regimen, identified with predefined genomic alterations. Two separate cohorts 
will be accrued in parallel, defined by genomic FGFR, as well as KIT, PDGFRα, ABL1, RET, 
and FLT3 alterations. 
Cohort A will consist of patients identified with activating mutations or fusions in FGFR as well 
as patients with FGFR amplifications. 
Cohort B will consist of patients identified with rare gene targets (KIT, PDGFRα, RET, ABL1, 
and FLT3 alterations) for whom there may be downstream targeting and efficacy associated with 
ponatinib.  
Our goal is to assess efficacy outcomes in these two cohorts when treated with ponatinib.  
 
(a) Definition of primary outcome/endpoint: 
The primary endpoint for each of the cohort in this study is overall response. Overall response is 
defined as the number of patients who achieve any response in the first 6 cycles of treatment. All 
eligible patients, selected by a CLIA approved assay, who have received at least one dose of 
ponatinib will be evaluable for response. Response for tumors would be assessed using the 
RECIST 1.1 criteria (using CT scans or calipers by clinical exam) where response will be 
defined as a partial or complete response.  
 
 (b) Definition of secondary outcomes/endpoints: 
-Toxicity is defined as adverse events that are classified as either possibly, probably, or definitely 
related to study treatment per NCI CTCAE v4.0 
-Overall survival is defined as the time from treatment initiation to death. 
-Progression-free survival defined as the time from treatment initiation to progression or death 
 
12.2 
Analysis of Primary Objectives 
 
Cohort A: FGFR mutations, fusions or amplifications 
 


78 
This cohort will utilize a two-stage Simon minimax phase II study design. In the 
relapsed/refractory setting for the multiple eligible disease types who have an FGFR mutation, 
fusion or amplification given the targeted nature of this regimen and preliminary data that 
support its use in those with FGFR mutations, fusions or amplifications, a true ORR of at least 
20% would be considered promising in this patient population. Therefore, this study is designed 
to detect an ORR of at least 20% vs. the null hypothesis that the true ORR is at most 5%, 
representing a response by chance alone. Based on preclinical data, we expect that those with 
FGFR amplification may not be as susceptible to the targeting effects of ponatinib as those with 
FGFR mutation/fusions. We also expect that those patients identified with FGFR amplifications 
will be much more prevalent than those identified with FGFR mutations/fusions. To 
accommodate the possible confounding scenario of accruing a large majority of FGFR 
amplification only patients vs. mutations/fusions, we will stratify accrual, with planned 
enrollment of an equal number of FGFR amplification only and of FGFR mutation/fusion 
patients. Also, no more than 10 patients would be enrolled for a specific tumor type. 
 
 
Decision Rule: The largest response rate where this treatment regimen would be considered 
ineffective in this population is 5%, and the smallest response rate that would warrant subsequent 
studies with this proposed regimen in this patient population is 20%. The following two-stage 
Simon minimax phase II study design requires a maximum of 30 evaluable patients to test the 
null hypothesis that the true response rate is at most 5%. 
 
Constraining the Type I error rate to 5% and with at least 80% power, this two-stage Simon 
minimax study design will require 30 evaluable patients to test these hypotheses regarding the 
ORR with ponatinib in this patient population. As described above, to address possible 
confounding that could result from accruing a large majority of FGFR amplification only 
patients, a subpopulation that may not be as susceptible to the targeting of ponatinib, we will 
restrict accrual of the FGFR amplification only patients to 15, and accrue 15 patients identified 
as having FGFR mutations/fusions. No more than 10 patients would be enrolled for a single 
tumor type regardless of FGFR alteration. 
 
Under this design, the first stage will enroll 10 evaluable patients.  If we observe at least one 
response in the first stage, the study will proceed to the second stage and enroll an additional 20 
evaluable patients. Given the expected greater prevalence rate of the FGFR amplifications, we 
expect that it is not unlikely that the first 10 patients accrued in this cohort will be all 
amplification only patients. If this is the case and no responses are observed, then we will 
consider this adequate early evidence that the regimen is not sufficiently active in the FGFR 
amplification only patients. At this point, we would keep accrual open, but only to the FGFR 
mutation/fusion patients. An interim decision rule would not be implemented in this subgroup of 
patients. If there are 0 responses in the first 10 all amplification patients, accrual of patients with 
FGFR amplifications would cease. Subsequently, 20 patients would be enrolled and enrollment 
would be restricted to patients with FGFR mutations and fusions.  
 
In the final analysis, if we see at least 4 patients who have a response to treatment out of the 
30 evaluable patients, we will consider this sufficient evidence that this combination regimen has 
promising activity in this patient population. Otherwise, if 3 or fewer patients have a response in 
the first 6 cycles of therapy, we will consider this regimen to not be sufficiently active in this 
population.   
 


79 
Analysis Plan: As described above, the proportion of responses for the purposes of this decision 
rule will be calculated out of all eligible patients who receive any treatment. Assuming the 
number of responses is binomially distributed, 95% binomial confidence intervals will also be 
calculated for the estimate of the proportion of responses. 
 
Cohort B: KIT, PDGFRα, RET FLT3, ABL1 alterations 
 
Design Summary: As mentioned above, this cohort will consist of patients identified with rare 
gene targets for whom there may still be downstream targeting and efficacy associated with 
ponatinib; these patients will include those identified with KIT, PDGFRα, RET, ABL1, and FLT3 
alterations. Given the variable types of genetic alterations that may be accrued to this cohort in 
addition to the multiple disease types, this cohort will be a pilot evaluation without a 
corresponding formal decision rule. This cohort will be open to accrual for the timeframe that 
Cohort A is open to accrual, with up to a maximum of 15 patients being accrued to this cohort. 
Our analyses for this cohort will be largely exploratory and descriptive, focusing on identifying 
the composition of patients who enrolled to this cohort in terms of their genetic alteration and 
disease type along with biomarker evaluations and clinical outcomes. While this cohort does not 
have specific endpoints associated with it, it provides a mechanism to make ponatinib available 
to those with rare genetic alterations and collects valuable preliminary data for ponatinib single 
agent therapy in the various types of patients who may be enrolled. 
 
 
 
12.3 
Sample Size/Accrual Rate 
This trial would be conducted at two institutions to accrue up to 45 patients across all cohorts: 30 
for Cohort A, and up to 15 for Cohort B. We have a Precision Cancer Study (Ohio State) that 
evaluates a pool of 400 patients per year with metastatic cancer through research tumor biopsies 
and comprehensive clinical tumor sequencing. From this pool, we would enrich patients with 
FGFR alterations. We expect to see actionable FGFR alterations in approximately 5% of 400 
patients screened a year (200 this year) with advanced solid tumors with any histology.  Similar 
precision trial is in place at University of Michigan (MI-ONCOSEQ), screening 400 patients a 
year. By combining screening from OSU and UM, we expect to see approximately 40 patients 
enrolled per year (5% of 800 screened). Quarterly review of accrual at each site would be carried 
out to identify the number of patients enrolled for therapy. Accrual should be complete in 12 to 
18 months. 
 
12.4 
Analysis of Secondary Objectives 
 Frequency and severity of adverse events and tolerability of the regimen will be collected and 
summarized by descriptive statistics.  As per NCI CTCAE v4.0, the term toxicity is defined 
as adverse events that are classified as either possibly, probably, or definitely related to study 
treatment. The maximum grade for each type of toxicity will be recorded for each patient, 
and frequency tables will be reviewed to determine toxicity patterns for each of the cohorts 
as well as across cohorts. In addition, we will review all adverse event data that is graded as 
3, 4, or 5 and classified as either “unrelated” or “unlikely to be related” to study treatment in 
the event of an actual relationship developing. The incidence of severe (grade 3+) adverse 
events or toxicities will be described. We will also assess tolerability of the regimen through 


80 
assessing the number of patients who required dose modifications and/or dose delays. In 
addition, we will capture the proportion of patients who go off treatment due to adverse 
reactions or even those who refuse further treatment for lesser toxicities that inhibit their 
willingness to continue participation on the trial. All patients who have received at least one 
dose of any of the therapeutic agent will be evaluable for toxicity and tolerability. 
 Overall and Progression Free Survival as time-to-event outcomes.  Kaplan-Meier curves will 
be used to estimate the survival distributions of overall survival and progression-free survival 
for each cohort. Each of these variables is measured from the date of study registration to the 
date of event (ie, death and/or disease progression) or the date of last follow-up if no event 
has occurred.  
 Clinical benefit rate (CBR) at 6 months. The 6-month CBR will be calculated by the number 
of patients who have achieve a response and/or are progression-free and alive at 6 months 
divided by the total number of evaluable patients. Exact binomial 95% confidence intervals 
for CBR will be calculated.   
 Correlative markers will be explored in this trial in relation to clinical outcomes of interest, 
and in particular in relation to the primary endpoint of overall response. Given the limited 
overall sample size as well as the relatively limited expected proportion of responses, these 
analyses will be largely exploratory and hypothesis-generating in nature. Correlative gene 
and protein markers will be summarized univariately in a quantitative manner and also 
summarized by clinical outcome group (e.g. response vs. no response). Graphical analyses 
will be largely used to assess potential patterns and relationships; e.g. side-by-side boxplots 
to assess differences in continuous marker levels between those with vs. without the clinical 
improvement (e.g. response vs. no response). Overall, hypothesis testing will largely be 
avoided given the sample size limitations but we will still obtain important preliminary data 
that can inform future studies and help better understand the mechanisms of this treatment 
regimen in this patient population. 
 We would also evaluate and summarize the logistical aspects of the trial, including the rate of 
participation and enrollment of those screened and identified with the eligible genetic 
alterations. Also, of those enrolled, we will characterize the composition of the cohorts. 
Disease group-specific outcomes will also be summarized and described, although we will 
not be powered for any formal evaluation within a disease or histology subset. Still, these 
will be used as valuable preliminary data for hypothesis generation and designing future 
trials with this regimen and/or this treatment approach. 
 
12.5 
Reporting and Exclusions 
 
12.5.1 Evaluation of Toxicity 
 
All patients would be evaluable for toxicity from the time of their first treatment with 
ponatinib. 
 
12.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 


81 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  All 
conclusions should be based on all eligible patients.  Subanalyses may then be performed 
on the basis of a subset of patients, excluding those for whom major protocol deviations 
have been identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.).   
 
 


82 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


Version: 03/23/2020 
OSU IRB Approved:  5/22/2020 
0 
APPENDIX B 
MEDICATION DIARY  
 
PATIENT ID: _______________ 
PATIENT INITIALS (F  M  L):    ____   ____   ____ 
DOSE PONATINIB ______________ daily 
CYCLE # ______ 
Date 
Day of 
Cycle 
Day of 
Week 
Time 
Dose 
Missed 
Patient Comments 
Blood Pressure ###/## 
mmHg 
Take Twice Weekly 
Example1: 
1/22/14 
1 
Mon 
3   :  15 
□ AM  □ PM 
□ 
 
 
Example 2: 
1/23/14 
2 
Tues 
_____:_____ 
□ AM   □ PM 
. 
Forgot to take my pills and didn't remember until the next day 
 
 
1 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
2 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
3 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
4 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
5 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
6 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
7 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
8 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
9 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
10 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
11 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
12 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
13 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
14 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
15 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 


1 
PATIENT ID: _______________ 
PATIENT INITIALS (F  M  L):    ____   ____   ____ 
DOSE PONATINIB ______________ daily 
CYCLE # ______ 
Date 
Day of 
Cycle 
Day of 
Week 
Time 
Dose 
Missed 
Patient Comments 
Blood Pressure ###/## 
mmHg 
Take Twice Weekly 
 
16 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
17 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
18 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
19 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
20 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
21 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
22 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
23 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
24 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
25 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
26 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
27 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
 
28 
 
_____:_____ 
□ AM   □ PM 
□ 
 
 
DIRECTIONS:    Take by mouth daily with or without food. You will take the medication once per day, at the same time each day.   If you miss a dose of your medication, you should 
take it as soon as you remember that day up to 6 hours past the scheduled time. If more than 6 hours has passed since the scheduled time, do NOT take the missed dose.   Please 
inform your study doctor of any new medications you are taking. 
 
PLEASE REMEMBER:    bring this calendar and all pill bottles with you when you return to the clinic at the end of this cycle. Sign and date below. Thank you! 
Patient Signature: 
Date: 
OFFICIAL 
USE ONLY 
Med. Amt. Dispensed: 
Date Dispensed: 
Completed By: 
 
Date: 
Med. Amt. Returned: 
Date Returned: 
 


Version: 03/23/2020 
OSU IRB Approved:  5/22/2020 
0 
 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent ponatinib. This clinical trial is sponsored by Takeda. This form is addressed 
to the patient, but includes important information for others who care for this patient.  
 
The agent ponatinib can interact with many drugs that are processed by your liver.  Because of 
this, it is very important to tell your study doctors about all of your medicine before you start this 
study.  It is also very important to tell them if you stop taking any regular medicine, or if you 
start taking a new medicine while you take part in this study.  When you talk about your 
medicine with your study doctor, include medicine you buy without a prescription at the drug 
store (over-the-counter remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
Ponatinib interacts with (a) certain specific enzyme(s) in your liver.  
 The enzyme(s) in question are CYP3A4, CYP2C8 and CYP2D6. CYP 3A4 is responsible 
for breaking down ponatinib in your liver.   
 Ponatinib must be used very carefully with other medicines that need these liver enzymes 
to be effective or to be cleared from your system.  
 Other medicines may also affect the activity of these enzymes.   
o Substances that increase the activity of CYP 3A4 (“inducers”) could reduce the 
effectiveness of ponatinib and should be avoided, while substances that decrease 
this enzyme’s activity (“inhibitors”) could result in high levels of the active drug, 
increasing the chance of harmful side effects. 
o Co-administration with drugs that block acid production (e.g. antacids, proton 
pump inhibitors can reduce the absorption of ponatinib. They should be avoided 
unless the benefits outweigh the possible risk. 
 
 You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
 Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4, CYP2C8, CYP2D6, BCRP, and p-glycoprotein. 
 Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid.   
 Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 


1 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
   Be careful:  
o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly: Avoid these until the study is over. You 
should not take herbal supplements including, but not limited to, St. John’s wort, 
kava, ephedra (ma huang), gingko biloba, yohimbe, saw palmetto, or ginseng. You 
should abstain from taking any herbal and dietary supplements for at least 2 weeks 
prior to the first dose of the study drug. 
 
Other medicines can be a problem with your study drugs. You should check with your doctor or 
pharmacist whenever you need to use an over-the-counter medicine or herbal supplement.  
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.   
Your study doctor’s name is Sameek Roychowdhury, MD. PhD and he can be contacted at. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the agent ponatinib.  This 
clinical trial is sponsored by Ariad Pharmaceuticals. Ponatinib can 
interact with drugs that are processed by your liver.  Because of this, 
it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 Ponatinib interacts with specific liver enzymes called CYP3A4, 
CYP2C8, CYP2D6  , and must be used very carefully with other 
medicines that interact with these enzymes.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A4, CYP2C8, 
CYP3A or BCRP.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is  Sameek Roychowdhury and can be 
contacted at  (614) 293-6196 


2 
APPENDIX D  PONATINIB MEDICATION GUIDE 
Ponatinib- (ponatinib hydrochloride tablet), film coated  
Takeda, Inc. 
What is the most important information I should know about ponatinib? 
Ponatinib can cause serious side effects, including: 
Blood clots or blockage in your blood vessels (arteries and veins). Blood clots or blockage in 
your blood vessels may lead to heart attack, stroke, or death. A blood clot or blockage in your 
blood vessels can prevent proper blood flow to your heart, brain, bowels (intestines), legs, eyes, 
and other parts of your body. You may need emergency surgery or treatment in a hospital. Get 
medical help right away if you get any of the following symptoms:  
 
chest pain or pressure 
 
pain in your arms, legs, back, neck or jaw 
 
shortness of breath 
 
numbness or weakness on one side of your body 
 
trouble talking 
 
headache 
 
dizziness 
 
severe stomach area pain  
 
decreased vision or loss of vision  
Blood clots or blockage in your blood vessels can happen in people with or without risk factors 
for heart and blood vessel disease, including people 50 years of age or younger. Talk to your 
healthcare provider if this is a concern for you.  
Heart problems. Ponatinib can cause heart problems, including heart failure which can be serious 
and may lead to death. Heart failure means your heart does not pump blood well enough. 
Ponatinib can also cause irregular slow or fast heartbeats and heart attack. Your healthcare 
provider will check your heart function before and during your treatment with ponatinib. Get 
medical help right away if you get any of the following symptoms: shortness of breath, chest 
pain, fast or irregular heartbeats, dizziness, or feel faint.  
Liver problems. Ponatinib can cause liver problems, including liver failure, which can be severe 
and may lead to death. Your healthcare provider will do blood tests before and during your 
treatment with ponatinib to check for liver problems. Get medical help right away if you get any 
of these symptoms of liver problems during treatment:  
 
yellowing of your skin or the white part of your eyes (jaundice) 
 
dark "tea-colored" urine 
 
sleepiness 
See "What are the possible side effects of ponatinib?" for information about side effects.  


3 
What is ponatinib? 
Ponatinib (Iclusig®) is a prescription medicine approved to treat adults who have:  
 
a specific type of abnormal gene (T315I-positive) chronic phase, accelerated phase, or 
blast phase chronic myeloid leukemia (CML), T315I-positive Philadelphia chromosome 
positive acute lymphoblastic leukemia (Ph + ALL)  
 
chronic phase, accelerated phase, or blast phase CML or Ph+ ALL who cannot receive 
any other tyrosine kinase inhibitor (TKI) medicines  
It is not known if ponatinib is safe and effective in children less than 18 years of age. 
What should I tell my healthcare provider before taking ponatinib? 
Before you take ponatinib, tell your healthcare provider if you: 
 
have a history of blood clots in your blood vessels (arteries or veins) 
 
have heart problems, including heart failure, irregular heartbeats, and QT prolongation 
 
have diabetes  
 
have a history of high cholesterol 
 
have liver problems 
 
have had inflammation of your pancreas (pancreatitis) 
 
have high blood pressure 
 
have bleeding problems 
 
plan to have any surgical procedures 
 
are lactose (milk sugar) intolerant. ponatinib tablets contain lactose. 
 
drink grapefruit juice  
 
have any other medical conditions 
 
are pregnant or plan to become pregnant. ponatinib can harm your unborn baby. You 
should not become pregnant while taking ponatinib. Tell your healthcare provider right 
away if you become pregnant or plan to become pregnant.  
 
are breastfeeding or plan to breastfeed. It is not known if ponatinib passes into your 
breast milk. You and your healthcare provider should decide if you will take ponatinib or 
breastfeed. You should not do both.  
Tell your healthcare provider about all the medicines you take, including prescription medicines 
and over-the-counter medicines, vitamins, and herbal supplements. Ponatinib and other 
medicines may affect each other causing side effects.  
Know the medicines you take. Keep a list of them to show your healthcare provider and 
pharmacist when you get a new medicine. 
How should I take ponatinib? 
 
Take ponatinib exactly as your healthcare provider tells you to take it. 


4 
 
Your healthcare provider may change your dose of ponatinib or tell you to stop taking 
ponatinib. 
 
Do not change your dose or stop taking ponatinib without talking to your healthcare 
provider. 
 
Swallow ponatinib tablets whole. Do not crush or dissolve ponatinib tablets. 
 
You may take ponatinib with or without food.  
 
If you miss a dose of ponatinib, take your next dose at your regular time. Do not take 2 
doses at the same time to make up for a missed dose.  
 
If you take too much ponatinib, call your healthcare provider or go to the nearest hospital 
emergency room right away. 
What are the possible side effects of ponatinib? 
Ponatinib may cause serious side effects, including: 
 
See "What is the most important information I should know about ponatinib?" 
 
High blood pressure. Your blood pressure should be checked regularly and any high 
blood pressure should be treated while you are taking ponatinib. Tell your healthcare 
provider if you get headaches, dizziness, chest pain or shortness of breath.  
 
Inflammation of the pancreas (pancreatitis). Symptoms include sudden stomach-area 
pain, nausea, and vomiting. Your healthcare provider should do blood tests to check for 
pancreatitis during treatment with ponatinib.  
 
Neuropathy. Ponatinib may cause damage to the nerves in your arms, brain, hands, legs, 
or feet (Neuropathy). Tell your healthcare provider if you get any of these symptoms 
during treatment with ponatinib:  
o muscle weakness, tingling, burning, pain, and loss of feeling in your hands and 
feet 
o double vision and other problems with eye sight, trouble moving the eye, 
drooping of part of the face, sagging or drooping eyelids  
 
Effects on the eye. Serious eye problems that can lead to blindness or blurred vision may 
happen with ponatinib. Tell your healthcare provider if you get any of the following 
symptoms: perceived flashes of light, light sensitivity, floaters, dry or itchy eyes, and eye 
pain. Your healthcare provider will monitor your vision before and during your treatment 
with ponatinib.  
 
Severe bleeding. Ponatinib can cause bleeding which can be serious and may lead to 
death. Tell your healthcare provider if you get any signs of bleeding while taking 
ponatinib including:  
o vomiting blood or if your vomit looks like coffee-grounds 
o pink or brown urine 
o red or black (looks like tar) stools 
o coughing up blood or blood clots 
o unusual bleeding or bruising of your skin 
o menstrual bleeding that is heavier than normal 
o unusual vaginal bleeding 
o nose bleeds that happen often 
o drowsiness or difficulty being awakened 


5 
o confusion 
o headache 
o change in speech 
 
Fluid retention. Your body may hold too much fluid (fluid retention). Tell your 
healthcare provider right away if you get any of these symptoms during treatment with 
ponatinib:  
o swelling of your hands, ankles, feet, face, or all over your body 
o weight gain 
o shortness of breath and cough 
 
Low blood cell counts. Ponatinib may cause low blood cell counts. Your healthcare 
provider will check your blood counts regularly during treatment with ponatinib. Tell 
your healthcare provider right away if you have a fever or any signs of an infection while 
taking ponatinib.  
 
Possible wound healing problems. If you need to have a surgical procedure, tell your 
healthcare provider that you are taking ponatinib. You should stop taking ponatinib at 
least 1 week before any planned surgery.  
 
A tear in your stomach or intestinal wall (perforation). Tell your healthcare provider right 
away if you get:  
o severe pain in your stomach-area (abdomen) 
o swelling of the abdomen 
o high fever 
The most common side effects of ponatinib include: 
 
skin rash 
 
stomach-area (abdomen) pain 
 
tiredness 
 
headache 
 
dry skin 
 
constipation 
 
fever 
 
joint pain 
 
nausea 
Tell your healthcare provider if you have any side effect that bothers you or that does not go 
away. 
These are not all of the possible side effects of ponatinib. For more information, ask your 
healthcare provider or pharmacist. 
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-
800-FDA-1088. 
How should I store ponatinib? 
Store ponatinib at room temperature between 68°F to 77°F (20°C to 25°C). Keep ponatinib and 
all medicines out of the reach of children. 
 


6 
General information about ponatinib 
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. 
Do not use ponatinib for a condition for which it was not prescribed. Do not give ponatinib to 
other people, even if they have the same symptoms you have. It may harm them.  
You can ask your healthcare provider or pharmacist for information about ponatinib that 
is written for health professionals. 
For more information, go to www.iclusig.com or call 1-855-552-7423. 
What are the ingredients in ponatinib (Iclusig®)? 
Active ingredient: ponatinib  
Inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate 
(type B), colloidal silicon dioxide and magnesium stearate. The tablet coating consists of talc, 
polyethylene glycol, polyvinyl alcohol and titanium dioxide.  
This Medication Guide has been approved by the U.S. Food and Drug Administration. 
Manufactured for: 
ARIAD Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company 
Limited) . 
40 Landsdowne Street 
Cambridge, MA 02139-4234  
Revised: March 2017 
 
 
 


7 
APPENDIX E COVID-19 PRECAUTIONS 
 
Due to the emerging pandemic for SARS-CoV-2 virus, it has become necessary to enact social 
distancing and limit hospital and outpatient facility interactions and visits for vulnerable patient 
populations. Patients receiving active therapy to control their metastatic cancer are particularly 
vulnerable. 
 
This study involves patients receiving an oral targeted therapy that can either control cancer growth 
(stable disease) and shrink cancer disease (partial or complete responses), thereby prolonging life 
and maintaining quality of life. It is vital that these patients continue to receive these therapies, but 
also important that we mitigate the risk of virus transmission for patients, providers, and family 
members. In the coming weeks and months, as governments manage the SARS-CoV-2 virus 
pandemic, it is quite possible that travel between states and cities may be limited, or that cities may 
have curfews. This amendment seeks to mitigate risk and enable ongoing care as feasible.  
 
This appendix proposes the following changes for this investigator-initiated trial: 
 Convert whenever possible all outpatient office visits to tele-medicine (video and phone) 
as necessary to continue monitoring, care, and treatment. Patients with concerning 
symptoms or labs from tele-medicine visits may be escalated to in-person evaluations as 
needed in the appropriate setting. This will serve to triage patients based on needs versus 
risk.  
o For example, some patients on this study may be on a well-tolerated and effective 
therapy dose for 6 to 30 months, and have little need to be seen in-person in the 
clinic if there are no changes or new issues. 
 Patients will continue to have necessary blood work and scans to monitor for toxicities and 
disease status. Basic study procedures such as blood draws, radiographic scans, ECHO, 
ECG can be done by patients’ local providers. These results will be reviewed by the Study 
Team centrally. 
 ECHO and ECGs are for data collection, but are not expected to find rare abnormalities. 
These can be deferred unless prompted by symptoms or clinical concern. 
 We will provide the option for oral therapies to be shipped to patients from our 
Investigational Drug Pharmacy or patients/family members could pick them up.  
 Depending on circumstances, local healthcare providers in another city may be required to 
assess and evaluate patients, and the PI will communicate with these providers to facilitate 
care as it relates to study treatment.  
 On-treatment biopsies, as well as post-progression studies or biopsies, may be deferred 
depending on the availability of resources in the healthcare system. 
 
Our Team has over 5 years of experience treating and managing patients with this oral therapy, 
and we are confident that this will ensure ongoing therapy that is beneficial and safe. 
 
Time Frame: This amendment is expected to span a duration of 6 months, and will re-assess the 
clinical situation prior to the end of this period. 
 
 


8 
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ICF_001.pdf: 
CONSENT 
Biomedical/Cancer 
 
 
 
IRB Protocol Number: 
2014C0143 
IRB Approval date:  5/22/2020 
Version:  3/23/2020  
 
 
Page 1 of 20 
Form date: 
07/18/2016  
 
The Ohio State University Combined Consent to Participate in 
Research and HIPAA Research Authorization 
 
Study Title: 
Phase II study of ponatinib for advanced cancers with 
genomic alterations in fibroblastic growth factor receptor 
(FGFR) and other genomic targets (KIT, PDGFRα, RET 
FLT3, ABL1) 
Principal Investigator: 
Sameek Roychowdhury, MD, PhD 
Sponsor:  
Funding Sponsors: 
OSU  
National Institutes of Health (NIH) and Takeda Pharmaceutical 
Company 
 
 This is a consent form for research participation.  It contains important information 
about this study and what to expect if you decide to participate.  Please consider the 
information carefully. Feel free to discuss the study with your friends and family and to 
ask questions before making your decision whether or not to participate. 
 Your participation is voluntary.  You may refuse to participate in this study.  If you 
decide to take part in the study, you may leave the study at any time.  No matter what 
decision you make, there will be no penalty to you and you will not lose any of your usual 
benefits.  Your decision will not affect your future relationship with The Ohio State 
University.  If you are a student or employee at Ohio State, your decision will not affect 
your grades or employment status. 
 You may or may not benefit as a result of participating in this study.  Also, as 
explained below, your participation may result in unintended or harmful effects for you 
that may be minor or may be serious depending on the nature of the research. 
 You will be provided with any new information that develops during the study that 
may affect your decision whether or not to continue to participate.  If you decide to 
participate, you will be asked to sign this form and will receive a copy of the form.  You 
are being asked to consider participating in this study for the reasons explained below.   
 
1.   Why is this study being done? 
The purpose of this study is to find out what effects; good and/or bad, ponatinib has on you 
and your cancer. Your body has proteins that are involved in a cancer’s ability to grow and 
survive. Ponatinib may prevent these proteins from causing cancer growth. 
 
To enter the study, you must have genetic testing performed on your cancer. The testing will 
determine which cancer genes are altered in your cancer and may be targeted by the study 
drug ponatinib. 
 
The genetic testing being used to decide if you qualify for this study is not an FDA (Food and 
Drug Administration) approved test; therefore its accuracy in identifying you as a candidate 
for this trial is unknown and there is a possibility you may not benefit from ponatinib. 


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IRB Approval date:  5/22/2020 
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Ponatinib has been approved by the FDA for use in blood cancers for whom no other therapy 
with similar drugs is indicated. Ponatinib has not been approved for use in other cancers. 
Therefore, this study will evaluate whether Ponatinib is effective in other types of cancers 
such as yours. 
 
2.   How many people will take part in this study? 
About 45 people will take part in this study with approximately 25 people participating at The 
Ohio State University Wexner Medical Center. 
 
3.   What will happen if I take part in this study? 
 
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  Some of these exams, tests or procedures are part of regular cancer care and may be 
done even if you do not join the study.  If you have had some of them recently, they may not 
need to be repeated.  This will be up to your study doctor. 
 You will need to supply a complete list of your current medications to the study doctor.  
This includes over-the-counter medications and herbal supplements.  Some 
medications may interact adversely with ponatinib and it is important that your study 
doctor and prescribing physician be aware of any potential risks so that they can 
prescribe alternative medications as necessary.   
 The study team will ask you questions about your demographics (examples are sex, 
race, age, height, weight, etc.) and your medical history  
 The study team will ask what medications you are currently taking  
 Physical exam  
 Vital signs (including blood pressure, temperature and pulse)  
 The study team will ask you how you are currently feeling and your ability to do your 
daily tasks (performance status) 
 Routine blood tests (serum chemistry and CBC - complete blood count)  
 Additional blood tests (serum lipase, a fat digesting enzyme) 
 EKG (Electrocardiogram) a line graph that shows changes in the electrical activity of 
the heart over time.  
 Eye exam 
 A urine pregnancy test if you are a woman  
 Tests to measure your tumor. This could be any of the following tests:   
o Clinical measurement of superficial lesions – these will be done with a ruler or 
tape measure to measure the lesion on the skin. This will be done in patients who 
have lesions that can be measured by physical exam 
o CT – a series of detailed pictures of areas inside the body. The pictures are taken 
from different angles.  
o MRI – a procedure in which radio waves and a powerful magnet linked to a 
computer is used to make detailed pictures of inside the body.  


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o PET scan is a procedure in which a small amount of radioactive imaging agent is 
injected into a vein. Then a scanner is used to make detailed pictures of areas inside 
the body where the sugar is used. A PET-CT scan is a type of scan which uses a 
combination of PET and CT scanning. 
o Ultrasound is a procedure in which high-energy sound waves are bounced off 
internal tissue or organs and make echoes. The echo patterns are shown on the 
screen of an ultrasound machine, forming a picture of body tissues. 
 Either an echocardiogram or a MUGA scan (measures your heart’s ability to pump) 
to assess the strength of your heart  
 Genetic testing of your cancer is required to enter the study. If it has not been 
previously tested, then you will need to have genetic testing of your cancer. You will 
be asked to sign a separate consent form for Precision Cancer Medicine in order for 
researchers to perform genetic testing on blood and tissue samples. The study doctor 
will discuss this additional portion of the study with you, if your genetic testing has 
not previously been performed on your tissue.  
 A tumor biopsy or a previously collected tumor biopsy sample will be collected, as 
described in the bullet-point above, for research purposes and is required for this study. 
This will be used to study your cancer in relation to the study drug ponatinib. If your 
samples have already been collected for Precision Cancer Medicine, you will not need 
to complete the testing again before entering this study. 
 
During the study… 
You will not need to be hospitalized to take part in this study unless you experience a serious 
side effect. 
 
Ponatinib should be taken by mouth daily with or without food. Tablets should be swallowed 
whole. Do not crush or dissolve the tablets. 
 
You will be required to take aspirin (81 or 325 mg daily) for the duration of ponatinib 
treatment to protect against blood clots.  
 
Some of the following exams, tests, and procedures may be completed via Telehealth visit 
(phone, video call, or email) if the investigator deems it appropriate. Ask your physician if 
you have quetsions about Teleheath or Telehealth visits. 
 
If the exams, tests and procedures show that you can be in the study, and you choose to take 
part, then you will need the following tests and procedures.  They are part of regular cancer 
care.  
 The study team will also ask you how you are currently feeling and your ability to do 
your daily tasks.  
 Routine physical exam, which will include measurement of your tumor with a ruler or 
tape if it is measurable by physical exam.  
 Routine vital signs – pulse, blood pressure, temperature 
 Weight 


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 Routine blood tests will be performed at the beginning of every cycle which will be 
every 28 days. Some blood tests would be repeated every 2 weeks for the first two 
cycles. 
 Routine scans to look for a response to treatment will be done every 2 cycles. This 
will be a CT scan most commonly, but may also include a bone scan, an MRI, or a 
PET-CT scan (more often if your doctor tells you to).  
 
 
 
You will need these tests and procedures that are part of regular cancer care.   They are 
being done more often because you are in this study.   
 The study team will ask you what medications you are currently taking, if you are 
having any side-effects.  
 Blood tests would be performed every 2 weeks for the first 2 cycles and every cycle 
after that (or more often if your doctor feels it is necessary). 
 EKG may be obtained if your doctor feels it is necessary. 
 Either an echocardiogram or a MUGA scan may be obtained if your doctor feels it is 
necessary. 
  
You will need these tests and procedures that are either being tested in this study or 
being done to see how the study is affecting your body. 
 You will take your blood pressure twice per week at home using a blood pressure cuff.  
The cuff will be provided by Takeda. You will be given a medication diary on which 
you will also record your blood pressure readings. Blood pressure will be monitored 
at home, because high blood pressure or hypertension may require treatment with 
medication to prevent further complications. 
o If any reading is greater than or equal to 160/90, you must contact the 
study team using the phone number in Section 14.  
o You will need to come into clinic where the study staff will measure your blood 
pressure again to confirm the reading. If you develop high blood pressure or 
hypertension during the study, the study doctor may prescribe medication, 
reduce your dose of ponatinib, or stop it altogether.  
 You will be asked to maintain a medication diary documenting when you take the 
therapy and must bring it to each visit with your physician.  
 Please check with your doctor/prescriber or pharmacist before using any new over-
the-counter medications or herbal supplements. 
 A mandatory second tumor biopsy sample may be performed for research purposes 
after completion of ponatinib, if your disease progresses. This will be used to study 
why your cancer was resistant to ponatinib and will also be used to test for any new 
gene alterations that might make you eligible to consider participating in another 
Precision Cancer Study with a different drug. This will only be performed if your 
treating physician considers it safe for you to complete.  
 Research specimens from the Precision Cancer Study will be shared with this study, 
in order to facilitate your eligibility, enrollment, and further our understanding of 
cancer. 


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 Characterization of your cancer in relation to ponatinib will be performed to better 
understand which patients may benefit from ponatinib therapy. This study will work 
closely with another study at Ohio State University, the Precision Cancer Study, to 
facilitate this research.  
 
 
 
 
 
When I am finished taking ponatinib… 
 
You will need the following tests and procedures, part of regular cancer care.  
 The study team will also ask you how you are currently feeling and your ability to do 
your daily tasks.  
 The study team will ask you what medications you are currently taking, if you are 
having any side-effects.  
 Physical Exam, which will include measurement of your tumor with a ruler or tape if 
it is measurable by physical exam.  
 Vital signs – pulse, blood pressure, temperature 
 Weight 
 
4.   How long will I be in the study? 
You can stay on this study until one of the following happens:  
 Your cancer gets worse,  
 You get sick and cannot stay on this study,  
 You have unacceptable side-effects,  
 You decide to stop being on this study,  
 Your study doctor thinks it is best for you not to be on this study any more.  
 
After you stop this study, you will be followed for 52 weeks or until death, whichever occurs 
first. If you stop this study because of a side-effect, you will be followed until the side effect 
gets better or is stabilized. 
 
5. Can I stop being in the study? 
You may leave the study at any time.  If you decide to stop participating in the study, there 
will be no penalty to you, and you will not lose any benefits to which you are otherwise 
entitled.  Your decision will not affect your future relationship with The Ohio State University.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
ponatinib can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful 
for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes 
it is in your best health interest; if you do not follow the study rules; or if the study is 
stopped. 


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If you decide to withdraw from the study, or if you are withdrawn, additional data will not 
be collected from you. Information that has already been collected for the research cannot 
be withdrawn. Any specimens that were previously collected from you cannot be 
withdrawn from the research. 
 
 
6.   What risks, side effects or discomforts can I expect from being in the study? 
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, doctors don’t know all the side effects that 
may happen.  Side effects may be mild or very serious.  Your health care team may give you 
medicines to help lessen side effects.  Many side effects go away soon after you stop taking 
ponatinib.  In some cases, side effects can be serious, long lasting, or may never go away.  
There also is a risk of death. 
 
It is very important that you report any side effects (also referred to as “adverse events”) to 
your study doctor as soon as possible. 
 
The following are the most rare and serious risks of ponatinib. 
 Vascular Occlusion (or blockage of a blood vessel) 
Blood clots or bloackages in your arteries of veins (blood vessels) or narrowing in 
your arteries can occur in your heart, brain, and legs and may lead to:  
o heart attack  
o stroke  
 
These risks may lead toamputation, or death. They may require medical treatment, or 
urgent medical attention, possibly including surgery to re-open or “bypass” the 
blocked arteries or veins.  
 
Blood clots or narrowing of the arteries in your arms or legs can cause pain or swelling, 
which may require urgent medical attention, including blood-thinning medication, 
surgery to re-open or bypass the arteries or vein, or amputation. 
 
Blood clots or narrowing of the arteries can occur in the lungs (causing fluid buildup 
in the lungs, eyes (which may lead to difficulty seeing or loss of sight), or other organs. 
 
These events have occurred in clinical studies, with humans, throughout the treatment 
period, both early on and even after 2 or 3 years of treatment. They were more frequent 
in older patients and in those with preexisting conditions, such as poor blood flow to 
organs, high blood pressure, diabetes, or high cholesterol. However, these events have 
been experienced by patients both older and younger than 50, and those with and 
without pre-existing conditions. 
 
Seek immediate medical attention if you experience symptoms suggesting: 
o A heart attack, such as:  


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o Chest pain or pressure 
o Pain in your arms, back, neck or jaw, or shortness of breath 
o A stroke, such as: 
o Numbness or weakness on one side of the body 
o Trouble talking 
o Severe headache 
o Dizziness 
o Blood clots in a vein, such as: 
o Pain or swelling in an arm or leg 
o Artery blockage or narrowing in an arm or leg, such as: 
o Cold, discolored, painful arm, leg, hand, foot, fingers, or toes 
 
 Heart Failure  
Heart failure is a condition in which the heart does not pump enough blood to the rest 
of the body. It can cause fatigue, shortness of breath, and swelling of the legs. It can 
lead to death. Seek medical attention right away if you experience any of the following 
symptoms: 
o Difficulty breathing 
o Chest pain 
o Fast or irregular heartbeats 
o Dizziness 
o Feeling faint 
 
 High Blood Pressure  
Elevations in your blood pressure could occur, with the potential to become serious 
and lead to hospitalization. Contact the study doctor if you have symptoms of high 
blood pressure, including: 
o Headache 
o Dizziness 
o Chest pain 
o Difficulty breathing 
 
 Liver Problems  
Problems, including liver failure or blood markers suggesting your liver may not be 
working well, which can be severe and may lead to death. Your study doctor will do 
blood tests before and during your treatment with ponatinib to check for liver 
problems. Get medical help right away if you have any of these symptoms of liver 
problems during treatment:  
o Yellowing of your skin of the white part of your eyes (jaundice) 
o Dark “tea-colored” urine 
o Sleepiness 
Hepatitis B (HBV) reactivation is an abrupt increase in HBV in a patient with inactive or 
past HBV. HBV reactivation can lead to elevations in liver enzymes, and in some 
cases the development of acute liver failure, and even death. People who have 
previously had HBV are at an increased risk of reactivation when treated with a TKI, 


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like the study drug. An HBV test will be done to determine whether or not you are at 
risk for HBV reactivation. You may need to be treated with an antiviral if you test 
positive for HBV, depending on your risk category and/or symptoms. 
 
 Inflammation of your Pancreas (Pancreatitis) 
Ponatinib is associated with pancreatitis, an inflammation of the pancrease (an organ 
in the abdomen which produces insulin and certain digestive enzymes. They are 
released into the blood when the pancreas is diseased or inflamed. Inflammation of 
the pancreas can affect it’s ability to function and can cause pain in the abdomen 
(belly), which can be severe and increase blood sugar levels. Pancreatitis most 
commonly occurs during the first 2 months of treatment. 
 
 Low Blood Cell Counts 
Ponatinib may cause low platelets in your blood cell counts . With low platelets, this 
may increase your risk of bleeding. Your study doctor will check your blood counts 
regularly during treatment with ponatinib. Tell the study doctor right away if you 
experience excess bruising, nose bleeds, or other types of bleeding.  
 
Ponatinib may cause low neutrophils in your blood, called neutropenia.These are 
white blood cells that help your body fight off infection. If you experience neutopenia, 
you will be greater risk of developing an infection. 
 
If platelets and red and white blood cells are decreased , you may experience increased 
risk of infection, easy bruising, fatigue, shortness of breath, weakness, and bleeding.  
 
 Bleeding 
Bleeding can be serious and if uncontrolled, may lead to death. You must tell the study 
doctor if you have unusual bleeding or bruising.  
 
 Tumor Lysis Syndrome 
Patients with ALL are at increased risk of Tumor lysis syndrome (TLS) with 
cytotoxic/cytolytic therapy. In patients with ALL, those with white blood cell (WBC) 
count ≥100,000 are considered high risk. In TLS, the dying tumor cells release their 
contents into the blood which can cause changes to important blood chemicals and 
may cause damage to organs including the kidneys, heart and liver.  Before starting 
ponatinib, your doctor will ensure that you are hydrated and may check levels of uric 
acid in your blood to reduce the risk of TLS developing.  You will be monitored 
throughout the study for any signs or symptoms of TLS.  If you develop TLS, your 
doctor will decide on your treatment, which may include intravenous hydration, 
dialysis, or medications to normalize the levels of your blood chemicals. 
 
Common Side Effects: 
 An upper respiratory infection, like the common cold 
 Low blood platelet counts (which may increase the risk of bleeding) 


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 Skin rash (reddened skin or red rash with or without raised bumps, may be itchy, dry 
with flaking or peeling skin, less commonly may resemble acne) 
 Dry skin 
 Pain in the belly (abdominal pain) 
 Constipation 
 Nausea 
 Headache 
 Low blood counts including white blood cells (which may increase the risk of 
infection) or red blood cells (which can cause you to feel tired or short of breath) 
 Shortness of breath 
 Cough 
 Vomiting 
 Diarrhea 
 Fever 
 Decreased appetite 
 Trouble getting amounts of, or quality of, sleep 
 Dizziness 
 Weakness 
 Increased lipase level (an enzyme measured in the blood that reflects function of the 
pancreas.  Elevations in lipase may indicate inflammation of the pancreas) 
 Increased enzymes from the liver in the blood, alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) 
 Pain that may occur in the joints, muscles, bones, back, or limbs 
 Muscle cramps and pain 
 Fatigue 
 High blood pressure (hypertension) 
 
Uncommon Side Effects:  
 Pneumonia (an inflammation of the lung, generally caused by infection, that may be 
accompanied by cough, phlegm, fever, sharp chest pain, skaing, chills, sweating, 
difficulty breathing, and requires immediate medical attention) 
 Stomach acid, or bile in your digestive system, may occasionally flow back up (reflux) 
into your food pipe (esophagus), which can cause heartburn 
 Lack of energy, or lack of interest in doing things you usually do 
 Neck pain 
 Muscle pain caused by too little flow of blood during walking or exercise 
 Confusional state (delirium) is a state that causes your mind to be unclear 
 Inflammation of the pancreas (an organ in the abdomen which produces insulin and 
certain digestive enzymes) which may affect the function of the pancreas and which 
may cause pain in the abdomen (belly) which can be severe and may increase blood 
sugar 
 Irregular heart rhythms including atrial fibrillation (an abnormal rapid or irregular 
heart rhythm which may cause light-headedness, shortness of breath or weakness) and 
abnormally  rapid or slow heart rates 


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 Increased pressure of the blood vessels in your lungs, which can cause symptoms such 
as shortness of breath during routine activity (for example, climbing two flights of 
stairs), tiredness, chest pain, and a racing heartbeat. 
 Chest pain not due to heart disease 
 Chills 
 Skin problems that may include rash, be itchy or painful with dry, flaking, and/or 
peeling skin, sometimes over a large area of your body (dermatitis exfoliative). This 
may include bruising, redness, change or loss of skin color due to bleeding below the 
skin surface, or darkening or thickening of the outer layer of skin 
 Dry mouth 
 Hot flush (a feeling of warmth that spreads over the body most strongly felt in the 
head and neck region) 
 Hair loss 
 Bloating 
 Abdominal discomfort 
 Weight decreased 
 Excessive sweating sometimes during sleep 
 Bleeding such as nosebleeds or petechiae (in which tiny purple or red dots appear on 
the skin due to bleeding under the skin’s surface) or other more severe bleeding 
 A rash with spots that may look like a target (erythema multiforme) 
 Low levels of important electrolyte levels in your  blood including abnormally low 
levels of potassium (which can cause irregular heartbeats),  low levels of calcium 
(which can cause muscle spasms, twitches or cramps or numbness/tingling in your 
fingers, toes and around your mouth), and  low levels of phosphorus (which can cause 
bone pain, confusion, muscle weakness) 
 Increased enzymes moving from the liver into the blood, called alkaline phosphatase 
(ALP) and glutamyltransferase (GGT) 
 High blood sugar levels 
 Increased triglyceride and cholesterol levels (blood fat) 
 High concentration of uric acid in the blood which could result in inflammation of a 
joint ("gout"), problems with urination or kidney stone, fever, chills, fatigue 
 An increase in the blood of a substance produced by the liver (bilirubin) that could 
indicate liver disease and in high amounts can cause yellowing of the skin and eyes 
 Indigestion or upset stomach 
 Feeling sick or discomfort 
 Voice impairment such as hoarseness 
 Febrile neutropenia (a condition marked by fever and lower-than-normal number of a 
certain kind of white blood cell in the blood which could increase the risk of infection) 
 Flu like symptoms, which can include fever, chills, body aches, nausea, loss of appetite 
 Cranial or peripheral neuropathy, conditions in which nerves that come from the brain 
(cranial nerves), supplying the face and eyes, and nerve that come from the spinal cord 
(peripheral nerves) have been damaged. This can cause visual disturbances, weakness, 
face droop, numbness, tingling, prickling sensation, and either decreased or increased 
sensitivity of the skin to touch or pain, or the ear to sound. 


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 Inflammation or infection of one or more hair follicles.  A hair follicle is an opening 
in the skin that encloses a strand of hair from which the hair grows 
 Dehydration 
 Impotence (inability to achieve or maintain an erection long enough to engage in 
sexual intercourse) 
 A severe infection in the body, sometimes known as blood poisoning, which can cause 
difficulty breathing, coagulation of the blood, malfunction of your organs and is 
usually treated in an intensive care unit of a hospital 
 Migraine headache 
 Inflammation of the mucous lining of any of the structures in the mouth, including 
cheeks, gums, tongue, lips, throat and roof or floor of the mouth 
 Eye problems can occur, including dry eye, blurred vision, eye irritation or pain, 
redness of the eye, eyelid swelling. Less frequently, inflammation or an ulcer of the 
cornea can occur. The cornea is the clear, dome-shaped tissue on the front of your eye 
that covers the pupil and iris. 
 Narrowing of blood vessels that restricts flow to areas away from the center of the 
body, such as legs, arms, toes, fingers, ear lobes, and penis. 
 Pericardial effusion (an abnormal buildup of fluid inside the sac that surrounds the 
heart which may cause chest pain, difficulty breathing, fever) 
 Pleural effusion (an abnormal buildup of fluid around the lungs which may cause chest 
pain, cough, or shortness of breath)  
 
Rare Side Effects:  
 Bleeding that can be serious and can lead to death including bleeding in the brain or 
in the gastrointestinal tract (which extends from the mouth to the anus) 
 Shortness of breath 
 Abnormal buildup of fluid which may cause swelling in the hands, feet, ankles, face, 
or all over the body 
 Itching of the skin 
 Hypersensitivity 
 Sudden, severe increase in blood pressure occurring in individuals who have 
untreated high blood pressure or have stopped taking antihypertensive medication 
 Erythema nodosum (an inflammation of the fat cells under the skin that causes 
tender lesions on the skin) 
 Formation of an abnormal connection between internal organs in the belly that are 
not normally connected 
 A condition that occurs after the start of anti-cancer treatment in which the dying 
tumor cells release their contents into the blood. This causes changes to important 
blood chemicals and may cause damage to organs including the kidneys, heart, and 
liver. 


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 Poor peripheral circulation is a condition in which the blood vessels cannot supply 
enough blood to your feet or legs. You could experience numbness and cramping in 
the feet or lower legs, or experience a tingling sensation in the feet and toes. 
 Splenic infarction, a condition in which oxygen supply to the spleen is interrupted, 
leading to partial or complete infarction (tissue death due to oxygen storage) in the 
spleen 
 QT Prolongation, a change in heart rhythm detected on an electrocardiogram (ECG) 
that may be associated with sudden death 
 Impaired wound healing 
 Development of a hole in the esophagus, stomach, or intestines, which may be 
associated with pain, infection, or bleeding, and may require surgery to repair it. 
 Blood vessels inside your skull becoming blocked  by a blood clot, which is one of 
the causes of stroke 
 Blood vessels inside your eyes becoming blocked  by a blood clot, which may cause 
severe damage to your eyes. It may cause you to not be able to see clearly or could 
even cause blindness 
 Splenic infarction, a condition in which oxygen  supply to the spleen is interrupted, 
leading to  partial or complete infarction (tissue death due to oxygen shortage) in the 
spleen 
 Narrowing of arteries that carry blood to one or both of the kidneys 
 Cerebrovascular accident, commonly known as a stroke, in which some of the brain 
tissue is damaged by a disruption of blood flow to the brain and may cause sudden 
weakness or numbness on one side of the body, and difficulty speaking which  
requires immediate medical attention 
 Cerebral infarction, an area of brain tissue damaged by a disruption of blood to the 
brain, which may be associated with stroke 
 Transient ischemic attacks, commonly known as a TIA or mini stroke, a TIA is an 
episode in which blood flow to the brain is temporarily reduced which may cause 
temporary sudden weakness or numbness on one side of the body, difficulty 
speaking and requires immediate medical attention 
 Myocardial infarction, commonly known as heart attack, is an episode in which 
some of the heart's blood supply is severely cut off or restricted due to severe 
narrowing or blockage of arteries in the heart, causing the heart muscle to be 
damaged due to lack of oxygen 
 Pain, discomfort or pressure in the chest caused by insufficient blood supply to the 
heart muscle 
 Blood clot in  blocking the major veins in the legs, pelvis, or elsewhere 
 Obstruction of a blood vessel in the lungs resulting in fluid build-up in the lungs and 
affecting the respiratory functions (breathing)  


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 Increased pressure of the blood vessels in your lung, which causes symptoms such as 
shortness of breath during routine activity (for example, climbing two flights of 
stairs), tiredness, chest pain 
 Hypothyroidism (less active thyroid gland) 
 Heart failure, a chronic condition in which the heart does not pump blood as well as 
it should 
 
Additionally, some discomforts and risks that occur with lesser frequency (<1%) than those 
previously mentioned should be noted because they are severe, life-threatening or fatal and may 
involve: 
 
• 
Rash 
• 
Blistering 
• 
Skin peeling and mouth sores, including erythema  
• 
Multiforme and Stevens Johnson syndrome have also been reported in some 
patients taking ponatinib. These rashes are disorders of the immune system, which 
differ from regular skin rashes and are generally more severe. 
 
Unexpected Side Effects 
Ponatinib may cause side effects that we cannot know ahead of time, some of which could be 
serious or even cause death in rare circumstances. Also, allergic reactions could happen in 
some people. Ponatinib may interfere with other drugs you need, or other drugs you take may 
interfere with ponatinib.  
 
You should tell the study doctor about any changes in your health that develop while 
you are in this study, even if you don’t think they are related to the study.  
 
Reproductive and Pregnancy Risks 
Information for women: 
There is not enough medical information to know about the effects of ponatinib on an unborn 
child. Ponatinib may cause harm to your unborn baby. It is also not yet known if ponatinib 
passes into breast milk, or if it will harm a nursing infant. You should not become pregnant 
or breastfeed while taking ponatinib. Tell the study doctor right away if you become pregnant, 
think you may be pregnant, or plan to become pregnant.  
 
You will be required to take a pregnancy test at the Screening Visit to ensure you are not 
pregnant before entering the trial. You are required to use a reliable method of birth control 
during study dosing and at least 4 months after your last dose of study drug.  If you become 
pregnant while you are on this trial, or within 4 months of your last dose of study drug, you 
must tell the study doctor. The study doctor may remove you from the trial. You will be asked 
for your consent for researchers to collect information about the health of your baby. 
 
Acceptable methods of contraception for women: 


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 Any form of hormonal contraception (birth control pills or intra-uterine devices, IUD) 
 Condom or diaphragm with spermicide 
 
Information for men: 
You are required to use a reliable method of birth control during trial dosing and until at least 
4 months after your last dose of study drug. If your partner becomes pregnant while you are 
on this trial, or at least four months after your last dose of study drug, you must tell the study 
doctor. You and your partner will be asked for your consent for researchers to collect 
information about the mother’s health and that of the baby. 
 
Medications to Avoid: 
Herbal medications, such as St. John’s Wort, Blue Cohash, and Estroven, must not be taken 
for 2 weeks prior to the first dose of study drug and for as long as you continue taking the 
study drug. You must tell the study doctor about all drugs and supplements you are 
taking while in this study.  
 
Biopsy: The risk of a biopsy can include bleeding, pain, and infection. To reduce these risks, 
the site of the biopsy will be numbed and sterile techniques will be used.  Your doctor will 
discuss the safest method and location to perform the biopsy. 
 
Blood draws: A blood draw may cause faintness, inflammation of the vein, pain, bruising, or 
bleeding at the site of puncture.  There is also a slight chance of infection. The blood samples 
will be taken by individual needle sticks into one of your arm veins or, if necessary, by an 
indwelling catheter (a thin plastic tube placed in a vein in your arm). 
 
Genetic Research Risks:  This research involves genetic studies and information. Although 
procedures have been put into place that are designed to make it very difficult for the results 
from genetic research to be linked to you, there is a remote possibility that information from 
your participation in this study could adversely affect you or your family in some way if a 
genetic disorder were discovered.  
 
7.   What benefits can I expect from being in the study? 
Taking part in this study may or may not make your health better.  While doctors hope that 
ponatinib will be more beneficial against your cancer compared to the usual treatment, there 
is no proof of this yet.  We do know that the information from this study will help doctors 
learn more about ponatinib as a treatment for cancer.  This information could help future 
cancer patients. 
 
8.   What other choices do I have if I do not take part in the study? 
You may choose not to participate without penalty or loss of benefits to which you are 
otherwise entitled. 
Your other choices may include: 
 Getting treatment or care for your cancer without being in a study 
 Taking part in another study 
 Getting no treatment 


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 Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat 
the cancer directly, but instead tries to improve how you feel. Comfort care tries to 
keep you as active and comfortable as possible. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
 
9. What are the costs of taking part in this study? 
Study drug ponatinib will be provided by the Takeda Pharmaceutical Company at no cost to 
you. You and / or your insurance company will not be charged for the cost of any tests or 
procedures that are required as part of the research study and are outside the standard of care 
(what is normally done) for your condition. 
 
You and / or your insurance company will be responsible for the cost of routine medications, 
tests and procedures that you would receive even if you were not in this research study.  You 
and / or your insurance company will be responsible for any co-payments, co-insurance and 
deductibles that are standard for your insurance coverage. 
 
Participating in this research study may lead to additional costs to you.  In some cases, it is 
possible that your insurance company will not pay for these costs because you are taking part 
in a research study.  Before deciding to be in this research study you should check with your 
insurance company to find out what they will pay for. 
 
The National Institutes of Health is providing funding to The Ohio State University for this 
study. The MUGA scan or echocardiogram will be paid for by the research study.  The 
research study will also pay for the mandatory second biopsy if your disease progresses.  
 
10. Will I be paid for taking part in this study? 
You will not be paid for taking part in this study. 
 
11. What happens if I am injured because I took part in this study? 
If you suffer an injury from participating in this study, you should notify the researcher or 
study doctor immediately, who will determine if you should obtain medical treatment at The 
Ohio State University Medical Center.   
 
The cost for this treatment will be billed to you or your medical or hospital insurance. The 
Ohio State University has no funds set aside for the payment of health care expenses for this 
study.  
 
12. What are my rights if I take part in this study? 
If you choose to participate in the study, you may discontinue participation at any time without 
penalty or loss of benefits.  By signing this form, you do not give up any personal legal rights 
you may have as a participant in this study. 
 


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You will be provided with any new information that develops during the course of the research 
that may affect your decision whether or not to continue participation in the study. 
 
You may refuse to participate in this study without penalty or loss of benefits to which you 
are otherwise entitled. 
 
An Institutional Review Board responsible for human subjects research at The Ohio State 
University reviewed this research project and found it to be acceptable, according to 
applicable state and federal regulations and University policies designed to protect the rights 
and welfare of participants in research. 
 
13.   Will my study-related information be kept confidential? 
Efforts will be made to keep your study-related information confidential.  However, there may 
be circumstances where this information must be released.  For example, personal information 
regarding your participation in this study may be disclosed if required by state law.   
 
Also, your records may be reviewed by the following groups (as applicable to the research): 
 Office for Human Research Protections or other federal, state, or international 
regulatory agencies; 
 U.S. Food and Drug Administration; 
 The Ohio State University Institutional Review Board or Office of Responsible 
Research Practices; 
 The sponsor supporting the study, their agents or study monitors; and 
 Your insurance company (if charges are billed to insurance). 
 The National Institutes of Health 
 
If this study is related to your medical care, your study-related information may be placed in 
your permanent hospital, clinic, or physician’s office records. Authorized Ohio State 
University staff not involved in the study may be aware that you are participating in a research 
study and have access to your information.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the results.  You can search the website at any 
time.  
 
You may also be asked to sign a separate Health Insurance Portability and Accountability Act 
(HIPAA) research authorization form if the study involves the use of your protected health 
information. 
 
A new Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. This law generally will protect 
you in the following ways: 
 


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 Health insurance companies and group health plans may not request your genetic 
information that we get from this research. 
 Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums. 
 Employers with 15 or more employees may not use your genetic information that we get 
from this research when making a decision to hire, promote, or fire you or when setting 
the terms of your employment. 
 
GINA does not protect you against genetic discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance.  GINA also will not protect you 
against discrimination based on a previously diagnosed genetic disease or condition.  GINA’s 
provisions prohibiting discrimination by employers based on genetic information generally 
do not apply to employers with fewer than 15 employees. 
 
The NIH issues Certificates of Confidentiality for all NIH-funded studies, including this 
study. This Certificate provides extra protection for you and your study information, 
documents, or samples (blood, tissue, etc.). The Certificates are issued so that we cannot be 
required to disclose any identifiable information collected about you as a part of this study in 
a lawsuit or legal proceeding. This is a layer of protection over and above the already existing 
protections in place for you and your information, documents, or samples. 
 
However, these protections do not apply in some situations. For example, we may have to 
release your information if a law requires us to do so, if the NIH and ARIAD that is funding 
this study requests the information, or if the FDA tells us to release this information. 
 
Please talk to your study team, or contact the Office of Responsible Research Practices at 614-
688-8641, if you have questions. 
 
Please visit the NIH website at https://humansubjects.nih.gov/coc/faqs to learn more. 
 
 
 
14. HIPAA AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR 
      RESEARCH PURPOSES  
 
I. 
What information may be used and given to others? 
 
 Past and present medical records; 
 Research records; 
 Records about phone calls made as part of this research; 
 Records about your study visits; 
 Information that includes personal identifiers, such as your name, or a number 
associated with you as an individual; 
 Information gathered for this research about: 
HIV / AIDS 
Physical exams 


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Laboratory, x-ray, and other test results 
Diaries and questionnaires 
The diagnosis and treatment of a mental health condition 
 Records about any study drug you received; 
 
II. 
Who may use and give out information about you? 
 
Researchers and study staff.   
 
III. Who might get this information? 
 
 The sponsor of this research.  “Sponsor” means any persons or companies that are: 
 working for or with the sponsor; or  
 owned by the sponsor. 
 Authorized Ohio State University staff not involved in the study may be aware that 
you are participating in a research study and have access to your information; 
 If this study is related to your medical care, your study-related information may be 
placed in your permanent hospital, clinic or physician’s office record; 
 Others: Takeda, the Drug Sponsor for this trial 
 
IV. 
 Your information may be given to: 
  
 The U.S. Food and Drug Administration (FDA), Department of Health and Human 
Services (DHHS) agencies, and other federal and state entities; 
 Governmental agencies in other countries; 
 Governmental agencies to whom certain diseases (reportable diseases) must be 
reported; and  
 The Ohio State University units involved in managing and approving the research 
study including the Office of Research and the Office of Responsible Research 
Practices. 
 
V. 
Why will this information be used and/or given to others? 
 
 To do the research;  
 To study the results; and  
 To make sure that the research was done right.   
 
VI. 
 When will my permission end? 
 
There is no date at which your permission ends. Your information will be used indefinitely. 
This is because the information used and created during the study may be analyzed for many 
years, and it is not possible to know when this will be complete. 
 
VII. May I withdraw or revoke (cancel) my permission? 
 


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Yes. Your authorization will be good for the time period indicated above unless you change 
your mind and revoke it in writing. You may withdraw or take away your permission to use 
and disclose your health information at any time. You do this by sending written notice to 
the researchers. If you withdraw your permission, you will not be able to stay in this study. 
When you withdraw your permission, no new health information identifying you will be 
gathered after that date. Information that has already been gathered may still be used and 
given to others. 
 
VIII. What if I decide not to give permission to use and give out my health 
information? 
 
Then you will not be able to be in this research study and receive research-related treatment.  
However, if you are being treated as a patient here, you will still be able to receive care. 
 
IX. 
 Is my health information protected after it has been given to others? 
 
There is a risk that your information will be given to others without your permission. Any 
information that is shared may no longer be protected by federal privacy rules. 
 
X. 
May I review or copy my information? 
Signing this authorization also means that you may not be able to see or copy your study-
related information until the study is completed.   
 
15. Who can answer my questions about the study? 
 
 
For questions, concerns, or complaints about the study you may contact Sameek 
Roychowdhury, MD, PhD at (614) 293-6196. 
 
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact 
Ms. Sandra Meadows in the Office of Responsible Research Practices at 1-800-678-6251. 
 
For questions related to your privacy rights under HIPAA or related to this research 
authorization, please contact: 
 
HIPAA Privacy Officer 
Suite E2140, 600 Ackerman Road 
Columbus, Ohio 43201 
Telephone: 614-293-4477 
 
If you are injured as a result of participating in this study or for questions about a study-related 
injury, you may contact Sameek Roychowdhury, MD, PhD at (614) 293-6196. 


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Signing the consent form 
 
I have read (or someone has read to me) this form and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study.  
 
I am not giving up any legal rights by signing this form.  I will be given a copy of this form. 
 
 
 
 
 
Printed name of subject 
 
Signature of subject 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
 
 
 
 
Printed name of person authorized to consent for subject 
(when applicable) 
 
Signature of person authorized to consent for subject  
(when applicable) 
 
 
 
 
 
AM/PM 
Relationship to the subject 
 
Date and time 
 
 
 
 
Investigator/Research Staff 
 
I have explained the research to the participant or his/her representative before requesting the 
signature(s) above.  There are no blanks in this document.  A copy of this form has been given to 
the participant or his/her representative. 
 
 
 
 
 
Printed name of person obtaining consent 
 
Signature of person obtaining consent 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
Witness(es) - May be left blank if not required by the IRB 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
AM/PM 
 
 
Date and time 
 
 
 
 
 
Printed name of witness 
 
Signature of witness 
 
 
 
 
 
 
AM/PM 
 
 
Date and time