Conditions: Non Small Cell Lung Cancer
Keywords: RET gene mutation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the drug is being studied.

It has been found that some people with NSCLC have a change (mutation) in a certain gene called the RET gene. This mutated gene may help cancer cells grow. Only participants with a RET mutation will be allowed to participate. In this study, investigators are testing the strategy of using a study drug designed to inhibit or shut off growth signals that results from the mutated RET gene.

Ponatinib is an anti-cancer drug that has been used in research studies for other types of cancer. Ponatinib blocks several growth signals in cancer cells, including RET. In this research study, investigators are looking to see whether ponatinib is effective and safe in treating NSCLC harboring RET rearrangements.

Detailed description:
Participants in this research study will be asked to undergo some screening tests or procedures to confirm that eligibility. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that participants do not take part in the research study. These tests and procedures include the following: medical history, vital signs, physical exam, performance status, electrocardiogram, echocardiogram, routine blood tests, pregnancy test and an assessment of tumor by CT or MRI. If these tests show that a participant is eligible to participate in the research study, he/she will begin the study treatment. If a patient does not meet the eligibility criteria, he/she will not be able to participate in this research study.

Participants will take the study drug once a day, every day of the cycle. Each treatment cycle lasts 28 days (4 weeks). Participants will be given a drug diary to record the drug they take each day. The diary will also include special instructions for taking the study drug.

For cycles 1-20, participants will visit the clinic to have tests and procedures done at the time points listed here: On Day 1-physical exam, vital signs, performance status, electrocardiogram, routine blood tests, pharmacokinetic test, clinical exam and assessment of tumor. On day 15 of cycle 1-vital signs, routine blood tests and clinical exam.

For cycles 11 and on, participants will visit the clinic every 6 weeks. Some of these visits will happen on Day 1 of the cycle and some of these visits will happen on Day 15 of the cycle. At each visit, the following tests and procedures will be done: physical exam, vital signs, performance status, electrocardiogram, routine blood tests, clinical exam, and an assessment of your tumor.

Participants will visit the clinic when their study doctor takes them off study drug permanently. They will also visit the clinic 30 days after stop taking the study drug. The following tests and procedures will be done: physical exam, vital signs, performance status, electrocardiogram, routine blood tests, pregnancy test, clinical exam and a tumor assessment.

Investigators would also like to keep track of participant's medical condition for two years after their first study dose. Investigators will contact participants by telephone every 3 months. If participants still come to the clinic, visits might be used as contact.

Arms:
arm 1: Ponatinib 30 mg PO daily

Interventions: intervention 1: Ponatinib
Intervention descriptions: intervention 1: 28 day cycle

Protocol document:
Prot_SAP_000.pdf: 
A Phase II, open-label study of ponatinib, a multi-targeted oral tyrosine kinase inhibitor, in advanced non-
small cell lung cancer harboring RET translocations  
Version 8/22/2018 
Confidential 
1 
A Phase II, open-label study of ponatinib, a multi-targeted oral 
tyrosine kinase inhibitor, in advanced non-small-cell lung cancer 
harboring RET translocations 
NCT01813734
Protocol ID: 13-103
Version Date: August 22, 2018 




A Phase II, open-label study of ponatinib, a multi-targeted oral tyrosine kinase inhibitor, in advanced non-
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3 
 
 
 
 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping of tumor for RET 
translocation  
(Pre-study evaluation) 
Register 
Ponatinib  
Progressive disease, 
Unacceptable toxicity 
Stable disease, partial or 
complete response 
Off study 
Continue 
Treatment 


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Schema ................................................................................................................................3 
Table of Contents ................................................................. Error! Bookmark not defined. 
1 
Objectives ...................................................................................................................8 
1.1 Study Design ..............................................................................................................8 
1.2 Primary Objective .....................................................................................................8 
1.3 Secondary Objectives ................................................................................................8 
1.4 Primary Endpoint ......................................................................................................8 
1.5 Secondary Endpoints .................................................................................................8 
2 
Background ................................................................................................................9 
2.1 Study Agent ................................................................................................................9 
2.2 Study Disease ............................................................................................................15 
2.3 Study Rationale ........................................................................................................16 
3 
Participant Selection ................................................................................................17 
3.1 Eligibility Criteria ....................................................................................................17 
3.2 Exclusion Criteria ....................................................................................................19 
4 
Registration Procedures ..........................................................................................21 
4.1 General Guidelines for DF/HCC and DF/PCC Institutions ................................21 
4.2 Registration Process for DF/HCC and DF/PCC Institutions ..............................21 
4.3 General Guidelines for Other Participating Institutions .................................21 
4.4 Registration Process for Other Participating Institutions ...................................22 
5 
Study Procedures .....................................................................................................22 
5.1 Study Procedures Descriptions .............................................................................22 
5.2 Screening Period ......................................................................................................24 
5.3 Screen Failures .........................................................................................................24 
5.4 Active Study Period .................................................................................................24 
5.5 End of Treatment .....................................................................................................25 
5.6 30 Days After End of Treatment ............................................................................25 
5.7 Follow-up Period ......................................................................................................25 
5.8 Duration of Therapy / Subject Discontinuation ....................................................25 
6 
Treatment Plan ........................................................................................................26 
6.1 Study Drug ...............................................................................................................26 
6.2 Selection of Starting Dose .......................................................................................27 
6.3 Treatment Administration ......................................................................................27 
6.4 Formulation, Packaging, and Labeling .................................................................27 
6.5 Handling ...................................................................................................................27 
6.6 Availability ...............................................................................................................28 


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6.7 Storage ......................................................................................................................28 
6.8 Ordering ...................................................................................................................28 
6.9 Accountability ..........................................................................................................28 
6.10 Destruction and Return ...........................................................................................28 
6.11 Required Concomitant Therapy ............................................................................29 
6.12 Permitted Treatment ...............................................................................................29 
6.13 Prohibited Treatment ..............................................................................................30 
6.14 Treatments to be Used with Caution .....................................................................30 
6.15 Potential Drug-Drug Interactions ..........................................................................30 
7 
Expected Toxicities and Dose Modifications .........................................................30 
7.1 Management of Adverse Drug Reactions ..............................................................31 
7.2 Dose Delays and Reductions ...................................................................................31 
7.3 Dose Delay and/or Reduction for Adverse Events (AEs) Attributable to the Study 
Drug 31 
7.4 Management of Selected Adverse Events ...........................................................34 
8 
Study Calendar ........................................................................................................37 
9 
Measurement of Effect ............................................................................................40 
9.1 Antitumor Effect– Solid Tumors ..........................................................................40 
9.1.1 Definitions .................................................................................................................40 
9.1.2 Disease Parameters ..................................................................................................40 
Methods for Evaluation of Measurable Disease ............................................................41 
9.1.3 Response Criteria.....................................................................................................42 
9.1.4 Duration of Response ..............................................................................................45 
9.1.5 Progression-Free Survival.......................................................................................45 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to time 
of objective disease progression. .....................................................................................45 
9.1.6 Response Review ......................................................................................................45 
10 
Adverse Event Reporting Requirements ...............................................................45 
10.1 Definitions ................................................................................................................45 
10.1.1 Adverse Event (AE) .............................................................................................45 
10.1.2 Serious adverse event (SAE) ...............................................................................46 
10.1.3 Expectedness .........................................................................................................46 
10.1.4 Attribution ............................................................................................................47 
10.2 Procedures for AE and SAE Recording and Reporting ......................................47 
10.3 Reporting Requirements .........................................................................................48 
10.4 Reporting to the Study Sponsor ...........................................................................48 
10.4.1 DF/HCC Reportable Adverse Event Reporting ................................................48 
10.4.2 Reporting SAE to ARIAD Pharmaceuticals......................................................49 
10.4.3 Non-Serious Adverse Event Reporting ..............................................................49 
10.5 Reporting to the Institutional Review Board (IRB) ..........................................50 
10.6 Reporting to the Food and Drug Administration .................................................50 
10.7 Reporting to Hospital Risk Management ..............................................................50 
10.8 Monitoring of Adverse Events and Period of Observation ..................................50 
11 
Data and Safety Monitoring ...................................................................................51 


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11.1 Data Reporting ........................................................................................................51 
11.1.1 Method ..................................................................................................................51 
11.1.2 Data Submission ...................................................................................................51 
11.2 Safety Meetings .......................................................................................................52 
11.3 Monitoring ...............................................................................................................52 
12 
Regulatory Considerations .....................................................................................52 
12.1 Protocol Review and Amendments ......................................................................52 
12.2 Informed Consent ....................................................................................................53 
12.3 Ethics ........................................................................................................................53 
12.4 Study Documentation ..............................................................................................54 
12.5 Records Retention ....................................................................................................54 
12.6 Multi-center Guidelines .........................................................................................54 
13 
Statistical Considerations ........................................................................................54 
13.1 Study Design/Endpoints .........................................................................................54 
13.2 Sample Size/Accrual rate ........................................................................................55 
13.3 Analysis of Secondary Endpoints .........................................................................55 
13.3.1 Disease Control Rates ..........................................................................................55 
13.3.3 Safety .....................................................................................................................55 
14 
Publication Plan .......................................................................................................55 
15 
References .................................................................................................................57 
Appendix A: Performance Status Criteria ....................................................................60 
Appendix B: Prohibited Drugs Affecting the QT interval ...........................................61 
Appendix C: List of co-medications with known CYP3A4 interaction ......................62 
Appendix D: Data and Safety Monitoring Plan ............................................................63 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 Objectives 
1.1 Study Design 
This is a phase II, open label study evaluating ponatinib, an oral multi-target tyrosine kinase 
inhibitor (TKI), in patients with advanced, non-small-cell lung cancer (NSCLC) harboring 
translocations in RET. The purpose of this study is to investigate the efficacy, safety and 
tolerability of ponatinib in this molecularly-defined subpopulation. Eligible participants will 
have advanced, NSCLC and documented RET translocations. Eligible participants will receive 
ponatinib at a dose of 30 mg orally daily. Treatment will continue until disease progression, 
unacceptable toxicity, participant withdrawal, death or discontinuation from the study for any 
other reason. Participants will be allowed to continue receiving ponatinib despite progressive 
disease if they are deriving clinical benefit. Efficacy will be evaluated by radiographic 
assessments using RECIST (version 1.1) criteria at baseline and at two cycle intervals. After a 
participant has completed 10 cycles, disease assessments will be performed at three cycle 
intervals.  
1.2 Primary Objective 
• To evaluate the objective response rate (ORR) of ponatinib in RET-positive NSCLC as 
assessed by RECIST criteria.  
1.3 Secondary Objectives 
• To evaluate the disease control rate (DCR).  
• To evaluate progression-free survival (PFS).  
• To evaluate the 1-year overall survival (OS) rate.  
• To determine the safety and tolerability of ponatinib in patients with RET translocation 
positive NSCLC.  
• To determine the plasma PK profile of ponatinib. 
1.4 Primary Endpoint 
• The primary efficacy endpoint is ORR, defined as partial response (PR) or complete 
response (CR), occurring at any point post treatment according to RECIST (version 1.1) 
criteria.  
1.5 Secondary Endpoints 
• Disease control rate (DCR), defined as PR, CR, or stable disease (SD) as assessed by 
RECIST.  
• Progression-free survival (PFS), defined as time from study entry to progression or death, 
whichever comes first.  
• 1-year overall survival (OS) rate, defined by the number of subjects alive 1 year from the 
time of study entry.  
• Safety parameters: Adverse drug reactions and serious adverse drug reactions. Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used.  


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• Plasma PK parameters will be assessed as shown in the Schedule of Events (Table 8.1) 
2 Background 
2.1 Study Agent 
Ponatinib (AP24534) is a novel, synthetic, orally-active tyrosine kinase inhibitor recently 
approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic 
myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic 
leukemia (ALL). Ponatinib was initially developed as an inhibitor of the BCR-ABL fusion 
protein, which is formed by a reciprocal translocation involving chromosomes 9 and 22 in 
hematopoietic stem cells and characterizes approximately 95% of cases of chronic myeloid 
leukemia (Faderl S, 1999). In addition to its inhibitory activity against the BCR-ABL fusion 
oncoprotein, ponatinib is a potent inhibitor of a number of tyrosine kinases relevant to the 
treatment of human malignancies, including FLT3, KIT, VEGFR2, FGFR1, PDGFR and RET 
(Table 2.1).  
 
Table 2.1  
Ponatinib Kinase Screening Data 
Kinase 
IC50 (nM) 
ABL 
0.37 
ABLT315I 
2.00 
FLT3 
12.6 
KIT 
12.5 
RET 
0.16 
SRC 
5.4 
VEGFR2 
1.5 
FGFR1 
2.2 
PDGRFα 
1.1 
 
Two clinical trials are currently being conducted with ponatinib: phase I study AP24534-07-
101 and phase 2 study AP24534-10-201. Additionally, three clinical trials examining the 
clinical pharmacology of ponatinib in healthy subjects have been completed (AP24534-11-
102, AP24534-11-103, and AP24534-11-104).  
 
A summary of the pharmacokinetic, safety and clinical activity data are provided below. 
Complete details for clinical and non-clinical studies performed with ponatinib are provided 
in the Investigator Brochure (Ponatinib Clinical Investigator’s Brochure Version 5, Feb2013; 
Addendum 29Oct2013).  
 
 
Preclinical Toxicology of Ponatinib 
 
The preclinical safety profile of ponatinib was characterized in a series of in vitro and in vivo 
studies in mice, rats and cynomolgus monkeys. These nonclinical toxicology studies support 
the repeat administration of oral ponatinib to cancer patients in clinical studies.  
 


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Preclinical safety assessments of ponatinib included 6-month oral toxicology studies in rats 
and cynomolgus monkeys. In the 6 month oral toxicology study in rats, the no observed adverse 
effect level was 0.25 mg/kg/day. Higher doses of 0.75 mg/kg/day resulted in mortality in some 
animals. At the time of histological examination, decreased chondrocytes along the physis of 
the femur were observed in rats at dose levels of 0.75 mg/kg/day and 2 mg/kg/day. Moreover, 
lymphoid depletion was observed in the thymus at doses of 2 mg/kg/day. In the 6-month 
toxicology studies in cynomolgus monkeys, oral doses of 0.25, 0.75 and 2 mg/kg/day of 
ponatinib were well-tolerated. No ponatinib-related microscopic findings were observed at any 
dose level.  
 
The mutagenic potential of ponatinib was investigated in three separate assays. These included 
assessments for the potential to reverse mutations in S. typhimurium and E. coli strains in vitro 
in the standard Ames assay. Additionally, human lymphocytes were assessed in vitro to assess 
the potential for induction of chromosomal aberrations. No evidence of mutagenic potential 
was observed in any of these studies.  
 
Ponatinib has been demonstrated to be embryo-toxic in rats. Data from an embryo-fetal 
development study of ponatinib in rats showed maternal and developmental toxicity, including 
both embryo-toxicity (post-implantation loss) and teratogenicity (cleft palates). Maternal and 
developmental toxicity in rats occurred at a dosage of 10 mg/kg/day. Embryo and fetotoxicity 
occurred at 3 mg/kg/day. A teratogenic effect (cleft palate at 3 mg/kg/day) was also observed.  
 
The cardiovascular effects of ponatinib were evaluated in conscious telemetered male dogs. 
Oral administration of ponatinib at doses of 2-10 mg/kg did not result in any significant 
changes in heart rate or blood pressure. Increases in the QTc of 11 and 14% were observed in 
dogs treated with the 10 mg/kg dose of ponatinib but the magnitude of this increase is not 
thought to be biologically relevant.  
 
The potential for phototoxicity was also evaluated in a study involving pigmented rats. 
Animals treated with high doses of ponatinib (5 and 10 mg/kg) showed minimal ocular 
phototoxicity. Specifically, animals showed microscopic signs of inflammation of the cornea.  
 
Safety of Ponatinib in Clinical Studies 
 
Two clinical trials with ponatinib are currently being conducted: the phase 1 study AP24534-
07-101 and the phase 2 registration study AP24534-10-201.  
 
AP24534-07-101 
 
AP24534-07-101 is a phase 1 dose escalation trial to determine the safety, tolerability and 
maximum tolerated dose (MTD) of ponatinib in patients with refractory chronic myeloid 
leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ 
ALL). Enrollment in the United States was completed at 81 patients as of October 2010. The 
primary objective of the trial was to determine the MTD of daily oral ponatinib. Secondary 


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objectives included safety and pharmacokinetics (PK), anti-tumor activity, and 
pharmacodynamic activity.  
 
Following oral administration, maximum plasma levels of ponatinib occurred between 4 and 
6 hours after dosing. The steady-state terminal elimination half-life (t1/2) was 20-28 hours for 
doses exceeding 15mg. Initial ponatinib dosing was 2 mg orally once daily, escalating up to 
60 mg once daily. At the 45 mg dose level, 1 dose limited toxicity (DLT) of grade 3 rash was 
observed. At the 60 mg dose level, 4 patients experienced DLTs of clinical pancreatitis or 
elevation of pancreatic enzymes. At this dose level, 1 patient also experienced grade 3 fatigue 
and an additional patient experienced grade 3 elevated AST and ALT. Based upon these 
findings, the recommended ponatinib dose was 45 mg once daily.  
 
Eighty-one patients (100%) experienced at least one adverse event (AE) during the study 
period. Sixty-seven (83%) experienced at least one treatment-related AE (TRAE). The most 
common TRAEs included: rash (32%); thrombocytopenia (27%); arthralgia (17%); lipase 
increased (15%); fatigue, nausea, dermatitis acneiform, dry skin (14%); and headache, elevated 
triglycerides, myalgia, neutrophil count decreased, and pancreatitis (12%).  
 
During this phase 1 trial, ponatinib was found to have anti-leukemic activity. Among 43 
patients with chronic phase CML, 42 patients (98%) achieved or maintained a complete 
hematologic response. Major cytogenetic responses were seen in 72%, and complete 
cytogenetic responses were observed in 63%.  
 
AP24534-10-201 
 
AP24534-10-201 is a phase 2 registration trial of ponatinib in patients with refractory CML 
and Philadelphia chromosome-positive ALL. The primary objective of the trial is to determine 
the efficacy of ponatinib at a dose of 45 mg once daily in this population of patients. As of 
December 2011, 449 patients have enrolled and 301 remain on therapy.  
 
Adverse events have been documented in 441 patients (98.2%). TRAEs were seen in 409 
(89.3%) patients. Ninety-seven (21.6%) patients experienced at least 1 treatment-related AE. 
The most common TRAEs were: rash (32.1%), thrombocytopenia (31.2%), dry skin (23.8%), 
abdominal pain (18.5%), headache (16.7%), neutrophil count decreased (15.1%), fatigue 
(14.5%), myalgia (14.0%), lipase increased (13.6%), arthralgia (13.6%), constipation (12.2%), 
anemia (11.6%), and nausea (10.5%). Please see Table 2.2 for a listing of additional TRAEs.  
 
 
 
 


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Table 2.2 Treatment-Related Adverse Events Occurring in >5% of Patients in Phase 2 
Clinical Trial AP24534-10-201, Safety Population (n = 449) 
 
*Source: Ponatinib Clinical Investigator’s Brochure, 10Apr2012.  
**Database cutoff date 02 December 2011.  
 
Five treatment-related deaths were reported during the study period following grade 5 SAEs 
of pneumonia, sudden death, fungal pneumonia, pancytopenia and gastritis hemorrhagic, and 
cardiac arrest. Grade 3 or 4 AEs occurring in ≥5% of patients include: platelet count decreased 
(24.5%), neutrophil count decreased (13.6%), lipase increased (7.8%), anemia (6.9%), and 
abdominal pain (5.1%). In the phase 1 study AP24534-07-101, pancreatic events were the 
DLT. In the phase 2 study AP24534-10-201, Grade 3 or 4 pancreatitis was observed in 4.7% 
of patients.  
 
Among patients with chronic phase CML, 248/271 (92%) achieved or maintained a complete 
hematologic response. Major cytogenetic responses were seen in 116/248 (47%). At the time 
of study entry, 64 patients with chronic phase CML possessed the T315I resistance mutation, 
a known target of ponatinib. In this subpopulation of patients, 55/64 (86%) experienced a 
complete hematologic response and 37/64 (65%) had a major cytogenetic response.  
 
Among the study population of 449 patients, 94 patients were enrolled with blast phase CML 
or Philadelphia chromosome-positive ALL. In this subpopulation, major hematologic 
responses were observed in 33 (37%). Major cytogenetic responses were experienced in 35%.  
 


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Adverse Events of Special Concern 
 
Vascular Occlusion 
 
Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, 
stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need 
for urgent revascularization procedures have occurred in at least 27% of ponatinib-treated 
patients from the phase 1 and phase 2 trials conducted in CML/ALL patient populations 
(Ponatinib Package Insert, Accessed 4/17/2014). Ponatinib has been associated with fatal and 
life-threatening vascular occlusion within 2 weeks of starting treatment. Ponatinib has also 
been associated with recurrent or multi-site vascular occlusion. 
 
In the dose-escalation (phase 1) clinical trial, 48% (31/65) of patients with CML or Ph+ ALL 
developed vascular occlusive events. The median time to onset of the first vascular occlusion 
event was 5 months. Ponatinib can cause fatal and life threatening vascular occlusion in 
patients treated at dose levels as low as 15 mg per day. 
 
Patients with and without cardiovascular risk factors, including patients age 50 years or 
younger, experienced these events. Vascular occlusion adverse events were more frequent 
with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or 
hyperlipidemia (see Table 2.3). 
 
Table 2.3: Vascular Occlusion Incidence in Ponatinib-Treated Patients in Phase 2 Trial 
According to Risk Categories 
 
 
Prior history of ischemia, hypertension, 
diabetes, or hyperlipidemia 
No history of ischemia, hypertension, 
diabetes, or hyperlipidemia 
Age: 49 or 
younger 
18% 
(6/33) 
12% 
(13/112) 
 
Age: 50 to 
74 years 
33% 
(50/152) 
18% 
(20/114) 
 
Age: 75 
and older 
56% 
(14/25) 
46% 
(6/13) 
 
All age 
groups 
33% 
            (70/210) 
16% 
(39/239) 
 
Total 
                                                    24% 
                                                (109/449) 
 
Arterial Occlusion and Thrombosis 
 
Arterial occlusion and thrombosis occurred in at least 20% (91/449) of ponatinib-treated 
patients with some patients experiencing events of more than one type. Patients have required 


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revascularization procedures (cerebrovascular, coronary, and peripheral arterial) due to 
vascular occlusion from ponatinib. 
Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and 
coronary artery occlusion has occurred in 12% (55/449) of ponatinib-treated patients. 
Patients have developed heart failure concurrent or subsequent to the myocardial ischemic 
event. 
 
Cerebrovascular occlusion, including fatal stroke, has occurred in 6% (27/449) of ponatinib-
treated patients. Iclusig can cause stenosis over multiple segments in major arterial vessels 
that supply the brain (e.g., carotid, vertebral, middle cerebral artery). 
 
Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-
threatening peripheral arterial disease, have occurred in 8% (36/449) of ponatinib-treated 
patients. Patients have developed digital or distal extremity necrosis and have required 
amputations. 
 
Venous Thromboembolism 
 
Venous thromboembolic events occurred in 5% (23/449) of ponatinib-treated patients, 
including deep venous thrombosis (8 patients), pulmonary embolism (6 patients), superficial 
thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients).  
 
Human Clinical Pharmacology Studies of Ponatinib 
 
Three separate studies of ponatinib have been performed in healthy subjects to examine the 
clinical pharmacology of ponatinib.  
 
AP24534-11-102 
 
Trial AP24534-11-102 compared the effects of either a high fat meal, low fat meal, or fasting 
conditions on the bioavailability and pharmacokinetics of a single oral dose of ponatinib 
administered to healthy subjects. A total of 24 subjects enrolled, each receiving a single dose 
of 45 mg of ponatinib. Independent of diet or fasting conditions, mean ponatinib plasma 
concentrations reached a maximum at approximately 5-6 hours after ingestion of ponatinib. 
Similarly, no differences were observed across the three groups in terms of maximum time 
(tmax), maximum concentration (Cmax), and AUC0-∞.  
 
AP24534-11-103 
 
Trial AP24534-11-103 investigated potential drug-drug interactions of ponatinib. The 
objective of this study was to determine the effects of concomitant ketoconazole administration 
on the pharmacokinetic profile of single-dose ponatinib in 22 healthy subjects. Ketoconazole 
is a strong inhibitor of CYP3A4. This study demonstrated a statistically significant effect of 
ketoconazole co-administration on the relative bioavailability of ponatinib along with its 


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CYP3A4/5 metabolite, AP24567. Specifically, ketoconazole co-administration increased the 
Cmax and AUC of ponatinib by 47% and 78%, respectively.  
 
AP24534-11-104 
 
In study AP24534-11-104, the absorption and excretion of 14C-labeled ponatinib was evaluated 
in 6 healthy subjects. The median time to achieve maximal [14C] radioactivity concentrations 
(Tmax) in plasma and whole blood was 5 and 8 hours, respectively. Geometric mean ponatinib 
Cmax was 58.4 ng/mL. Geometric mean ponatinib AUC0-∞ was 1861 h*ng/mL. The mean half-
life for ponatinib was 38.1 hours. A majority of radioactivity (86.6%) was recovered in feces, 
while 5.4% was recovered in urine. This study confirms that hepatic elimination is the major 
excretory route for ponatinib in humans.  
2.2 Study Disease 
Lung cancer is the leading cause of cancer-related mortality in the United States (Jemal, et al 
2008). The disease is traditionally divided into non-small-cell and small-cell variants, with 
non-small-cell lung cancer (NSCLC) accounting for approximately 85% of cases (Herbst, et 
al 2008). NSCLCs can be further distinguished based upon histologic subtypes, which include 
adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (West, et al 2009). 
Despite advances, a majority of patients with NSCLC present with locally advanced or 
metastatic disease, at which time the disease is considered incurable (Pfister, et al 2004).  
 
Platinum-based doublets with or without bevacizumab have become the standard of care for 
the first-line management of advanced or metastatic NSCLC (Bunn, 2002; Azzoli, 2009; 
Sandler, 2006). At the time of disease progression, second-line therapies include docetaxel, 
pemetrexed, and erlotinib (Azzoli, 2009). While these agents are superior to best supportive 
care, their clinical activity is quite modest with response rates of less than 10% (Shepherd, 
2000; Shepherd, 2005; Hanna, 2004). Given these limited results, additional effective therapies 
or treatment strategies are needed.  
 
Recently, a new paradigm has emerged in the management of NSCLC based upon stratification 
of patients into molecularly-defined subgroups. Broad genotyping efforts have revealed that 
approximately 50% of lung adenocarcinomas possess at least one mutation in a driver 
oncogene (Sequist, 2011). Importantly, recognition of these driver mutations may have 
implications for therapy. In NSCLC, this approach was initially established with the 
identification of activating mutations in the epidermal growth factor receptor (EGFR). 
Mutations in EGFR are identified in approximately 10% of unselected NSCLC patients, but 
the incidence of EGFR mutations increases to nearly 50% in never-smokers (Pham, 2006). 
Multiple randomized phase III trials have demonstrated the superior efficacy of EGFR tyrosine 
kinase inhibitors (TKIs) compared to first line cytotoxic chemotherapy in this molecularly 
defined subpopulation of patients (Mok, 2009; Maemondo, 2010; Zhou, 2011; Rossell; 2012). 
As a result, EGFR testing has now become an established clinical practice in order to guide 
clinical decision making in NSCLC (Keedy, 2011).  
 


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The success of EGFR-directed therapies in NSCLC has led to the recognition of additional 
driver mutations or translocations involving oncogenes such as ALK, ROS, HER2, and BRAF 
(Pao, 2011). Like patients with EGFR mutations, patients harboring ALK translocations derive 
substantial clinical benefit from targeted tyrosine kinase inhibition with crizotinib (Kwak, 
2010). In light of these successes and given the limited efficacy of cytotoxic chemotherapy in 
NSCLC, efforts are underway to identify novel therapies directed at molecularly-defined 
subpopulations of patients.  
2.3 Study Rationale 
Chromosomal translocations involving the RET oncogene have recently been identified as 
potential new driver mutations in NSCLC, occurring in approximately 1-2% of patients 
(Kohno et al, 2012, Takeuchi et al, 2012, Lipson et al, 2012). Specifically, pericentric 
chromosomal inversion results in a fusion transcript of KIF5B and RET, leading to aberrant 
activation of the RET kinase (Ju et al, 2012). Recently, CCDC6 has been identified as an 
alternative RET fusion partner in NSCLC (Li et al, 2012; Taekeuchi et al, 2012). In the setting 
of these translocations, RET signaling promotes cell survival and proliferation through the 
RAS-MAPK and PI3K-AKT pathways (Li et al, 2012). In cell lines, the KIF5B-RET fusion 
gene leads to oncogenic transformation (Lipson et al, 2012; Kohno et al, 2012). The presence 
of RET fusion genes also leads to the formation of subcutaneous tumors in a nude mouse 
tumorigenicity assay (Takeuchi et al, 2012), lending support to the idea that RET fusions may 
represent a new independent oncogenic driver. Clinically, this is supported by the finding that 
among patients with KIF5B-RET or CCDC6-RET fusion positive tumors, specimens were 
negative for concomitant mutations such as EGFR, KRAS, ALK, ROS or Her2 (Kohno et al, 
2012).  
 
Preclinical data suggests that RET is a viable target for tyrosine kinase inhibition. Indeed, cell 
lines expressing KIF5B-RET are sensitive to multi-target kinase inhibitors possessing RET 
activity, including sunitinib, sorafenib, and vandetanib (Lipson et al, 2012; Kohno et al, 2012). 
Conversely, gefitinib and crizotinib, multi-targeted TKIs without known RET activity, were 
ineffective at inhibiting proliferation in these same cell lines possessing RET translocations 
(Lipson et al, 2012; Kohno et al, 2012).  
 
Clinically, RET has served as a therapeutic target in the treatment of other malignancies, such 
as medullary thyroid cancer (Wells et al, 2010). Germline mutations in RET underlie multiple 
endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma, while somatic 
mutations in RET are seen in approximately 50% of sporadic medullary thyroid carcinomas 
(Romei et al, 1996; Marsh et al, 1996). Given the central oncogenic role of RET in medullary 
thyroid carcinoma, recent efforts have focused on targeting this oncogene through targeted 
tyrosine kinase inhibition. Vandetanib is an oral TKI that selectively targets RET, vascular 
endothelial growth factor (VEGF), and EGFR. In a phase III randomized trial in patients with 
locally advanced or metastatic medullary thyroid carcinoma, vandetanib resulted in improved 
response rates and progression-free survival compared to placebo, suggesting that RET can be 
a viable novel target (Wells et al, 2010).  
 


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In this phase II, open label study, we propose use of the orally available TKI ponatinib in the 
treatment of patients with NSCLC harboring translocations in RET. Ponatinib has broad 
activity against a range of tyrosine kinases, including extremely potent inhibition of RET. In 
vitro, ponatinib inhibits RET kinase activity with an IC50 of 0.16 nM (Ponatinib Clinical 
Investigator’s Brochure, 10Apr2012). Given its favorable toxicity profile and potent RET 
inhibition, there is strong rationale for the use of ponatinib in this molecularly-defined 
subpopulation of patients with NSCLC.  
 
Participants will receive ponatinib at a dose of 30 mg orally once daily, which is below the 
maximum tolerated dose (45 mg once daily). This is based upon available pharmacokinetic, 
safety, and efficacy data from CML patients treated with ponatinib. In prior studies of 
ponatinib in the CML population, rates of adverse events (e.g. thrombocytopenia, neutropenia,  
rash, ALT/AST elevation, pancreatitis, and lipase elevation) appeared to correlate with increasing doses 
of ponatinib 
(http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pd
f. Accessed 10/13/2013). In addition, larger doses of ponatinib were associated with higher grades of 
ischemia 
(http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000ClinPharmR.pd
f. Accessed 10/13/2013). We have chosen a ponatinib dose of 30 mg once daily in order to 
reduce the risk of adverse events. Participants will also be required to receive concomitant 
thromboprophylaxis as detailed in Section 6.11. Since ponatinib is an extremely potent 
inhibitor of RET, we expect to achieve adequate target inhibition at this dose. However, in 
patients who do not achieve an objective response response within the first 2-4 cycles of 
treatment, dose escalation to a ponatinib dose of 45 mg once daily may be permitted provided 
certain criteria are met (Section 7.4) and after discussion with the Sponsor.  
 
Patients will be eligible for participation regardless of prior treatment with TKIs known to have 
anti-RET activity (e.g. vandetanib, sorafenib, XL-184). The rationale for including RET-
positive patients with prior RET TKI exposure in the study population is based upon recent 
experience in other subtypes of oncogene-driven NSCLC, namely ALK-positive NSCLC. 
Among patients with ALK rearrangements, the ALK TKI crizotinib is associated with response 
rates of approximately 60% (Kwak et al, 2010). However, in a preliminary report of the second 
generation ALK TKI LDK378, response rates were greater than 80% in patients who had 
previously progressed on crizotinib (Mehra et al, 2012), suggesting that use of more potent 
TKIs may still be effective in patients with acquired resistance. This has yet to be examined in 
a RET-positive patient population.  
3 Participant Selection 
3.1 Eligibility Criteria 
Patients must meet the following criteria on screening examination to be eligible to participate 
in this study:  
 
3.1.1 Signed informed consent. 


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3.1.2 Age ≥ 18 years.  
 
3.1.3 Histologically or cytologically confirmed advanced (stage IIIB or IV) NSCLC.  
 
3.1.4 Molecular confirmation of a RET translocation is required to begin protocol 
therapy. Methods of acceptable molecular confirmation include RET FISH and 
next-generation sequencing performed in a CLIA certified lab.   
 
3.1.5 At least one measurable lesion as defined by RECIST v1.1 criteria. Previously 
irradiated lesions are not measurable unless the lesion has demonstrated clear 
progression after radiation. See Section 9.0 for the evaluation of measurable 
disease.  
 
3.1.6 Eligible participants must have received at least one line of prior therapy. Note: 
Patients will be eligible for participation despite prior treatment with known RET 
TKIs (e.g. vandetanib, sorafenib, XL-184).  
 
3.1.7 Performance status score of 0-2 according to the Eastern Cooperative Group 
(ECOG) scale.  
 
3.1.8 Estimated life expectancy ≥ 12 weeks.  
 
3.1.9 Able to swallow and retain orally administered medication. Does not have any 
clinically significant gastrointestinal abnormalities, such as malabsorption 
syndrome or major resection of the stomach or small bowel that may alter 
absorption of the medication.  
 
3.1.10 Adequate bone marrow function as defined by the following criteria: 
• Absolute neutrophil count (ANC) ≥ 1.5x109/L 
• Hemoglobin ≥ 9 g/dL 
• Platelets ≥ 100x109/L 
 
3.1.11 Adequate hepatic function as defined by the following criteria:  
• Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN), unless due to Gilbert’s 
syndrome.  
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN 
• Aspartate aminotransferase (AST) ≤ 2.5 x ULN 
 
3.1.12 Adequate renal function as defined by the following criteria:  
• Serum creatinine < 1.5 x ULN 
 
3.1.13  Adequate pancreatic function as defined by the following criterion:  
• Serum lipase and amylase ≤ 1.5 x ULN 


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3.1.14 Women of childbearing potential must have a negative pregnancy test.  
 
3.1.15 Female and male patients who are of childbearing potential must agree to use an 
effective form of contraception with their sexual partners from enrollment through 
30 days after the end of treatment.  
 
3.1.16 Willingness and ability to comply with scheduled visits and study procedures.  
3.2 Exclusion Criteria 
Patients who exhibit any of the below findings at the time of screening will not be eligible for 
admission into the study.  
 
3.2.1 Major surgery within 28 days prior to initiating therapy.  
 
3.2.2 History of CNS disease. Note: Patients with brain metastases will be eligible if 
treated appropriately and if they remain clinically stable neurologically. For 
asymptomatic brain metastases, appropriate clinical treatment may include 
observation with serial imaging. 
 
3.2.3 Participants who have received systemic chemotherapy within 3 weeks of starting 
study drug.  
 
3.2.4 Participants who have received treatment with a TKI within 7 days of the first dose 
of study treatment. An alternative appropriate wash-out period based upon the 
known half-life of the agent and reversibility of drug-related adverse events may 
be considered after consultation with the study sponsor.  
 
3.2.5 Participants who have received radiation therapy within 2 weeks of starting study 
drug. Note: Participants who have received radiation therapy to a small volume 
(e.g. stereotactic radiosurgery to the CNS) will be eligible if completed > 1 week 
prior to starting study drug.   
 
3.2.6 History of significant bleeding disorder unrelated to cancer. 
 
3.2.7 History of acute pancreatitis within 1 year of study entry or history of chronic 
pancreatitis.  
 
3.2.8 History of or ongoing alcohol abuse that, in the opinion of the Investigator, would 
compromise compliance or impart excess risks associated with study participation. 
 
3.2.9 Uncontrolled hypertriglyceridemia (triglycerdies > 450 mg/dL). If a patient is 
excluded solely based upon a non-fasting triglyceride level, a fasting test should be 
performed to determine eligibility.  


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3.2.10 Study participants must have had prior EGFR and ALK testing. Participants with 
sensitizing mutations in EGFR or ALK rearrangements will be excluded.  
 
3.2.11 History of arterial thrombotic disease, specifically including, but not restricted to:  
• Myocardial infarction or unstable angina. 
• Cerebrovascular event (CVA) or transient ischemic attack (TIA). 
• Peripheral vascular disease or claudication.  
 
3.2.12 Significant uncontrolled or active cardiovascular disease, specifically including, 
but not restricted to:  
• History of clinically significant (as determined by the treating physician) atrial 
arrhythmia; or any ventricular arrhythmia.  
• History of congenital long QT syndrome.  
• Abnormal QTcB (≥ 450 msec in males and ≥ 470 msec in females) 
• Ejection fraction ≤ 50% as assessed by echocardiogram.  
 
3.2.13 Uncontrolled hypertension (Diastolic blood pressure > 100 mmHg; Systolic blood 
pressure > 150 mmHg).  
 
3.2.14 History of venous thromboembolism (e.g. deep venous thrombosis or pulmonary 
embolism) within 6 months of study entry. Note: Participants enrolled after this 
window must be on appropriate therapeutic anticoagulation.  
 
3.2.15 Taking medications that are known to be associated with Torsades de Pointes. 
Medications include but are not limited to:  
• Quinidine, procainamide, disopyramide 
• Amiodarone, sotalol, ibutilide, dofetilide 
• Erythromycins, clarithromycin 
• Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide  
• Zyprasidone, cisapride, bepridil, droperidol, methadone, arsenic 
• Chloroquine, domeperidone, halofantrine, levomethdyl, pentamidine 
• Sparfloxacin, lidoflazine 
 
Note: Participants who have taken a medication associated with Torsades de 
Pointes will still be eligible for participation if the medication is discontinued at 
least 14 days before the initiation of study treatment.   
 
3.2.16 Ongoing active infection. The requirement for intravenous (IV) antibiotics is 
considered active infection.  
 
3.2.17 Known history of human immunodeficiency virus (HIV). Testing is not required in 
the absence of history.  


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3.2.18 Pregnant or breastfeeding.  
 
3.2.19 Diagnosed with or received anti-cancer therapy for another primary malignancy 
within 3 years prior to entry (except for non-melanoma skin cancer or in situ 
cancers).  
 
3.2.20 Any condition or illness that, in the opinion of the Investigator, would compromise 
patient safety or interfere with the evaluation of the drug.  
4 
Registration Procedures 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office 
for Clinical Trials (QACT) central registration system. Registration must occur prior to the 
initiation of therapy. Any participant not registered to the protocol before treatment 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 treatment. Issues that would cause 
treatment delays should be discussed with the Principal Investigator (PI). If a participant does 
not receive protocol therapy following registration, the participant’s registration on the 
protocol may cancelled. Registration cancellations must be made in OnCore as soon as 
possible.   
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
DF/HCC Standard Operative Procedure for Human Subject Research titled “Subject Protocol 
Registration (SOP #: REGIST-101) must be followed. 
4.3 
General Guidelines for Other Participating Institutions 
Eligible participants will be entered on study centrally at Massachusetts General Hospital 
by the Coordinating Center. All sites should contact the Coordinating Center to verify 
treatment availability. 
 
Following registration, participants should begin protocol treatment within 72 hours or as soon 
as possible. Issues that would cause treatment delays should be discussed with the Principal 
Investigator/Sponsor. If a participant does not receive protocol therapy following registration, 
the participant’s protocol status must be changed. The Coordinating Center should be notified 
of participant status changes as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order the study 
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the initial IRB approval for the site has been forwarded by the Coordinating Center to the 
supplier. 
4.4 
Registration Process for Other Participating Institutions 
Refer to section 3.7 of Appendix D (Data and Safety Monitoring Plan) of protocol for 
instructions on registration process. 
 
5 Study Procedures 
5.1 Study Procedures Descriptions 
See the Schedule of Events (Table 8.1) for the required assessments at each visit. The following 
list describes the procedures/tests required for this study.  
 
1.  Informed consent:  Informed consent, documented by a signed consent form, must be 
obtained prior to any screening activities not otherwise part of the participant’s care. A note 
documenting the informed consent procedure should be included in the participant’s 
medical record. 
 
2.  Demographics: Demographic information consists of the participant’s age, gender, race, 
and ethnicity (as allowed by local law and regulations). 
 
3.  Medical and Surgical History: Medical and surgical history includes diagnoses, 
therapies, medical and surgical treatments, and current medications. 
 
4.  Prior Cancer Therapy:  Prior cancer therapy history consists of the specific oncologic 
regimens a patient has received, the dates of the regimen and the best response to the 
regimen, and the reason for failure or intolerance to each regimen. Stem cell transplant or 
experimental or investigational therapy history must also be recorded. 
 
5.  Diagnosis: The initial cancer diagnosis and the current cancer diagnosis at the time of 
screening (if different), along with dates of diagnosis need to be recorded. 
 
6.  Mutation Status: Any previously identified RET translocations, method of identification 
and the dates of identification must be recorded. If available, the presence of additional 
mutations such as KRAS, EGFR, ALK or ROS should be recorded.  
 
7.  Physical Exam: A complete physical examination will be performed, the extent of which 
should be consistent with the medical history and the participant’s underlying disease.   
 
8. Vital Signs: Vital signs include temperature, pulse, respiratory rate, and blood pressure 
(when patient is seated). In addition, the screening assessment should include height and 
weight.  
 


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9. ECOG Performance Status: The participant’s performance status must be assessed using 
the ECOG performance scale (Appendix A). 
 
10. Hematology: Hematology measurements include complete blood count (CBC) with 
differential and platelet count. 
 
11. Serum Chemistry: Serum chemistry (either fasting or non-fasting) consists of a peripheral 
blood draw with the following assessments: sodium, potassium, chloride, bicarbonate, 
blood urea nitrogen (BUN, or urea), albumin and total protein, creatinine, total bilirubin 
(direct and indirect), ALT (SGPT), AST (SGOT), alkaline phosphatase, magnesium, 
phosphorous, calcium, amylase and lipase. Triglycerides will only be obtained at baseline. 
 
12. Pharmacokinetics: Plasma PK samples will be obtained on cycle 1, day 1 and cycle 2, 
day 1. Please refer to the Schedule of Events (Table 8.1). Samples will be sent to Advion 
Bioanalytical Labs for analysis. Refer to the study-specific laboratory manual for details. 
 
13. Electrocardiogram (ECG): All ECGs must be 12-lead ECGs. Please refer to the Schedule 
of Events (Table 8.1) for the required ECG schedule.  Additional ECGs may be performed 
at the investigator’s discretion to ensure patient safety. In particular, ECG monitoring 
should be performed during the study if a patient is taking medications that can potentially 
prolong the QT interval (other than medications explicitly prohibited). For consistency, the 
Bazett correction (QTcB) method must be used for calculating all QTc intervals. 
 
14. Echocardiogram: An echocardiogram to establish left ventricular ejection fraction (EF) 
is required at screening to determine eligibility. An additional echocardiogram may be 
performed at C4D1 at the discretion of the investigator based upon participant symptoms.  
 
15. Safety Assessments – Adverse Events: Participants must be followed for all adverse 
events (AEs) from the start of study treatment until at least 30 Days After the End of 
Treatment, and for all serious or study drug-related toxicities until the AEs are resolved or 
are considered chronic or stable or until patient contact discontinues. Serious adverse 
events (SAEs) should be monitored and reported as described in Section 10.0. 
 
 
Type, incidence, severity (graded in accordance with the National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.0), timing, 
seriousness and relatedness, outcome, action taken with study drug, and treatment will be 
assessed and documented by the investigator throughout the study. 
 
Malignancy-related signs and symptoms noted at study entry will be recorded as AEs 
during the trial if they worsen in severity or increase in frequency. 
 
16. Concomitant Medications: Concomitant medications for all ongoing medical history 
conditions or AEs must be reported from the date the informed consent is signed until at 
least 30 Days After the End of Treatment, and for all concomitant medications related to 


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serious or study drug-related toxicities until the medication is no longer taken or until 
patient contact discontinues. 
 
17. Pregnancy Test: The pregnancy test must be a beta-human chorionic gonadotropin (β-
HCG) test and either urine or serum can be used. Women who are not of childbearing 
potential (status post-hysterectomy, status post-bilateral oophorectomy, or post-
menopausal [defined as amenorrhea for at least 12 months]) and men do not need to have 
the test performed. The test must be known to be negative prior to the study drug 
administration and be performed within 7 days prior to first study drug administration. 
 
18. Disease Assessment: At screening, disease assessment must include imaging of the chest, 
abdomen, pelvis and brain using appropriate radiological procedures (computed 
tomography [CT] scan, MRI scan) and physical examination (for palpable lesions). Brain 
imaging is required at entry. Follow-up brain imaging need not be routinely performed in 
the absence of findings. Target and non-target lesions must be selected at study start and 
followed throughout the course of treatment for response assessment according to RECIST 
guidelines (See Section 9).  Imaging assessment is also required to be performed at the End 
of Treatment. Note: RECIST-defined responses will be confirmed with an imaging 
assessment ≥4 weeks later.  
 
19. Survival: All participants should be followed for survival every 3 months, up to 2 years 
after the initial dose of ponatinib.   
5.2 Screening Period 
The screening period begins when the informed consent form is signed, and continues until the 
first dose of ponatinib is administered. Screening physical examination, vital signs, and ECOG 
assessments can be used as the Day 1 assessment, without the need for having to repeat the 
tests, if these screening assessments are accomplished within 7 days prior to Day 1.  
 
Assessments required at screening are shown on the Schedule of Events (Table 8.1). A detailed 
description of procedures is provided in Section 5.1.   
5.3 Screen Failures 
Patients who have signed informed consent and subsequently fail to meet the inclusion and/or 
exclusion criteria are defined as screen failures. For all screen failures, the Investigator is to 
maintain a screening log that documents the patient initials and reason(s) for screen failure. A 
copy of the log should be retained in the Investigator’s study files. 
5.4 Active Study Period 
The active study period begins when the participant receives the first dose of ponatinib. 
Assessments required during the active study period are shown on the Schedule of Events 
(Table 8.1). A detailed description of procedures and timing is provided in Section 5.1.  
 


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Note: Clinical laboratory assessments do not need to be repeated on Cycle 1 Day 1 if they were 
performed for screening within 7 days prior to Cycle 1 Day 1. 
 
Note: Cycle 1 day 1 labs must be reviewed prior to initiation of study treatment. See Table 7.1 
for administration criteria and dose modifications for cycle 1 day 1.  
5.5 End of Treatment 
The End of Treatment is defined as the point when the participant receives the last dose of 
ponatinib or the participant discontinues taking ponatinib. Study procedures at the End of 
Treatment must be conducted within 14 days following the last dose of study drug. 
 
Assessments required at the End of Treatment are shown on the Schedule of Events (Table 
8.1). A detailed description of procedures and timing is provided in Section 5.1. 
5.6 30 Days After End of Treatment 
Participants are required to complete all post treatment discontinuation assessments 30 Days 
After End of Treatment. Study procedures at 30 Days After End of Treatment must be 
conducted within 30 days (± 7 days) following the last dose of study drug. 
 
Assessments required at 30 Days After End of Treatment are shown on the Schedule of Events. 
A detailed description of procedures and timing is provided in Section 5.1. 
5.7 Follow-up Period 
The follow-up period for a participant begins after the last completed assessment during the 
active study period. Any participant who discontinued study treatment for any reason other 
than disease progression, death or withdrawal of consent will continue to have tumor 
assessments every 12 weeks (±14 days) until the participant starts another anti-cancer therapy.  
 
All participants should be followed for PFS and survival at least every 3 months (± 14 days), 
up to 2 years after the initial dose of ponatinib. 
5.8 Duration of Therapy / Subject Discontinuation 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. Treatment will continue until one of the following: 
 
• Intolerable toxicity as determined by the Investigator.  
• Progression of disease requiring an alternative therapy. Note: In some cases, despite 
disease progression by RECIST criteria, participants may be continued on study drug if 
deemed beneficial by the participant and investigators as well as approval from the 
Principal Investigator/Sponsor. 
• Entry into another therapeutic clinical trial or implementation of another anti-cancer 
therapy.  


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• Significant deviation from the protocol or eligibility criteria, in the opinion of the 
Investigator.  
• Noncompliance with study or follow-up procedures.  
• Withdrawal of participant consent.  
• Termination of the trial by the Principal Investigator/Sponsor.  
• Any other reason that, in the opinion of the Investigator, would justify removal of the 
participant from the study.  
 
In the event that a participant is withdrawn from the study, every effort will be made by the 
Investigator to document and report the reason(s) for withdrawal as thoroughly as possible. 
The reason(s) for withdrawal must be clearly reported on the appropriate page of the 
participant’s electronic case report form (eCRF). An eCRF must be completed for any 
participant who receives study drug. An End-of-Treatment reason must be recorded for any 
participant who receives study medication. 
 
If a participant is discontinued from the trial for any reason, every effort must be made to 
perform all End of Treatment assessments per the schedule of events. In the event that the 
participant fails to return for the necessary visit(s), an effort must be made to contact the 
participant to determine the reason, and this information should be recorded in the appropriate 
source record and reported as a deviation. All participants who discontinue prematurely from 
the active study period will be followed for PFS and survival at least every 3 months (± 14 
days), up to 2 years after the initial dose of ponatinib.  
6 Treatment Plan 
Treatment will be administered on an outpatient basis. Expected toxicities and guidelines for dose 
modifications for ponatinib are described in Section 7 (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. 
 
 
Treatment Description 
Agent 
Pre-medication /  
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Ponatinib 
Anti-thrombotic 
therapy (e.g. 
aspirin), Lipid-
lowering therapy 
(e.g. statin) 
30 mg 
daily 
Orally 
Daily 
28 days 
6.1 Study Drug 
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6.2 Selection of Starting Dose 
The starting dose of ponatinib is 30 mg per day (see Section 2.3 for more details on the starting 
dose rationale).  
6.3 Treatment Administration 
Participants will self-administer ponatinib at home at a dose of 30 mg by mouth daily. 
Ponatinib will be taken on a continuous daily basis. Each 28-day dosing period is referred to 
as 1 cycle. Dose adjustments will be made as necessary as outlined in Section 7. Participants 
will be instructed to keep a study diary of drug administration. In addition, participants will be 
provided with a copy of the FDA’s medication guide on ponatinib. This guide can be accessed 
at:  
 
http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm 
 
Participants will be instructed to take ponatinib at approximately the same time of day. 
Participants have a +6 hour window. There must be a minimum of 18 hours between doses. 
Participants who forget to take their scheduled dose of study drug will be instructed not to 
make up the missed dose. Ponatinib can be taken with or without food.   
 
Missed doses should be recorded in the appropriate source record (e.g. clinic chart), study diary 
card and study drug administration electronic case report form (eCRF). Vomited doses should 
not be made up.  
6.4 Formulation, Packaging, and Labeling  
Ponatinib is supplied as 15 mg and 45 mg round, white, film-coated tablets. The tablet 
formulation includes inactive ingredients: lactose monohydrate, microcrystalline cellulose, 
sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, polyethylene glycol, 
tale, polyvinyl alcohol, and titanium dioxide.  
 
All of the excipients used in ponatinib tablets 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.  
6.5 Handling 
Procedures for proper handling and disposal of anticancer drugs should be considered. 
 
If tablets are crushed or broken, pharmacy and clinical personnel should wear disposable 
chemotherapy gloves. Personnel who are pregnant should avoid exposure to crushed and/or 
broken tablets. 
 
The Investigator (or assigned designee, i.e., study pharmacist) will dispense the proper number 
of each strength tablet to the participant to satisfy dosing requirements for the study. The 


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containers provided to the participant should be labeled with proper instructions for use. The 
lot numbers, dosing start dates and the number of tablets for each dosage strength must be 
recorded on the drug accountability pages of record for the site. The participant must be 
instructed to return all unused ponatinib in the provided packaging at each subsequent visit. 
6.6 Availability 
Ponatinib will be provided free of charge to study participants by Ariad.  
6.7 Storage 
Bottles containing ponatinib tablets should be stored at room temperature. 
 
All investigational products should be stored in a secure area according to local regulations. 
The investigator is responsible for ensuring that it is dispensed only to study participants and 
only from official study sites. 
6.8 Ordering 
Each investigative site will order ponatinib directly through Ariad. Shipments will be at 
appropriate intervals, depending on patient accrual. Each site must use an appropriate 
dispensing log/accountability form provided by the Sponsor, or an acceptable substitute 
approved by the Sponsor. Each time study medication is dispensed for a participant, the 
following information must be recorded: the patient’s initials, the patient’s study number, 
tablet strength (45 mg or 15 mg), the number of tablets dispensed with the corresponding lot 
number, and the initials of the person dispensing the drug. Ponatinib may be repackaged by 
the site pharmacy and is typically supplied in bottles containing 60 tablets. If repackaged, 
ponatinib should be placed into a high density polyethylene (HDPE) bottle. These logs are to 
be maintained by the study pharmacist in the pharmacy throughout the duration of the study. 
Logs at non-DF/HCC sites will be periodically verified by a representative of the Sponsor. The 
Investigator is responsible for ensuring that the patient diary card(s) and study drug provided 
to the participant and returned from the participant are accounted for and noted in source 
documentation. 
6.9 Accountability 
The investigator will ensure that a current record of disposition of investigational product is 
maintained at each study site where the investigational product is inventoried and disposed. 
 
Ponatinib dispensing record/inventory logs and copies of signed packing lists must be 
maintained at the investigational site. Batch numbers for ponatinib must be recorded in the 
drug accountability records. 
6.10 Destruction and Return 
If the investigational product is to be destroyed on site, it is the investigator’s responsibility to 
ensure that arrangements have been made for disposal, and that procedures for proper disposal 


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have been established according to applicable regulations, guidelines, and institutional 
procedures. Appropriate records of the disposal must be maintained. 
 
Consult with the Principal Investigator for instructions on disposal of unused ponatinib tablets. 
6.11 Required Concomitant Therapy 
Ponatinib has been associated with an increased risk for arterial thrombotic events, such as 
myocardial infarction, peripheral vascular disease and cerebrovascular accident.  
 
Thromboprophylaxis is required for all participants receiving ponatinib. It is recommend that 
participants receive daily aspirin (81 or 325 mg). Note: This does not apply to participants 
who are already receiving therapeutic anticoagulation (e.g. low molecular weight heparin), 
provided that these participants meet the eligibility criteria outlined in Sections 3.1 and 3.2. It 
is recommended that if the platelet count falls below 50,000/mm3, thromboprophylaxis be 
held to minimize the risk of bleeding. It should then be resumed when platelet counts are 
equal to or above this level.  
 
All patients should also be treated with a statin to reduce the risk of cardiovascular events. 
We recommend atorvastatin (Lipitor) administered at a minimum of 10 mg/day, but other 
statins and doses may be substituted if appropriate. The specific regimen should correspond 
with moderate-intensity or high-intensity statin therapy as defined by the recent AHA/ACC 
guidelines (Stone et al, Circulation 2013, 
http://circ.ahajournals.org/content/suppl/2013/11/07/01.cir.0000437738.63853.7a.DC1.html). 
High-intensity therapy should be considered in patients in high risk categories, such as those 
with a history of cardiovascular disease, diabetes, or LDL cholesterol greater than 190 
mg/dL, but patient age and risk of side effects due to statin therapy (myopathy, elevated 
CPK, elevated liver enzymes) should be taken into consideration. Measurement of 
cholesterol and dose adjustment to meet a cholesterol target is not necessary but could be 
considered to ensure compliance or per physician or patient preference.  
6.12 Permitted Treatment 
All routine and appropriate supportive care, including blood products, will be provided during 
this study, as clinically indicated, and in accordance with the standard of care practices. Please 
see Section 7 for management of expected adverse events (AEs).  
 
Palliative radiation therapy will be permitted for participants with symptomatic bone 
metastases or CNS metastases as long as they have demonstrated stability in terms of systemic 
disease. Disease stability for these purposes will be defined as complete response, partial 
response, stable disease or clinical benefit in the opinion of the Investigator. For participants 
undergoing radiation, ponatinib must be held for at least 72 hours before the initiation of 
radiation. Ponatinib may be resumed no sooner than 72 hours after the completion of radiation.  


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6.13 Prohibited Treatment 
The following concurrent medications and treatments are prohibited:  
 
• Any other anti-cancer therapy including, but not limited to, chemotherapeutic agents, 
immunotherapy, biological response modifiers, surgery and/or systemic hormonal therapy 
(hematopoietic growth factors are permitted).  
• Use of any other investigational drug or device.  
• Use of medications that are known to be associated with the development of Torsades de 
Pointes (see Appendix B). 
• Herbal preparations or related over-the-counter preparations containing herbal ingredients 
either during or within 2 weeks prior to the first dose of ponatinib.  
• Elective surgery requiring in-patient care.  
6.14 Treatments to be Used with Caution 
Medications that are potent substrates, inhibitors or inducers of P450 cytochromes, in 
particular CYP3A4 (see Appendix C), should be avoided when possible but are not prohibited.  
 
Medications that prolong the QTcB interval should be avoided when possible but are not 
prohibited. If such medications are deemed necessary and used while a participant is on study, 
additional ECG monitoring should be performed as clinically indicated.  
6.15 Potential Drug-Drug Interactions 
In vitro and in vivo studies have demonstrated that CYP3A4 is involved in the metabolism of 
ponatinib. Therefore, drug-drug interactions (DDIs) are possible if ponatinib is given with 
substrates, inhibitors or inducers of CYP3A4 (see Appendix C). Investigators are encouraged 
to avoid administration of drugs that are substrates, inhibitors or inducers of CYP3A4 if 
clinically feasible.  
 
Additionally, medications associated with prolongation of the QTc interval may interact with 
ponatinib and contribute to further QTc prolongation, which has the potential to contribute to 
ventricular arrhythmia. In addition, some medications associated with QTc prolongation also 
interact with the CYP3A4 cytochrome and an effect on the QTc interval might thus be 
exacerbated.  
 
7 Expected Toxicities and Dose Modifications 
The most common expected toxicities for ponatinib include rash, dry skin, thrombocytopenia, 
abdominal pain, elevations in amylase and lipase, pancreatitis, anemia, neutropenia, hypertension, 
QTc prolongation, hepatotoxicity, headache, fatigue and myalgias. Please see Table 2.2 for the 
frequencies of adverse events in the previous ponatinib phase II trial AP24534-10-201. For dose 
modifications and toxicity-specific management, please refer to Table 7.1 and Section 7.5.  


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7.1 Management of Adverse Drug Reactions 
Comprehensive assessments of any study drug-related adverse events experienced by the 
participant will be performed throughout the course of the study. The severity of the event, as 
well as clinical judgment, will be utilized to determine appropriate management of the 
participant for any AE experienced while participating in this trial. 
7.2 Dose Delays and Reductions 
Dose delays and/or reductions will be implemented for participants who experience adverse 
drug reactions as indicated in the following sections. 
7.3 Dose Delay and/or Reduction for Adverse Events (AEs) Attributable to the Study 
Drug 
Table 7.1 describes suggested guidelines for dose modification due to study-drug-related 
toxicity, graded according to NCI CTCAE 4.0. However, for an individual participant, dose 
interruptions, reductions and treatment discontinuation should also be based on the clinical 
circumstance and investigators should use clinical judgment in deciding whether a dose 
reduction, delay or discontinuation is appropriate for any given clinical circumstance. In 
general, when the observed toxicity has resolved to ≤ grade 1, the investigator may resume full 
dosing if clinically indicated. 
 
No dose reduction below 15 mg once daily is permitted for ponatinib. If the participant cannot 
tolerate a minimum dose of 15 mg per day of ponatinib, despite any allowed interruptions, the 
participant must be discontinued from study treatment. Doses may be interrupted for study-
drug related toxicities for up to 28 days. If a non-hematologic study-drug related toxicity does 
not resolve to Grade 1 or less after dose interruption for more than 28 days, the participant 
must be discontinued from study treatment. If a hematologic study-drug related toxicity does 
not resolve to Grade 1 or less after dose interruption for more than 28 days, the Principal 
Investigator/Sponsor must be contacted. Additionally, the Principal Investigator/Sponsor must 
be contacted if any adverse event deemed unrelated to treatment requires dose interruption for 
more than 28 days. Lastly, for each participant, once a dose reduction has occurred, the dose 
level may not be re-escalated during subsequent treatment cycles of ponatinib.  
 
 
 
 
 








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7.5.2 Myelosuppression 
 
Neutropenia, anemia, and thrombocytopenia have all been commonly reported either 
together or individually in patients treated with ponatinib. While myelosuppression can 
occur any time during treatment, its onset most commonly occurs within the first month on 
treatment. 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 (see Table 7.1). Rarely, one or more cytopenias can lead to permanent 
discontinuation of treatment. The use of hematopoietic growth factors such as granulocyte 
colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor 
(GM-CSF) 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 adverse event 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]. 
 
7.5.3 Rash and/or Pruritus 
Skin rashes have been commonly reported to be associated with ponatinib. The vast 
majority of the skin events are 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 an acneiform 
dermatitis or diffuse maculo-papular rash that is non-pruritic. 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. 
 
7.5.4 Pancreatitis and Amylase or Lipase Elevations 
 
Pancreatitis (symptomatic abdominal pain associated with pancreatic enzyme elevation) 
and/or elevations in lipase and amylase are known AEs associated with ponatinib. 
Pancreatitis was reported in 7% of patients in the phase 2 study of ponatinib and 12% in 
the phase 1 dose-escalation study. Most cases of pancreatitis or elevated pancreatic 
enzymes occur within the first month 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.  


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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. 
 
7.5.5 Diarrhea, Nausea, and Vomiting 
 
Diarrhea is a less-common side effect of ponatinib. The use of anti-diarrhea medications is 
permitted.  Participants 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 not commonly seen with ponatinib. The use of an antiemetic 
prophylactically is not recommended. However, if a participant is symptomatic, 
appropriate antiemetic medications may be used as clinically indicated. 
 
7.5.6 Constitutional Symptoms / Joint Pain 
 
Certain constitutional symptoms such as myalgia, arthralgia, headache, weakness, fatigue, 
asthenia, and low grade fever have been commonly reported with ponatinib.  For patients 
treated with ponatinib, these symptoms have been reported mainly at the initiation of 
treatment. They 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. 
 
7.5.7 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 7.1.  
 
7.5.8 Severe 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. 
 
 


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7.5.9 Hypertension 
 
Blood pressure should be monitored at each visit.  Hypertension (HTN) by at least two 
blood pressure measurements should be graded according to CTCAE version 4.0.  For 
participants who develop HTN or worsening HTN during study treatment, anti-
hypertensive 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-hypertensive therapy 
including titration of anti-hypertensive medication or introduction of additional anti-
hypertensive medications, or if grade 4 HTN develops, dose interruption and reduction is 
recommended according to Dose Modification Guidelines for general non-hematologic 
AEs in Table 7.1. 
 
7.5.10 Prolonged QTcB 
 
If a prolongation of QTcB 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 participant is on and discontinue medications that are known or suspected 
to cause QT prolongation. 
 
If no contributing reason is identified and the reason for QTcB prolongation is believed to 
be due to study medication, dose interruption and reduction guidelines for general non-
hematologic toxicities in Table 7.1 for ponatinib should be followed.  Additionally, weekly 
ECG monitoring is recommended for 4 weeks upon resumption of study drug, then 
monthly for 6 months, and then per the routine ECG schedule.  
 
8 Study Calendar 
Table 8-1 lists all of the assessments and indicates with an “X” the visit when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation and recorded on the corresponding eCRF pages.  
 
 


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Table 8-1 Schedule of Events 
Assessment1,11 
Baseline10 
Cycle 1 
Cycle 2 
Day 1 
Every 4 
weeks (Cycle 
3-10) 
Every 8 weeks 
(Cycle 3-10) 
Every 6 weeks 
(Cycle 11 +)9 
End of 
Treatment 
30 Days After 
End of 
Treatment 
Follow-
up 
Day 1 
Day 15 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Medical & Surgical 
History 
X 
 
 
 
 
 
 
 
 
 
Diagnosis & Extent of 
Tumor 
X 
 
 
 
 
 
 
 
 
 
Prior Cancer Therapy 
X 
 
 
 
 
 
 
 
 
 
Tumor Mutational 
Status2 
X 
 
 
 
 
 
 
 
 
 
Smoking Status 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Physical Exam 
X 
X 
 
X 
X 
 
X 
X 
X 
 
Electrocardiogram 
(ECG)3 
X 
 
 
 
(X)3 
 
(X)3 
X 
 
 
Cardiac Imaging 
(ECHO) 
X 
 
 
 
(X)4 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Serum Chemistry 
X5 
X 
X 
X6 
X 
 
X 
X 
X 
 
Pregnancy Test 
X 
 
 
 
 
 
 
X 
 
 
PK Sample 
 
X7 
 
X7 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Disease Assessment8 
X 
 
 
 
 
X 
X8 
X 
 
X9 
Survival 
 
 
 
 
 
 
 
 
 
X 


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Footnotes for Schedule of Events: 
 
1 
This schedule of events table is meant to provide a convenient display of the timing and scope of required assessments expected 
at each visit. It is not a comprehensive description of each assessment. A complete list of all study related assessments as well 
as a detailed description of which is expected can be found in Section 5.  
2 
Tumor mutational status: Any previously identified RET translocation, method of identification, and the dates of identification 
must be recorded. If available, the presence of additional mutations such as KRAS, EGFR, ALK or ROS should be recorded.  
3 
All ECGs should be 12-lead ECGs. ECGs are to be performed at screening, Cycle 4 Day 1, Cycle 7 Day 1, and Cycle 13 Day 1. 
Please see Table 7.1 and Section 7.5 for a description of ECG monitoring requirements if a prolonged QTcB develops in the 
course of the study period.  
4 
An additional echocardiogram may be performed on Cycle 4 Day 1 at the discretion of the Investigator based upon participant 
symptoms.  
5 
Triglycerides will be collected during the baseline assessment only. 
6 
Chemistries, including serum lipase, should also be drawn on Cycle 2 Day 15.  
7 
PK samples will be collected pre-dose on Cycle 1 Day 1 and Cycle 2 Day 1. Additional PK samples will be collected on Cycle 
1 Day 1 only at the following time-points: 1, 2, and 4 hours (±10 minutes), and 6 and 8 hrs (±20 minutes) post dose. Whole blood 
will be collected in EDTA-K2 tubes (lavender top). Refer to site-specific laboratory manual for further details.  
8 
Disease assessments will initially be performed at 8 week intervals (after cycle 2 [at the beginning of cycle 3 in the table above], 
after cycle 4 [at the beginning of cycle 5], and so on until cycle 11). From cycle 11 forward, disease assessments will be performed 
at 12 week intervals (after cycle 13 [at the beginning of cycle 14] and so on). Disease assessments may be limited to the sites of 
disease. RECIST-defined responses will be confirmed with a repeat assessment in ≥4 weeks (See Section 9). Disease assessments 
will also be performed at the End of Treatment.  
9 
Any participant who discontinued study treatment for any reason other than disease progression, death or withdrawal of consent 
will continue to have disease assessments every 12 weeks (±14 days) until the participant starts another anti-cancer therapy.  
10 
From cycle 11 forward, study visits will be every 6 weeks but disease assessments will be every 12 weeks (after cycle 13, 16, 
etc).  
11 
Baseline procedures are to be obtained within 14 days of the start of study treatment with the exception of obtaining informed 
consent and baseline disease assessments, which should be obtained within 28 days prior to the start of study treatment. 
12 
All assessments and procedures (with the exception of baseline) have a +/- 3 day window. 


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9 Measurement of Effect 
Participants will be assessed by RECIST version 1.1 criteria. For the purposes of this study, 
participants should be reevaluated every 8 weeks. In addition to a baseline scan, confirmatory 
scans should also be obtained ≥4 weeks following initial documentation of an objective response. 
If a confirmation scan is performed within 2 weeks of a regularly scheduled scan, then the regularly 
scheduled scan can be delayed until the next required time point. In practice, the confirmation scan 
will likely be obtained 8 weeks after the original responsive scan, concurrent with the next 
scheduled radiographic assessment.  
9.1 Antitumor Effect– Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) (Eisenhauer et al, 
2009) guideline. Changes in the diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria.  
9.1.1 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 cycle of therapy, 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.) 
9.1.2     Disease Parameters 
Measurable disease. Measurable disease is the presence of at least one (1) lesion that can 
be accurately measured in at least one dimension with longest diameter >20 millimeters 
(mm) using conventional techniques (x-ray) or >10 mm with spiral CT scan. Measurable 
lesions must be at least 2 times the slice thickness in mm. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
Note: A lesion in a previously irradiated area is not eligible for measurable disease unless 
there is objective evidence of progression of the lesion prior to study enrollment. Lesions 
in previously irradiated areas must be clearly identified as such. 
  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice 


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thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter < 10 mm or pathological lymph nodes with > 10 to < 15mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses identified by physical exam that are not measurable by reproducible 
imaging techniques, and cystic lesions are all considered non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Lesions must be accurately measured in 1 dimension 
with a minimum size of 10 mm by CT or MRI (slice thickness no greater than 5 mm), 20 
mm by chest x-ray. Nodes must have a short axis > 15 mm. The short axis should be 
included in the sum of the lesions in the calculation of response. Nodes that shrink to < 10 
mm are considered normal. Target lesions should be selected on the basis of their size, be 
representative of all the involved organs, and should be lesions that can be followed with 
reproducible repeated measurements.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered target lesions if the soft tissue component meets the definition of measurability 
as defined above. Cystic lesions thought to represent cystic metastases can be considered 
as target lesions. However, if non-cystic lesions are present, these are preferred for 
selection as target lesions. Lesions in previously irradiated areas or areas subject to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression of that lesion.  
Non-target lesions. All other lesions, including small lesions < 10 mm or pathological 
lymph nodes measuring > 10 mm to < 15 mm in short axis, as well as truly non-measurable 
lesions, which include leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses 
identified by physical exam that are not measurable by reproducible imaging techniques.  
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, 
or digital measurement tool. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 14 days before the beginning 
of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 


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evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of a treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or 
less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and 
pelvis. Head and neck tumors and those of extremities usually require specific protocols. 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should 
follow the NCI Guidelines for using FDG PET as an indicator of therapeutic response (L.K. 
Shankar, J.M. Hoffman, S. Bacharach, M.M. Graham, J. Karp, A.A. Lammertsma, S. 
Larson, D.A. Mankoff, B.A. Siegel, A. Van den Abbeele, J. Yap, D. Sullivan. Consensus 
recommendations for the use of 18F-FDG PET as an indicator of therapeutic response in 
patients in National Cancer Institute Trials. J Nucl Med, 47(6):901-903, 2006). Participants 
should avoid strenuous exercise and be on a low carbohydrate diet for 24 hours prior to the 
scan. Participants should fast for 4 hours or longer prior to the FDG injection and should 
have a serum glucose of less than 200 mg/dL at the time of FDG injection. A 10-20 mCi 
dose of FDG should be injected for typical adult patients. For longitudinal studies with 
multiple scans, particular attention should be paid to ensure consistent patient preparation 
and acquisition parameters between the follow-up scan and the baseline scan. When 
designing a study where PET scans are going to be utilized as one of the modalities to 
evaluate efficacy, it is important to consult with physicians in nuclear medicine in 
designing the appropriate criteria to be utilized. 
9.1.3    Response Criteria  
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
node must have reduction in short axis to < 10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study with at least a 5 mm absolute 
increase in the sum of all lesions. The appearance of one or more new lesions* denotes 
disease progression.  


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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
Note: If tumor response data is missing for target lesions, the overall assessment must be 
UN unless there is new disease that would result in an overall assessment of PD. However, 
if there is missing or unevaluable data for non-target lesions, but data is available for all 
target lesions, the overall response for that time point will be assigned based on the sum 
LD of all target lesions. Additionally, the assessment of CR cannot be made if there is 
missing or unevaluable data for non-target lesions. In this case, the overall assessment 
would be PR. 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not 
due to difference in scanning technique, imaging modality, or findings thought to represent 
something other than tumor (ex: new bone lesions may be healing or flare of pre-existing 
lesions)). However, a lesion identified on a follow-up scan in an anatomical location that 
was not scanned at baseline is considered new and will indicate PD. If a new lesion is 
equivocal (because of small size, etc.), follow-up evaluation will clarify if it truly 
represents new disease and if PD is confirmed, progression should be declared using the 
date of the initial scan on which the lesion was discovered.  
 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 
10 mm short axis).  
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesions 
and/or maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions* (new lesions must be 
> slice thickness) and/or unequivocal progression of existing non-target lesions. 
Overall level of substantial worsening that merits discontinuation of therapy. A useful test 
that can be applied when assessing non-targets for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease. 
Unknown (UN): Assessment of non-target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 


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*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not 
due to difference in scanning technique, imaging modality, or findings thought to represent 
something other than tumor (ex: new bone lesions may be healing or flare of pre-existing 
lesions). However, a lesion identified on a follow-up scan in an anatomical location that 
was not scanned at baseline is considered new and will indicate PD. If a new lesion is 
equivocal (because of small size, etc.), follow-up evaluation will clarify if it truly 
represents new disease and if PD is confirmed, progression should be declared using the 
date of the initial scan on which the lesion was discovered.  
 
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 participant's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for 
when Confirmation is 
Required: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/Not 
evaluated 
No 
SD 
Documented at least once 
>4 wks from baseline 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:   Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 


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9.1.4    Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrence or PD is objectively documented, taking as reference for PD the 
smallest measurements recorded since the treatment started. 
Duration of overall complete response: The duration of overall CR is measured from 
the time measurement criteria are first met for CR until the first date that recurrent 
disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
9.1.5    Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to time 
of objective disease progression.  
9.1.6    Response Review 
Tumor assessment for RECIST criteria will be performed by independent central review 
through the DF/HCC Tumor Imaging Metrics Core (TIMC). These reviews will be used 
only for determining response by RECIST criteria, and do not need to be used for clinical 
decision making in real time. 
For sites outside of DF/HCC, real time clinical decision making will be based upon 
investigator review of scans. However, copies of required scans (reports plus electronic 
images on CD) should be sent to the Coordinating Center within 1 week of completion, at 
which time they will undergo central review through the DF/HCC TIMC. The results of 
the central review will not be routinely made available to the sites. 
10 Adverse Event Reporting Requirements 
10.1 Definitions 
10.1.1 Adverse Event (AE) 
 
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.  
 


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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.  
10.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that:  
• Results in death 
• 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 sever form. 
• 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). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• 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. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• 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 
• respite care 
10.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
Expected adverse event 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 


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expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.   
 
Please refer to the Investigator’s Brochure for a listing of expected adverse events 
associated with the study agent(s). 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the current adverse event list, 
the Investigator’s Brochure, the package insert or when it is not included in the informed 
consent document as a potential risk.   
Please refer to the Investigator’s Brochure for a listing of expected adverse events 
associated with the study agent(s). 
10.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
 
• 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. 
10.2 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.  
 
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 website at: 
 
 http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  


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10.3 Reporting Requirements 
For multi-site trials where a DF/HCC investigator is serving as the principal 
investigator/sponsor, each participating investigator is required to abide by the reporting 
requirements set by the DF/HCC. The study must be conducted in compliance with FDA 
regulations, local safety reporting requirements, and reporting requirements of the principal 
investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution to their 
respective IRB. It is the responsibility of each participating investigator to report serious 
adverse events to the study sponsor and/or others (Coordinating Center) as described below.  
10.4 Reporting to the Study Sponsor 
10.4.1 
DF/HCC Reportable Adverse Event Reporting 
 
In addition to SAEs that meet criteria from Section 10.1.2, the Sponsor requires additional 
events to be reported to the Coordinating Center. All DF/HCC reportable adverse events 
that occur after the initial dose of study treatment, during treatment, or within 30 days of 
the last dose of treatment must be reported to the Coordinating Center on the local 
institutional SAE form. This includes the following: 
 
• Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are unexpected 
and possibly, probably or definitely related/associated with the intervention. 
 
Note: Grade 2 and Grade 3 lab abnormalities that are considered by the investigator 
to be clinically insignificant and do not require therapy, or adjustment in prior 
therapy, do not need to be reported. 
 
• All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting 
 
• All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the last study 
intervention.  
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  
 
Due to the additional expedited reporting criteria, the table below is a tool to summarize 
the reporting requirements and timelines for SAEs and DF/HCC reportable adverse events 
to the Coordinating Center. 
 
 
 






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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 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 
Principal Investigator/Sponsor, Coordinating Center 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.   
11 
Data and Safety Monitoring 
11.1 Data Reporting 
11.1.1 Method  
The QACT and Coordinating Center will collect, manage, and monitor data for this 
study.  
11.1.2 Data Submission  
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 


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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 
 
11.2 Safety Meetings 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. 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 Principal 
Investigator/Sponsor and study team. 
 
The DSMC will meet quarterly and/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 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.  
11.3 Monitoring  
Involvement in this study as a participating investigator implies acceptance of potential audits 
or inspections, including source data verification, by representatives designated by the 
Principal Investigator/Sponsor or Coordinating Center. The purpose of these audits or 
inspections 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, and any applicable regulatory 
requirements.  
 
All 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.  Refer to Appendix D for details. 
12 
Regulatory Considerations 
12.1 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 participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly constituted 
IRB governing each study location.  


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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 Coordinating Center will disseminate protocol amendment information to all 
participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
12.2 Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants 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.  
12.3 Ethics 
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 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html  
o 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/  


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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.  
12.4 Study Documentation 
The investigator 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.  
12.5 Records Retention 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
12.6 Multi-center Guidelines 
This protocol will adhere to the policies and requirements of the Dana-Farber/Harvard Cancer 
Center. The specific responsibilities of the DF/HCC Overall Principal Investigator (or Protocol 
Chair), Coordinating Center, and Participating Institutions are presented in the Dana-
Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan. 
• The DF/HCC Overall Principal Investigator/Coordinating Center is responsible 
for distributing all IND Action Letters or Safety Reports to all participating 
institutions for submission to their individual IRBs for action as required. 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.  
• Except in very unusual circumstances, each participating institution will order the 
agent(s) directly from the supplier. A participating site may order the agent(s) only 
after the initial IRB approval for the site has been forwarded to the Coordinating 
Center.  
13 
Statistical Considerations 
13.1 Study Design/Endpoints 
This study will enroll patients with advanced (stage IIIB or IV) NSCLC harboring RET 
translocations. Participants will receive oral ponatinib on an open-label basis, undergoing 
radiographic assessments of response every 2 cycles. After a participant has completed 10 
cycles, disease assessments will be performed at three cycle intervals. Response will be scored 
by RECIST criteria and consist of partial responses and complete responses. Treatment with 


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ponatinib will continue until disease progression, unacceptable toxicity, participant 
withdrawal, death or discontinuation from the study for any other reason. Participants will be 
allowed to continue receiving ponatinib despite progressive disease if they are deriving clinical 
benefit. 
 
In order to investigate the preliminary efficacy of ponatinib, the primary endpoint for this 
cohort is the overall response rate using RECIST criteria. If at least 4 of 20 participants were 
to achieve a complete or partial response, ponatinib will be considered to have promising 
clinical activity in this molecularly defined population. The decision rule is associated with 
89% power if 30% of patients in the targeted population truly were to have tumors responsive 
to ponatinib. In contrast, the probability of type 1 error is only 13% if the underlying rate of 
overall response were 10%, indicating a minimal level of anti-tumor activity. A relatively high 
rate of overall response is assumed under the alternative hypothesis, as ponatinib is an inhibitor 
against a molecular target.  
13.2 Sample Size/Accrual rate 
RET translocations are present in approximately 1-2% of patients with NSCLC. We expect to 
enroll approximately 1 participant per month between Massachusetts General Hospital, Yale 
New Haven Hospital and UC Irvine Douglas Hospital. This estimate is in keeping with accrual 
rates for other trials involving NSCLC patients with mutations (e.g. ROS1) present at a rate of 
1%.  Thus, we would complete enrollment of 20 patients in approximately 2 years.  
13.3 Analysis of Secondary Endpoints 
Secondary endpoints will be analyzed for exploratory purposes only. 
 
13.3.1 Disease Control Rates 
Disease control rates (DCR) will be scored according to RECIST criteria and consist of 
complete response, partial response, and stable disease.  
 
13.3.2 Progression-free survival and 1- year overall survival rate 
Progression free survival (PFS) rates will be calculated from the endpoints described in 
Section 9. All time-to-event variables will be recorded from the day of study enrollment. 
For 1-year overall survival (OS) rate, death events will be recorded. One-year OS rate will 
be defined by the number of participants alive 1 year from the time of study entry.  
 
13.3.3 Safety 
Toxicity will be assessed using CTC v4.0 criteria. All participants who receive any 
amount of study drug will be evaluable for toxicity. 
14 
Publication Plan 
Upon study completion and finalization of the study report, the results of this study will either be 
submitted for publication and/or posted in a publically accessible database of clinical study results.  


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15 
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Appendix A: Performance Status Criteria 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 
 
 
 
 


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Appendix B: Prohibited Drugs Affecting the QT interval 
Drugs Accepted by the QTDrugs.org Advisory Board of the Arizona CERT to have a Risk 
of Causing Torsades de Pointes and Prohibited in this Study 
 
Generic Name 
Clinical Use 
Amiodarone 
Anti-arrhythmic 
Arsenic trioxide 
Anti-cancer 
Astemizole 
Anti-histamine 
Bepridil 
Anti-anginal 
Chloroquine 
Anti-malarial 
Chlorpromazine 
Anti-psychotic / Anti-emetic / 
Schizophrenia 
Cisapride 
GI stimulant / heartburn 
Clarithromycin 
Antibiotic  
Disopyramide 
Anti-arrhythmic 
Dofetilide 
Anti-arrhythmic 
Domperidone 
Anti-nausea 
Droperidol 
Sedative / Anti-nausea 
Erythromycin 
Antibiotic / GI stimulant 
Halofantrine 
Anti-malarial 
Haloperidol 
Anti-psychotic / schizophrenia 
Ibutilide 
Anti-arrhythmic 
Levomethadyl 
Opiate agonist / pain control 
Mesoridazine 
Anti-psychotic 
Methadone 
Opiate agonist / pain control 
Pentamidine 
Anti-infective 
Pimozide 
Anti-psychotic 
Probucol 
Anti-lipemic 
Procainamide 
Anti-arrhythmic 
Quinidine 
Anti-arrhythmic 
Sotalol 
Anti-arrhythmic 
Sparfloxacin 
Antibiotic 
Terfenadine 
Anti-histamine 
Thioridazine 
Anti-psychotic 
 
 
 
 
 
 
 


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Appendix C: List of co-medications with known CYP3A4 interaction 
The following medications should be used with caution. This is not a comprehensive list of 
medications. Please contact the medical monitor with any questions.  
 
Drug Name 
Class 
Afentanil 
Analgesic 
Alprazolam 
Benzodiazepine 
Budesonide 
Corticosteroid 
Buspirone 
Anxiolytic 
Carbamazepine 
Anti-epileptic 
Chlorpheniramine 
Anti-histamine 
Clarithromycin 
Antibiotic 
Diazepam 
Benzodiazepine 
Ebastine 
Anti-histamine 
Efavirenz 
Anti-viral 
Eletriptan 
5-HT agnoist 
Everolimus 
Immune modulator 
Felodipine 
Calcium channel blocker 
Imatinib 
Anti-leukemia 
Itraconazole 
Anti-fungal 
Lovastatin 
HMG CoA reductase inhibitor 
Midazolam 
Benzodiazepine 
Nisoldipine 
Calcium channel blocker 
Phenobarbital 
Barbiturate 
Phenytoin 
Anti-epileptic 
Rifampin 
Antibiotic 
Ritonavir 
Anti-viral 
Sildenafil 
PDE-5 agonist 
Simvastatin 
HMG CoA reductase inhibitor 
Triazolam 
Benzodiazepine 
Voriconazole 
Anti-fungal 
 
Source:  
FDA guidance drug interaction studies: study design, data analysis, and implications for dosing 
and labeling, 2006.  
 
 
 
 


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Appendix D: Data and Safety Monitoring Plan 
 
 
 
 
 
 
DFCI IRB Protocol #: 13-103 
 
 
 
 
 
APPENDIX D 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1.0 INTRODUCTION ...................................................................................................66 
1.1 .. Purpose...........................................………………………………………………66 
1.2 .. Multi-Center Data and Safety Monitoring Plan Definitions……………………..66 
2.0 GENERAL ROLES AND RESPONSIBILITIES .................................................67 
2.1 .. DF/HCC Sponsor………………………………………………………………...67 
2.2 .. Coordinating Center……………………………………………………………...68 
2.3 .. DF/HCC Quality Assurance Office for Clinical Trials (QACT)………………...68 
2.4 .. Participating Institution…………………………………………………………..68 
3.0 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ..............69 
3.1 .. Protocol Distribution……………………………………………………………..69 
3.2 ... Protocol Revisions and Closures………………………………………………...69 
3.3 ... Informed Consent Requirements………………………………………………...70 
3.4 .. IRB Documentation……………………………………………………………...70 
3.5 .. IRB Re-Approval………………………………………………………………...71 
3.6 .. Participant Confidentiality and Authorization Statement………………………..71 
3.6.1............. DF/HCC Multi-Center Protocol Confidentiality……………………..71 
3.7 .... DF/HCC Multi-Center Protocol Registration Policy…………………………...71 
3.7.1 ....... Participant Registration and Randomization…………………………….72 
3.7.2 ....... Initiation of Therapy……………………………………………………..72 
3.7.3 ...... Eligibility Exceptions…………………………………………………….69 
3.7.4 ...... Verification of Registration, Dose Levels, and Arm Designation……….69 
3.8 .. DF/HCC Protocol Case Number…………………………………………………69 
3.9 ... Protocol Deviations, Exceptions and Violations………………………………...69 
3.9.1 ...... Definitions………………………………………………………………..73 
3.9.2 ...... Reporting Procedures…………………………………………………….73 
3.10 . Safety Assessments and Toxicity Monitoring…………………………………...74 
3.10.1 ..... Guidelines for Reporting Serious Adverse Events………………………74 
3.10.2 ..... Guidelines for Processing IND Safety Reports………………………….74 
3.11  Data Management………………………………………………………………..75 
3.11.1 .... Data Forms Review………………………………………………………75 
4.0 REQUISITIONING INVESTIGATIONAL DRUG .............................................75 
5.0 MONITORING: QUALITY CONTROL .............................................................76 
5.1 .. Ongoing Monitoring of Protocol Compliance…………………………………...76 
5.2 .. Evaluation of Participating Institution Performance……………………………..77 
5.2.1 ...... Monitoring Reports………………………………………………………77 
6.0 AUDITING: QUALITY ASSURANCE ................................................................77 
6.1 .. DF/HCC Sponsored Trials……………………………………………………….77 
6.2 .. Participating Institution…………………………………………………………..77 
6.3 ... DF/HCC Sponsor and Coordinating Center……………………………………..77 
6.4 ... Sub-Standard Performance………………………………………………………78 
6.4.1 ....... Corrective Actions……………………………………………………….78 
 
 
 


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1.0 INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol. 
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.       
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel 
Deaconess Medical Center (BIDMC), Children’s Hospital Boston (CHB), Brigham and 
Women’s Hospital (BWH)) responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments per the DFCI IRB and 
applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of 
Biotechnology Activities (OBA) etc.).  The Lead Institution is typically the home of the 
DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating Center for 
the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory agencies 
(i.e. CTEP Protocol and Information Office (PIO), FDA, OBA etc.). The DF/HCC Sponsor 
has ultimate authority over the protocol and is responsible for the conduct of the study at 
DF/HCC and all Participating Institutions. In most cases the DF/HCC Sponsor is the same 
person as the DF/HCC Principal Investigator; however, both roles can be filled by two 
different people. 
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC 


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Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor as having 
the ultimate authority and responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc.) that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP 
Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center for 
the DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO, 
the CRO will be deemed the Coordinating Center.   
 
DF/HCC Quality Assurance Office for Clinical Trials: A unit within DF/HCC developed 
to computerize and manage data, and to provide a Quality Control and Quality Assurance 
function for DF/HCC trials.   
 
2.0 GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general responsibilities:  
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Alice Shaw, MD will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Submit the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and 
throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all site personnel when English is not the primary language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. FDA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with FDA (investigator-held IND trials), as applicable. 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 


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• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site.  
 
2.2 Coordinating Center  
 
The Coordinating Center will assume the following general responsibilities: 
• Assist in protocol development  
• Maintain copies of Federal Wide Assurance and Institutional Review Board (IRB) 
approvals from all Participating Institutions. 
• Maintain FDA correspondence, as applicable. 
• Maintain updated roster of participants.  
• Verify eligibility. 
• Verify response. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to DF/HCC Sponsor for timely review.   
• Distribute adverse events reported to the DF/HCC Sponsor that fall under the DFCI 
IRB Adverse Event Reporting Policy to all participating investigators. 
• Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with. 
 
 
• Monitor Participating Institutions either by on-site or virtual monitoring.  
• Maintain Regulatory documents of all Participating Institutions.  
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc).  
• Maintain documentation of all communications. 
• Ensure that each Participating Institution has the appropriate assurance on file with 
the Office of Human Research Protection (OHRP).     
 
2.3 DF/HCC Quality Assurance Office for Clinical Trials (QACT) 
 
In addition to the Coordinating Center, the DF/HCC QACT provides the following support 
services to assist the DF/HCC Sponsor: 
• Develop protocol specific case report forms (CRF/eCRFS). 
• QA/QC data of protocol specific CRFs.  
• Provide a central participant registration, which includes review of consent and 
eligibility. 
• Provide auditing services (funding and QACT approval required). 
 
2.4 Participating Institution 
 


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Each Participating Institution is expected to comply with all applicable Federal Regulations 
and DF/HCC requirements, the protocol and HIPAA requirements. All Participating 
Institutions will provide a list of personnel assigned to the role for oversight of data 
management at their site to the Coordinating Center.  
 
The general responsibilities for each Participating Institution are as follows: 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain a regulatory binder in accordance with DF/HCC requirements. 
• Provide the Coordinating Center with regulatory documents as requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial 
as needed (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center.  
• Submit source documents, research records, and CRFs per protocol specific 
submission guidelines to the Coordinating Center. 
• Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements. 
• Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Secure and store investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• For protocols using investigational agents, the Participating Institution will order 
their own investigational agents regardless of the supplier (i.e. National Cancer 
Institute (NCI), pharmaceutical company). 
 
3.0 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
  
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 


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notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB approved 
and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating 
Center, will update the Participating Institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating Institutions must follow the DF/HCC requirement that 
only attending physicians obtain informed consent and re-consent.   
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Approval letter of the Participating Institution's IRB  
• Copy of the Informed Consent Form approved by the Participating Institution’s IRB  
• Participating Institution’s IRB approval for all amendments 
 


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It is the Participating Institution's responsibility to notify its IRB of protocol amendments.  
Participating Institutions will have 90 days from receipt to provide the Coordinating Center 
their IRB approval for amendments to a protocol.    
 
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval date.   
 
3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPAA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose PHI during the course of a study, the study 
participant must sign an Authorization.  This Authorization may or may not be separate 
from the informed consent document.  The Coordinating Center, with the approval from the 
DFCI IRB and if applicable NCI/CTEP, will provide a consent template, which covered 
entities (Participating Institutions) must use.  
 
The DF/HCC Sponsor will use all efforts to limit its use of PHI in its trials.  However, 
because of the nature of these trials, certain PHI must be collected per NCI requirements. 
These are the primary reasons why DF/HCC has chosen to use Authorizations, signed by 
the participant in the trial, rather than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center must 
have the participant’s full name & social security number “blacked out” and the assigned 
DF/HCC QACT case number (as described below) and DF/HCC protocol number written 
in (with the exception of the signed informed consent document). Participant initials may 
only be included or retained for cross verification of identification. 
 
3.7 DF/HCC Multi-Center Protocol Registration Policy 
 


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3.7.1 Participant Registration and Randomization  
To register a participant, the following documents should be completed by the 
Participating 
Institution 
and 
faxed 
or 
e-mailed 
(
 to the Coordinating Center: 
• Copy of source documentation for all inclusion/exclusion criteria 
• Signed informed consent document 
• HIPAA authorization form (if separate from the informed consent document) 
• Eligibility Checklist 
 
The Coordinating Center will review the submitted documents in order to verify 
eligibility and consent. To complete the registration process, the Coordinating Center 
will: 
• Register the participant on the study with the DF/HCC QACT 
• Upon receiving confirmation of registration by the QACT, the Coordinating Center 
will inform the Participating Institution and provide the study specific participant 
case number, and if applicable the dose treatment level.  
 
Treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered.  
 
Randomization can only occur during QACT’s normal business hours, Monday through 
Friday from 8:00 AM to 5:00 PM Eastern Time. 
 
3.7.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC QACT before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives a faxed or e-mailed 
copy of the participant’s registration confirmation memo from the Coordinating Center. 
Therapy must be initiated per protocol guidelines.  The DF/HCC Sponsor and DFCI IRB 
must be notified of any exceptions to this policy. 
 
3.7.3 Eligibility Exceptions 
 
CTEP specifically prohibits registration of a participant on any NCI Sponsored protocol that 
does not fully and completely meet all eligibility requirements. The DF/HCC QACT will 
make no exceptions to the eligibility requirements for a protocol without DFCI IRB 
approval. The DF/HCC QACT requires each institution to fully comply with this 
requirement. 
 
3.7.4 Verification of Registration, Dose Levels, and Arm Designation 
 
A registration confirmation memo for participants registered to DF/HCC Multi-Center 
Protocol will be faxed or emailed to the registering institution within one business day of 


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the registration. Treatment may not be initiated until the site receives a faxed or e-mailed 
copy of the registration confirmation memo. 
 
3.8 DF/HCC Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the 
participant is assigned a five digit protocol case number.  This number is unique to the 
participant on this trial and must be used for QACT CRF/eCRF completion and 
correspondence, and correspondence with the Coordinating Center.   
 
3.9 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review and 
approval, except when necessary to eliminate apparent immediate hazards to the participant. 
DF/HCC requires all departures from the defined procedures set forth in the IRB approved 
protocol to be reported to the DF/HCC Sponsor, who in turn is responsible for reporting to 
the DFCI IRB. 
  
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe derivations from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy 
for reporting to their local IRB. 
 
3.9.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
  
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB 
prior to its initiation or implementation.  
 
 
3.9.2  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 


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Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, 
the 
Coordinating 
Center 
will 
complete 
the 
DFCI 
Major 
Deviation/Violation/Exception – Other Event Reporting Form and submit the report to the 
DF/HCC Sponsor for review. Subsequently, the Coordinating Center will submit the event 
to the DFCI IRB for review per DFCI IRB reporting guidelines. 
 
3.10 Safety Assessments and Toxicity Monitoring 
 
The study teams at all Participating Institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants. All toxicities encountered during the study will be 
evaluated according to the NCI criteria specified in the protocol. Life-threatening toxicities 
must be reported immediately to the DF/HCC Sponsor via the Coordinating Center. 
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.10.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol Section 10. 
 
 
 
 
 
 
Participating Institutions must report the AEs to the DF/HCC Sponsor and the Coordinating 
Center following the DFCI IRB AE Reporting Requirements.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all Participating 
Investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Investigators will review any distributed AE reports, send a copy to their IRB 
according to their local IRB’s policies and procedures, and file a copy with their regulatory 
documents. 
 
3.10.2 Guidelines for Processing IND Safety Reports  


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FDA regulations require sponsors of clinical studies to notify the FDA and all Participating 
Investigators of any adverse experience associated with the use of the investigational agent 
that is both serious and unexpected. The DF/HCC Sponsor will review all IND Safety 
Reports and ensure that all IND Safety Reports are distributed to the Participating 
Institutions.  The Participating Investigators are to review, send a copy to their IRB 
according to their local IRB’s policies and procedures, and file a copy with their regulatory 
documents. 
  
3.11 Data Management 
The DF/HCC QACT develops a set of either paper or electronic case report forms 
(CRF/eCRFs), for use with the protocol.  These forms are designed to collect data for each 
study. The DF/HCC QACT provides a web based training for eCRF users. 
   
3.11.1 Data Forms Review 
 
When data forms arrive at the DF/HCC QACT, they are reviewed for completeness, 
protocol treatment compliance, adverse events (toxicities) and response. Data submissions 
are monitored for timeliness and completeness of submission. Participating Institutions are 
notified of their data submission delinquencies in accordance with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC QACT Data Analyst or study 
monitor.  Responses to all queries should be completed and submitted within 14 calendar 
days.  Responses may be returned on the written query or on an amended paper case report 
form, or in the case of electronic queries, within the electronic data capture (eDC) system. 
In the case of a written query for data submitted on a paper case report form, the query must 
be attached to the specific data being re-submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms.  These reports 
are compiled by the DF/HCC QACT and distributed a minimum of four times a year.  
 
4.0 REQUISITIONING INVESTIGATIONAL DRUG 
 
 
The ordering of investigational agent is specified in section 6.5 of the protocol.  
 
Participating Institutions should order their own agent regardless of the supplier (i.e., NCI or 
a pharmaceutical company.)   
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed of 


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who will supply the agent (i.e., NCI or a pharmaceutical company) so that any regulatory 
responsibilities can be met in a timely fashion.  
 
 
 
 
5.0 MONITORING: QUALITY CONTROL 
 
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. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
  
The Participating Institutions will 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.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring will occur before the clinical phase of the 
protocol begins, continue during protocol performance and through study completion. 
Monitoring practices may include, but are not limited to, review of the following; source 
verification, review and analysis of the following: eligibility requirements of all 
participants, informed consent procedures, adverse events and all associated documentation, 
study drug administration/treatment, regulatory files, protocol deviations, pharmacy 
records, response assessments, and data management.  
 
One on-site monitoring visit will be conducted after the first participant is enrolled at each 
site.  Monitors should be given full access to participants’ complete medical record and 
source documentation. Subsequent monitoring visits will be conducted remotely at least 
every five months. Participating Institutions will be required to forward copies of 
participants’ de-identified medical records and source documentation to the Coordinating 
Center. 
 
Participating institutions will be required to participate in monthly Coordinating Center 
initiated teleconferences while patients are on treatment. Communication via email 
highlighting overall protocol progress and important announcements will be distributed on 
an as-needed basis. 
 
All data submitted to the DF/HCC QACT will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements. The Coordinating Center and if 
applicable, QACT Data Analysts assigned to the protocol, will perform the ongoing protocol 
data compliance monitoring. 


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5.2 Evaluation of Participating Institution Performance 
 
5.2.1 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports for on-site and virtual monitoring 
of Participating Institutions to ensure protocol compliance and ability to fulfill 
responsibilities of participating in the study. The DF/HCC Sponsor may increase the 
monitoring activities at Participating Institutions that are unable to comply with the 
protocol, DF/HCC Sponsor requirements or federal and local regulations. Participating 
Institutions may also be subject to an audit as determined by the DF/HCC Sponsor. 
 
6.0 AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1 DF/HCC Sponsored Trials 
 
One on-site audit will be scheduled by the QACT, assuming at least three participants have 
been treated on protocol at the site. Approximately 3-4 participants would be audited at the 
site over a 2 day period.  If violations which impact participant safety or the integrity of the 
study are found, more participant records may be audited.  
 
6.2 Participating Institution 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or external) and re-audit dates (if applicable), which involve 
this protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the 
audit date.  
 
6.3 DF/HCC Sponsor and Coordinating Center  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC QACT per 
DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up.  For unacceptable audits, the 


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DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
 
6.4 Sub-Standard Performance 
 
The DF/HCC Sponsor and DFCI IRB, is charged with considering the totality of a 
Participating Institution’s performance in considering institutional participation in the 
protocol. 
 
6.4.1 Corrective Actions 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely accurate data, adherence to protocol requirements, and compliance with state and 
federal regulations, will be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation.