Conditions: Glioblastoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
This research study is studying a chemotherapy as a possible treatment for recurrent glioblastoma that has not responded to bevacizumab. The name of the study drug involved in this study is Ponatinib.

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Ponatinib for your specific disease but it has been approved for other uses.

Ponatinib is a drug that may stop cancer cells from growing by affecting different kinds of proteins in cancer cells. Glioblastoma cells can be driven by mutated forms of a protein called c-kit (KIT) which are present in glioblastoma cells. Laboratory studies suggest that ponatinib has activity against mutated forms of (KIT) which is important in glioblastoma and therefore suggests that ponatinib may help to control the growth of glioblastoma. In this research study the study team is looking to see if ponatinib is safe and is able to control the growth of glioblastoma in people who have not responded to treatment with bevacizumab.

Arms:
arm 1: Drug will be administered once daily per cycle through oral ingestion.

Interventions: intervention 1: Ponatinib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
Local Protocol #: 
15-163 
 
TITLE:  Phase II Trial of Ponatinib in Patients with Bevacizumab-Refractory 
Glioblastoma 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
Principal Investigator (PI): 
Eudocia Lee, MD, MPH 
 
Participating Institutions: 
Dana-Farber Cancer Institute 
Brigham and Women’s Hospital 
Massachusetts General Hospital 
 
MGH Site Principal Investigator: 
Co-Investigator: 
Jorg Dietrich, MD, PhD 
Patrick Y. Wen, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Responsible Study Nurse / PA: 
Statistician: 
Lisa Doherty, NP, APRN, OCN 
Alona Muzikansky  
 
 
Study Coordinator: 
 
  
Sarah Gaffey 
 
 
Agent:   
 
 
   Ponatinib (AP24534); supplied by ARIAD Pharmaceutical 
IND #:  
 
Exempt 
 
Version # / Version Date: 
 
Version #7.0/ 15-March-2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SCHEMA 
 
Definitions: 
CR – Complete Response   
SD – Stable Disease 
PR – Partial Response   
 
PD – Progressive Disease 
 
Footnotes: 
*Total of 27 Participants 
Note: To account for drop outs, 2 additional participants (up to 17 participants) may enroll in 
Stage 1.  If at least 5 or more of the first 15 participants achieve PFS3, 12 more participants 
will be accrued for a total of 27 participants. To account for drop outs in the second stage, 3 
more additional participants may enroll, increasing total enrollment up to 32 participants. 
** Cycle Length = 28 Days 
  


TABLE OF CONTENTS 
1. 
OBJECTIVES .......................................................................................................................................... 1 
1.1 
Study Design ............................................................................................................................................... 1 
1.2 
Primary Objectives ..................................................................................................................................... 1 
1.3 
Secondary Objectives ................................................................................................................................. 1 
1.4 
Exploratory Objectives ............................................................................................................................... 1 
2. 
BACKGROUND ...................................................................................................................................... 1 
2.1 
Study Agent ................................................................................................................................................. 1 
2.2 
Study Disease.............................................................................................................................................. 4 
2.3 
Rationale .................................................................................................................................................... 5 
2.4 
Correlative Studies Background ................................................................................................................. 5 
3. 
PARTICIPANT SELECTION ................................................................................................................ 7 
3.1 
Eligibility Criteria ...................................................................................................................................... 7 
3.2 
Exclusion Criteria .................................................................................................................................... 9 
3.3 
Inclusion of Women and Minorities .......................................................................................................... 12 
4. 
REGISTRATION PROCEDURES ...................................................................................................... 13 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ..................................................................... 13 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ................................................................. 13 
5. 
TREATMENT PLAN ............................................................................................................................ 13 
5.1 
Treatment Regimen and Agent Administration ......................................................................................... 13 
5.2 
General Concomitant Medication and Supportive Care Guidelines ........................................................ 14 
5.3 
Criteria for Taking a Participant Off Protocol Therapy .......................................................................... 17 
5.4 
Duration of Follow Up ............................................................................................................................. 17 
5.5 
Criteria for Taking a Participant Off Study .............................................................................................. 18 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .......................... 18 
6.1 
Anticipated Toxicities ............................................................................................................................... 19 
6.2 
Dose Modifications/Delays ....................................................................................................................... 20 
6.3 
Toxicity Management ............................................................................................................................... 33 
7. 
DRUG FORMULATION AND ADMINISTRATION ....................................................................... 38 
7.1 
Ponatinib .................................................................................................................................................. 38 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................................... 39 
8.1 
Plasma Biomarkers .................................................................................................................................. 39 
8.2 
Tissue Submissions ................................................................................................................................... 41 
9. 
STUDY CALENDAR ............................................................................................................................ 44 


10. 
MEASUREMENT OF EFFECT .......................................................................................................... 46 
10.1 
Antitumor Effect ........................................................................................................................................ 46 
10.2 
Response Review ...................................................................................................................................... 50 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ..................................................................... 51 
11.1 
Adverse Event Characteristics and Definitions: ....................................................................................... 51 
11.2 
Procedures for AE and SAE Recording and Reporting ............................................................................ 54 
11.3 
Expedited Adverse Event Reporting Requirements (By Site to Overall PI and ARIAD Pharmaceuticals)
 ................................................................................................................................................................. 55 
11.4 
Reporting to the Food and Drug Administration (FDA) .......................................................................... 57 
11.5 
Reporting to Participating Institutions ..................................................................................................... 57 
11.6 
Reporting of Pregnancy ............................................................................................................................ 57 
11.7 
Reporting to Hospital Risk Management .................................................................................................. 57 
11.8 
Monitoring of Adverse Events and Period of Observation ....................................................................... 58 
12. 
DATA AND SAFETY MONITORING ............................................................................................... 59 
12.1 
Data Reporting ......................................................................................................................................... 59 
12.2 
Data Safety Monitoring ............................................................................................................................ 59 
12.3 
Monitoring ................................................................................................................................................ 60 
13. 
REGULATORY CONSIDERATIONS ................................................................................................ 60 
13.1 
Protocol Review and Amendments ........................................................................................................... 60 
13.2 
Informed Consent ..................................................................................................................................... 61 
13.3 
Study Documentation ................................................................................................................................ 61 
13.4 
Records Retention ..................................................................................................................................... 61 
14. 
STATISTICAL CONSIDERATIONS ................................................................................................. 61 
14.1 
Study Design/Endpoints ............................................................................................................................ 62 
14.2 
Sample Size, Accrual Rate, Study Duration, and Analysis of Primary Endpoint ..................................... 62 
14.3 
Analysis of Secondary and Exploratory Endpoints .................................................................................. 63 
14.4 
Reporting and Exclusions ......................................................................................................................... 63 
15. 
PUBLICATION PLAN.......................................................................................................................... 63 
16. 
REFERENCES ....................................................................................................................................... 64 
Appendix A: 
Performance Status Criteria ........................................................................................................ 1 
Appendix B: 
Medications and substances known or with the potential to interact with CYP3A4 isoenzymes . 2 
Appendix C: 
Medications known to be associated with Torsades de Pointes ................................................... 3 
Appendix D: 
Pill Diary ...................................................................................................................................... 5 
Appendix E: 
Instructions for Local Processing of Plasma Biomarkers ............................................................ 8 
Appendix F: 
Study Safety Reporting Coversheet ............................................................................................ 10 


 
1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a single arm, open label, Phase II trial in adult participants with recurrent 
glioblastoma who have progressed on bevacizumab.  
 
1.2 
Primary Objectives 
 
• To determine the efficacy of ponatinib in participants with recurrent GBM who have 
progressed on bevacizumab as measured by 3-month progression-free survival 
(PFS3) 
 
1.3 
Secondary Objectives 
 
• Radiographic Response (RR) 
• Overall survival (OS) and progression free survival (PFS) 
• Safety profile  
1.4 
Exploratory Objectives 
 
• To explore the extent to which the tumor’s genotype and expression profile correlate 
with outcome 
• To explore the correlation between serum angiogenic peptides, circulating endothelial 
cells, and circulating progenitor cells with response to therapy 
• To explore the correlation between dynamic-contrast MRI, perfusion and diffusion 
MRI and response to therapy. 
2. BACKGROUND 
 
2.1 
Study Agent 
 
Ponatinib (AP24534) is a novel, orally available tyrosine kinase inhibitor (TKI). In 
addition to targeting Breakpoint Cluster Region-Abelson (BCR-ABL), other targets of 
clinical interest include the kinases c-KIT (KIT), ret proto-oncogene (RET), Fms-like 
tyrosine kinase-3 (FLT3), vascular endothelial growth factor (VEGF), and fibroblast 
growth factor receptors (FGFRs).  
 
Chemical 
Ponatinib is a chemical entity prepared by chemical synthesis. The ponatinib active 
pharmaceutical ingredient is the mono-hydrochloride salt (AP24534 hydrochloride). 
Ponatinib for investigational use is supplied as white opaque capsules containing 
nominally 5 mg of ponatinib, or as 15 mg or 45 mg round, white, film-coated tablets. 
The commercial dosage form, Ponatinib, is supplied as 15 mg or 45 mg round, white 
film-coated tablets. 
 


 
Nonclinical 
A nonclinical development program was implemented to support clinical studies of 
ponatinib. In vitro assays demonstrated that ponatinib potently inhibits the enzymatic 
activity of T315I ABL kinase, as well as that of the native (unmutated) enzyme. In 
leukemia cell lines expressing these BCR-ABL variants, ponatinib potently inhibited 
BCR-ABL signaling, leading to inhibition of cellular proliferation and induction of 
apoptosis. Ponatinib also potently inhibits proliferation of cell lines expressing other 
major, clinically observed imatinib-, nilotinib-, and dasatinib resistant mutants of BCR-
ABL. In vivo antitumor activity has been shown in tumor-bearing mouse models. 
Ponatinib has been shown to be a potent inhibitor of certain other tyrosine kinases 
implicated in the initiation and progression of leukemias and other tumor types. In 
particular, it inhibits FLT3, which is frequently mutationally activated in acute myeloid 
leukemia (AML), and inhibits all members of the FGFR family, which are implicated in 
a variety of myeloproliferative disorders and solid tumor indications. Ponatinib also 
inhibits several other kinases, including KIT, RET, vascular endothelial growth factor 
receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), receptor tyrosine 
kinase expressed on vascular endothelium (TIE2), and tyrosine kinase homologous to 
the Rous sarcoma virus oncogene protein PP60 (SRC). The kinase inhibition profile of 
ponatinib suggests potential for clinical activity in other hematologic and 
nonhematologic malignancies, in addition to Chronic Myeloid Leukemia (CML).  
 
Nonclinical safety assessment studies were performed on ponatinib, including 6-month 
oral toxicology studies in rats and cynomolgus monkeys. The rat was shown to be the 
most sensitive species to toxicologic effects of ponatinib; in a 6-month oral toxicology 
study, the no-observed adverse-effect level (NOAEL) in the rat was 0.25 mg/kg/day. 
Higher dose levels of 0.75 and 2 mg/kg/day caused mortality of some animals. 
Histologic examination revealed decreased numbers of chondrocytes along the physis in 
the femur at the 0.75 and 2 mg/kg/day dose levels, and lymphoid depletion was 
observed in the thymus at the 2 mg/kg/day dose level. Toxicity studies in pregnant rats 
demonstrated fetal malformations and embryo-fetal toxicity at dose levels of 1 and 3 
mg/kg/day, respectively, and higher. In a phototoxicity study in pigmented rats, signs of 
minimal ocular phototoxicity were observed at 5 and 10 mg/kg. Administration of 
ponatinib to cynomolgus monkeys for 6 months at oral dose levels of 0.25, 0.75, and 2 
mg/kg/day was well tolerated, with no ponatinib-related microscopic findings being 
observed at any dose level. 
 
Clinical 
Ponatinib received accelerated approval in the United States (US) (December 2012) and 
approval in the European Union (EU) (July 2013) for patients with refractory CML or 
Philadelphia chromosome-positive (Ph+) leukemias. 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 the EU, more than 900 patients have 
been treated with ponatinib commercially. Regulatory actions were taken by ARIAD 
Pharmaceuticals (ARIAD) and/or the competent authorities following increased 


 
cumulative risk of vascular occlusive events observed in patients using ponatinib. From 
a development perspective, on 08 October 2013, the US Food and Drug Administration 
(FDA) placed a partial clinical hold on all new patient enrollments in clinical studies 
with ponatinib, and a phase 3 study (EPIC: AP24534-12-301) was terminated on 17 
October 2013. From a postmarketing authorization perspective, prior approval 
supplement/type II variation were evaluated by the FDA and the European Medicines 
Agency (EMA), respectively, to revise ponatinib product information to include 
updated data and warning/precautions on arterial thromboembolic events, venous 
thromboembolic events, cardiac failure/left ventricular dysfunction (LVD), and 
cardiovascular deaths. The type II variation received a positive opinion from Europe’s 
Committee for Human Medicinal Products (CHMP) on 21 November 2013. Subsequent 
to completion of the Type II variation procedure, a referral procedure under article 20 of 
regulation (EC) No. 726/2004 was triggered. In the US, while evaluation of new safety 
data was ongoing, the FDA requested ARIAD on 31 October 2013 to temporarily 
suspend commercial distribution and marketing of Ponatinib in the US. On 20 
December 2013, the FDA agreed with the revised US Prescribing Information, and 
commercialization of Ponatinib was resumed in the US in January 2014.  
 
Five company-sponsored clinical studies with ponatinib have been or are being 
conducted in adult patients: 
• A phase 1 dose-escalation study in patients with hematologic malignancies 
(AP24534-07-101) 
• A pivotal phase 2 study in patients with refractory CML (chronic phase [CP], 
accelerated phase [AP], or blast phase [BP]) or Ph+ acute lymphoblastic leukemia 
(ALL) (AP24534-10-201; PACE) 
• A pivotal randomized phase 3 study of ponatinib versus imatinib in patients with 
newly diagnosed CP-CML (AP24534-12-301; EPIC) 
• A phase 1/2 study in Japanese patients with CML or Ph+ ALL (AP24534-11-106) 
• A phase 2 study of patients with metastases and/or unresectable gastrointestinal 
stromal tumor (GIST; AP24534-12-202) 
 
Seven clinical pharmacology studies in healthy subjects have been completed: 
• A food-effect study (AP24534-11-102) 
• A drug-drug interaction (DDI) study with ketoconazole (a cytochrome P450 
[CYP]3A4 inhibitor; AP24534-11-103) 
• An absorption, distribution, metabolism, and elimination (ADME) study with 
[14C]ponatinib (AP24534-11-104) 
• A DDI study with rifampin (a CYP3A4 inducer; AP24534-12-107) 
• A DDI study with lansoprazole (a proton-pump inhibitor; AP24534-12-108) 
• A study of ponatinib in subjects with various degrees of hepatic impairment 
(matched to control subjects; AP24534-12-109) 
• A bioequivalence study of ponatinib in healthy volunteers (AP24534-13-111) 
 
 
 


 
In addition, ponatinib has been provided via an expanded access program through the 
following mechanisms: 
• A company-sponsored expanded access study (AP24534-12-901 in the US; this 
study was closed on 14 December 2012, coinciding with the approval and 
commercialization of Ponatinib in the US). 
• An expanded-access study (AP24534-12-903) in France in patients with refractory 
disease; the study is ongoing and accepting new patients. 
• An expanded-access study (AP24534-12-904) in Belgium in patients with 
refractory disease; this study also is ongoing and enrolling new patients. 
• Individual-patient treatment investigational new drug (IND) applications in the US 
• Named Patient Programs (NPPs) outside the US 
 
Multiple investigator-sponsored trials (ISTs) are underway to evaluate the response of 
hematologic cancers as well as solid tumors to ponatinib. Two of these have had 
preliminary efficacy results published: 
• AP24534-11-001 (clinicaltrials.gov # NCT01424982) is a phase 2 study of 
ponatinib (45 mg QD) in combination with hyper-CVAD (fractionated 
cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating with 
high-dose methotrexate and cytarabine every 21 days, in patients with Ph+ ALL. 
As of 07 October 2013, 30 patients received ponatinib.  
• AP24534-11-002 (clinicaltrials.gov # NCT01570868) is a phase 2 study of 
ponatinib in newly-diagnosed CP-CML patients, with 41 patients treated as of 07 
October 2013. 
 
Full descriptions of all clinical, clinical pharmacology, and investigator-sponsored 
studies can be found in the Investigator Brochure 
 
2.2 
Study Disease 
 
Glioblastomas (GBMs) are the most common type of malignant primary brain tumors in 
adults. The annual incidence in the United States is 3-4 per 100,000, with over 10,000 new 
cases each year (Wen and Kesari 2008, Dolecek, Propp et al. 2012). Despite optimal 
treatment with surgery, radiation therapy, and chemotherapy, the prognosis remains poor. In 
2005, results from a randomized Phase III trial indicated that the addition of temozolomide 
chemotherapy to radiation therapy for treatment of newly-diagnosed GBM prolonged median 
survival from 12.1 to 14.6 months (Stupp, Mason et al. 2005). For participants with recurrent 
GBM, treatment options are limited (Wen and Kesari 2008). The median time to tumor 
progression is only 9 weeks for standard cytotoxic agents (Wong, Hess et al. 1999) and 4-5 
months with bevacizumab containing regimens (Friedman, Prados et al. 2009, Kreisl, Kim et 
al. 2009). 
 
Tumors that progress during bevacizumab therapy often cannot be treated successfully. A 
retrospective series of 37 participants treated with various non-antiangiogenic approaches 
following bevacizumab failure reported a median overall survival of 4.5 months (Iwamoto, 
Abrey et al. 2009).  Continuation of bevacizumab is also typically followed by progressive 
clinical deterioration and death. Among 54 recurrent high-grade glioma participants who 


 
were treated with bevacizumab and cytotoxic chemotherapy, continuing bevacizumab and 
changing to another chemotherapy agent at recurrence was ineffective (Quant, Norden et al. 
2009). The median PFS was only 6 weeks, and there were no radiographic responses. In a 
Phase II study of 48 recurrent GBM participants treated with bevacizumab monotherapy, 19 
participants received bevacizumab and irinotecan at recurrence (Kreisl, Kim et al. 2009). The 
median PFS was approximately one month, and there were no radiographic responses using 
standard criteria (Macdonald, Cascino et al. 1990). At this time, no treatment has proven 
even modestly effective in the post-bevacizumab setting. 
 
2.3 
Rationale 
 
Although anti-angiogenic approaches for GBM therapy show promise, GBMs usually 
develop resistance to treatment within months or even weeks of starting therapy. The 
predominant mechanisms of resistance to anti-angiogenic therapies are still being elucidated, 
but at the time of tumor progression, there are increases in plasma levels of basic fibroblast 
growth factor (bFGF) and stromal cell-derived factor 1α (SDF-1α) (Casanovas, Hicklin et al. 
2005, Batchelor, Sorensen et al. 2007).  Drugs such as ponatinib targeting not only vascular 
endothelial growth factor receptor (VEGFR) and platelet derived growth factor (PDGFR), 
but also fibroblast growth factor receptor (FGFR), may potentially help overcome some of 
the putative mechanisms of resistance and result in increased antitumor effects. The 
additional activity that ponatinib has on members of the Src family of tyrosine kinases may 
also contribute to a therapeutic effect since there is increasing evidence that Src is also 
important in glioma invasion (Stettner, Wang et al. 2005, Du, Bernasconi et al. 2009).   
 
In addition, ponatinib is a potent pan-FGFR inhibitor and may be particularly active against 
patients with FGFR-driven cancers (Gozgit, Wong et al. 2012). In patients with glioblastoma, 
approximately 3.1% harbor oncogenic chromosomal translocations that fuse the tyrosine 
kinase coding domains of FGFR genes to the transforming acidic coiled-coil (TACC) coding 
domains (Gozgit, Wong et al. 2012). The FGFR-TACC fusion protein demonstrates 
oncogenic activity and inhibition of this with use of an FGFR inhibitor has shown prolonged 
survival in mice with intracranial glioma harboring the FGFR3-TACC3 fusion (Singh, Chan 
et al. 2012). 
 
2.4 
Correlative Studies Background 
1.1.1 Tumor Tissue Markers 
Archival tissue will be analyzed for FGFR-TACC fusion protein and correlated with 
clinical outcomes. 
1.1.2 Plasma Markers 
 
Serial monitoring of plasma biomarkers that reflect the effects of anti-angiogenic agents 
would be an ideal tool to track tumor response and elucidate tumor escape mechanisms. 
Since angiogenesis requires an exquisite balance of signaling from pro- and anti-
angiogenic to maintain the vascular supply (Jain, di Tomaso et al. 2007), multiple 
biomarkers will need to be monitored. In addition to the VEGF and CXCR4 pathways 


 
described previously, several other molecules have been implicated in tumor 
angiogenesis, including: placental growth factor (PlGF), angiopoietin-1 (ANG1), 
angiopoietin-2 (ANG2) and the soluble receptor Tie-2 (Reiss, Machein et al. 2005); the 
angiogenesis inhibitors tumstatin and thrombspondin-1 (Nyberg, Xie et al. 2005); and the 
pro-inflammatory chemokine interleukin-8 (IL-8) (Waugh and Wilson 2008).  
 
Additionally, studies have shown that the structure of collagen IV is modified after 
VEGFR2 blockade (Inai, Mancuso et al. 2004, Tong, Boucher et al. 2004, Winkler, 
Kozin et al. 2004). Collagen IV degradation subsequently leads to release of tumstatin 
into the blood stream, whose levels are inversely correlated with angiogenic activity and 
tumor growth rate (Hamano, Zeisberg et al. 2003).  
 
More recently, clinical studies have shown that plasma levels of angiogenic proteins 
change with anti-VEGF treatments. A pattern that has been described in several cancers 
including GBMs is an increase in VEGF and PIGF, along with reduced levels of soluble 
VEGFR-2 (sVEGFR-2) (Willett, Boucher et al. 2005, Motzer, Michaelson et al. 2006, 
Batchelor, Sorensen et al. 2007, Drevs, Siegert et al. 2007). One of these studies also 
demonstrated that plasma levels of circulating cytokines SDF1-α, soluble Tie-2 (sTie-2), 
bFGF, and collagen IV were predictive of radiographic responses and increased survival 
to cediranib, a pan-VEGFR inhibitor (Batchelor, Sorensen et al. 2007). Serial monitoring 
allowed investigators to show that treatment with cediranib elicited a reactive increase in 
plasma VEGF and PIGF, which reversed during treatment interruptions. These studies 
demonstrate the feasibility of serum angiogenic cytokines and soluble receptors as 
predictive and prognostic biomarkers for anti-angiogenesis treatments. 
 
Circulating endothelial cells (CECs, with a CD31+CD45– phenotype) and circulating 
precursor cells (CPCs, CD34+ cells), may also be potentially useful as a surrogate 
angiogenesis marker. The use of CECs and CPCs as surrogate angiogenesis markers has 
been reported in several clinical studies of angiogenesis inhibitors. Bevacizumab, an anti-
VEGF agent, decreased the number of viable CECs and CPCs in rectal carcinoma 
patients (Willett, Boucher et al. 2004).  
 
In patients with recurrent glioblastoma treated with cediranib, progression during 
treatment with this pan-VEGF receptor tyrosine kinase inhibitor was associated with an 
increase in viable CEC counts whereas progression during drug interruptions correlated 
with elevations in circulating progenitor cell counts (Batchelor, Sorensen et al. 2007). 
These findings may suggest a differential role for viable CECs versus CPCs in 
assessment of clinical outcomes in recurrent GBM. In addition, preclinical and clinical 
evidence show that certain CD45+ CD11b+ myelomonocytic cells may have a 
particularly important role in tumor vasculogenesis and their influx into tumors can be 
prevented by plerixafor (Kioi, Vogel et al. 2010). Serial monitoring of CECs, CD34+ 
CPCs, and VEGFR2+CD11b+CD45+ myelomonocytic cells will be measured 
concomitantly by 8-color flow cytometry. The following biomarkers will be obtained 
from serial plasma samples of patients treated with plerixafor and bevacizumab: SDF1α, 
collagen IV, sTie2 and G-CSF (using ELISA kits), and VEGF, PlGF, sVEGFR1, and 
bFGF (growth factor 1 array plate, Meso-Scale Discovery) and IL-1b, TNF-a, IL-6 and 
IL-8 (cytokine array plate, Meso-Scale Discovery). 
 


 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
Within 14 days of registration except where otherwise noted, participants must meet the 
following criteria on screening examination to be eligible to participate in the study: 
1.1.3 Age ≥ 18 years 
 
1.1.4 Karnofsky performance status ≥ 60 (see Appendix A) 
 
1.1.5 Participants must have histologically confirmed glioblastoma or variants. Subjects 
with initial diagnosis of a lower grade glioma are eligible if a subsequent biopsy is 
determined to be glioblastoma or variants. 
 
1.1.6 Patients must have an unequivocal progression by magnetic resonance imaging 
(MRI) or computed tomography (CT) scan. A scan must be performed within 14 
days prior to registration and on a steroid dose that has been stable or decreasing for 
at least 5 days. If the steroid dose is increased between the date of imaging and 
initiation of study treatment, a new baseline MRI/CT is required.  
 
1.1.7 Participants must have bi-dimensionally measurable disease with a minimum 
measurement of 1 cm per dimension on MRI performed within 14 days prior to 
registration. If receiving corticosteroids, participants must be on a stable or 
decreasing dose of corticosteroids for at least 5 days prior to baseline MRI. 
 
1.1.8 There is no limit on the number of prior relapses but the most recent relapse must 
be the first relapse on a bevacizumab-containing regimen. 
 
1.1.9 Participants must have normal organ and marrow function as defined below: 
• Leukocytes > 3,000/mcL (> 3,000/mm3) 
• Absolute neutrophil count > 1,500/mcL (> 1,500/mm3) 
• Platelets > 100,000/mcL (> 100,000/ mm3) 
• Total bilirubin ≤ 1.5 X institutional upper limit of normal, unless due to 
Gilbert’s syndrome. 
• AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal 
• Serum Creatinine ≤ 1.5 X institutional upper limit of normal or or 
creatinine clearance > 60 mL/min/1.73 m2 (per 24 hour urine collection 
or calculated according to the Cockcroft-Gault formula) for subjects with 
creatinine levels above the institutional normal 
• Serum lipase and amylase ≤ 1.5 X institutional upper limit of normal. 
 
 


 
1.1.10 Participants must have fully recovered (grade ≤ 1 or baseline or deemed 
irreversible) from any clinically significant acute toxicity related to prior therapy 
(with the exception of lymphopenia, which is common after therapy with 
temozolomide). Patients who discontinued bevacizumab previously due to a 
bevacizumab-related toxicity will not be allowed to participate.   
1.1.11 The following time periods must have elapsed prior to the planned start date of 
study treatment:  
• ≥2 weeks or 6 half lives from any approved TKIs or investigational agent, 
whichever is shorter 
• ≥4 weeks from prior cytotoxic therapy, except ≥ 3 weeks from last dose of 
temozolomide and ≥6 weeks from nitrosoureas or mitomycin C 
• ≥2 weeks from non-cytotoxic agents 
• ≥ 3 weeks from bevacizumab 
 
1.1.12 Participants must have developed progressive disease after receiving prior radiation 
therapy and must have an interval of at least 12 weeks from the completion of any 
radiation therapy to study entry (unless progressive tumor growth is outside the 
radiation field or there is histopathological confirmation of recurrent tumor). 
1.1.13 Participants may not have received prior therapy with any other Src, PDGFR, or 
FGFR inhibitor. Prior treatment with an anti-VEGFR or anti-VEGF agent is also 
allowed but only one relapse following a bevacizumab-containing regimen is 
allowed. 
1.1.14 For women of childbearing potentia (defined as women with menses within the past 
2 years) l, a negative serum pregnancy test must be documented prior to 
registration. 
NOTE: In addition to screening, serum pregnancy test must be performed on 
females of childbearing potential within 72 hours before the start of 
investigational product. When possible, these tests can be one-in-the-same (if 
screening pregnancy test was performed within 72 hours of first ponatinib 
dose, no need to repeat). 
 
1.1.15 The effects of ponatinib on the developing human fetus are unknown. For this 
reason and because ponatinib is known to be teratogenic in animal models, women 
of child-bearing potential (defined as women with menses within the past 2 years) 
and men must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry, for the duration of study 
participation, and through 4 months after the end of treatment. Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
 
 
1.1.16 Ability to understand and the willingness to sign a written informed consent 
document. 
 


 
NOTE: Consent documents can be signed up to 30 days prior to registration.  If >30 
days has elapsed since patient signed the consent document, s/he must re-consent 
(new signature) before proceeding to register onto study. 
 
1.1.17 Participants must have sufficient tissue from prior surgery revealing glioblastoma 
or variants for confirmation of diagnosis and correlative studies.  The following 
amount of tissue is required: 
• 15 (5 μm thick) unstained formalin fixed paraffin embedded (FFPE) sections 
• 1-2 H&E stained slides, or additional unstained 5 μm slide(s) for staining 
•  
NOTE:  The Overall PI will allow for up to 2 participants to enroll with insufficient 
tissue.  If a site is hoping to enroll a patient with less than the tissue required per 3.1.15, 
prospective approval by the Overall PI is required.  
 
1.1.18 Protocol treatment plan must include beginning therapy within 5 consecutive days 
after registration. 
 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study. 
1.1.19 Participants may not be receiving any other investigational agents. 
 
1.1.20 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to ponatinib. 
 
1.1.21 Participants who have received prior treatment with interstitial brachytherapy, 
stereotactic radiosurgery, or implanted chemotherapy sources, such as wafers of 
polifeprosan 20 with carmustine 
 
1.1.22 Participants with poorly controlled diabetes defined as a HgbA1c ≥ 7.0% 
 
1.1.23 Participants with grade ≥ 3 peripheral motor or sensory neuropathy. 
 
1.1.24 Participants receiving any medications or substances that are moderate and strong 
inhibitors or inducers of CYP3A4, including enzyme-inducing anti-epileptic drugs 
(EIAEDs) within 14 days before the first dose of ponatinib will be excluded. This 
category includes phenobarbital, phenytoin, fosphenytoin, primidone, 
carbamazepine, and oxcarbazepine. Lists including medications and substances 
known or with the potential to interact with CYP3A4 isoenzymes are provided in 
Appendix B. 
 
NOTE: Participants must avoid consumption of Seville orange (and juice), 
grapefruit or grapefruit juice, grapefruit hybrids, pummelos and exotic citrus fruits 


 
from 7 days prior to the first dose of study drug and during the entire study 
treatment period due to potential CYP3A4 interaction. 
1.1.25 Participants taking medications that are known to be associated with Torsades de 
Pointes or QT prolongation within 14 days of starting treatment.  Refer to Tables C-
1 and C-2 of Appendix C for a list of prohibited drugs. 
1.1.26 Participants cannot take any herbal preparations/medications on study or within 7 
days prior to first dose of study drug, including but not limited to: St. John‘s wort, 
Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, ginseng.  
1.1.27 Participants who underwent major surgery (including craniotomy) or significant 
traumatic injury within 28 days prior to initiating therapy. Baseline MRIs for 
participants who underwent salvage surgery must be obtained within 14 days of 
registration (similar to other patients who do not have surgery) and there must be 
measurable disease.   
 
1.1.28 Participants who underwent minor surgical procedure within 7 days prior to 
initiating therapy. 
 
1.1.29 History of a bleeding disorder. 
 
1.1.30 Patients with gastrointestinal bleeding or any other hemorrhage/bleeding event 
CTCAE Grade ≥ 3 within 30 days prior to study entry. 
 
1.1.31 Patients whose screening MRI scan demonstrates intratumoral hemorrhage or 
peritumoral hemorrhage are not eligible for treatment if deemed significant by the 
treating physician. If there are questions, the treating physician should contact the 
study’s Overall PI, Dr. Lee at 617.632.2166. 
 
1.1.32 History of acute pancreatitis within 1 year of study treatment or a history of chronic 
pancreatitis.  
 
1.1.33 History of alcohol abuse. 
 
1.1.34 Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL) 
 
1.1.35 Clinically significant, uncontrolled, or active cardiovascular disease, specifically 
including, but not restricted to: 
• Any history of myocardial infarction  
• Any history of clinically significant (as determined by the treating 
physician) atrial arrhythmia  
• Any history of ventricular arrhythmia 
• Any history of Cerebrovascular accident or transient ischemic attack (TIA)  


 
• Any history of peripheral arterial occlusive disease requiring 
revascularization 
• Unstable angina within 6 months prior to enrollment 
• Congestive heart failure within 6 months prior to enrollment 
• Venous thromboembolism including deep venous thrombosis or pulmonary 
embolism within 6 months prior to enrollment 
• Unacceptable Screening Baseline Cardiovascular Assessment: 
o Baseline MUGA (to be done within 30 days of registration) or 
Echocardiogram demonstrating LVEF < 50 % 
o QTc > 480 msec on screening ECG (using the QTcF formula) 
1.1.36 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. 
1.1.37 Ongoing or active infection.  The requirement for intravenous (IV) antibiotics is 
considered active infection. 
1.1.38 Known history of human immunodeficiency virus (HIV).  Testing is not required in 
the absence of prior documentation or known history. 
1.1.38.1 HIV-positive individuals on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with 
ponatinib. In addition, these individuals are at increased risk of lethal 
infections when treated with marrow-suppressive therapy. Appropriate 
studies will be undertaken in participants receiving combination 
antiretroviral therapy when indicated. 
1.1.39 Pregnant or breastfeeding. 
1.1.39.1 Pregnant women are excluded from this study because ponatinib has 
potential for teratogenic or abortifacient effects in animal models. Because 
there is an unknown but potential risk of adverse events in nursing infants 
secondary to treatment of the mother with ponatinib, breastfeeding should 
be discontinued if the mother is treated with ponatinib. These potential 
risks may also apply to other agents used in this study. 
1.1.40 Malabsorption syndrome or other gastrointestinal illness that could affect oral 
absorption of study drugs. 
1.1.41 Individuals with a history of a different malignancy, other than cervical cancer in 
situ, basal cell or squamous cell carcinoma of the skin, are ineligible, except if they 
have been disease-free for at least 5 years, and are deemed by the investigator to be 
at low risk for recurrence of that malignancy OR if the other primary malignancy is 
neither currently clinically significant nor requiring active intervention. 
 


 
1.1.42 Any condition or illness that, in the opinion of the Investigator, would compromise 
patient safety or interfere with the evaluation of the drug. 
3.3 
Inclusion of Women and Minorities  
 
Both men and women of all races and ethnic groups are eligible for this trial. 
  
 
 
 


 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management 
System (OnCore) . Registrations must occur prior to the initiation of protocol 
therapy. Any participant not registered to the protocol before protocol therapy begins 
will be considered ineligible and registration will be denied.  
 
An investigator will confirm eligibility criteria and a member of the study team will 
complete the protocol-specific eligibility checklist. 
  
Following registration, participants may begin protocol therapy. As noted in 3.1.16, 
protocol treatment must begin within 5 consecutive days after registration.  Issues 
that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If a participant does not receive protocol therapy following registration, 
the participant’s registration on the study must be cancelled. Registration cancellations 
must be made in OnCore as soon as possible. 
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed.  
 
5. TREATMENT PLAN  
 
5.1 
Treatment Regimen and Agent Administration 
 
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks 
as well as dose modifications for ponatinib are described in Section 6 (Expected Toxicities 
and Dosing Delays/Dose Modification). No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant’s 
malignancy. 
 
Protocol treatment must begin within 5 consecutive days after registration. The starting dose 
of ponatinib will be 45 mg taken orally once-daily.  Patients will take the prescribed number 
of tablets with water, with or without food, at approximately the same time each day.  Patients 
will be provided a medication diary (Appendix D) where administration specifics will be 
recorded (dose, date, time). The medication diary will be returned to clinic staff at the end of 
each cycle and a new one will be given to the participant for the next cycle. Participants are to 
return all ponatinib pill bottles and unused ponatinib pills.   
 
Patients who forget to take their dose more than 6 hours after it is due should not make up the 
missed dose.  Patients who vomit after taking their dose should not make up that dose, but 
take the next dose at the planned time, if clinically indicated.  Any missing doses should be 
recorded, and subsequent training of patients should be documented in the appropriate source 
record.  Pills must not be crushed, chewed, or dissolved in water.  
 


 
Treatment cycles are 28 days in length; days are counted continuously, even if treatment is 
held for toxicity.  During dose interruptions, continue to observe the study schedule as 
planned. All study evaluations and treatments should continue as if study treatment is not 
being held.  Following a dose delay which resumes mid cycle, day 1 procedures not 
associated with the adverse event do not need to be repeated.  If study drug is held across a 
time point which requires collection of a research blood sample, please contact Dr. Eudocia 
Quant Lee to confirm whether or not the sample should be collected or if the drug hold will 
negate the value of collection of the sample in question.  If you anticipate the occurrence of 
such a scenario, please contact the DFCI Coordinating Center as soon as possible in order to 
establish a plan prior to the time point in question. If a participant requires a treatment hold > 
28 days, then the participant must be discontinued from study treatment.  
 
Criteria for dose modifications and delays apply to intracycle administration and Day 1 
administrations; there are no separate ‘start of cycle’ criteria.  However Day 1 treatments 
may not begin until the respective results of the Day 1 procedures are reviewed.  
Required assessments and windows for assessments are detailed in Section 9. 
 
All patients are to be started at a 45-mg dose once daily.  For patients with stable disease or 
better at the end of Cycle 6, as determined by RANO (Wen, Macdonald et al. 2010), the dose 
of ponatinib must be reduced to 30 mg QD, if not already dose-reduced for other reasons.   
 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
An analysis of baseline risk factors in patients from the PACE study assessed the impact of 
hypertension, hypercholesterolemia, diabetes, and obesity, and revealed several risk factors 
that pre-dispose patients to vaso-occlusive events (VOEs) on ponatinib.  Based on an analysis 
of odds ratios (OR), the leading risk factors for serious arterial VOEs are cardiovascular 
disorders such as any history of MI (OR = 6.86), coronary artery disease (OR = 7.14), and 
coronary revascularization (OR = 6.19).  The OR for serious arterial VOEs is 3.53 for history 
of ischemic cerebrovascular disease, 3.78 for diabetes mellitus, 2.49 for hypertension, and 
2.07 for hypercholesterolemia.  Based on this analysis, the following supportive care 
recommendations are provided to decrease the risk of VOEs for patients taking ponatinib. 
 
Anti-diabetic Treatment 
Patients with diabetes are at increased risk of experiencing arterial thrombotic events while 
being treated with ponatinib.  Therefore, as a part of the assessment and management of the 
patient’s cardiovascular risk factors, initiation of or modifications to diabetic care should be 
considered in patients being treated with ponatinib who have elevated glucose levels.  The 
American Diabetes Association guidelines should be followed, and anti-diabetic treatment 
and lifestyle intervention (includes but are not limited to weight loss, decreased fat intake, 
calorie restriction, increased physical activity, and smoking cessation) should be started in 
any patient with fasting glucose >130 mg/dL (7.2 mM/L) and/or HbA1c ≥7% {Knowler, 
2002 #129}{American Diabetes, 2003 #131}.   
Hypertension Treatment 


 
Hypertension (HTN) may contribute to risk of arterial thrombotic events.  Patients who have 
HTN should be managed appropriately before initiating treatment.  During ponatinib 
treatment, blood pressure elevations should be monitored and managed.  Hypertension 
should be treated to achieve a goal of <150/90 mmHg.  Initial antihypertensive treatment 
should generally include a thiazide-type diuretic, calcium channel blocker (CCB), 
angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker 
(ARB){James, 2014 #132}.  Ponatinib treatment should be temporarily interrupted if HTN is 
not medically controlled (refer to Section 6.2.5below for additional management 
recommendations).  Patients may require urgent clinical intervention for HTN associated 
with confusion, headache, chest pain, or shortness of breath. 
 
OTHER CONCOMITANT MEDICATIONS 
Participants must be instructed not to take any additional medications (including over-the-
counter products) during the trial without prior consultation with the investigator. All 
medications taken within 30 days of screening should be recorded. If concomitant therapy 
must be added or changed, including over-the-counter medications or alternative therapies, 
the reason and name of the drug/therapy should be recorded. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
participant are allowed, including drugs given prophylactically (e.g., antiemetics) with the 
following exceptions: 


 
5.2.1 Moderate and strong CYP3A inhibitors and CYP3A inducers are prohibited. In 
vitro studies suggest that ponatinib is a sensitive CYP3A4 substrate. Co-
administration of ponatinib with strong and moderate CYP3A4 inhibitors is 
predicted to increase the systemic exposure to ponatinib; likewise CYP3A 
inducers can be expected to decrease systemic exposure to ponatinib, possibly 
resulting in sub-therapeutic drug levels.  Refer to Appendix B for a list of CYP3A 
inhibitors and inducers. 
5.2.2 QT interval prolonging medications known to induce Torsades de Pointes (TdP) 
or to promote QT prolongation are prohibited at study entry.  
5.2.2.1 If a participant, after initiating study drug, requires the concomitant use of a 
drug known to prolong the QT interval, then investigators, at their discretion 
may co-administer such medications with appropriate monitoring; however, 
participants must not initiate any medication known to induce TdP. Refer to 
Appendix C (Table C-1) for a list of prohibited drugs on study. 
5.2.2.2 Concomitant use of QT prolonging medications that have a conditional or 
possible risk to induce Torsades de Pointes is allowed with caution and 
monitoring. Please refer to Appendix C (Table C-2) for a list of drugs. 
5.2.3 Herbal preparations/medications are not allowed throughout the study. These 
herbal medications include, but are not limited to: St. John‘s wort, Kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, ginseng. Participants should stop using any herbal medications 7 days 
prior to first dose of study drug. 
5.2.4 Anti-seizure medications should be used as indicated. Only participants receiving 
non-EIAEDs are eligible. If for unavoidable clinical reasons (emergency 
department visit, severe allergies, toxicities, etc.) a participant‘s AED is switched 
to another AED, the participant should be started on another non-EIAED if at all 
possible. Participants who need to permanently change anticonvulsant, but who 
cannot change to another non-EIAED, must be discussed with the PI.  
5.2.5 Prophylactic use of aspirin and/or statins will be left to the discretion of the 
prescribing physician. 
5.2.6 Febrile neutropenia should be managed according to NCCN guidelines or the 
local institution's guidelines. Measures may include appropriate laboratory 
testing, including blood and urine cultures and the institution of broad-spectrum 
antibiotics. If a source for the fever is not identified or the fever resolves when the 
neutrophil count recovers, antibiotics may be discontinued and the participant 
observed. If a patient’s individual risk factors place them at high risk of 
developing febrile neutropenia, primary prophylaxis use of colony-stimulating 
growth factors for the prevention or reduction of febrile neutropenia is 
recommended according to the published NCCN guidelines 
5.2.7 Antiemetics: The use of antiemetics will be left to the investigators‘ discretion. 
The preferred antiemetic is metoclopramide which is not known to prolong QTc. 
Prophylactic anti-emetic is not recommended as it is not necessary. 
 
 


 
5.3 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse event(s), 
treatment may continue indefinitely, until one of the following criteria applies: 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements, 
• Participant has a confirmed positive serum pregnancy test, 
• Participant decides to withdraw from the protocol therapy, or 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  
The reason for removal from protocol therapy, and the date the participant was 
removed, must be documented in the case report form (CRF). Alternative care options 
will be discussed with the participant. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is 
removed from protocol therapy. This form can be found on the QACT website or 
obtained from the QACT registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must 
immediately notify the Overall PI, Eudocia Quant Lee, MD, at DFCI Page: 617-632-
3352, ID # 49318.  
 
5.4 
Duration of Follow Up  
 
Participants removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. All participants will be followed until 
resolution or stabilization of any serious adverse events occurring during treatment or 
starting within 30 days of last study drug. 
 
30-Day Follow-Up: A 30-day post-treatment evaluation is to be performed at 30 days 
(+/- 5 days) after last dose of study drug; these may be performed by documented 
clinician telephone call, if a physical visit is not feasible. 
 
Long Term Follow-Up: After the 30-day post-treatment evaluation, participants will be 
followed every 3 months (+/- 1 month) for survival, post-study-therapy therapies and 
future relapses until patient either passes away or is lost to follow-up. 
 
  
 
 


 
5.5 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply:  
• Lost to follow-up 
• Withdrawal of consent 
• Death 
 
The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care 
options will be discussed with the participant. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes 
off study. This form can be found on the QACT website or obtained from the QACT 
registration staff.  
 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Table 6.0: Ponatinib Dose Levels 
 
Dose Level 
Ponatinib 
0 (starting dose) 
45 mg daily 
-1 
30 mg daily 
-2 
15 mg daily 
-3 
15 mg every other day 
 
All patients are to be started at a 45-mg dose QD.  For patients with stable disease or better at the 
end of Cycle 6, as determined by RANO (Wen, Macdonald et al. 2010), the dose of ponatinib 
must be reduced to 30 mg QD, if not already dose-reduced for other reasons.   
 
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the participant on study drug. If administration of 
ponatinib must be interrupted because of unacceptable toxicity, drug dosing will be interrupted or 
modified according to rules described in Table 6.2.   
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Active Version (version 4.0) of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP 
website at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 


 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment until the 30-day post-treatment evaluation. Participants continuing to experience 
toxicity at the 30-day post-treatment evaluation may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible. 
 
6.1 
Anticipated Toxicities 
In order for an event to be considered expected (known correlation to study drug) for the 
purposes of adverse event reporting, the event must be included in this section.  
1.1.43 A list of adverse events of all grades suspected to be ponatinib related, organized by 
CTCAE v4.0 category, includes: 
 
• BLOOD and LYMPHATIC SYSTEM DISORDERS –  
o anemia, bone marrow hypocellular, febrile neutropenia, neutropenia, spleen disorder, 
& thrombocytopenia 
• CARDIAC DISORDERS –  
o acute coronary syndrome, atrial fibrillation, atrial flutter, atrioventricular block, 
cardiac arrest*, heart failure, left ventricular systolic dysfunction, myocardial 
infarction (this may include: cardiogenic shock, cardiopulmonary failure, myocardial 
ischemia)*, paroxysmal atrial tachycardia, pericardial effusion, restrictive 
cardiomyopathy, right ventricular dysfunction, sick sinus syndrome, sinus 
bradycardia, & supraventricular tachycardia,  
o cardiac disorders, other - specify: arrhythmia, coronary artery disease, coronary artery 
stenosis, & superventricular tachycardia 
• EYE DISORDERS –  
o blurred vision, dry eye, eye pain, eyelid edema, & retinal vascular disorder 
o eye disorders, other - specify: visual acuity reduced, visual disturbance, & visual 
impairment  
• GASTROINTESTINAL DISORDERS –  
o abdominal distention, abdominal pain, ascites, constipation, diarrhea, dry mouth, 
dyspepsia, gastric hemorrhage*, gastric perforation, hemorrhoidal hemorrhage, ileal 
fistula, intra-abdominal hemorrhage, mucositis oral, nausea, oral pain, pancreatitis, 
pharyngeal mucositis rectal hemorrhage, stomach pain, upper gastrointestinal 
hemorrhage, vomiting 
o gastrointestinal disorders, other - specify: hematemesis & lip blister 
• GENERAL DISORDERS and ADMINISTRATION SITE CONDITIONS –  
o chills, edema (face, limbs, and trunk), fatigue, ,fever, generalized muscle weakness, 
non-cardiac chest pain, pain, & wound complication 
• HEPATOBILIARY DISORDERS – 
o hepatic failure*, SGOT elevation, SGPT elevation, & viral hepatitis 
o hepatobiliary disorders, other - specify: portal vein thrombosis 
• IMMUNE SYSTEM DISORDERS –  
o allergic reaction 


 
• INFECTIONS and INFESTATIONS –  
o lung infection*, pharyngitis, sepsis, skin infection, upper respiratory tract infection, & 
urinary tract infection 
o infections and infestations, other - specify: folliculitis & influenza   
• INVESTIGATIONS –  
o alanine aminotransferase increased, alkaline phosphatase increased, aspartate 
aminotransferase increased, blood bilirubin increased, CPK increased, creatinine 
increased, electrocardiogram QT corrected interval prolonged, GGT increased, 
hypophosphatemia, lipase increased, lymphocyte count decreased, neutrophil count 
decreased, pancreatic enzymes increased, platelet count decreased, serum amylase 
increased, weight loss, white blood cell decreased 
• METABOLISM and NUTRITION DISORDERS –  
o acidosis, anorexia, dehydration*, hypercalcemia, hyperkalemia, hyperglycemia, 
Hypernatremia, hypertriglyceridemia, hyperuricemia, hypocalcemia, hypokalemia, 
hypoalbuminemia, hypoglycemia, hypophosphatemia, tumor lysis syndrome 
• MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERS –  
o arthralgia, back pain, bone pain, myalgia, neck pain,  pain in extremity 
o musculoskeletal and connective tissue disorder, other - specify: muscle spasms 
• NERVOUS SYSTEM DISORDERS –  
o dizziness, dysesthesia, edema cerebral*, headache, intracranial hemorrhage, 
neuralgia, peripheral motor neuropathy, peripheral sensory neuropathy, stroke 
o nervous system disorders, other - specify: transient ischemic attack 
• PSYCHIATRIC DISORDERS –  
o insomnia 
• REPRODUCTIVE SYSTEM and BREAST DISORDERS –  
o erectile dysfunction 
• RESPIRATORY, THORACIC, and MEDIASTINAL DISORDERS –  
o cough, dyspnea, epistaxis, hoarseness, pleural effusion, pulmonary edema, pulmonary 
fibrosis 
• SKIN and SUBCUTANEOUS TISSUE DISORDERS –  
o alopecia, bullous dermatitis, dry skin, erythema multiforme, hyperhidrosis, pruritus, 
rash acneiform, rash maculo-papular, Stevens Johnson syndrome 
o skin and subcutaneous tissue disorders, other - specify: hyperkeratosis & night sweats 
• VASCULAR DISORDERS –  
o flushing, hot flashes, hypertension, peripheral ischemia, thromboembolic event  
o vascular disorders, other - specify: aortic thrombosis, carotid artery stenosis, cerebral 
artery stenosis, extremity necrosis, femoral artery occlusion, peripheral arterial 
occlusive disease, peripheral artery stenosis, peripheral vascular disease, subclavian 
artery stenosis, vertebral artery stenosis 
 
*Asterisked events include fatal outcome 
6.2 
Dose Modifications/Delays 


 
 
Criteria for disrupting treatment, dose modification, or discontinuation are found below and 
in Table 6.2. Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for 
Adverse Events, version 4.0 (CTCAEv4.0).  These guidelines should be followed by clinical 
investigators; however, for an individual patient, dose interruptions, reductions, and 
treatment discontinuation should also be based on the clinical circumstance.  Deviation from 
these guidelines must be documented and communicated with the study’s Overall PI, Dr. 
Eudocia Quant Lee (prospectively whenever possible). 
 
NOTE: Section 6.3 provides additional guidance for management of selected AEs for 
ponatinib. 
 
Comprehensive assessments of any AEs (adverse events) experienced by the patient will be 
performed throughout the course of the study.  Anticipated study-drug related adverse drug 
reactions that may be experienced are described in section 6.1.1 above.  The severity of the 
event, as well as clinical judgment, will be utilized to determine appropriate management of 
the patient for any AE experienced while participating in this study. 
 
Any medication, including those administered for therapy of symptoms considered 
associated with study drug administration, should be reported on the appropriate concomitant 
medication page of the patient’s eCRF.  The symptoms should be reported on the AE page. 
 
NOTE: When choosing medications to manage toxicities per the instructions below (Sections 
6.2 & 6.3), please refer to sections 5.2.1 – 5.2.7 for a list of prohibited and discouraged 
concomitant medication/therapies. 
 
No dose re-escalation will be allowed.  
 
No dose reduction below 15 mg every other day is permitted for ponatinib. If the patient 
cannot tolerate a minimum dose of 15 mg every other day of ponatinib, despite any allowed 
interruptions, the patient must be discontinued from study treatment.  Doses may be 
interrupted for study-drug related toxicities for up to 28 days. If a nonhematologic study-drug 
related toxicity does not resolve to ≤ grade 1 or baseline after dose interruption for more than 
28 days, the patient must be discontinued from study treatment. If a hematologic study-drug 
related toxicity does not resolve to ≤ grade 1 or baseline after dose interruption for more than 
28 days, the study’s Overall PI, Dr. Eudocia Quant Lee, must be contacted. Additionally, the 
Overall PI must be contacted if any adverse event deemed unrelated to treatment requires 
dose interruption for more than 28 days. 
 
Cycle length will be 4 weeks (28 days), even if treatment is held for toxicity.  During dose 
interruptions, continue to observe the study schedule as planned. All study evaluations and 
treatments should continue as if study treatment is not being held. 
 
Following a dose delay which resumes mid cycle, day 1 procedures not associated with the 
adverse event do not need to be repeated.   
 


 
If study drug is held across a time point which requires collection of a research blood sample, 
please contact Dr. Eudocia Quant Lee to confirm whether or not the sample should be collected 
or if the drug hold will negate the value of collection of the sample in question.  If you anticipate 
the occurrence of such a scenario, please contact the DFCI Coordinating Center as soon as 
possible in order to establish a plan prior to the time point in question.  
 
Participants who experience an adverse event that requires a treatment delay or dose reduction 
should be monitored with appropriate laboratory testing or other clinical evaluation at least 
weekly until resolution. 
 
Participants whose treatment is interrupted or permanently discontinued due to an adverse 
event or clinically significant laboratory value, must be followed as outlined in Table 6.2, 
at least once a week for 4 weeks, and subsequently at 4-week intervals, until resolution 
or stabilization of the event, whichever comes first. All participants must be followed for 
adverse events and serious adverse events up to the 30-day post treatment evaluation 
(section 5.4). All SAEs must be reported as detailed in Table 11.3. 
 
When treatment must be held pending resolution of toxicity to grade 1 or return to baseline, 
and the toxicity is a lab abnormality, in cases where participant had a pre-existing laboratory 
abnormality at baseline, the toxicity can be considered “resolved” from a hold perspective 
when it has resolved to within 1 grade of the baseline value.  
 
NOTE: For the purposes of data entry, values from screening assessments should be 
entered in as ‘baseline’ values.   However, true “baseline values” - for the purpose of 
dose modifications on study, etc. - will be considered the last assessments/tests 
performed prior to initiation of study therapy. 
 
Exception: In instances where the value within 1 grade of the baseline value would still 
require a hold, continue to hold until resolution of toxicity to grade 1 or return to 
baseline. 
 
Interrupt ponatinib for at least 1 week prior to any major surgery.  Contact Dr. Lee to 
determine when participant may resume treatment ponatinib after his/her surgery. 


 
Table 6.2: Ponatinib Dose Modifications for Adverse Drug Reactions Attributed to Ponatinib 
Ponatinib dose modifications listed below are to be followed for adverse events considered at least 
possibly related to Ponatinib.  
NOTE: In the event of a grade 4 toxicity deemed unrelated to treatment, Investigator Team can hold 
drug in patient’s best interest after discussion with and approval from the study’s Overall PI, Dr. 
Eudocia Quant Lee. 
SOC 
Toxicity 
Dose Modifications for Ponatinib 
Non-Hematologic Toxicity 
General (not otherwise specified 
General (not otherwise specified) 
General (not otherwise specified), 
Grade 1 or transient grade 2 
Maintain ponatinib at current dose 
General (not otherwise specified), 
Grade 2 lasting ≥7 days with optimal care 
First occurrence at any dose level: 
Hold ponatinib 
Resume at current dose level after recovery to ≤ grade 1 or return to 
baseline 
 
Recurrence* at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Recurrence at 15 mg every other day: 
Discontinue ponatinib 
General (not otherwise specified), 
Grade 3 or 4 
Occurrence** at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Occurrence at 15 mg every other day:  
Discontinue ponatinib 
Cardiac Disorders 
Myocardial Infarction 
Serious Myocardial Infarction (Any Grade) 
Discontinue ponatinib 
Urgent Revascularization (Cardiac Disorders, Other) 
Cardiac Disorders, Other: Specify: Urgent 
Revascularization (Any Grade) 
Discontinue ponatinib 
LV systolic dysfunction/Heart Failure (CHF)  


 
SOC 
Toxicity 
Dose Modifications for Ponatinib 
Grade 2  
LV systolic dysfunction: N/A 
 
Heart failure: Symptoms with mild to 
moderate activity or exertion 
First occurrence at any dose level: 
Hold ponatinib 
Resume at current dose level after recovery to ≤ grade 1 or return to 
baseline 
 
Recurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Recurrence at 15 mg every other day: 
Discontinue ponatinib 
Grade 3 
LV systolic dysfunction: Symptomatic due 
to drop in ejection fraction responsive to 
intervention 
 
Heart failure: Severe with symptoms at rest 
or with minimal activity or 
exertion; intervention indicated 
Occurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Occurrence at 15 mg every other day:  
Discontinue ponatinib 
Cardiac Disorders 
Grade 4 
LV systolic dysfunction: Refractory or 
poorly controlled heart failure due to drop 
in ejection fraction; intervention 
such as ventricular assist device, 
intravenous vasopressor support, or heart 
transplant indicated 
 
Heart failure: Life-threatening 
consequences; urgent intervention 
indicated (e.g., continuous IV therapy or 
mechanical hemodynamic support) 
Hold ponatinib 
Consult Overall PI (Dr. Lee) about how to proceed with treatment 


 
SOC 
Toxicity 
Dose Modifications for Ponatinib 
GI Disorders /  Investigations 
Pancreatitis and Elevation of Lipase 
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 × ULN) or asymptomatic 
radiologic pancreatitis (grade 2 pancreatitis) 
Occurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib  
Resume after recovery to ≤ grade 1 (≤ 1.5 x ULN) or return to 
baseline; reduce dose by one dose-level  
 
Occurrence at 15 mg every other day: 
Discontinue ponatinib  
Symptomatic grade 3 pancreatitis [severe 
pain, vomiting, medical intervention 
indicated (eg, analgesia, nutritional 
support)] 
Occurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib  
Resume after complete resolution of symptoms and after recovery of 
lipase elevation to ≤ grade 1 or return to baseline; reduce dose by one 
dose-level 
 
Occurrence at 15 mg every other day: 
Discontinue ponatinib 
Grade 4 pancreatitis (life-threatening 
consequences; urgent intervention 
indicated) 
Discontinue ponatinib 


 
SOC 
Toxicity 
Dose Modifications for Ponatinib 
Investigations 
Serum Amalyse Increased 
Serum amylase increased, Grade 1 or 2 
Continue ponatinib without dose reduction, and monitor closely with 
serial enzyme level determinations 
Serum amylase increased, Grade 3 or 4 
First occurrence at any dose level: 
Hold ponatinib 
Resume at current dose level after recovery to ≤ grade 1 or return to 
baseline 
 
Recurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Recurrence at 15 mg every other day: 
Discontinue ponatinib 
Hepatic Toxicity  
Elevation of liver transaminase >3 × ULN 
(grade 2 or higher) 
Occurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib and monitor hepatic function 
Resume after recovery to ≤ grade 1 (≤3 × ULN) or return to baseline; 
reduce dose by one dose-level 
 
Occurrence at 15 mg every other day: 
Discontinue ponatinib 
Elevation of AST or ALT ≥3 × ULN 
concurrent with an elevation of bilirubin >2 
× ULN and alkaline phosphatase >2 × ULN 
Discontinue ponatinib 
General disorders and 
Edema (limbs, trunk, face, localized)  
Edema, Grade 1 
Maintain ponatinib at current dose 
Edema, Grade 2 lasting ≥7 days with 
optimal care 
First occurrence at any dose level: 
Hold ponatinib 
Resume at current dose level after recovery to ≤ grade 1 or return to 
baseline 
 
Recurrence* at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Recurrence at 15 mg every other day: 
Discontinue ponatinib 


 
SOC 
Toxicity 
Dose Modifications for Ponatinib 
Edema, Grade 3 
First occurrence at any dose level: 
Hold ponatinib 
Resume at current dose level after recovery to ≤ grade 1 or return to 
baseline 
 
Recurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Recurrence at 15 mg every other day: 
Discontinue ponatinib 
 
 


 
Metabolis
m and 
Hyperglycemia 
Hyperglycemia, All Grades 
Maintain ponatinib at current dose 
The American Diabetes Association guidelines should be followed 
 
Nervous System Disorders 
Peripheral Neuropathy (motor or sensory) 
Peripheral Neuropathy (motor or sensory), 
Grade 1 or 2 
Maintain ponatinib at current dose 
Peripheral Neuropathy (motor or sensory), 
Grade 3 or 4 
Occurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib  
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Occurrence at 15 mg every other day: 
Discontinue ponatinib  
Stroke  
Serious Stroke (Any Grade) 
Discontinue ponatinib 


 
Skin and subcutaneous 
tissue disorders
Skin rash (Any type of rash) 
Skin rash, Grade 1 or 2 or tolerable Grade 3 
Maintain ponatinib at current dose. 
Consider initiating therapy (e.g. antihistamine, steroid, emmolient) as 
per section 6.3.12. 
Skin rash, Grade 4 or Intolerable Grade 3 
despite optimal symptomatic therapy 
Occurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib  
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Occurrence at 15 mg every other day: 
Discontinue ponatinib 
Vascular Disorders 
Hypertension 
Hypertension, Grade 1 
Maintain ponatinib at current dose 
Hypertension, Grade 2 or 3 
See Section 6.3.5 for HTN management. 
If unable to control hypertension (<150/100 mmHg) within 28 days, 
discontinue ponatinib 
Hypertension, Grade 4 
Discontinue ponatinib 
 
 


 
Vascular Disorders 
Thromboembolic Event  
Thromboembolic Event, Grade 1 or 2 
Maintain ponatinib at current dose 
Thromboembolic Event, Grade 3 
Thromboembolic Event, Asymptomatic 
Grade 4 
1st event and not with a post inferior vena cava filter and not on 
fully therapeutic anticoagulation therapy: Hold ponatinib. 
Treatment may resume at pre-hold dose as soon as the patient is 
considered clinically stable and is on full dose anticoagulation therapy 
and has not had a Grade 3 or 4 hemorrhagic event since initiating 
anticoagulation therapy. For anticoagulation therapy, the patient may 
only receive low molecular weight heparin or a Factor Xa inhibitor; 
Warfarin is not permitted. As an alternative to anticoagulation 
therapy, the patient may resume treatment as soon as clinically stable 
and is status post inferior vena cava filter placement; however 
anticoagulation therapy is preferred over IVC filter placement. (Since 
patients must be on anticoagulation therapy or have an IVC filter in 
order to resume, no second event shall occur). 
Event with a post inferior vena cava filter and not on fully 
therapeutic anticoagulation therapy: Hold ponatinib. Treatment 
may resume at pre-hold dose as soon as the patient is considered 
clinically stable and is on full dose anticoagulation therapy and has 
not had a Grade 3 or 4 hemorrhagic event since initiating 
anticoagulation therapy. For anticoagulation therapy, the patient may 
only receive low molecular weight heparin or a Factor Xa inhibitor; 
Warfarin is not permitted. 
Event while on therapeutic anticoagulation therapy: Discontinue 
ponatinib. 
Thromboembolic Event, Symptomatic  
Grade 4 
Discontinue ponatinib 
Arterial Thromboembolic Event, Any 
Grade 
(New onset, worsening, or unstable angina, 
myocardial infarction, transient ischemic 
attack, cerebrovascular accident, and any 
other arterial thromboembolic event) 
Discontinue ponatinib 
Multiple System Organ 
Classes 
Hemorrhage of any kind 
Non-CNS event, Grade 1  
Maintain ponatinib at current dose  
Non-CNS hemorrhage, Grade > 1  
Discontinue ponatinib 
New CNS hemorrhage, Grade ≥ 1  
Discontinue ponatinib 


 
Hematologic Toxicity 
Investigations 
Drug-Related ANC/platelets 
Grade 1 or 2 
Neutrophil count decreased 
o 
<LLN - 1000/mm3;  
o 
<LLN - 1.0 x 10e9 /L 
Platelet count decreased 
o 
<LLN - 50,000/mm3;  
o 
<LLN - 50.0 x 10e9 /L 
Maintain ponatinib at current dose 
Grade 3 or 4 
Neutrophil count decreased 
o 
< 1000/mm3; 
o 
< 1.0 x 10e9 /L  
Platelet count decreased 
o 
< 50,000/mm3; 
o 
< 50.0 x 10e9 /L  
First occurrence at any dose level: 
Hold ponatinib 
Resume at current dose level after recovery to ≤ grade 1 or return to 
baseline 
 
Recurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Recurrence at 15 mg every other day: 
Discontinue ponatinib 
General (not otherwise specified) 
General (not otherwise specified) 
General (not otherwise specified), 
Grade 1 or transient grade 2 
Maintain ponatinib at current dose 
General (not otherwise specified), 
Grade 2 lasting ≥7 days with optimal care 
First occurrence at any dose level: 
Hold ponatinib 
Resume at current dose level after recovery to ≤ grade 1 or return to 
baseline 
 
Recurrence at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Recurrence at 15 mg every other day: 
Discontinue ponatinib 
General (not otherwise specified), 
Grade 3 or 4 
Occurrence** at 45 mg, 30 mg, or 15 mg daily: 
Hold ponatinib 
Resume after recovery to ≤ grade 1 or return to baseline; reduce dose 
by one dose-level 
 
Occurrence at 15 mg every other day:  
Discontinue ponatinib 
 
* “Recurrence” means the second time an AE is encountered by a patient at a given dose level.  
** “Occurrence” means the first time an AE is encountered by a patient at a given dose level.   


 
Definitions:  ANC = absolute neutrophil count; CHF = congestive heart failure; CT = computed tomography; LV = left 
ventricular. 
 
 
 


 
6.3 
Toxicity Management 
 
Criteria for disrupting treatment, dose modification, or discontinuation are found in Section 
6.2 above, including Table 6.2. This section provides additional guidance for management of 
selected AEs for ponatinib. 
1.1.44 Vascular Occlusion 
Serious arterial and venous thrombotic and occlusive adverse events, 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 ponatinib-treated patients.  Patients with and without 
cardiovascular risk factors, including patients age 50 years or younger, 
experienced these events.  Vascular occlusive adverse events were more frequent 
with increasing age and in patients with prior history of ischemia, hypertension, 
diabetes, or hyperlipidemia. 
1.1.44.1 Arterial Occlusion and Thrombosis 
Serious arterial thrombotic adverse events occurred in ponatinib-treated patients 
with some patients experiencing events of more than one type.  Serious 
cardiovascular thrombotic adverse events included myocardial infarction and 
coronary artery disease.  Some patients developed congestive heart failure 
concurrent or subsequent to the myocardial ischemic event. 
Serious cerebrovascular adverse events were also reported in ponatinib-treated 
patients.  There were patients who developed stenosis of large arterial vessels of 
the brain (eg, carotid, vertebral, middle cerebral artery).   
Serious peripheral arterial adverse events were reported in ponatinib-treated 
patients; some patients developed digital or distal extremity necrosis with 
complications of diabetes mellitus and peripheral arterial disease that required 
amputations.   
Monitor and aggressively treat factors that increase cardiovascular risk, such as 
hypertension, cigarette smoking, hypercholesterolemia, and hyperglycemia.  
Interrupt and consider discontinuation of study drug in patients who develop 
arterial thrombotic adverse events.  Any patient who experiences a serious 
adverse event of myocardial infarction, stroke, or urgent revascularization while 
on trial must be discontinued from the trial unless, for that individual patient, the 
investigator believes the potential benefits of ponatinib treatment are likely to 
exceed the risks of continued treatment and the patient has no other treatment 
options.   
1.1.44.2 Venous Thromboembolism 
Serious venous thromboembolic adverse events occurred in ponatinib-treated 
patients, including deep venous thrombosis, pulmonary embolism, superficial 
thrombophlebitis, and retinal vein thrombosis.  Consider dose modification or 
discontinuation of ponatinib in patients who develop serious venous 
thromboembolic adverse events.   


 
Ponatinib should not be restarted in patients with serious venous occlusive 
adverse events unless the potential benefit outweighs the risk of recurrent venous 
occlusions and the patient has no other treatment options.   
1.1.45 Neuropathy 
Serious peripheral and cranial neuropathic adverse events have occurred in 
ponatinib-treated patients.  In clinical trials, serious peripheral neuropathic 
adverse events reported included the following: peripheral neuropathy, 
paresthesia, hypoesthesia, and hyperesthesia.  Of the patients who developed 
neuropathy, many developed neuropathy during the first month of treatment.  
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 neuropathy is 
suspected. 
1.1.46 Hepatotoxicity 
Hepatotoxicity, most commonly manifested by reversible transaminase and 
alkaline phosphatase elevation and hyperbilirubinemia, has been observed with 
ponatinib.  Monitoring of hepatic function is recommended and management of 
laboratory abnormalities should be managed with dose interruption and/or dose 
reduction according to Table 6.2. 
1.1.47 Congestive Heart Failure and Left Ventricular Dysfunction 
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. 
In patients who develop severe CHF (grade 4 left ventricular dysfunction), 
ponatinib should be held and the overall PI (Dr. Lee) should be consulted to 
determine how/if to proceed with treatment.  
 
1.1.48 Hypertension 
Blood pressure should be monitored at each visit.  Hypertension (HTN) by at least 
2 blood pressure measurements should be graded according to CTCAE version 
4.0, which defines HTN as a disorder characterized by a pathological increase in 
blood pressure; a repeated elevation in the blood pressure exceeding 140 mm Hg 
for systolic over 90 mm Hg for diastolic.  For patients who develop HTN or 
worsening HTN during study treatment, aggressive 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 and reduction is 
recommended according to Dose Modification Guidelines in Table 6.2. 


 
1.1.49 Ocular Toxicity 
Serious ocular adverse event toxicities leading to blindness or blurred vision have 
occurred in ponatinib-treated patients.  Retinal toxicities including macular 
edema, retinal vein occlusion, and retinal hemorrhage have also occurred in 
ponatinib-treated patients.  Other ocular toxicities include cataracts, glaucoma, 
iritis, iridocyclitis, and ulcerative keratitis.  Conduct comprehensive eye exams at 
baseline and when clinically indicated.  See the ‘Non-Heme: General (not 
otherwise specified)’ category of Table 6.2 for dose modification details. 
1.1.50 Pancreatitis and Lipase or Amylase 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.  The events are generally 
uncomplicated and reversible and can be managed with a brief interruption of 
treatment and standard medical therapies.  Almost all patients are able to continue 
on 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.  See Table 6.2 for details. 
1.1.51 Hemorrhage 
Hemorrhagic events have occurred in patients receiving ponatinib.  Most 
hemorrhagic events occurred in patients with grade 4 thrombocytopenia.  
Maintain or discontinue ponatinib as outlined in Table 6.2. 
1.1.52 Fluid Retention and Edema 
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 as outlined in Table 6.2. 
1.1.53 Cardiac Arrhythmias 
Supraventricular tachyarrhythmias were reported in patients treated with 
ponatinib.  Advise patients to report signs and symptoms of rapid heart rate 
(palpitations, dizziness).  Symptomatic bradyarrhythmias have also been reported.  
Advise patients to report signs and symptoms suggestive of slow heart rate 
(fainting, dizziness, or chest pain, see Table 6.2). 
 
 


 
1.1.54 Myelosuppression 
Neutropenia, anemia, and thrombocytopenia have been observed in clinical 
studies of ponatinib in patients with CML.  While myelosuppression can occur at 
any time during treatment, its onset in CML patients most commonly occurs 
within the first month on treatment. Myelosuppression can partially be attributed 
to the CML itself; however, treatment with ponatinib could also contribute.  These 
events can typically be managed with supportive care and, if felt to be treatment-
related, either a reduction or interruption of treatment with ponatinib should 
occur.  Rarely, one or more cytopenias can lead to permanent discontinuation of 
treatment.  The use of hematopoietic growth factors such as granulocyte colony-
stimulating factor, and granulocyte-macrophage colony-stimulating factor is 
permitted on study; these agents may be used to support blood counts as clinically 
indicated to minimize treatment interruptions or repeated dose reductions. 
The important clinical AE of febrile neutropenia falls under the broad category of 
myelosuppression.  If a patient’s individual risk factors place them at high risk of 
developing febrile neutropenia, primary prophylaxis use of colony-stimulating 
growth factors for the prevention or reduction of febrile neutropenia is 
recommended according to the published NCCN guidelines [NCCN Guidelines 
Version 1.2012 – Myeloid Growth Factors]. 
1.1.55 Rash and/or Pruritus 
Skin rashes have been commonly reported to be associated with 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 maculo-papular 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 a psoriasiform dermatitis.  Rarely, an erythema 
multiforme type of rash has been associated with ponatinib.   
Most patients can be maintained on the current dose of ponatinib, uninterrupted, 
and if necessary their symptoms can be managed with antihistamines, emollients, 
or topical steroids.  Follow the dose modification guidelines for ’Skin rash’ in 
Table 6.2. 
 
 


 
1.1.56 Diarrhea, Nausea, and Vomiting 
Diarrhea is a common side effect of ponatinib.  The use of anti-diarrhea 
medications is permitted.  Patients who experience ≥grade 2 diarrhea may begin 
loperamide at its standard treatment schedule (4 mg orally x 1, than 2 mg orally 
after each loose stool, up to a maximum of 16 mg/day). 
Nausea and vomiting are also reported as side effects of 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. 
1.1.57 Constitutional Symptoms/Joint Pain 
Certain constitutional symptoms such as myalgia, arthralgia, headache, weakness, 
fatigue, asthenia, and low grade fever have been very 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. 
1.1.58 Compromised Wound Healing and Gastrointestinal Perforation 
Based on its mechanism of action, ponatinib may compromise wound healing.  
Interrupt ponatinib for at least 1 week prior to major surgery.  Contact Dr. Lee to 
determine when participant may resume treatment ponatinib after his/her surgery. 
1.1.59 Prolonged QTcF 
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 the patient is on 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 study medication, dose interruption and reduction guidelines 
for general non-hematologic toxicities in Table 6.2 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 treatment, or more frequently as clinically indicated. 
 
 


 
7. DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
Ponatinib 
1.1.60 Description 
 
The drug substance ponatinib (laboratory code AP24534) HCl is the mono-
hydrochloride salt of the active moiety ponatinib free base. 
 
Chemical International Union of Pure and Applied Chemistry (IUPAC) name: 
3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-
yl)methyl]-3-(trifluoromethyl)phenyl} benzamide, hydrochloride salt 
 
Chemical Abstracts Service (CAS) Index name: Benzamide,3-(2-imidazo[1,2-
b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-
(trifluoromethyl)phenyl]-, hydrochloride (1:1) 
 
International Non-Proprietary Name (INN): ponatinib 
 
CAS Registry number: 1114544-31-8 (HCl salt), 943319-70-8 (free base) 
 
Ponatinib HCl is an off-white to yellow crystalline, anhydrous solid. The 
molecular formula of ponatinib HCl is C29H28ClF3N6O, and the molecular 
weight is 569.02. A single crystal form of ponatinib HCl has been identified by X-
ray powder diffraction. The melting point by differential scanning calorimetry 
(DSC) is in the range of 250°C to 265°C. Ponatinib HCl has a thermodynamic 
solubility in hydrochloric acid-potassium chloride of 2.64 mg/mL at pH 1.7. The 
free base ponatinib has a solubility in hydrochloric acid-potassium chloride at pH 
1.7 of 2.64 mg/mL, and has an aqueous solubility of less than 0.0001 mg/mL at 
pH 7.5; it can exist in polymorphic forms. Ponatinib free base has been observed 
in amorphous and 4 crystalline forms. Ponatinib has no chiral centers. 
 
1.1.61 Form 
 
Ponatinib for investigational use is supplied as off-white opaque capsules 
containing nominally 5 mg of ponatinib, or as 15 mg and 45 mg round, white, 
film-coated tablets. On this trial, ponatinib will be provided as 15 mg tablets in 
90-count bottles.  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, and 
magnesium stearate; tablet film coating is comprised of polyethylene glycol, talc, 
polyvinyl alcohol, and titanium dioxide.  
 


 
All excipients used in the manufacture of ponatinib tablets and capsules are of 
compendial grade. Lactose anhydrous, lactose monohydrate, and gelatin comply 
with applicable regulatory guidelines regarding materials of animal origin. No 
other excipients of human or animal origin are used in the formulation of 
ponatinib tablets or capsules. 
 
1.1.62 Storage and Handling 
 
Ponatinib drug product is recommended for storage below 30°C.  
 
1.1.63 Availability 
 
Ponatinib is an investigational agent and will be supplied free-of-charge from 
Ariad Pharmaceuticals. 
 
1.1.64 Ordering 
 
The initial shipment of ponatinib will be ordered by ARIAD upon receipt of 
IRB approval and other required documentation.  Ponatinib re-supplies will be 
ordered from each institution’s individual pharmacy (or designee) using an 
ARIAD Investigational Product Re-Supply Request Form.  This form will be 
supplied to each institution’s pharmacy by the coordinating center once the 
study meets the requirements for activation.  The number of requested bottles 
and the shipping address to where the drug should be sent are detailed on the 
Re-Supply Request Form. All sites should anticipate 3-5 business days to 
receive drug after the order is placed. 
 
1.1.65 Accountability 
 
The investigator, or a responsible party designated by the investigator, should 
maintain a careful record of the inventory and disposition of the agent using the 
NCI Drug Accountability Record Form (DARF) or another comparable drug 
accountability form. (See the NCI Investigator’s Handbook for Procedures for 
Drug Accountability and Storage.) 
 
Ponatinib dispensing record/inventory logs and copies of signed packing lists 
should be maintained at the investigational site. Batch numbers for ponatinib 
should be recorded in the drug accountability records. 
 
1.1.66 Destruction and Return 
 
Participating sites will follow their institutional policy regarding destruction of 
returned empty and partially used investigational drug.  
 
8. CORRELATIVE/SPECIAL STUDIES  
8.1 
Plasma Biomarkers 
 


 
NOTE:  Given the large number of samples to be processed, please notify Anna 
Khachatryan and Julia Kahn (annak@steele.mgh.harvard.edu; 
julia@steele.mgh.harvard.edu) two days prior to each blood sample collection. 
 
NOTE:  Each site is responsible for providing tubes. 
 
NOTE:  The submitting institution is responsible for the costs of shipping and handling. 
 
NOTE:  For all submissions, please notify the Dana Farber NeuroOncology Coordinating 
Center Team by e-mail at NeuroOnc_Coor@dfci.harvard.edu regarding shipment 
(date mailed, mail carrier, tracking number, participant case numbers). 
 
Blood samples will be obtained for protein analysis of potential biomarkers for anti-
angiogenic therapy and for cell collection at the following time points: 
 
Blood Collection Timepoints: 
• Cycle 1, Day 1: prior to the first ponatinib dose 
• Cycle 1, Day 2: 24 hours (+/- 4 hrs) following the first ponatinib dose but prior 
to the second ponatinib dose 
• Subsequent Cycles, Day 1 pre-ponatinib (+/- 3 days) 
• Off Treatment  
1.1.67 Sample Collecting and Processing 
 
At the time points specified above, TWO blood samples (~8 ml each) will be 
collected using either SARSTEDT Monovette® EDTA KE (9 ml), Part # 
02.1333.001 or Becton-Dickinson VacutainerTM K2E (10 ml), Part # 367525 or 
Greiner Bio-One Vacuette® K3E EDTA K3 (9 ml), Part 455036. Tubes must be 
processed within 2 hours after collection*. Each site is responsible for providing 
tubes. 
 
Sample processing: 
 
Collect 2 tubes of ~8 ml each of blood. The tubes must be pre-cooled in an 
ice bath. 
 
Gently invert five to six times to ensure adequate mixing and prevent 
coagulation. 
 
Cool the tubes immediately in an ice bath. 
 
Place tubes on wet ice and send to Steele Laboratory (see Section 8.2.3) 
 
Call courier for pick-up and delivery of specimen  
 
*   Should a sample be drawn without sufficient time to be processed at the Steele Lab 
within 2 hours of collection, (e.g. in the event patient is drawn at 4 pm), please 
refer to processing instructions provided in Appendix E.  This alternative should 
be avoided whenever possible. 
 
 


 
1.1.68 Sample Labeling 
 
Each site is responsible for providing tubes and labels. The vial is to be labeled with 
the following information: 
Patient study number 
Patient Initials 
Military time sample was obtained 
Date sample was obtained 
Cycle #/Day# of sample 
 
If a paper labels are used, protective tape, such as Scienceware* Protective Lab 
Labeling Tape > 1-1/2 in. x 108 ft.; (Fisher catalog # 11-867B; Bel-Art 
No.:134530015), should cover the label in its entirety to prevent the label from 
degrading. Otherwise, indelible marker is to be used directly on the tube. 
1.1.69 Shipment and Packaging of the Samples 
 
Each site is responsible for providing shipping of the samples. The tubes should 
remain on wet ice and delivered to the Steele Laboratory using a courier. 
Dan G. Duda, DMD, PhD 
Attn: Anna Khachatryan and Julia Kahn 
Steele Laboratory 
Massachusetts General Hospital, Cox-734 
100 Blossom Street 
Boston, MA 02114 
Phone (617) 724-1352 
Partners pager 14082 
Email: annak@steele.mgh.harvard.edu; julia@steele.mgh.harvard.edu  
1.1.70 Plasma Sample Analysis 
 
Analyses will be performed in the laboratory of Rakesh K. Jain, PhD, and Dan G. 
Duda, DMD, PhD, in the Department of Radiation Oncology at Massachusetts 
General Hospital per established protocols (Batchelor, Sorensen et al. 2007). 
8.2 Tissue Submissions  
 
NOTE:  The submitting institution is responsible for the costs of shipping and handling. 
 
NOTE:  For all submissions, please notify the Dana Farber NeuroOncology 
Coordinating Center Team by e-mail at NeuroOnc_Coor@dfci.harvard.edu 
regarding shipment (date mailed, mail carrier, tracking number, participant case 
numbers). 
1.1.71 Pathology Review (mandatory for all patients) 
 
a. 
Following registration, slides from the prior surgery/biopsy  revealing 
glioblastoma or variants must be submitted for review. The purpose of this 
review is to verify the histologic diagnosis. 


 
 
The materials are to be submitted within approximately 60 days of 
registration to: 
Keith L. Ligon, M.D., Ph.D.  
c/o Sarah Gaffey 
 
b. 
Pathology Materials Required for Review: 
 
1. 
One to two representative H&E stained slides from a pre-registration 
biopsy or resection demonstrating lesion (ideally from patient’s most 
recent surgery/biopsy) 
o or additional unstained 5 μm slide(s) for staining 
 
2. 
A copy of the corresponding pathology report and operative report. 
 
3. 
A printout of The Central Path Review Study eCRF 
 


 
1.1.72 Archival Tissue for Tissue Biomarker Analysis 
 
Paraffin slides will be used for DNA isolation and immunohistochemistry to evaluate 
molecular pathways such as the VEGFR, FGFR, and PDGFR pathways. We will attempt 
to correlate tumor genotype and vascularity with response to treatment.  
 
At the completion of the study, any unused/remaining material will be stored for future 
research according to the patient consent permission. Potential future research may include 
immunohistochemistry (IHC) analyses, DNA extraction, and/or tissue microarray (TMA) 
construction to analyze predictive biomarkers, changes in expression pattern with therapy, 
and correlation with response and/or adverse events.   
 
The following will be submitted to the Steele Laboratory for tissue biomarker analysis: 
• 
15 (5 μm thick) unstained formalin fixed paraffin embedded (FFPE) sections 
from archival surgery/biopsy 
 
The materials are to be submitted within approximately 60 days of registration to: 
Dan G. Duda, DMD, PhD  
Attn: Anna Khachatryan and Julia Kahn 
Steele Laboratory 
Massachusetts General Hospital, Cox-734 
100 Blossom Street 
Boston, MA 02114 
Phone (617) 724-1352 
Partners pager 14082 
Email: annak@steele.mgh.harvard.edu; julia@steele.mgh.harvard.edu  
 
Pathology Materials Required for Review: 
 
1. 
Slides as specified above 
 
2. 
A copy of the applicable pathology reports and operative reports 
 
3. 
A printout of The Tissue Biomarker Study eCRF 
 


 
9.  STUDY CALENDAR 
Baseline evaluations (including MRI/CT scan) are to be conducted within 14 days prior to 
registration, unless otherwise noted. In the event that the participant's condition is deteriorating, 
laboratory evaluations should be repeated within 72 hours prior to initiation of the next cycle of 
therapy. 
All study labs and assessments: 
• Must be resulted prior administration of any study medication on Day 1 of each Cycle, unless 
otherwise specified (e.g., plasma biomarkers).  
• And can be performed within 3 days prior to Day 1 of each Cycle, including Cycle 1  
 
 
Pre-
Studya 
Cycle 1, 
Day 1b 
Subsequent 
Cycles, Day 1b,c 
Off 
Treatment 
30 Days 
After Study 
Drug Visitd 
Long-Term 
Follow Upe 
Ponatinib 
 
Xm ------------------------------------X 
 
 
Informed consentq 
X 
 
 
 
 
 
Documentation of tumor diagnosis 
X 
 
 
 
 
 
History and Height 
X 
 
 
 
 
 
Concurrent Medicationsr 
X 
X--------------------------------------X 
X 
 
Physical exam (weight, vital signs 
including blood pressure)n 
X 
X 
X 
X 
 
 
KPS 
X 
X 
X 
X 
X 
 
Neurologic Exam 
X 
X 
X 
X 
 
 
Comprehensive Eye Exams 
X 
If clinically 
indicated 
If clinically 
indicated 
If clinically 
indicated 
If clinically 
indicated 
 
EKGf 
X 
X 
Xf 
 
 
 
CBC w/differential 
X 
X 
X 
X 
 
 
Serum Chemistryg (2- hours 
Fasting) 
X 
X 
X 
X 
 
 
Serum Beta-HCGh 
X 
X 
X 
 
 
 
Lipid Panel and HgbA1c 
Xo 
 
 
 
 
 
MUGA or ECHO 
Xt 
 
 
 
 
 
Adverse Eventsi 
 
X--------------------------------------X 
X 
 
Submission of Tissue 
 
Xp 
 
 
 
 
Tumor measurementj,k 
Xj 
 
Prior to every 
even-numbered 
cyclej, 
Xk 
 
 
Plasma Biomarkersl 
 
X 
X 
X 
 
 
Survival, post-study-therapies, 
future relapses 
 
 
 
 
X 
X 
 
a. 
Screening labs and assessments may be used for C1D1, provided they are taken within 3 days prior to day 1 of study drug. 
b. 
All Day 1 evaluations must be performed within 3 days of Day 1. 
c. 
A window of +/- 2 day is permitted for Day 1 starts for Cycle 2 and beyond. 
d. 
30-day off-study evaluation is to be performed at 30 days (+/- 5 days) after last dose of study drug; these may be performed by 
documented clinician telephone call, if a physical visit is not feasible. 


 
e. 
Participants will be followed every 3 months (+/- 1 month) for survival, post-study-therapy therapies and future relapses until 
patient either passes away or is lost to follow-up. 
f. 
EKG at screening and prior to every odd cycle. 
• NOTE: For participants who develop prolonged QTcF as described in section 6.3.16, participants should be monitored with 
weekly EKG x 4 weeks, then monthly EKG x 6 months, then EKG every 3 months for remainder of the study treatment, or 
more frequently as clinically indicated. 
g. 
Chemistry: Creatinine or creatinine clearance, total bilirubin (if total bilirubin is greater than the upper limit of normal, direct 
and indirect bilirubin should be performed), SGOT [AST], SGPT [ALT], LDH, alkaline phosphatase, albumin, total protein, 
BUN, calcium, fasting plasma glucose (2 hours fasting), phosphorus, potassium, sodium, bicarbonate, chloride, magnesium. 
GGT, amylase, and lipase. 
h. 
Serum pregnancy test (women of childbearing potential) must be performed at screening and again within 72 hours before the 
start of investigational product. When possible, these tests can be one-in-the-same (if screening pregnancy test was performed 
within 72 hours of first ponatinib dose, no need to repeat); otherwise, pregnancy test must be repeated within 72 hours prior to 
first ponatinib dose. 
i. 
Adverse events will be collected from the time of the first dose of study treatment until the 30-day post-dose evaluation. 
Participants continuing to experience toxicity at the 30-day post-dose evaluation may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible. 
j. 
Brain MRI (standard contrast enhanced MRI of the head) will be performed at baseline, prior to Cycle 2, and then prior to 
every even-numbered cycles (approximately every 8 weeks) thereafter. Perfusion and diffusion MRI should be performed at 
baseline and prior to Cycle 2. The baseline scan must be performed within 14 days prior to registration. Each scan should be 
performed on a steroid dose that has been stable or decreasing for at least 5 days. If the steroid dose is increased within 5 days 
from the date of scheduled imaging or if it is increased between the date of imaging and initiation of study treatment, a new 
baseline MRI/CT is required. The same type of scan (i.e., MRI or CT) must be used throughout the period of protocol 
treatment for tumor measurement. A patient who develops a contraindication to undergo an MRI scan during study treatment 
may remain on study and undergo contrast enhanced CT scans. 
k. 
Off-Treatment MRI/CT is to be performed within 14 days of the last dose of study drug administration. 
l. 
Details regarding collection of plasma biomarkers are available in Section 8.1. These do not need to be resulted prior to study 
drug administration. 
m. 
Protocol treatment must begin within 5 consecutive days after registration. 
n. 
Vital signs: weight, heart rate, blood pressure, respiration rate, temperature, and oxygen saturation. Repeat BP if systolic > 140 
mm Hg or if diastolic >  over 90 mm Hg. 
o. 
Lipid panel to screen for possible hypercholesterolemia (to include HDL, LDL, triglycerides and VLDL) ; HgbA1c to screen for 
possible diabetes 
p. 
Submission of tissue is to occur within approx 60 days after registration (please see Section 8.2). 
q. 
Consent documents can be signed up to 30 days prior to registration.  If > 30 days has elapsed since patient signed the consent 
document, s/he must re-consent (new signature) before proceeding to register on study.  
r. 
All medications taken within 30 days of screening should be recorded.  If concomitant therapy must be added or changed, 
included over-the-counter medications or alternative therapies, the reason and name of the drug/therapy should be recorded.  
s. 
A comprehensive eye exam must be performed at screening.  Additional exams should be performed as clinically indicated.  The 
eye exam should test visual acuity, refraction, pupillary function, ocular motility, visual fields, and introcular pressure.  
t. 
MUGA or ECHO to be done within 30 days of registration in order to screen for possible cardiovascular issues. 
 
 
 
 


 
10. MEASUREMENT OF EFFECT  
10.1 
Antitumor Effect 
 
For the purposes of this study, patients should be reevaluated for response prior to even 
cycles (C2D1 and every 8 weeks thereafter). In addition to a baseline scan, confirmatory 
scans should also be obtained not less than 4 weeks after the initial documentation of 
objective response. 
 
Response and progression will be evaluated in this study using RANO response criteria 
(Section 10.1.4) (Wen, Macdonald et al. 2010). Efficacy evaluations will occur every 8 
weeks and will consist of imaging and clinical assessment.  
1.1.73 Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study 
treatment will be evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants who have 
measurable disease present at baseline, have received at least one dose of 
ponatinib, and have had their disease re-evaluated will be considered 
evaluable for response. These participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit 
objective disease progression or die prior to the end of cycle 1 will also be 
considered evaluable.) 
1.1.74 Disease Parameters 
 
Measurable disease. Measurable disease is defined as bidimensionally contrast-
enhancing lesions with clearly defined margins by CT or MRI scan, with two 
perpendicular diameters of at least 10 mm, visible on 2 or more axial slices which 
are preferably at most 5 mm apart with 0 mm skip. In the event the MRI is 
performed with thicker slices, the size of a measurable lesion at baseline should be 
two times the slice thickness. Measurement of tumor around a cyst or surgical 
cavity represents a particularly difficult challenge. In general such lesions should 
be considered non-measurable unless there is a nodular component measuring > 10 
mm in diameter. The cystic or surgical cavity should not be measured in 
determining response. 
 
Non-measurable disease. Non-measurable disease is defined as either 
unidimensionally measurable lesions, masses with margins not clearly defined, or 
lesions with maximal perpendicular diameters < 10 mm. 
 
Number of lesions. If there are multiple contrast-enhancing lesions, a minimum of 
the two largest lesions should be measured and the sum of the products of the 
perpendicular diameters of these lesions determined. However, given the 
heterogeneity of high-grade gliomas, and the difficulty in measuring some lesions, 
a maximum of 5 of the largest lesions may be measured. 


 
1.1.75 Methods for Evaluation of Measurable Disease 
 
Neurological Examination 
A neurological examination will be performed at baseline and before each 28-day 
course of therapy. The clinical examination will be conducted by a member of the 
neuro-oncology study team (neuro-oncologist or nurse practitioner). Evaluation 
will be based on changes in signs or symptoms compared to the prior examination 
and deemed unrelated to a post-ictal state or an unrelated event such as an infection 
or venous thrombosis. Relative changes will be graded as definitely better, possibly 
better, unchanged, possibly worse or definitely worse. 
 
Radiologic Assessment 
All patients will be followed with contrast-enhanced brain MRI (preferred) or 
contrast-enhanced head CT. All efficacy determinations will be based on RANO 
response criteria (Section 10.1.4) (Wen, Macdonald et al. 2010).  
 
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 14 days prior to registration. 
Thereafter, tumor measurements will be obtained prior to every even cycle 
(approximately every 8 weeks) days after the first dose as long as the patient 
remains on the study drug. 
1.1.76 Response Criteria  
 
Radiographic response should be determined in comparison to the tumor 
measurement obtained at pretreatment baseline for determination of response, and 
the smallest tumor measurement at either pretreatment baseline or following 
initiation of therapy for determination of progression. Table 10-1 outlines the 
criteria for radiographic changes following therapy. Table 10-2 contains a summary 
of RANO response criteria. In the event that the radiographic changes are equivocal 
and it is unclear whether the patient is stable or has developed progressive disease, 
it is permissible to continue treatment and observe the patient closely, for example 
at 4 weekly intervals. If subsequent imaging studies demonstrate that progression 
has occurred, the date of progression should be the scan at which this issue was first 
raised.  
 
All measurable and non-measurable lesions should be assessed using the same 
techniques as baseline. Ideally patients should be imaged on the same MRI, or least 
with the same magnet strength, for the duration of the study to reduce difficulties 
in interpreting changes. 


 
Table 10.1: Criteria for Response Assessment Incorporating MRI And Clinical Factors 
 
All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline.   
 
Complete Response: 
 
Requires all of the following: 
a) Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks.   
b) No new lesions. 
c) Stable or improved non-enhancing (T2/FLAIR) lesions.  
d) Patients must be off corticosteroids (or on physiologic replacement doses only).   
e) Stable or improved clinically. 
 
NOTES:  
• Patients with non-measurable disease only cannot have a complete response. The best 
response possible is stable disease. 
• In the absence of a scan confirming sustained response 4 weeks later, best response 
would be considered a Non-Sustained Complete Response  
Partial Response: 
 
Requires all of the following: 
a) Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 
weeks.  
b) No progression of non-measurable disease.   
c) No new lesions.  
d) Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
e) The corticosteroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan.  
f) Stable or improved clinically. 
 
NOTES:  
• Patients with non-measurable disease only cannot have a partial response. The best 
response possible is stable disease. 
• In the absence of a scan confirming sustained response 4 weeks later, best response 
would be considered a Non-Sustained Partial Response 
 
 


 
Stable Disease: 
 
Requires all of the following: 
a) Does not qualify for complete response, partial response, or progression.   
b) Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose was increased for 
new symptoms and signs without confirmation of disease progression on neuroimaging, 
and subsequent follow-up imaging shows that this increase in corticosteroids was 
required because of disease progression, the last scan considered to show stable disease 
will be the scan obtained when the corticosteroid dose was equivalent to the baseline 
dose.  
c) Stable clinically. 
NOTE: In the absence of a scan confirming stable disease 4 weeks later, best response would 
be considered Non-Sustained Stable Disease 
Progression:  
 
Defined by any of the following: 
a) Greater than > 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions compared to the smallest tumor measurement obtained either at 
baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids.* 
b) Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of 
corticosteroids compared to baseline scan or best response following initiation of 
therapy,* not due to co-morbid events (e.g. radiation therapy, demyelination, ischemic 
injury, infection, seizures, post-operative changes, or other treatment effects). 
c) Any new lesion. 
d) Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.) or changes in corticosteroid dose.  
e) Failure to return for evaluation due to death or deteriorating condition. 
f) Clear progression of non-measurable disease.  
 
*Stable doses of corticosteroids include patients not on corticosteroids 
 
 
Table 10.2: Summary of RANO Response Criteria 
 
 
CR 
PR 
SD 
PD# 
T1-Gd + 
None 
≥50% decrease 
<50% decrease- 
<25% increase 
≥25% increase* 
T2/FLAIR 
Stable or decrease 
Stable or decrease 
Stable or decrease 
Increase* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or decrease 
Stable or decrease 
NA 
Clinical Status 
Stable or increase 
Stable or increase 
Stable or increase 
Decrease* 
Requirement for Response  
All 
All 
All 
Any* 
CR=complete response;   PR=partial response;   SD=stable disease;   PD=progressive disease 
#:    Progression occurs when any of the criteria with * is present 
NA: Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration 
 


 
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. Complete and partial responses should be 
confirmed by two consecutive evaluations done at least four weeks apart. Stable 
disease will be accepted if it is measured at least two cycles (8 weeks) after the start 
of treatment and confirmed at least four weeks apart. 
1.1.77 Efficacy Assessments 
 
Progression free survival (PFS) will be defined from the time the patient enters 
the study until there is clinical or radiographic evidence of progressive disease 
(see definition of PD above). 
 
Overall survival (OS) will be defined from the time the patient enters the study to 
the date of death. Patients not known to have died will be censored for survival as 
of the last date known alive.   
 
PFS and overall survival will be estimated by using the Kaplan-Meier method. 
 
The proportion of patients alive and progression free at 3 months (PFS3) is 
defined as the number of patients alive and progression free at 3 months divided 
by the total number of patients enrolled.  
 
Radiographic response is defined as the proportion of patients with a best overall 
response of CR or PR divided by the total number of patients enrolled. 
 
 
10.2 Response Review 
Central review of MRI or CT scans is planned for participants who achieve CR, PR, or PFS3.   
 
Central review will be performed by Dr. Lee on registered participants who have been 
determined by the enrolling institution as having achieved PFS3, complete radiographic 
response, or partial radiographic response. When a participant’s films are requested, all films 
of all views from pre-registration and subsequent scans must be submitted for central review. 
Once the Central Review is complete, the central review results will be made available to 
the local PI. 
 
The submitting institution is responsible for the costs of shipping scans for central review. 
 
 


 
11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 
Adverse Event Characteristics and Definitions: 
1.1.78 Adverse Event (AE) Definition: 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not 
considered to be related to the study.  
Abnormal laboratory values or diagnostic test results constitute adverse events only 
if they induce clinical signs or symptoms or require treatment or further diagnostic 
tests.  
1.1.79 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. 
1.1.80 General Considerations: 
o Information on all adverse events, whether reported by the participant, directly 
observed, or detected by physical examination, laboratory test or other means, 
will be collected, recorded, followed and reported as described in the following 
sections.  
o The occurrence of adverse events should be sought by non-directive questioning 
of the participant at each visit during the study. Adverse events also may be 
detected when they are volunteered by the participant during or between visits or 
through physical examination, laboratory test, or other assessments. As far as 
possible, each adverse event should be evaluated to determine: 
 the severity grade (using CTCAE v. 4.0) 
 its attribution to the study drug 
 its duration (start and end dates or if continuing at final exam) 
 action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse event; 
concomitant 
medication 
taken; 
non-drug 
therapy 
given; 
hospitalization/prolonged hospitalization) 
 whether it constitutes a serious adverse event (SAE) 
o Adverse events experienced by participants will be collected and reported from 
initiation of study medication, throughout the study, and within 30 days of the 
last dose of study medication. Participants who experience an ongoing adverse 
event related to a study procedure and/or study medication beyond 30 days will 
continue to be contacted by a member of the study team until the event is resolved, 
stabilized, or determined to be irreversible by the participating investigator.  


 
o All adverse events should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or 
discontinuation, starting or stopping concomitant treatments, changes in the 
frequency or nature of assessments, hospitalization, or any other medically 
required intervention. Once an adverse event is detected, it should be followed 
until its resolution, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to 
the study drug, the interventions required to treat it, and the outcome. 
o Participants should be instructed to report any serious post-study-treatment 
event(s) that might reasonably be related to participation in this study. The 
investigator should notify the IRB and any other applicable regulatory agency of 
any unanticipated death or adverse event occurring after a participant has 
discontinued or terminated study participation that may reasonably be related to 
the study.  
1.1.81 For expedited reporting purposes only:   
o AEs for ponatinib should be reported only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information which is provided. 
o Other AEs for the protocol that do not require expedited reporting are outlined in 
the next section (Expedited Adverse Event Reporting) under the sub-heading of 
Protocol-Specific Expedited Adverse Event Reporting Exclusions. 
1.1.82 Expectedness of the AE: Adverse events can be 'Expected' or 'Unexpected.' 
o Expected adverse event 
“Expected” adverse events are those that have been previously identified as 
resulting from administration of the agent. For recording and reporting purposes 
on this trial, an adverse event is considered expected when it appears in the 
Ponatinib expected adverse events list Section 6.1.1 of the protocol.   
o Unexpected adverse event 
For recording and reporting purposes on this trial, an adverse event is 
considered “unexpected” when it varies in nature, intensity or frequency from 
information provided in the Ponatinib expected adverse events list Section 
6.1.1 of the protocol.   
1.1.83 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. 
 
 


 
1.1.84 Serious Adverse Event (SAE) Definition: 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
o Results in death 
o Is life-threatening. Life-threatening means that the person was at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a 
reaction which hypothetically might have caused death had it occurred in a 
more severe form. 
o Requires or prolongs inpatient hospitalization (i.e., the event required at least 
a 24-hour hospitalization or prolonged a hospitalization beyond the expected 
length of stay). Hospitalization admissions and/or surgical operations 
scheduled to occur during the study period, but planned prior to study entry 
are not considered SAEs if the illness or disease existed before the person was 
enrolled in the trial, provided that it did not deteriorate in an unexpected 
manner during the trial (e.g., surgery performed earlier than planned). 
o Results in persistent or significant disability/incapacity. Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life 
functions. 
o Is a congenital anomaly or birth defect; or 
o Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
All serious adverse events, whether “reportable” as defined in this protocol or not, 
must be reported to ARIAD. 
1.1.84.1 Protocol-Specific Expedited Adverse Event Reporting Exclusions:  
Events not considered to be serious adverse events are: 
 Hospitalization for routine treatment or monitoring of the studied 
indication, not associated with any deterioration in condition, or for 
elective procedures 
 Hospitalization for elective or pre-planned treatment for a pre-existing 
condition that did not worsen 
 Emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
 Hospitalization for respite care not associated with an adverse event 
attributed to the study drug 
 Hospitalization for seizure, if felt related to patient’s underlying disease 
 Hospitalization for treatment of patient’s underlying disease (e.g. 
admission after patient is removed from active study treatment for 
craniotomy) 
 Lymphopenia (grades 2-4) 


 
1.1.85 Adverse Events of Special Interest (AESIs) Definition: 
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 ARIAD.   
 
ARIAD has determined that the events listed below (whether considered serious 
or non-serious by investigators) should be considered AESIs: 
A. 
Myocardial infarction: The Third Universal Definition of Myocardial 
Infarction (Thygesen et al, 2012) is used to define MI  
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 
(Thygesen et al, 2012) 
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 
(Easton et al, 2009)   
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 
 
Any event of a vascular occlusive nature, either serious or non-serious, must be 
reported to ARIAD within 2 business days of the study sponsor’s awareness.  
 
ARIAD 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). 
 
11.2 
Procedures for AE and SAE Recording and Reporting 
 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 


 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-specific 
case report forms (eCRFs).  
11.3 
Expedited Adverse Event Reporting Requirements (By Site to Overall PI and ARIAD 
Pharmaceuticals)  
 
The study must be conducted in compliance with FDA regulations, local safety reporting 
requirements, and reporting requirements of the principal investigator.  
 
Each adverse event will be assessed to determine if it meets the criteria for reporting. 
Adverse event reporting is to occur according to the site’s specific IRB guidelines, and as 
outlined in this Section. Any serious adverse event occurring after the participant is 
registered in the study and until 30 days after the participant has stopped the study drug, 
participation must be reported.  Serious adverse events must be followed until resolution. 
 
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  
 
It is the responsibility of each participating investigator to report adverse events to the 
Overall PIARIAD Pharmaceuticals, DF/HCC IRB, and/or others as described below.  
The Overall PI or representative Coordinating Center personnel will ensure the report is 
forwarded to the proper parties, as appropriate (FDA, etc.). 
 
Adverse event reporting by each site is detailed in Table 11.3. Adverse event reporting 
by the DF/HCC Overall Principal Investigator (Dr. Eudocia Quant Lee) /or their 
designees follows in Sections 11.4 and 11.5.   
 
For trials where a DF/HCC investigator is serving as the Overall Principal Investigator, 
each participating institution must abide by the reporting requirements set by the 
DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 
with a possible, probable or definite attribution, and any grade 4 toxicities or grade 5 
(death) regardless of attribution. 
 
Whenever feasible, the participating investigator should provide follow-up information 
on the serious adverse event within the following 24-48 hours.  Follow-up information 
should describe whether the event has resolved or continues, if and how the event was 
treated, and whether the participant will continue or discontinue study participation. 
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  


 
Table 11.3: Reporting to the ARIAD Pharmaceuticals, Study’s Overall PI, and IRB: 
Adverse Event Characteristics 
Notification Requirement 
Serious- 
ness 
Toxicity 
Known 
correlation 
Attribu-
tion to 
study drug 
ARIAD Pharmaceuticals 
- 
Via Faxc  
Use Facsimile Coversheet c 
and Medwatch 3500A d 
E. Lee, MD: Overall PI - 
Via Email b 
Use Facsimile Coversheet c 
and Medwatch 3500A d 
DF/HCC IRB 
Serious 
Any 
Any 
(Expected or 
Unexpected) 
Any 
Within 24 hours from 
notification a 
Within 24 hours from 
notification a 
 
As needed if required per local IRB  
To be submitted within IRB 
established reporting timelines. 
Please ensure that Dr. Lee 
prospectively approves all 
submissions. 
Any 
Adverse Events of 
Special Interest 
(AESIs)e 
Vascular occlusive 
events, Any Grade 
Any 
(Expected or 
Unexpected) 
Any 
Within 2 working days  from 
notification a 
Within 2 working days  from 
notification a 
Non-
Serious 
Grade 4 (unless 
expressly noted in 
Section 11.1.7.1) 
Any 
(Expected or 
Unexpected) 
Any 
_ _ 
Within 5 working days  from 
notificationa 
Non-
Serious 
Grade 2 or 3; 
moderate or 
severe 
Unexpected 
Possible, 
probable, 
definite 
_ _ 
Within 7 working days  from 
notificationa 
a. 
In the event that the participating investigator does not become aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and document the time of his or her first awareness of the adverse event. 
b. 
Email the Medwatch 3500A form, facsimile coversheet, and the IRB SAE report to the DFCI Coordinating Site with the subject title as “Ponatinib SAE” to 
NeuroOnc_SAE@dfci.harvard.edu.  All SAE reports received at this account are forwarded immediately to study’s Overall PI, Dr. Eudocia Quant Leeand to the DFCI Coordinating 
Center personnel.  
c. 
Facsimile Coversheet is found in Appendix F.  Adverse Event Reporting Facsimile Coversheet contains all FAX numbers/e-mails and destinations.   
d. 
Medwatch 3500A downloadable form at  http://www.fda.gov/medwatch/getforms.htm  
e. 
See section 11.1.8 of the protocol for definition of Adverse Events of Special Interest (AESIs) 


 
11.4 
Reporting to the Food and Drug Administration (FDA) 
The IND has been exempt by the FDA; therefore, IND reporting requirements do not 
apply.  
11.5 
Reporting to Participating Institutions 
 
The Overall Principal Investigator (or her designee) will circulate to all participating 
Investigator Teams: 
• All reportable AEs occurring on this study protocol. A cover letter will indicate the 
protocol title, the IND#, and whether the FDA and/or DF/HCC IRB were informed. 
• And all IND safety reports received on study that have not occurred directly on this 
protocol, within 30 days of lead site notification. A letter will accompany the report 
indicating whether a consent form change or protocol change is required or other actions 
including a statement re: whether the report has been or will be submitted to DF/HCC 
IRB for review. 
11.6 
Reporting of Pregnancy 
Any pregnancy occurring during study participation (through long-term follow-up), 
regardless of whether or not a serious outcome occurred, will be reported to the study PI 
using the same procedures outlined in Table 11.3 within 7 days of learning of its occurrence.  
The pregnancy is to be followed up to determine outcome, including spontaneous or 
voluntary termination, details of birth, and the presence or absence of any birth defects, 
congenital abnormalities or maternal and newborn complications. 
11.7 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
 
 


 
11.8 
Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating investigator 
assesses them as stable, or the participating investigator determines the event to be 
irreversible, or the participant is lost to follow-up. The presence and resolution of AEs 
and SAEs (with dates) should be documented on the appropriate case report form and 
recorded in the participant’s medical record to facilitate source data verification.  
 
For some SAEs, the study sponsor, Overall PI, or designee may follow-up by telephone, 
fax, and/or monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.   
 
 


 
12. DATA AND SAFETY MONITORING 
12.1 
Data Reporting 
12.1.1 Method  
The QACT will collect, manage, and perform quality checks on the data for this 
study.  
12.1.2 Responsibility for Data Submission  
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data 
and/or data forms to the QACT according to the schedule set by the QACT.  The 
schedule for completion and submission of case report forms (paper or electronic) to 
the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up 
visit date or call 
 
12.2 Data Safety Monitoring 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this study. The committee is composed of clinical specialists 
with experience in oncology and who have no direct relationship with the study. Information 
that raises any questions about participant safety will be addressed with the Overall PI and 
study team. 
 
The DSMC will review each protocol up to four times a year or more often if required to 
review toxicity and accrual data.  Information to be provided to the committee may include:  
up-to-date participant accrual; current dose level information; DLT information; all grade 2 
or higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days of intervention for Phase I or II protocols; for gene transfer 
protocols, summary of all deaths while being treated and during active follow-up; any 
response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  


 
12.3 Monitoring  
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the QACT, provides quality 
control oversight for the protocol. 
Involvement in this study as a participating investigator implies acceptance of planned 
study monitoring, as well as potential audits or inspections, including both on-site and 
remote source data verification, by representatives designated by the DF/HCC Overall 
Principal Investigator (or Protocol Chair). The purpose of these reviews is to examine 
study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with 
the protocol, institutional policy, Good Clinical Practice (GCP), the Code of Federal 
Regulations (CFR), and any additional applicable regulatory requirements.  
 
The Participating Institutions may be required to submit participant source documents to 
the Coordinating Center for monitoring. Participating Institution may also be subject to on-
site monitoring conducted by the Coordinating Center.  
 
Data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and will 
continue during protocol performance and completion.  
 
13. 
REGULATORY CONSIDERATIONS 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit patients) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB 
governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or a representative) will 
disseminate protocol amendment information to all participating investigator teams.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
 


 
13.2 Informed Consent 
All patients must be provided a consent form describing this study and providing 
sufficient information for patients to make an informed decision about their participation 
in this study. The formal consent of a participant, using the IRB approved consent form, 
must be obtained before the participant is involved in any study-related procedure. The 
consent form must be signed and dated by the participant or the participant’s legally 
authorized representative, and by the person obtaining the consent. The participant must 
be given a copy of the signed and dated consent document. The original signed copy of 
the consent document must be retained in the medical record or research file.  
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
• 
Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
• 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
• 
Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
• 
Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures  
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.  
13.3 Study Documentation 
The investigator (or a representative) must prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the study 
data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  
13.4 Records Retention 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
14. STATISTICAL CONSIDERATIONS  


 
14.1 
Study Design/Endpoints 
 
This is a single arm, open label, Phase II trial in adult participants with recurrent 
glioblastoma who have progressed on bevacizumab.  Although anti-angiogenic approaches 
for GBM therapy show promise, GBMs usually develop resistance to treatment within 
months or even weeks of starting therapy. Drugs such as ponatinib, which target multiple 
receptors, may potentially help overcome some of the putative mechanisms of resistance and 
result in increased antitumor effects. Its additional activity may also contribute to a 
therapeutic effect. 
Primary Endpoint:  
a) To determine the efficacy of ponatinib in participants with recurrent GBM who 
progressed on bevacizumab as measured by 3-month progression-free survival 
(PFS3) 
Secondary Endpoints: 
• Radiographic Response (RR) 
• Overall survival (OS) and progression free survival (PFS) 
• Safety profile  
Exploratory Endpoints: 
• To explore the extent to which the tumor’s genotype and expression profile 
correlate with outcome 
• To explore the correlation between serum angiogenic peptides, circulating 
endothelial cells, and circulating progenitor cells with response to therapy 
• To explore the correlation between dynamic-contrast MRI, perfusion and 
diffusion MRI and response to therapy. 
14.2 
Sample Size, Accrual Rate, Study Duration, and Analysis of Primary Endpoint 
 
The primary objective of the study is to determine the efficacy of ponatinib in participants 
with recurrent GBM who have progressed on a bevacizumab containing regimen as measured 
by 3-month progression-free survival (PFS3). PFS3 was chosen since agents with anti-
VEGFR activity may produce pseudoresponses, making response a less reliable endpoint. 
Based on retrospective data, PFS3 rate among recurrent GBM patients who received a second 
bevacizumab-containing regimen after failing bevacizumab treatment once is 15% (Quant, 
Norden et al. 2009). This trial will enroll enough patients to discriminate between a 15% and 
35% PFS3 rate. A Simon optimal two-stage design will be used to permit early cessation of 
the study if the agent is unlikely to be effective. The first stage will accrue 15 participants. To 
account for drop outs, 2 additional participants (up to 15 + 2 = 17 participants) may enroll in 
the first stage. If at least 5 or more of the first 15 participants achieve PFS3, 12 more 
participants will be accrued for a total of 27 participants. To account for drop outs in the 
second stage, 3 more additional participants may enroll, increasing total enrollment for Stage 
1 + 2 up to 32 participants. The study will be declared successful if at least 10 or more out of 
27 participants achieve PFS at 3 months.  This design assumes alpha error of 0.10 and beta 
error of 0.2. The probability of early termination if the drug is ineffective is 69%.  
 


 
A total of 32 participants may be accrued. With an accrual rate of 3-4 participants per month, 
the anticipated enrollment period will be 8-11 months. 
14.3 
Analysis of Secondary and Exploratory Endpoints 
 
Response rate will be the proportion of participants with measurable disease who experience 
complete or partial radiographic response determined by the RANO Criteria (Wen, 
Macdonald et al. 2010). Progression free survival, PFS3, and overall survival will be 
calculated using standard statistical methods. Safety will be summarized using descriptive 
statistics. Participants will not be replaced for any reason.  
 
In general the circulating biomarker and neuro-imaging results will be summarized in a 
descriptive manner with comparison between pre- and post-treatment assay results when 
possible. 
14.4 
Reporting and Exclusions 
1.1.86 Evaluation of toxicity. All participants will be evaluable for toxicity from the time 
of their first treatment. 
1.1.87 Evaluation of response.  Only those participants who have measurable disease 
present at baseline and have received at least one dose of study treatment with 
Ponatinib will be considered evaluable for response. 
1.1.88 Evaluation of other efficacy endpoints. All participants who receive at least one 
dose of study treatment will be included in analyses of all other endpoints. Time-to-
event endpoints will be measured from first dose date. 
 
15. PUBLICATION PLAN 
 
Participant medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted herein is prohibited. Data generated by this study must be available 
for inspection upon request by representatives of the FDA, national and local health authorities, 
Pharmaceutical company providing the agent, and the IRB for each study site, if appropriate. The 
intention is to publish the results of this study in a medical journal such as Journal of Clinical 
Oncology or Neuro-Oncology. Results may be presented at national meetings of the American 
Society for Clinical Oncology and/or Society for Neuro-Oncology. Results will be made publicly 
available as required by law. 


 
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34. Wong, E. T., K. R. Hess, M. J. Gleason, K. A. Jaeckle, A. P. Kyritsis, M. D. Prados, V. A. 
Levin and W. K. Yung (1999). "Outcomes and prognostic factors in recurrent glioma patients 
enrolled onto phase II clinical trials." J Clin Oncol 17(8): 2572-2578. 


 
35. Thygesen K, Alpert JS, Jaffe AS,  et al. Third Universal Definition of Myocardial Infarction. 
Circulation. 2012;126 (16):2020-2035. 
36. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic 
attack: A Scientific Statement for Healthcare Professionals From the American Heart 
Association/American Stroke Association Stroke Council; Council on Cardiovascular 
Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on 
Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. 
Stroke. 2009;40 (6):2276-2293. 
 
 


 
 
Appendix A: Performance Status Criteria 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
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. 
60 
Requires occasional assistance, but is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly.  
0 
Dead. 
 
 


 
 
Appendix B: Medications and substances known or with the potential to interact with CYP3A4 
isoenzymes 
List of CYP3A Inhibitors and CYP3A Inducers***  
Strong CYP3A4,5,7 
Inhibitors 
Moderate CYP3A4,5,7 
Inhibitors 
Other CYP3A4,5,7 
Inhibitors 
CYP3A4 Inducers 
boceprevir 
amprenavir 
Alprazolam  
amprenavir 
clarithromycin 
aprepitant 
amiodarone 
aprepitant 
conivaptan 
atazanavir 
amlodipine  
armodafinil 
grapefruit juice 
crizotinib 
atorvastatin  
avasimibe* 
indinavir 
ciprofloxacin 
NOT azithromycin 
barbiturates 
itraconazole 
darunavir 
bicalutamide  
bosentan** 
ketoconazole 
diltiazem 
 chloramphenicol 
carbamazepine* 
lopinavir 
erythromycin 
cilostazol  
echinacea 
mibefradil 
fluconazole 
 cimetidine 
efavirenz** 
nefazodone 
fosamprenavir 
cyclosporine  
etravirine** 
nelfinavir 
imatinib 
delaviridine 
esclicarbazepine 
posaconazole 
suboxone 
diethyl-dithiocarbamate 
felbamate 
ritonavir 
verapamil  
elvitegravir  
fosphenytoin 
saquinavir 
 
fluoxetine  
glucocorticoids 
telithromycin 
 
fluvoxamine  
modafinil** 
telaprevir 
 
gestodene 
nafcillin** 
voriconazole  
 
ginkgo 
nevirapine 
 
 
goldenseal 
oxcarbazepine 
 
 
isoniazid 
phenobarbital 
 
 
mifepristone 
phenytoin* 
 
 
nilotinib 
pioglitazone 
 
 
norfloxacin 
prednisone 
 
 
norfluoxetine 
primidone 
 
 
oral contraceptives 
rifabutin 
 
 
ranitidine 
rifampin* 
 
 
ranolazine 
rufinamide 
 
 
starfruit 
ritonavir 
 
 
tipranavir/ritonavir 
St. John's Wort* 
 
 
tofisopam 
talviraline 
 
 
troleandomycin 
tipranavir 
 
 
zileuton 
topiramate (not prohibited but to be used 
with caution at doses >200mg/day) 
 
 
 
troglitazone 
This database of CYP 3A inhibitors and inducers was compiled from: 
• 
the Indiana University School of Medicine’s “Clinically Relevant” Table  
• 
the University of Washington’s Drug Interaction Database based on in vitro studies.  
• 
the FDA’s “Guidance for Industry, Drug Interaction Studies;”  
• 
and from (Pursche et al. 2008). 
* Strong Inducers 
** Moderate Inducers 
*** Strong inhibitors are predicted to increase ponatinib AUC > 5-fold, and moderate inhibitors are predicted to increase 
ponatinib AUC > 2-fold but < 5-fold.  


 
 
Appendix C:  Medications known to be associated with Torsades de Pointes 
Table C-1 
Prohibited QT prolonging drugs with risk of Torsades de Pointes 
Drug 
QT risk(*) 
Comment 
Amiodarone 
known risk for TdP 
Females>Males, TdP risk regarded as low 
Arsenic trioxide 
known risk for TdP 
 
Astemizole 
known risk for TdP 
No longer available in US.  
CYP3A4 substrate with narrow therapeutic index. 
Bepridil 
known risk for TdP 
Females>Males 
Chloroquine 
known risk for TdP 
 
Chlorpromazine 
known risk for TdP 
 
Cisapride 
known risk for TdP 
Restricted availability; Females>Males. 
CYP3A substrate with narrow therapeutic index. 
Disopyramide 
known risk for TdP 
Females>Males 
Dofetilide 
known risk for TdP 
 
Domperidone 
known risk for TdP 
Not available in the US. 
Droperidol 
known risk for TdP 
 
Halofantrine 
known risk for TdP 
Females>Males 
Haloperidol 
known risk for TdP 
When given intravenously or at higher-than- recommended 
doses, risk of sudden death, QT prolongation and torsades 
increases. 
Ibutilide 
known risk for TdP 
Females>Males 
Levomethadyl 
known risk for TdP 
Sensitive CYP3A substrate 
Mesoridazine 
known risk for TdP 
 
Methadone 
known risk for TdP 
Females>Males 
Pentamidine 
known risk for TdP 
Females>Males 
Pimozide 
known risk for TdP 
Females>Males. Sensitive CYP3A substrate with narrow 
therapeutic index 
Probucol 
known risk for TdP 
No longer available in U.S. 
Procainamide 
known risk for TdP 
 
Quetiapine 
possible risk for TdP 
Sensitive CYP3A substrate 
Quinidine 
known risk for TdP 
Females>Males. Sensitive CYP3A substrate  
Sotalol 
known risk for TdP 
Females>Males 
Sparfloxacin 
known risk for TdP 
 
Tacrolimus 
possible risk for TdP 
Sensitive CYP3A substrate with narrow therapeutic index 
Terfenadine 
Known risk for TdP 
No longer available in U.S. Sensitive CYP3A substrate with narrow 
therapeutic index 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
possible risk for TdP 
Sensitive CYP3A substrate 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered with a 
potent inhibitor of the respective enzyme. 
 
 
 


 
 
Table C-2 List of QT prolonging drugs prohibited at eligibility, but allowable - with caution and appropriate 
monitoring  – on study (see protocol section 5.2.2) 
Drug 
QT risk 
Drug 
QT risk 
Alfuzosin 
possible risk for Torsades de Pointes 
Lithium 
possible risk for Torsades de Pointes 
Amantadine 
possible risk for Torsades de Pointes 
Mexiletine 
conditional risk for Torsades de Pointes 
Amitriptyline 
conditional risk for Torsades de Pointes 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
Azithromycin 
possible risk for Torsades de Pointes 
Moxifloxacin 
possible risk for Torsades de Pointes 
Chloral hydrate 
possible risk for Torsades de Pointes 
Nicardipine 
possible risk for Torsades de Pointes 
Citalopram 
conditional risk for Torsades de Pointes 
Nortriptyline 
conditional risk for Torsades de Pointes 
Clomipramine 
conditional risk for Torsades de Pointes 
Octreotide 
possible risk for Torsades de Pointes 
Clozapine 
possible risk for Torsades de Pointes 
Ofloxacin 
possible risk for Torsades de Pointes 
Desipramine 
conditional risk for Torsades de Pointes 
Ondansetron 
possible risk for Torsades de Pointes 
Diphenhydramine 
conditional risk for Torsades de Pointes 
Oxytocin 
possible risk for Torsades de Pointes 
Dolasetron 
possible risk for Torsades de Pointes 
Paliperidone 
possible risk for Torsades de Pointes 
Doxepin 
conditional risk for Torsades de Pointes 
Paroxetine 
conditional risk for Torsades de Pointes 
Dronedarone 
possible risk for Torsades de Pointes 
Perflutren lipid 
microspheres 
possible risk for Torsades de Pointes 
Felbamate 
possible risk for Torsades de Pointes 
Protriptyline 
conditional risk for Torsades de Pointes 
Flecainide 
possible risk for Torsades de Pointes 
Ranolazine 
possible risk for Torsades de Pointes 
Fluoxetine 
conditional risk for Torsades de Pointes 
Risperidone 
possible risk for Torsades de Pointes 
Foscarnet 
possible risk for Torsades de Pointes 
Roxithromycin* 
possible risk for Torsades de Pointes 
 
 
Sertindole 
possible risk for Torsades de Pointes 
Galantamine 
conditional risk for Torsades de Pointes 
Sertraline 
conditional risk for Torsades de Pointes 
Gatifloxacin 
possible risk for Torsades de Pointes 
Solifenacin 
conditional risk for Torsades de Pointes 
Gemifloxacin 
possible risk for Torsades de Pointes 
Tizanidine 
possible risk for Torsades de Pointes 
Granisetron 
possible risk for Torsades de Pointes 
Trazodone 
conditional risk for Torsades de Pointes 
Imipramine 
conditional risk for Torsades de Pointes 
Trimethoprim-
Sulfa 
conditional risk for Torsades de Pointes 
Indapamide 
possible risk for Torsades de Pointes 
Trimipramine 
conditional risk for Torsades de Pointes 
Isradipine 
possible risk for Torsades de Pointes 
Venlafaxine 
possible risk for Torsades de Pointes 
Levofloxacin 
possible risk for Torsades de Pointes 
Ziprasidone 
possible risk for Torsades de Pointes 
(*) Classification according to the Qtdrugs.org Advisory Board of the Arizona CERT 
 
 
 
 


 
 
Appendix D: 
Pill Diary 
 
 
 
Completed by study personnel:  Participant ID #_______   Participant Initials: _______  Cycle #: ______ Month & Year: _________ 
Ponatinib Daily Dose________mg/day 
 
To be completed by Participant or Guardian:     # of 15 mg Pill Bottles Received: ______      # of 15 mg Capsules Received:  _______ 
 
 
 
 
DAY:  
DAY:  
DAY:  
DAY:  
DAY:  
DAY:  
DAY:  
 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
I_________ 
 
   Page 1 of 3 


 
 
 
Participant/Guardian Signature: _________________________________     Date: ________________   
 
To be completed by study personnel:  # of 15 mg Bottles Returned: ______           # of 15 mg Capsules Returned: ______ 
  
 
Compare w/ drug diary entries made by participant or guardian.  If discrepancy (in the # of bottles or the # of pills returned), please reconcile: 
 
 
Study Personnel Signature:________________________________  Date: _________________ 
DAY:  
DAY:  
DAY:  
DAY:  
DAY:  
DAY:  
DAY:  
 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
Date: 
Time: 
 
No. of 15 mg pills 
_____ 
 
 
Participant Initials 
_________ 
 
 Date: 
Time: 
 
No. of 15 mg pills 
_____ 
Participant Initials 
_________ 
 
   Page 2 of 3 


 
 
Ponatinib Dosing Instruction Sheet 
to Be Given to Study Participants with Participant Pill Diary 
 
 
Ponatinib Description:  
• Your study drug (Ponatinib) is supplied as 15 mg white, film-coated tablets. 
Ponatinib Instructions – When and How: 
• Take the prescribed number of Ponatinib tablets with water, with or without food.   
o Ponatinib tablets should be swallowed whole; do not crush, cut or chew them. 
• Take your dose of Ponatinib once daily, at approximately the same time each day.   
o NOTE: During your first Cycle of treatment, bring your Day 2 dose with you to 
clinic, as you will take it after your visit that day 
• If you forget to take a dose of Ponatinib, you may take it up to six hours after the 
scheduled dose.  DO NOT make up the missed dose any more than 6 hours later than 
the time you usually take your study drug; simply consider that day’s dose skipped.  
Take your next dose the following day as usual. 
• If you vomit your pills, do not take more pills; you will take your next dose on the 
next day as usual.  You should write down in your pill diary that you vomited the pills. 
Additional Instructions: 
• You must avoid eating or drinking any foods with Seville oranges (like marmalade), 
grapefruit or foods or drink with grapefruit, and any exotic fruits during the entire 
treatment period.   
• Keep your ponatinib tablets in their original container(s) at room temperature, and 
keep study drug away from children, others who cannot read the label, and pets. 
• Do not throw away empty pill bottles, and do not throw the study drug in the trash 
or flush into the toilet. 
• Bring this diary, all pill bottles, and any unused pills to your next clinic visit.  Your 
Treatment Team will collect your diary, all Ponatinib pill bottles and unused 
Ponatinib pills, and you will be given a new pill diary at that time. 
• Contact your study doctor or nurse if you are having any new or worsening side 
effects. 
• Do not begin any new medication, over-the-counter drug, or herbal preparation 
without first checking with your Study Treatment Team to determine if it is 
acceptable to take while on this study. 
 
   Page 3 of 3 


 
 
Appendix E: Instructions for Local Processing of Plasma Biomarkers 
 
Plasma Biomarkers 
Local Processing Instructions 
 
In the event that a Plasma Biomarkers sample is drawn without sufficient time to be processed at the Steele 
Lab within 2 hours of collection, (e.g. in the event patient is drawn at 4 pm), please refer to the following 
processing instructions. 
 
NOTE: The instructions below are provided on an as needed basis.  This alternative should be avoided whenever 
possible, as this additional process does render samples no longer analyzable by flow cytometry. 
 
1. Blood Draw and Centrifugation 
• 
As noted in protocol section 8.1.1: 
o Collect 2 tubes of ~8 ml each of blood. The tubes must be pre-cooled in an ice bath. 
o Gently invert five to six times to ensure adequate mixing and prevent coagulation. 
o Cool the tubes immediately in an ice bath. 
 
• 
Within 2 hours of collection, samples must be processed locally for storage.  To process these 
samples locally: 
o Centrifuge the blood tube at 700g (2000rpm) for 20 minutes at 4°C with no break at the end of 
centrifugation for plasma extraction. 
o Using a sterile pipette, pipette the top clear layer (careful not to disturb the bottom red layer) 
and aliquot equally into 3 pre-labeled 1.8 mL Nunc cryovials. 
o Visually check the plasma for hemolysis. 
 
If the plasma appears to be yellow and clear, please proceed with processing the plasma, 
record the observation internally per standard practice, and make the Study Team aware 
of any abnormality. 
 
If the plasma appears to be dark red, please discard the plasma, record the event 
internally per standard practice, and make the Study Team aware of the event. 
o After the plasma has been extracted, check the red blood cells by sticking two wooden 
applicator sticks in the tube and observe the sticks for clots. Record if there was clotting 
observed per standard practice, and make the Study Team aware of the any abnormality. 
o Immediately store the cryovials into a -80°C freezer*. 
o Record time of freeze and location of the vials (i.e., freezer number, shelf, box number, and 
room #, as applicable) per standard practice. 
 
2. Labeling and Storing Specimens 
 
Each specimen should be labeled with the following information:  
Patient study number 
Patient Initials 
Military time sample was obtained 
Date sample was obtained 
Cycle #/Day# of sample 
 
and that label affixed to the cryvials and then covered completely with protective cryogenic freezer tape 
(Fisher catalogue no. 11-867B).  
 
All cryovials should be stored in a monitored -80° C freezer.  
 
 


 
 
3. SHIPPING SPECIMENS TO CORE FACILITY 
 
Plasma samples should be shipped next day (if possible) in an isothermal container with plenty of dry ice 
and delivered to the Steele Laboratory using a courier. 
Steele Laboratory (Dan G. Duda, DMD, PhD) 
Attn: Anna Khachatryan and Julia Kahn 
Massachusetts General Hospital, Cox-734 
100 Blossom Street 
Boston, MA 02114 
Phone: (617) 724-1352; Partners pager: 14082 
Email: annak@steele.mgh.harvard.edu; julia@steele.mgh.harvard.edu 
 
Be sure to indicate/label shipment: “Notice: Keep Frozen”, Upright arrows, “Diagnostic Specimens – Not 
restricted, Packed in Compliance with IATA Packing Instruction 650”, and “Class 9 – Dry Ice”. 
 
Specimens should be shipped Monday to Wednesday only by overnight FedEx to the Testing Core 
Facility. On the day of shipment, the study coordinator will notify the Testing Core Facility via e-mail at 
annak@steele.mgh.harvard.edu; julia@steele.mgh.harvard.edu or FAX (617-724-5841, ATTN: A. 
Khachatryan & J. Kahn) so they know to expect the upcoming shipment. Include the estimated date of 
arrival and the FedEx tracking number. 
 
NOTE: The subject line of the e-mail/FAX should include the following so that the Testing Core 
Facility staff can distinguish plasma specimens sent for this trial: 
 
 
Notification of plasma specimen shipment for DF/HCC #15-163 
 
Upon receipt of specimens, the Testing Core Facility will reconcile the materials and notify the site study 
coordinator of missing specimens, damaged specimens, or any concerns to be addressed. 
 
Suggested packing process for dry ice shipments: 
• Place all plasma tubes in storage freezer boxes, tape the sides of the boxes; 
• Place one freezer box, each separately, in a large zip-locked bag; 
• Pack the Styrofoam container with plenty of dry ice; 
• Place the bagged freezer boxes in the middle of the bio-shipper (you can fit as many as the box allows); 
• Pack the Styrofoam container with an additional dry-ice on the top of the boxes to cover the top; 
• Close the lid, place any corresponding shipping forms on top of the lid, and seal the shipping container 
with tape. 
• Maintain a copy of the transmittal log at the site. 
 
4. Labeling Shipping Containers: FedEx shipping labeling will include the following: 
1. The study coordinator’s return address. 
2. The Testing Core Facility address: 
Steele Laboratory (Dan G. Duda, DMD, PhD) 
ATTN: Anna Khachatryan and Julia Kahn 
MGH, Cox-734 
100 Blossom St. 
Boston, MA 02114 
Phone: (617) 724-1352; Pager: 14082 
Emails: annak@steele.mgh.harvard.edu; julia@steele.mgh.harvard.edu 
3. “Notice: Keep Frozen”, “Class 9 – Dry Ice” stickers or “Keep Refrigerated”, Upright arrows, and 
“Diagnostic Specimens – Not restricted, Packed in Compliance with IATA Packing Instruction 
650”. 
 


 
 
Appendix F: 
Study Safety Reporting Coversheet 
DF/HCC Protocol No. 15-163    ARIAD Pharmaceuticals Protocol No. AP24534-13-020 
Date:____________________     Number of pages including cover sheet:______ 
 
To (check off recipient of this fax): 
        Eudocia Quant Lee, MD (Overall PI)  
   @ Dana Farber Cancer Institute                 Email: NeuroOnc_SAE@dfci.harvard.edu 
        ARIAD Pharmaceuticals Drug Safety,  attention ARIAD Pharmacovigilance (PV) 
              Fax:  888-427-7965                                         Email: ARIADPost-PVGSM@ppdi.com 
 
From: 
Institution: 
Phone No.: 
Fax No.: 
 
 
Participant # and Initials: 
 
Date Event Met Reporting Criteria (as defined in protocol): 
 
Type of Report:    Initial   Follow-up 
 
 
Event #1 Description: 
Event #2 (If Applicable) Description: (Please use 
another sheet if more than 2 events being 
reported at this time) 
 
 
Meets Definition of Serious AE:    
   Serious        Non-serious 
Meets Definition of Serious AE:    
   Serious         Non-serious 
Toxicity Grade:      
G1/mild   G2/moderate   G3/severe   
G4/life threatening   G5 
Toxicity Grade:      
G1/mild   G2/moderate   G3/severe   
G4/life threatening   G5 
Historical/Known Correlation to Ponatinib:    
Expected   Unexpected   
Historical/Known Correlation to Ponatinib:    
Expected   Unexpected   
Attribution to Ponatinib:     
Unrelated   Unlikely    Possible    
Probable    Definite 
Attribution to Ponatinib:     
Unrelated   Unlikely    Possible    
Probable    Definite 
 
Reporting Investigator (please print): 
 
Signature of Investigator: _____________________________Date:______________