Clinical trial NCT02094573
Conditions: Carcinoma, Non-Small-Cell Lung
Keywords: Drug Therapy
Sponsor: Ariad Pharmaceuticals
Start date: 2014-06-04; Completion date: 2020-02-27
Enrollment: 222 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of two different dosing regimens of brigatinib (AP26113) in participants with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib.

Detailed description:
The drug being tested in this study is called brigatinib (AP26113). Brigatinib was tested to treat people with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or were intolerant to crizotinib. This study looked at the efficacy of brigatinib.

The study enrolled 222 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

* Brigatinib 90 mg
* Brigatinib 90 mg -180 mg

All participants were asked to take a tablet, orally once daily until disease progression or intolerable toxicity. Participants in Brigatinib 90 mg - 180 mg received 180 mg with a 7-day lead-in at 90 mg.

This multi-center trial was conducted worldwide. The overall time to participate in this study is up to 3 years. Participants will make multiple visits to the clinic, and 3 months after the End-of-Treatment visit. Follow-up is intended to continue for 2 years after the last participants was enrolled into the study.

Arms: arm 1: Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days). arm 2: Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in Cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
Interventions: intervention 1: Brigatinib
Intervention descriptions: intervention 1: Brigatinib tablets

Protocol documents:
Prot_000.pdf: 



Title: A Randomized Phase 2 Study of AP26113 in Patients with ALK-positive, Non-small Cell 
Lung Cancer (NSCLC) Previously Treated with Crizotinib 
NCT Number: NCT02094573
Protocol Approve Date: 24 August 2015
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


ARIAD Pharmaceuticals, Inc. 
AP26113-13-201 
Version 4.0 24 August 2015 
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CLINICAL STUDY PROTOCOL 
Study Title: 
A Randomized Phase 2 Study of AP26113 in Patients with 
ALK-positive, Non-small Cell Lung Cancer (NSCLC) 
Previously Treated with Crizotinib 
Protocol Number: 
AP26113-13-201 
Study Phase: 
Phase 2 
Product Name: 
AP26113 
IND Reference Number: 
IND 110,935 
EudraCT Number: 
2013-002134-21 
Sponsor: 
ARIAD Pharmaceuticals, Inc. 
26 Landsdowne Street 
Cambridge, MA 02139-4234 
Telephone: +1 (617) 494-0400 
Protocol Issue Date: 
24 August 2015 
Version Number: 
Version 4.0 (South Korea only) 
PROTOCOL REVISION HISTORY: 
Amendment Number 
Protocol Version Number 
Date 
Original Protocol 
Version 1.0 
27 June 2013 
Amendment 1 
Version 2.0 
3 February 2014 
Amendment 2 
Version 3.0 
29 July 2014 
Amendment 3 
Version 4.0 (South Korea 
only) 
24 August 2015 
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2.2 
Investigator Signature 
I have read the protocol and agree that it contains all necessary details for carrying out the study 
as described.  I will conduct this protocol as outlined therein, including all statements regarding 
confidentiality.  I will make a reasonable effort to complete the study within the time designated.  
I will provide copies of the protocol and access to all information furnished by the sponsor to 
study personnel under my supervision.  I will discuss this material with them to ensure they are 
fully informed about the study drug and the study.  I understand that the study may be terminated 
or enrollment suspended at any time by the sponsor, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with all applicable regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s Signature  
 
 
 
 
Date (dd-mmm-yyyy)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s Name (print) 
 
 
 
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4 
PROTOCOL SYNOPSIS 
Sponsor 
ARIAD Pharmaceuticals, Inc. 
26 Landsdowne Street 
Cambridge, MA 02139-4234 
Study Treatment 
 
AP26113 
Protocol Title 
A Randomized Phase 2 Study of AP26113 in Patients with ALK-positive, Non-small 
Cell Lung Cancer (NSCLC) Previously Treated with Crizotinib  
Development Phase 
Phase 2 
Summary and Study 
Rationale 
AP26113 is a novel, synthetic, orally-active tyrosine kinase inhibitor (TKI) 
discovered and developed at ARIAD Pharmaceuticals, Inc. (ARIAD, the sponsor).  A 
primary target of AP26113 is anaplastic lymphoma kinase (ALK).  Activating gene 
rearrangements in ALK-positive (ALK+) tumors have been identified as driver 
mutations in patients with non-small cell lung cancer (NSCLC) and other cancers. 
Activating gene rearrangements in ALK have been identified as driver mutations in 
approximately 3% to 5% of patients with NSCLC (Perner et al, 2008; Wong et al, 
2009).  Crizotinib (XALKORI®, Pfizer, Inc.) has demonstrated clinical efficacy in 
ALK+ NSCLC (Kwak et al., 2010).  Results from a phase 1 study and a phase 2 
single-arm study of crizotinib demonstrated objective response rates (ORRs) of 61% 
and 50%, respectively (XALKORI®, Pfizer, Inc.).  These two studies served as the 
basis for crizotinib’s accelerated approval for treatment of ALK+ advanced NSCLC 
in the United States and conditional approval in the European Union. 
Although crizotinib is an effective treatment of ALK+ NSCLC, a substantial 
proportion (50% and 39%, respectively) of ALK+ NSCLC patients in the pivotal 
trials that supported its accelerated approval failed to achieve a response.  For those 
patients who did respond, the benefit was relatively short-lived with a median 
duration of response ranging from 42 to 48 weeks (XALKORI®, Pfizer, Inc.).  In 
many patients, loss of response manifests as systemic progression, but in some 
patients the disease progresses only within the brain, possibly as a result of low CNS 
penetration of crizotinib (Camidge et al, 2012; Costa et al, 2011). 
The underlying reason for failure to achieve a response to crizotinib (primary 
resistance) is difficult to identify, but suboptimal potency of the agent against the 
targeted oncogene could be a contributing factor.  The mechanisms underlying loss of 
response (secondary or acquired resistance) to crizotinib are becoming clearer 
(Camidge et al, 2012).  Emerging data suggest that an important acquired resistance 
mechanism is the emergence of point mutations in the kinase domain of ALK 
(Katayama et al, 2012).  Mutations that confer resistance to crizotinib (such as the 
gatekeeper mutant L1196M, and L1152R, G1269A, S1206Y, F1174L, D1203N, 
C1156Y, T1151Tins, and G1202R mutations) may act by reducing the binding 
affinity of crizotinib to ALK (Bang, 2012).  Other mechanisms of secondary 
resistance to crizotinib include the amplification of the ALK fusion gene, exploiting 
crizotinib’s suboptimal potency against ALK and the activation of alternate signaling 
pathways (Camidge et al, 2012; Katayama et al, 2012). 
In some patients, loss of response to crizotinib may also have a pharmacologic basis, 
with inadequate drug exposure resulting from dose modifications, or changes in drug 
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metabolism or transport over time.  In all of these scenarios, a rational approach to 
overcoming resistance is the use of a more potent ALK inhibitor with a broader 
therapeutic window that retains activity against all key crizotinib-resistance mutations 
and that can also achieve deep and prolonged target inhibition both systemically and 
in the CNS. 
AP26113 has demonstrated potent inhibitory activity against activated ALK (8-fold 
more potent than crizotinib) and pan-inhibitory activity against all 9 clinically 
identified crizotinib-resistant mutants identified to date. 
Based on favorable preclinical in vitro and in vivo pharmacology and toxicology 
studies, a phase 1/2 clinical study of AP26113 (study AP26113-11-101) was initiated 
on 20 September 2011.  Study 101 consists of a phase 1 dose escalation portion, 
followed by a phase 2 expansion portion with defined clinical cohorts.  The trial is 
still enrolling patients.  
As of 6 September 2013, 91 patients were treated with AP26113 at doses ranging 
from 30 mg QD to 300 mg QD, including 45 patients treated at 180 mg QD.  Of these, 
the median age was 57 years and 60% were female.  The majority (82%) of patients 
were diagnosed with adenocarcinoma of the lung (NSCLC).  Forty-two (46%) 
patients had a history of ALK rearrangement.  Approximately half (51%) of patients 
had received one or two prior systemic treatment regimens while 24% received more 
than 2 prior systemic treatment regimens.  
In the phase 1 dose-escalation portion of the study, patients were administered 
AP26113 at doses ranging from 30 mg once-daily (QD) to 300 mg QD.  Twice-daily 
(BID) dose regimens were also evaluated in some patients during dose-escalation.  At 
doses of 90 mg and higher, mean plasma steady-state trough drug concentrations that 
exceeded levels predicted preclinically to inhibit crizotinib-resistant ALK mutants 
were achieved.  No dose-limiting toxicities (DLTs) were observed in the phase 1 
portion at doses up to 180 mg QD.  At higher doses, DLTs of grade 3 alanine 
aminotransferase (ALT) increased (240 mg QD) and grade 4 dyspnea (300 mg QD) 
were reported.  The maximum tolerated dose (MTD) was not formally determined.  
However, based on these results, the dose of 180 mg QD was initially chosen as the 
RP2D for the phase 2 expansion portion of the study.    
In the phase 2 expansion portion of the study, 3 of 26 (12%) patients treated with 
180 mg QD experienced early onset pulmonary symptoms that in some cases 
constituted pneumonitis (described in more detail below and in Section 7.3).  
Consequently, two additional RP2Ds were tested: 90 mg QD and a 7-day dosing 
period of 90 mg QD followed by escalation to 180 mg QD.  Preliminary data (as 
described below and in Section 7.3) support testing these regimens further in this 
randomized trial. 
Among all enrolled patients (as of 6 September 2013), the most common treatment-
emergent AEs (≥10% of patients) were nausea (38.5%), fatigue (34.1%), diarrhea 
(31.9%), cough (20.9%), headache (19.8%), dyspnea (16.5%), vomiting (16.5%), 
amylase increased (12.1%), decreased appetite (12.1%), and muscle spasms (11.0%).  
Treatment-related AEs of grade ≥3 occurring in 2 or more patients included dyspnea 
(4%), fatigue (3%), diarrhea (2%), hypoxia (2%), and pneumonitis (2%).  Serious 
adverse events (SAEs) (treatment-related) occurring in 2 or more patients were 
dyspnea (7%), pneumonia (4%), hypoxia (2%), and pneumonitis (2%).   
The early onset pulmonary events that occurred immediately following initiation of 
treatment included dyspnea, hypoxia, pneumonia, ground glass and interstitial chest 
CT findings, and pneumonitis, and were moderate or severe.  The early onset 
pulmonary events are dose-related and not observed at 90 mg.  Symptoms typically 
occur within 48 hours of initial dosing.  Symptoms have recurred in some patients 
upon rechallenge; however, many patients were able to continue therapy, even at 
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higher doses, with optimal management.  In the phase 2 expansion portion of study 
101, early onset pulmonary events were observed in 3 out of 26 patients dosed at 
180 mg QD.  In the study overall, there were 6 cases (13%) of an early onset 
pulmonary syndrome in 45 patients dosed at 180 mg QD, and 4 additional cases 
observed at higher doses (2 at 240 mg QD and 2 at 300 mg QD) that comprise a total 
of 10 cases (15%) in 59 patients treated with 180 mg QD or higher doses of AP26113 
in the study.  All 10 were SAEs.  As of 6 September 2013, 21 patients have been 
enrolled in the 101 study utilizing the 90 mg to 180 mg regimen.  No cases of early 
onset pulmonary AEs have been observed using this regimen.  
Antitumor activity has been observed in patients with crizotinib-resistant ALK+ 
NSCLC as well as in TKI-naïve patients.  Overall, of the 34 ALK+ NSCLC patients 
treated with AP26113 who have been imaged, 22 responded (65% ORR; 95% CI: 
47%-80%).  In ALK+ NSCLC patients treated with prior crizotinib (and no other 
ALK TKIs), responses were documented in 19 out of 28 patients (68% ORR; 95% CI: 
48%-84%).  An ORR of 100% was observed for TKI-naïve patients (3/3), including 
one complete response.  Response duration ranged from 8+ to 40+ weeks in 14 
patients with confirmed responses.  In addition, 8 of 10 ALK+ NSCLC patients with 
active CNS lesions at baseline had evidence of radiographic improvement in the CNS 
(duration of CNS benefit in these patients ranged from 8+ to 40+ weeks).  Responses 
in CNS lesions were observed in patients receiving 180 mg QD or higher. 
Based on observations made from the phase 1/2 study, two RP2Ds are recommended 
for further study.  There is support for testing 90 mg QD, as this dose appears to have 
an acceptable safety profile and is productive of responses.  But there is reason for 
utilizing higher doses as well, particularly with regard to CNS penetration and activity 
in this sanctuary site.  The addition of a 90-mg QD 7-day lead-in to therapy with 
180 mg QD appears to lessen the incidence of early pneumonitis and pulmonary 
symptoms.  Therefore, this dose will be tested as a RP2D as well as the 90-mg QD 
regimen.  In summary, AP26113 was generally safe at doses up to 180 mg QD in the 
phase 1/2 trial.  AP26113 exhibited substantial anticancer activity in patients with 
crizotinib-resistant ALK+ NSCLC.  AP26113 is active in ALK+ brain metastases 
with frequent responses of clinically meaningful duration.   
In this trial, patients with ALK+ NSCLC who have experienced failure of crizotinib 
therapy will be randomized 1:1 to receive either 90 mg QD continuously (in Arm A) 
or a lead-in dose of 90 mg QD for 7 days followed by 180 mg QD continuously (in 
Arm B).   
Study Design 
Phase 2, open-label, randomized, multicenter, international study.  
Study Objectives 
The primary objective of the study is to determine the efficacy of AP26113, as 
evidenced by objective response rate, in patients with ALK-positive locally advanced 
or metastatic NSCLC whose disease has progressed on therapy with crizotinib.  Two 
dosing regimens will be tested.  
The secondary objectives of the study (for each dosing regimen) are: 
1. To further characterize the efficacy of AP26113 in patients with 
ALK-positive, locally advanced or metastatic NSCLC whose disease has 
progressed on therapy with crizotinib, as shown by disease control rate, time 
to/duration of response, progression-free survival (PFS), overall survival 
(OS), and time on treatment  
2. To assess CNS response and PFS, per RECIST v1.1, in those patients who 
have active brain metastases 
3. To assess the safety and tolerability of AP26113 in study patients 
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ARIAD Pharmaceuticals, Inc. 
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biopsy taken after progression with crizotinib.  If such a sample is not 
available, testing may be performed with archived tumor tissue. 
3. Had progressive disease while on crizotinib, as assessed by the investigator 
or treating physician. 
4. No longer a required criterion as of Amendment 2.  
5. Have at least 1 measurable lesion per RECIST v1.1 (see Appendix C).  Note: 
Previously irradiated lesions may not be used for target lesions, unless there 
is unambiguous radiological progression after radiotherapy.  Brain lesions 
may not be used as target lesions if they were: 1) previously treated with 
whole brain radiation therapy (WBRT) within 3 months, or 2) previously 
treated by stereotactic radiosurgery (SRS) or surgical resection. 
6. No longer a required criterion as of Amendment 2. 
7. Recovered from toxicities related to prior anticancer therapy to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE, v4.0) grade ≤2 (see Appendix A).  
8. Are a male or female patient ≥18 years old.  
9. Have a life expectancy ≥3 months. 
10. Have adequate organ and hematologic function, as determined by: 
a. 
Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
≤2.5 x upper limit of normal (ULN; ≤5 x ULN is acceptable if liver 
metastases are present)  
b. Total serum bilirubin ≤1.5 x ULN (<3.0 x ULN for patients with 
Gilbert syndrome) 
c. 
Serum creatinine ≤1.5 x ULN 
d. Serum lipase/amylase ≤1.5 x ULN 
e. 
Absolute neutrophil count (ANC) ≥1500/µL 
f. 
Platelets ≥75000/µL 
g. Hemoglobin ≥10 g/dL 
11. Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2 
(see Appendix B). 
12. Have normal QT interval on screening electrocardiogram (ECG) evaluation, 
defined as QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or 
≤470 ms in females.  
13. For female patients of childbearing potential, a negative pregnancy test must 
be documented prior to enrollment. 
14. Female and male patients who are fertile must agree to use a highly effective 
form of contraception with their sexual partners throughout study 
participation.   
15. Must provide a signed and dated informed consent indicating that the patient 
has been informed of all pertinent aspects of the study, including the 
potential risks, and is willingly participating.  
16. Have the willingness and ability to comply with scheduled visits and study 
procedures.  
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Exclusion Criteria 
Patients meeting any of the criteria below are ineligible for the study: 
1. Received any prior ALK-targeted TKI other than crizotinib. 
2. Received crizotinib within 3 days of the first dose of AP26113 (Day 1, Cycle 
1). 
3. Received cytotoxic chemotherapy, investigational agents, or radiation within 
14 days, except SRS or stereotactic body radiosurgery. 
4. Received monoclonal antibodies or had major surgery within 30 days of the 
first dose of AP26113 (Day 1, Cycle 1). 
5. Have been diagnosed with another primary malignancy within the past 
3 years (except for adequately treated non-melanoma skin cancer, cervical 
cancer in situ, or prostate cancer, which are allowed within 3 years).  
6. Have symptomatic CNS metastases that are neurologically unstable or 
require an increasing dose of corticosteroids. 
7. Have current spinal cord compression.   
8. Have significant, uncontrolled, or active cardiovascular disease, specifically 
including, but not restricted to: 
a. 
Myocardial infarction (MI) within 6 months prior to the first dose of 
AP26113  
b. Unstable angina within 6 months prior to first dose 
c. 
Congestive heart failure (CHF) within 6 months prior to first dose  
d. History of clinically significant (as determined by the treating 
physician) atrial arrhythmia  
e. 
Any history of ventricular arrhythmia 
f. 
Cerebrovascular accident or transient ischemic attack within 
6 months prior to first dose 
9. Have a history or the presence of pulmonary interstitial disease or 
drug-related pneumonitis. 
10. Have an ongoing or active infection.  The requirement for intravenous (IV) 
antibiotics is considered active infection. 
11. Have a known history of human immunodeficiency virus (HIV).  Testing is 
not required in the absence of history. 
12. Have a history of or active significant gastrointestinal (GI) bleeding within 
3 months of the first dose of AP26113. 
13. Have a known or suspected hypersensitivity to AP26113 or its excipients. 
14. Have malabsorption syndrome or other GI illness that could affect oral 
absorption of the study drug. 
15. Have any condition or illness that, in the opinion of the investigator, would 
compromise patient safety or interfere with evaluation of the study drug.  
16. Be pregnant or breastfeeding.  
Approximate Number of 
Patients 
Approximately 218 patients total (109 on each dosing regimen) 
Approximate Duration of 
Patients will continue to be dosed with AP26113 until they experience disease 
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Patient Participation 
progression or intolerable toxicity.  Treatment may be continued after progression, at 
the discretion of the investigator.  On Arm A, at the time of progression, the patient 
may continue at the same dose or the patient’s dose may be escalated from 90 mg QD 
to 180 mg QD.  For patients on either arm receiving 180 mg QD, at the time of 
progression, treatment may continue if there is still evidence of clinical benefit (see 
Section 13.1.2 for details on treatment continuation after progression).  Follow-up 
assessments (ie, contacting the patient for survival and subsequent anticancer therapy) 
must be performed every 3 months after the End-of-Treatment.  Follow-up will 
continue for 2 years after the last patient enrolls into the study. 
Approximate Duration of 
Study 
The total estimated duration of the study is at least 3 years, including approximately 
18 months to accrue patients, with 2 years for treatment and follow-up for the last 
patient.  Patients will be allowed to receive study drug beyond this period until 
disease progression or they discontinue treatment for other reasons. 
Approximate Number of 
Study Centers 
Approximately 100 centers 
Study Drug 
Administration and 
Modification 
Patients will be randomized 1:1 to receive AP26113 in one of two different dosing 
regimens.   
Arm A: AP26113 will be administered at a dose of 90 mg QD, continuously.   
Arm B: AP26113 will be administered at a dose of 90 mg QD for 7 days, then 180 mg 
QD, continuously. 
A cycle of therapy will comprise 28 days of treatment, regardless of dose.  Patients 
will take the prescribed dose with water (recommended 240 mL).   
Dose interruptions or reductions should be implemented for patients who experience 
treatment-related adverse events, upon clinical judgment of the investigator.  
Guidelines for continued treatment after disease progression are discussed in 
Section 13.1.2.  Re-escalation of doses will occur only in consultation with the 
sponsor (see Section 13.1.5).  Guidelines for management of treatment-related 
adverse events are described in Section 13.1.4.  
Concomitant Treatment 
Palliation and supportive care are permitted during the study for management of 
symptoms and underlying medical conditions that may develop during the study.  
Once a patient has begun treatment, a condition may arise that requires the initiation 
of a new concomitant treatment.  Patients with CNS lesions requiring SRS are 
allowed to continue study treatment after appropriate interruption, as determined by 
the investigator with sponsor agreement; however, for analysis purposes, these 
patients will be considered to have progressive disease.   
After a patient has begun the study, the addition of the following concurrent 
medications or procedures are prohibited: 
 
Any other systemic anticancer therapy. 
 
Use of any other investigational drug or device. 
 
Medications that are known to be associated with the development of 
Torsades de Pointes (see Appendix E).  Medications that prolong the QT 
interval, but are not known to be associated with Torsades de Pointes, should 
be avoided, but are not prohibited. 
 
Extensive surgery requiring in-patient care (patients may have an 
interruption in therapy for 14 days should emergency surgery be required). 
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secondary efficacy endpoints, which excludes patients with no history or confirmation 
of ALK rearrangement by Vysis® FISH.  
Each dosing regimen will be summarized separately.  No inferential comparisons 
between the two regimens will be performed.  For the primary efficacy test of the 
primary endpoint, ORR as assessed by the investigator, the overall alpha of 0.05 two-
sided will be split in half to adjust for the fact that a test of each regimen will be 
performed.  For each regimen, the primary analysis of the primary endpoint will be 
performed using a 2-sided exact 97.5% confidence interval.  The primary analysis is 
planned to be conducted when all ongoing patients have completed their Cycle 6 
disease assessment. 
Two-sided exact 95% binominal confidence intervals will be computed for confirmed 
ORR as assessed by the IRC, CNS ORR, and disease control rate.  Kaplan-Meier 
methods, including medians and confidence intervals, will be used to evaluate PFS, 
CNS PFS, OS, and duration of response.  Descriptive statistics will be used to 
summarize time to response in responders and time on treatment.  HRQoL and 
patient-reported symptoms will be analyzed using a mixed-effects model for repeated 
measures to evaluate changes in linearly transformed scores from baseline at each 
subsequent study visit through the end of the study.  Means and medians of 
questionnaire raw scores will be summarized by time point, overall, and for each 
scale. 
Further details of statistical analyses including the data handling rules will be 
provided in the Statistical Analysis Plan (SAP).  
Rationale for Number of 
Patients 
The purpose of this phase 2 study is to determine the ORR of two dosing regimens of 
oral AP26113 in patients with ALK+ NSCLC whose disease has progressed on 
therapy with crizotinib.  A sample size of at least 109 patients in each treatment group 
will allow the study to have an approximate 90% power to rule out an uninteresting 
rate of 20% when the true rate is 35% or higher with alpha=0.025 two-sided.   
 
 
 
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5 
TABLE OF CONTENTS 
1 
DISCLOSURE STATEMENT .....................................................................................2 
2 
SIGNATURE PAGES ...................................................................................................3 
2.1 
Signatory* ..........................................................................................................3 
2.2 
Investigator Signature ......................................................................................4 
2.3 
Sponsor Representative Signature...................................................................5 
3 
CONTACT INFORMATION ......................................................................................6 
4 
PROTOCOL SYNOPSIS .............................................................................................7 
5 
TABLE OF CONTENTS ............................................................................................16 
LIST OF ABBREVIATIONS .....................................................................................................21 
6 
DEFINITIONS OF TERMS ......................................................................................23 
7 
INTRODUCTION .......................................................................................................25 
7.1 
Background ......................................................................................................25 
7.2 
AP26113 Nonclinical Summary .....................................................................26 
7.2.1 
Nonclinical Activity against ALK ......................................................26 
7.2.2 
Nonclinical Activity against Other Targets ......................................28 
7.3 
AP26113 Clinical Summary ...........................................................................28 
7.3.1 
Overview of Safety Observations from the Phase 1/2 Trial ............29 
7.3.2 
Overview of Antitumor Activity ........................................................30 
7.3.3 
Pharmacokinetics ................................................................................31 
7.3.4 
Rationale for Proposed RP2Ds ..........................................................31 
7.4 
Rationale for the Phase 2 AP26113 Clinical Study ......................................32 
8 
STUDY OBJECTIVES ...............................................................................................32 
8.1 
Primary Objective ...........................................................................................32 
8.2 
Secondary Objectives ......................................................................................32 
8.3 
Exploratory Objectives ...................................................................................33 
9 
INVESTIGATIONAL PLAN .....................................................................................33 
9.1 
Overall Study Design and Plan ......................................................................33 
9.1.1 
Primary Endpoint ...............................................................................33 
9.1.2 
Secondary Endpoints ..........................................................................33 
9.1.3 
Exploratory Endpoints .......................................................................34 
9.2 
Randomization ................................................................................................34 
10 
SELECTION OF STUDY POPULATION ...............................................................34 
10.1 
Inclusion Criteria ............................................................................................34 
10.2 
Exclusion Criteria ...........................................................................................36 
11 
STUDY PROCEDURES .............................................................................................37 
11.1 
Study Procedure Descriptions ........................................................................37 
11.2 
Screening Period..............................................................................................45 
11.3 
Screen Failures ................................................................................................45 
11.4 
Treatment through 30 Days after Last Dose ................................................45 
11.5 
End-of-Treatment or Early Termination .....................................................45 
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11.6 
30 Days After Last Dose .................................................................................45 
11.7 
Follow-up Period Procedures .........................................................................45 
11.8 
Study Duration ................................................................................................45 
11.8.1 
Approximate Duration of Patient Participation ..............................45 
11.8.2 
Approximate Duration of Study ........................................................46 
11.9 
Patient Discontinuation ..................................................................................46 
11.10 
Study or Site Termination ..............................................................................47 
11.11 
Sample Collection, Storage, and Shipping ....................................................47 
12 
EFFICACY AND SAFETY ASSESSMENTS ..........................................................47 
12.1 
Efficacy Assessments .......................................................................................47 
12.2 
Safety Assessments ..........................................................................................47 
12.3 
Pharmacokinetic Assessments .......................................................................47 
12.4 
Exploratory Biomarker Evaluations in Tissue and Plasma ........................48 
12.5 
Patient Reported Symptoms and Quality of Life Assessments ...................48 
13 
STUDY TREATMENT(S) .........................................................................................48 
13.1 
Study Drug .......................................................................................................48 
13.1.1 
Treatment Administration .................................................................48 
13.1.2 
Continued Treatment after Disease Progression .............................49 
13.1.3 
Dose Modification(s) ...........................................................................49 
13.1.3.1  Dose Modifications for Treatment-related Adverse Events ....49 
13.1.4 
Dose Modification and Management of Specific Treatment-
related Adverse Events .......................................................................55 
13.1.4.1  Early Onset Pulmonary Syndrome ..........................................56 
13.1.4.2  Pneumonitis ..............................................................................56 
13.1.4.3  Nausea and Emesis ..................................................................58 
13.1.4.4  Diarrhea ....................................................................................58 
13.1.5 
Re-Escalation after Dose Modification..............................................58 
13.2 
Prior and Concomitant Treatment(s)/Therapy ............................................58 
13.3 
Prohibited Treatment(s)/Therapy .................................................................58 
13.4 
Potential Drug Interactions ............................................................................59 
13.5 
Treatment Compliance ...................................................................................59 
13.6 
Treatment Supply ...........................................................................................59 
13.6.1 
Formulation, Packaging and Labeling ..............................................60 
13.6.2 
Preparation and Dispensing ...............................................................60 
13.6.3 
Treatment Storage and Accountability .............................................60 
14 
ADVERSE EVENT REPORTING ............................................................................61 
14.1 
Adverse Events ................................................................................................61 
14.1.1 
Adverse Event Definition ....................................................................61 
14.1.2 
Abnormal Test Findings .....................................................................61 
14.1.3 
Performing Adverse Events Assessments .........................................62 
14.1.4 
Reporting Adverse Events ..................................................................62 
14.1.5 
Adverse Event Severity .......................................................................62 
14.1.6 
Causality ..............................................................................................62 
14.1.7 
Expectedness ........................................................................................64 
14.2 
Serious Adverse Events ..................................................................................64 
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14.2.1 
Serious Adverse Event Definition ......................................................64 
14.2.1.1  Progression of the Malignancy Under Study (including 
signs and symptoms of progression) ........................................65 
14.2.1.2  Hospitalizations ........................................................................65 
14.2.2 
Reporting Serious Adverse Events ....................................................65 
14.2.3 
Information to be Provided by the Investigator for a Serious 
Adverse Event ......................................................................................66 
14.2.4 
Follow-up Information on a Serious Adverse Event ........................66 
14.3 
Other Safety Issues ..........................................................................................67 
14.3.1 
Pregnancy ............................................................................................67 
14.3.2 
Overdose ..............................................................................................67 
15 
PLANNED STATISTICAL METHODS ..................................................................68 
15.1 
General Considerations ..................................................................................68 
15.2 
Analysis Populations .......................................................................................68 
15.3 
Study Endpoints ..............................................................................................69 
15.3.1 
Primary Endpoint ...............................................................................69 
15.3.2 
Secondary Endpoints ..........................................................................69 
15.3.3 
Exploratory Endpoints .......................................................................69 
15.4 
Determination of Sample Size ........................................................................69 
15.5 
Efficacy Analysis .............................................................................................70 
15.5.1 
Definitions of Efficacy Endpoints ......................................................70 
15.5.2 
Primary Efficacy Endpoint Analyses ................................................71 
15.5.3 
Secondary Efficacy Endpoint Analyses .............................................71 
15.5.4 
Data Handling Rules for Efficacy Endpoint Analyses .....................71 
15.6 
Safety Analysis .................................................................................................72 
15.6.1 
Pharmacokinetic Analysis ..................................................................72 
15.6.2 
QTcF Analysis .....................................................................................72 
15.7 
HRQoL Data Analysis ....................................................................................72 
15.8 
Correlation Analyses of Tumor and Plasma Biomarkers with Efficacy 
and Safety .........................................................................................................73 
15.9 
Protocol Deviations/Violations .......................................................................73 
16 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................73 
16.1 
Investigators and Study Administrative Structure ......................................73 
16.2 
Study Monitoring ............................................................................................74 
17 
ETHICAL CONDUCT OF THE STUDY ................................................................74 
17.1 
Institutional Review Board or Ethics Committee Approval .......................74 
17.2 
Patient Information and Consent ..................................................................75 
17.3 
Patient Confidentiality ....................................................................................75 
17.4 
Study Committees ...........................................................................................75 
17.4.1 
Data Monitoring Committee ..............................................................75 
17.4.2 
Independent Review Committee ........................................................76 
17.4.3 
Steering Committee .............................................................................76 
18 
DATA HANDLING AND RECORD KEEPING .....................................................76 
18.1 
Case Report Forms and Study Records ........................................................76 
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18.2 
Access to Source Documentation ...................................................................76 
18.3 
Retention of Data ............................................................................................76 
18.4 
Termination of Study ......................................................................................77 
19 
FINANCING AND INSURANCE .............................................................................77 
20 
PUBLICATION AND DISCLOSURE POLICY .....................................................77 
21 
REFERENCES ............................................................................................................79 
22 
APPENDICES .............................................................................................................81 
 
 
TABLE OF TABLES 
Table 1 
Treatment-emergent Adverse Events, Grade ≥3 ..............................................29 
Table 2 
Overall Response Rates and CNS Response Rates by Dose Cohort ...............31 
Table 3 
Schedule of Events ...............................................................................................43 
Table 4 
Arm A AP26113 Dose Modification Recommendations for Treatment-
related Adverse Events (Excluding Pneumonitis) .............................................50 
Table 5 
Arm B AP26113 Dose Modification Recommendations for Treatment-
related Adverse Events (Excluding Pneumonitis) prior to Dose 
Escalation ..............................................................................................................52 
Table 6 
Arm B AP26113 Dose Modification Recommendations for Treatment-
related Adverse Events (Excluding Pneumonitis) after Dose Escalation 
Period* ..................................................................................................................53 
Table 7 
AP26113 Dose Modification Recommendations for Treatment-related 
Pneumonitis ..........................................................................................................57 
Table 1.1 
Drugs Generally Accepted by the QTDrugs.org Advisory Board of the 
Arizona CERT to have a Known Risk of Causing Torsades de Pointes; 
Prohibited in this Study .......................................................................................87 
 
 
TABLE OF FIGURES 
Figure 1 
AP26113 and Crizotinib Potency Relative to Clinically Achievable 
Plasma Levels .......................................................................................................27 
 
 
 
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LIST OF APPENDICES 
APPENDIX A NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE) .................................82 
APPENDIX B EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS .............................................................................83 
APPENDIX C RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST VERSION 1.1) ..................................................................................84 
APPENDIX D DRUGS THAT INTERACT WITH CYP450 ENZYMES ............................86 
APPENDIX E DRUGS WITH A RISK OF TORSADES DE POINTES ..............................87 
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LIST OF ABBREVIATIONS  
Abbreviation 
Term 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ARIAD 
ARIAD Pharmaceuticals, Inc. 
AST 
aspartate aminotransferase 
ASCO 
American Society of Clinical Oncology 
AUC 
area under the curve 
β-HCG 
beta-human chorionic gonadotropin 
BAL 
bronchoalveolar lavage 
BNP 
B-type natriuretic peptide 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CHF 
congestive heart failure 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events (version 4.0) 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EMA 
European Medicines Agency 
EML4 
echinoderm mictrotubule-associated protein-like 4  
EORTC 
European Organisation for Research and Treatment of Cancer 
FDA 
Food and Drug Administration (United States) 
FFPE 
formalin-fixed, paraffin-embedded 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality-of-life 
IC50 
50% maximum inhibitory concentration 
ICMJE 
International Committee of Medical Journal Editors 
IHC 
immunohistochemistry 
IGF-1R 
insulin-like growth factor 1 receptor 
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Abbreviation 
Term 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRC 
independent review committee 
IV 
intravenous 
LD50 
oral lethal dose 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute (of the United States) 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PR 
partial response 
PRO 
patient-reported outcomes 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once-daily 
QLQ 
Quality of Life Questionnaire 
QT 
QT interval; a measure of the time between the start of the Q wave and 
the end of the T wave in the heart's electrical cycle 
QTc 
heart rate-corrected QT interval (calculated) 
QTcF 
QT interval corrected (Fridericia) 
RECIST 
Response Evaluation Criteria in Solid Tumors (version 1.1) 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SRS 
stereotactic radiosurgery 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
US 
United States 
WBRT 
whole brain radiation therapy 
 
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6 
DEFINITIONS OF TERMS  
Term 
Definition 
30 Days After Last 
Dose 
At 30 days after last dose of AP26113, a patient completes all 
post-treatment discontinuation assessments.  
Clinically 
Significant 
A clinical observation or laboratory result that leads to a new intervention 
or change in therapy is defined in the context of this study as clinically 
significant. 
Cycle 
For the purposes of this study, a cycle consists of 28 days. 
End-of-Treatment 
End-of-treatment occurs when a patient receives final dose of study drug 
or discontinues taking study drug and completes the end-of-treatment 
assessments.  
End-of-Study 
End-of-study (completion) date is when all patients have completed all 
study visits or have otherwise discontinued from the study. 
Enrolled Patient 
An enrolled patient is a patient who has signed the informed consent form, 
completed all screening evaluations, and has received study drug. 
Ethics Committee 
Throughout this document, the term Ethics Committee (EC) refers to all 
appropriate properly constituted committees or boards recognized by the 
appropriate regulatory agencies for approving clinical studies.  These 
include independent EC and Institutional Review Boards. 
Evaluable for 
Efficacy 
Any eligible patient who receives study drug is considered evaluable for 
efficacy analyses. 
Evaluable for 
Safety 
Any patient who receives study drug is considered evaluable for safety 
analyses. 
Follow-up Period 
The follow-up period for a patient begins after the last completed site visit 
and continues until patient contact discontinues. 
Institutional 
Review Board 
Throughout this document, the term Institutional Review Board (IRB) 
refers to all appropriate properly constituted committees or boards 
recognized by the appropriate regulatory agencies for approving clinical 
studies.  These include independent ECs and IRBs. 
Patient  
Throughout this document, the term patient refers to a patient in this 
clinical research study. 
QTcF 
QT corrected (Fridericia) Calculation Formula: QTcF = QT/(RR)1/3, where 
RR = the interval from the onset of one QRS complex to the onset of the 
next QRS complex, measured in seconds. 
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Term 
Definition 
Regulation 
Throughout this document, the term regulation refers to all appropriate 
regulations, laws, and guidelines.  This study will be conducted according 
to all appropriate regulations.  The regulations may be international, 
national, or local and may include but not be limited to the Code of 
Federal Regulations (United States); Ministry of Health, Labor, and 
Welfare (MHLW): Ethical Guidelines for Clinical Research (Japan); 
MHLW: Good Clinical Practice Guidelines (Japan); Japan 
Pharmaceuticals Affairs Law; the International Conference on 
Harmonisation Guideline for Good Clinical Practice; and the World 
Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Patients. 
Regulatory Agency 
Throughout this document, the term regulatory agency refers to all 
applicable health and regulatory agencies.  These may be international, 
national, or local and may include but not be limited to MHLW (Japan), 
Pharmaceuticals and Medical Devices Agency (PMDA), European 
Medicines Agency (EMA), and the United States Food and Drug 
Administration (FDA). 
Screening Period 
The screening period for a patient begins when the informed consent form 
is signed and continues until the first dose of study drug is administered. 
Sponsor 
Throughout this document, the term sponsor refers to all applicable 
departments within ARIAD Pharmaceuticals, Inc., or its designee. 
Study Reference 
Manual 
In the context of this study, Study Reference Manual is a general term for 
the information provided to sites on technical aspects of the study.  
Study Drug 
For the purposes of this protocol, the study drug is AP26113. 
Study Start Date 
The study start date is the date that the first patient signs the informed 
consent form. 
Suspected Adverse 
Reaction 
A suspected adverse reaction is any adverse event (defined in 
Section 14.1.1) for which there is a reasonable possibility that the drug 
caused the adverse event.  For the purposes of regulatory reporting, 
"reasonable possibility" means there is evidence to suggest a causal 
relationship between the drug and the adverse event. 
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7 
INTRODUCTION 
7.1 
Background 
AP26113 is a novel, synthetic, orally-active tyrosine kinase inhibitor (TKI) discovered and 
developed at ARIAD Pharmaceuticals, Inc. (ARIAD, the sponsor).  A primary target of 
AP26113 is anaplastic lymphoma kinase (ALK).  Activating gene rearrangements in ALK-
positive (ALK+) tumors have been identified as driver mutations in patients with non-small cell 
lung cancer (NSCLC) and other cancers.   
ALK is a tyrosine kinase encoded on chromosome 2 that is primarily involved in developmental 
processes and expressed at low levels in adults (Camidge et al, 2012).  The first genetic 
rearrangement of ALK seen in NSCLC involved a fusion between the echinoderm 
mictrotubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain.  
EML4-ALK had the capacity to transform fibroblasts grown in culture and as subcutaneous 
xenografts (Suda et al, 2007).  Since then, a number of additional ALK fusion partners have been 
described in NSCLC, such as tyrosine receptor kinase-fused gene (Rikova et al, 2007) and 
kinesin family member 5B (Takeuchi et al, 2009), all of which are believed to result in aberrant 
ALK signaling and oncogenic transformation.  Aberrant ALK, including ALK rearrangements, 
can potentially act as an oncogene in several different cancers, especially NSCLC (Camidge et 
al, 2012).   
The frequency of ALK rearrangements in the overall population of NSCLC patients ranges from 
3% to 5%, which represents approximately 8,000 patients in the United States (US) each year 
and approximately 40,000 patients worldwide each year (Perner et al, 2008; Wong et al, 2009).  
ALK rearrangements are more common among patients with adenocarcinoma histology, patients 
who have never smoked, and patients who have wild-type epidermal growth factor receptor 
(EGFR) and v-Ki-ras2 Kirsten RAt Sarcoma viral oncogene homolog (Camidge et al, 2010).   
Crizotinib (XALKORI®, Pfizer, Inc.) has demonstrated clinical efficacy in ALK+ NSCLC 
(Kwak et al, 2010).  In a phase 1 study of crizotinib that included 119 ALK+ NSCLC patients 
who were assessable for response, the objective response rate (ORR) was 61% and the median 
progression-free survival (PFS) was 48 weeks (XALKORI®, Pfizer, Inc.).  In a phase 2 
single-arm study of crizotinib that included 136 patients with ALK-positive tumors (PROFILE 
1005), the ORR was 50% and the median duration of response was 42 weeks (XALKORI®, 
Pfizer, Inc.).  These two studies served as the basis for crizotinib’s accelerated approval by the 
Food and Drug Administration (FDA) in the US and conditional approval by the European 
Medicines Agency (EMA) in the European Union.  The clinical benefit of treatment with 
crizotinib in ALK+ NSCLC patients (ie, improvement in disease-related symptoms or overall 
survival) has not yet been confirmed but additional randomized studies are ongoing.  Currently, 
crizotinib is the only ALK inhibitor that has obtained regulatory approval.   
Although crizotinib is an effective treatment of ALK+ NSCLC, a substantial proportion 
(50% and 39%, respectively) of ALK+ NSCLC patients in the pivotal studies that supported its 
accelerated approval failed to achieve a response.  For those patients who did respond, the 
benefit was relatively short-lived with a median duration of response ranging from 42 to 48 
weeks (XALKORI®, Pfizer, Inc.).  In many patients, loss of response manifests as systemic 
progression, but in many patients, the disease progresses only within the brain, possibly as a 
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result of low central nervous system (CNS) penetration of crizotinib (Camidge et al, 2012; Costa 
et al, 2011). 
The underlying reason for failure to achieve a response to crizotinib (primary resistance) is 
difficult to identify, but suboptimal potency of the agent against the targeted oncogene could be a 
contributing factor.  The mechanisms underlying loss of response (secondary or acquired 
resistance) to crizotinib are becoming clearer (Camidge et al, 2012).  Emerging data suggest that 
an important acquired resistance mechanism is the emergence of point mutations in the kinase 
domain of ALK (Katayama et al, 2012).  Mutations that confer resistance to crizotinib (such as 
the gatekeeper mutant L1196M, L1152R, G1269A, S1206Y, F1174L, D1203N, C1156Y, 
T1151Tins, and G1202R mutations) may act by reducing the binding affinity of crizotinib to 
ALK (Bang, 2012).  Other mechanisms of secondary resistance to crizotinib include the 
amplification of the ALK fusion gene, exploiting crizotinib’s suboptimal potency against ALK, 
and the activation of alternate signaling pathways (Camidge et al, 2012; Katayama et al, 2012).  
In some patients, loss of response to crizotinib may also have a pharmacologic basis, with 
inadequate drug exposure resulting from dose modifications, or changes in drug metabolism or 
transport over time.  In all of these scenarios, a rational approach to overcoming resistance is the 
use of a more potent ALK inhibitor with a broader therapeutic window that retains activity 
against all key crizotinib-resistance mutations and that can also achieve deep and prolonged 
target inhibition both systemically and in the CNS. 
Additionally, due to some of the serious adverse effects that are associated with crizotinib 
treatment (pneumonitis, hepatic laboratory abnormalities, and QT prolongation), some patients 
experience unacceptable toxicities requiring dose reduction or dose interruption.  When these 
toxicities are severe, discontinuation of crizotinib treatment is warranted.  In the pivotal studies 
of crizotinib that supported its accelerated approval, 4% of (10/255) patients became “intolerant” 
to crizotinib and discontinued treatment due to an adverse event (AE).   
7.2 
AP26113 Nonclinical Summary 
7.2.1 
Nonclinical Activity against ALK 
In nonclinical studies, AP26113 has been shown to: 
 Inhibit the activity of native ALK fusions with potency 8- to 10-fold greater than that of 
crizotinib 
 Potently inhibit ALK variants that confer resistance to crizotinib in patients through 
acquisition of secondary mutations in ALK 
 Suppress the emergence of any resistant ALK mutant in an in vitro assay, at 
concentrations that can be achieved clinically 
Studies in cultured cell lines revealed that AP26113 potently and selectively inhibited growth of 
NSCLC cell lines positive for the oncogenic EML4-ALK genetic rearrangement (GI50s of 
4.2-10.1 nM) relative to EML4-ALK negative NSCLC lines (GI50s of 503-1337 nM) (Rivera et 
al, 2010).  AP26113 was approximately 10-fold more potent and 10-fold more selective than 
crizotinib at inhibiting growth of these cell lines.   
To explore the activity of AP26113 against crizotinib-resistant ALK mutants, 9 different 
mutations that have been observed to date in the ALK kinase domain of crizotinib-resistant 
patient tumors were assessed in cellular viability assays.  The viability of Ba/F3 cells dependent 
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2010).  This assay successfully identified mutations known to confer clinical resistance to 
crizotinib such as L1196M and F1174L.  However, no mutations in ALK were identified that 
conferred resistance to 1 μM AP26113.  Clinical pharmacokinetic data from the ongoing phase 
1/2 study have shown that mean steady-state trough AP26113 plasma concentrations exceed 
1 μM in NSCLC patients receiving180 mg daily (QD) (Ctrough 1217 nM). 
In summary, preclinical studies have revealed potent in vitro activity of AP26113 against 
oncogenic ALK, as well as mutant variants of oncogenic ALK that confer resistance to crizotinib 
in NSCLC patients.  In addition, no ALK mutations have been identified in in vitro mutagenesis 
assays that can confer resistance to AP26113 at clinically achievable concentrations.  Further 
details regarding nonclinical studies on in vivo antitumor activity, absorption, distribution, 
metabolism, and excretion (ADME) and toxicology performed with AP26113 can be found in 
the Clinical Investigator’s Brochure for AP26113.  
7.2.2 
Nonclinical Activity against Other Targets  
In vitro kinase assays have revealed that AP26113 has potent inhibitory activity against other 
kinases implicated in NSCLC including activated epidermal growth factor receptor 
(EGFR-L858R), ROS1, and CHK2, comparable to the inhibitory activity observed against ALK 
(IC50s <10 nM).  AP26113 also inhibits the in vitro kinase activity of the insulin-like growth 
factor 1 receptor (IGF-1R), which has high sequence homology to the ALK kinase domain, with 
an IC50 of 32 nM.   
Additional in vitro and in vivo studies of AP26113 in relation to EGFR activity revealed that 
AP26113 does not inhibit native EGFR activity, but potently inhibits activated EGFR mutants 
commonly observed in NSCLC (eg, exon 19 deletion, L858R), as well as activated EGFR 
mutants containing the T790M gatekeeper mutation, which is known to confer resistance to other 
approved EGFR-TKIs such as erlotinib.  These results have served as the basis for exploration in 
a phase 1/2 clinical study of AP26113 activity in EGFR mutant, T790M-positive NSCLC 
patients resistant to prior EGFR TKI treatment.   
7.3 
AP26113 Clinical Summary 
Based on favorable preclinical in vitro and in vivo pharmacology and toxicology studies, a 
phase 1/2 clinical study of AP26113 (study AP26113-11-101) was initiated on 
20 September 2011.  Study 101 consists of a phase 1 dose escalation portion, followed by a 
phase 2 expansion portion with defined clinical cohorts.  As of protocol amendment 1, the trial is 
still enrolling patients.   
In the phase 1 dose-escalation portion of the study, patients were administered AP26113 at doses 
ranging from 30 mg QD to 300 mg QD.  Twice-daily (BID) dose regimens were also evaluated 
in some patients during dose-escalation.  At doses of 90 mg and higher, mean plasma steady-
state trough drug concentrations that exceeded levels predicted preclinically to inhibit crizotinib-
resistant ALK mutants were achieved.  No dose-limiting toxicities (DLTs) were observed in the 
phase 1 portion of the trial at doses up to 180 mg QD.  At higher doses, DLTs of grade 3 alanine 
aminotransferase (ALT) increased (240 mg QD) and grade 4 dyspnea (300 mg QD) were 
reported.  The maximum tolerated dose (MTD) was not formally determined.  However, based 
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on these results, the dose of 180 mg QD was initially chosen as the RP2D for the phase 2 
expansion portion of the study.   
In the phase 2 expansion portion of the study, 3 of 26 (12%) patients treated with 180 mg QD 
experienced early onset pulmonary symptoms that in some cases constituted pneumonitis 
(described in more detail below).  Consequently, two additional RP2Ds were tested: 90 mg QD 
and a 7-day dosing period of 90 mg QD followed by escalation to 180 mg QD.  Preliminary data 
(detailed below) support testing these regimens further in this randomized trial.  The most up-to-
date data can be found in the Clinical Investigator’s Brochure for AP26113.  
7.3.1 
Overview of Safety Observations from the Phase 1/2 Trial 
As of 6 September 2013, 91 patients were treated with AP26113 at doses ranging from 30 mg 
QD to 300 mg QD, including 45 patients treated at 180 mg QD.  Of these, the median age was 
57 years and 60% were female.  The majority (82%) of patients were diagnosed with 
adenocarcinoma of the lung (NSCLC).  Forty-two (46%) patients had a history of ALK 
rearrangement.  Approximately half (51%) of patients had received one or two prior systemic 
treatment regimens while 24% received more than two prior systemic treatment regimens.  
The most common treatment-emergent AEs (≥10% of patients) were nausea (38.5%), fatigue 
(34.1%), diarrhea (31.9%), cough (20.9%), headache (19.8%), dyspnea (16.5%), vomiting 
(16.5%), amylase increased (12.1%), decreased appetite (12.1%), and muscle spasms (11.0%).  
Treatment-related AEs of grade ≥3 occurring in 2 or more patients included dyspnea (4%), 
fatigue (3%), diarrhea (2%), hypoxia (2%), and pneumonitis (2%).  Serious adverse events 
(SAEs) (treatment-related) occurring in 2 or more patients were dyspnea (7%), pneumonia (4%), 
hypoxia (2%), and pneumonitis (2%).  Treatment-emergent AEs of grade 3 or higher are shown 
in Table 1. 
Table 1 
Treatment-emergent Adverse Events, Grade ≥3 
Preferred term  
(≥2 patients) 
30, 60 mg 
N=55 
n (%) 
90 mg  
N=8 
n (%) 
120 mg 
N=18 
n (%) 
180 mg* 
N=45 
n (%) 
240 mg 
N=12 
n (%) 
300 mg 
N=2 
n (%) 
Total 
N=91 
n (%) 
Dyspnea 
0 
0 
1 (6) 
1 (2) 
1 (8) 
1 (50) 
4 (4) 
Fatigue 
1 (17) 
0 
0 
1 (2) 
2 (7) 
0 
4 (4) 
Pneumonia 
0  
0 
3 (17) 
1 (2) 
0 
0 
4 (4) 
Hypoxia 
0 
0 
0 
1 (2) 
1 (8) 
1 (50) 
3 (3) 
Lung infection 
0 
0 
1 (6) 
1 (2) 
0 
0 
2 (2) 
Pneumonitis 
0 
0 
1 (6) 
1 (2) 
0 
0 
2 (2) 
Lipase increased 
0 
0 
1 (6) 
0 
2 (17) 
0 
3 (3) 
Diarrhea 
0 
0 
0 
0 
2 (17) 
0 
2 (2) 
Hyponatraemia 
0 
1 (13) 
0 
0 
1 (8) 
0 
2 (2) 
*Preferred terms ranked by incidence at 180 mg.  Data extraction date: 6 September 2013. 
Some patients experienced moderate or severe pulmonary AEs (dyspnea, pneumonia, hypoxia, 
lung infection, pneumonitis).  One might expect a variety of pulmonary AEs in a lung cancer 
population.  However, in the phase 2 expansion portion of study 101, the early onset of 
respiratory AEs was observed in 3 out of 26 patients dosed at 180 mg QD.  In the study overall, 
there were 6 cases (13%) of an early onset syndrome in 45 patients dosed at 180 mg QD, and 4 
additional cases observed at higher doses (2 at 240 mg QD and 2 at 300 mg QD) that comprise a 
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total of 10 cases (15%) in 59 patients treated with 180 mg QD or higher doses of AP26113 in the 
study. All 10 cases were SAEs.  
These early pulmonary AEs were observed only at doses of 120 mg and higher, and were more 
frequent and more severe at higher doses.  Most of these early pulmonary AEs occurred after a 
single dose of AP26113.  Typically, patients with early grade 3 or 4 pulmonary AEs experienced 
shortness of breath on Day 1 or 2 after the first dose of AP26113.  The temporal relationship to 
study drug administration suggests a causal relation to the drug.  The reports of early onset 
dyspnea were associated in some cases with cough, chest tightness, or fever, and in more severe 
cases with oxygen desaturation and ground glass opacities on chest computed tomography (CT) 
scans, consistent with an acute pneumonitis and constituting SAEs.  These events were reversible 
and responsive to AP26113 interruption and steroid support.  In some patients, re-challenge 
resulted in recurrence of symptoms and discontinuation of treatment.  One patient continued 
therapy after re-challenge, during which symptoms recurred but were amenable to medical 
management; some cases resolved with continued dosing in the absence of additional 
intervention.  One patient with these symptoms died due to concurrent progressive metastatic 
disease, and the investigator assessed the death as possibly related to study drug administration. 
Based on these safety observations, two additional potential RP2D regimens were tested in the 
phase 2 portion of the 101 study.  The first is 90 mg QD for 7 days followed by dose escalation 
to 180 mg QD.  That this regimen of initial lower dose exposure might ameliorate the early onset 
of pneumonitis is suggested by the observations that the pulmonary adverse event rate is dose-
related, and not observed at 90 mg; and that symptoms typically occur within 48 hours of initial 
dosing but do not recur with continued exposure to AP26113, even at higher doses.  As of 
6 September 2013, 21 patients have been enrolled in the 101 study utilizing the 90 mg to 180 mg 
regimen.  Twenty are evaluable for safety (1 patient was withdrawn after one dose when found to 
be ineligible for the study; the patient had no symptoms).  One patient experienced a cough on 
Day 1, but continued dosing and escalated to 180 mg without further events.  No other early 
onset pulmonary AEs or evidence of early pneumonitis were observed, and all patients’ doses 
escalated to 180 mg.  These data support the rationale of further testing of this regimen.  The 
second potential RP2D regimen is 90 mg QD; at this dose, no early onset or grade 3 or 4 
pulmonary AEs were observed in the phase 1 portion of the study and overall AE rates were low.  
At this time, additional patients are being enrolled to receive 90 mg QD. 
7.3.2 
Overview of Antitumor Activity 
Antitumor activity has been observed in patients with crizotinib-resistant ALK+ NSCLC as well 
as in TKI-naïve patients.  Overall, of the 34 ALK+ NSCLC patients treated with AP26113 who 
have been imaged, 22 responded (65% ORR; 95% CI: 47%-80%).  In ALK+ NSCLC patients 
treated with prior crizotinib (and no other ALK TKIs), responses were documented in 19 out of 
28 patients (68% ORR; 95% CI: 48%-84%).  An ORR of 100% was observed for TKI-naïve 
patients (3/3), including one complete response.  Response duration ranged from 8+ to 40+ 
weeks in 14 patients with confirmed responses.  In addition, 8 of 10 ALK+ NSCLC patients with 
active CNS lesions at baseline had evidence of radiographic improvement in the CNS (duration 
of CNS benefit in these patients ranged from 8+ to 40+ weeks).  Responses in CNS lesions were 
observed in patients receiving 180 mg QD or higher.  Overall response rates and CNS response 
rates by dose cohort are shown in Table 2.    
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Table 2 
Overall Response Rates and CNS Response Rates by Dose Cohort 
Dose# 
ORR Evaluable* 
(N) 
ORR** 
(N, %) 
CNS Evaluable*** 
(N) 
CNS RR 
(N, %) 
30 mg 
0 
NA 
0 
NA 
60 mg 
1 
1 (100) 
0 
0 
90 mg 
6 
6 (100) 
0 
0 
120 mg 
5 
4 (80) 
0 
0 
180 mg 
21 
11 (52) 
7 
6 (86) 
240 mg 
5 
3 (60) 
3 
2 (67) 
300 mg 
0 
NA 
0 
NA 
90-180 mg 
NA 
NA 
NA 
NA 
#Some patients received BID dosing; *ORR evaluable are patients with ALK+ NSCLC who had discontinued or undergone at 
least one scan at the time of reporting; **ORR: overall response rate; ***CNS evaluable are patients with active CNS disease 
(symptomatic or progressive) who had discontinued or undergone at least one scan at the time of reporting; Data extraction date: 
6 September 2013.   
7.3.3 
Pharmacokinetics 
Pharmacokinetic (PK) data from study 101 suggest that plasma AP26113 exposures (maximum 
plasma concentration [Cmax], steady-state trough plasma concentration [Ctrough]) generally 
increase with increasing dose.  At doses of 90 mg QD and higher, the mean AP26113 plasma 
concentration at steady-state (Day 29 Ctrough) exceeded the preclinically-defined IC50 values 
required to inhibit native ALK and 9 mutant ALK variants that confer resistance to crizotinib.  
The half-life of AP26113 is approximately 25-28 hours.  
7.3.4 
Rationale for Proposed RP2Ds 
Based on observations made from the phase 1/2 study, two RP2Ds are recommended for further 
study.  As might be expected, a higher incidence of AEs occurs with higher doses of AP26113, 
and grade 3 or 4 AEs are more frequent as well.  However, there is no clearly defined 
relationship between dose and antitumor activity at doses above 60 mg, although the dose 
escalation cohorts enrolled small numbers of patients that prevent drawing firm conclusions 
regarding response rates.  At 90 mg, mean plasma drug concentrations that surpass those that 
result in vitro in resistant mutant ALK inhibition are achievable.  Thus, there is a rationale for 
further testing in phase 2 studies of 90 mg QD, the minimum dose where adequate plasma drug 
concentration and antitumor activity (6/6 responses in evaluable patients) are coupled with a 
desirable safety profile.    
However, although preclinically defined active drug concentrations can potentially help interpret 
drug concentrations in the blood in the context of antitumor activity, or even assist in 
establishing minimum target concentrations, they are not precisely predictive of efficacious 
clinical doses.  Higher drug concentrations might be necessary to overcome all mutational, as 
well as non-mutational, factors that contribute to resistance such as those that interfere with drug 
access to target at both the cellular and organ level.  Of particular import for ALK+ NSCLC 
patients whose treatment has failed is that brain metastases are a well identified sanctuary site 
from antitumor agents, and especially from crizotinib (Camidge et al, 2012; Costa et al, 2011).   
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Numerous authors have hypothesized that higher drug concentrations enable penetration of the 
CNS by active agents to potential therapeutic advantage (Bachelot et al, 2013; Togashi et al, 
2012).  In the 101 phase 1/2 study, CNS response rates utilizing at least 180 mg QD are high.  
Moreover, higher concentrations may contribute to rapidity of response to drug, depth of 
response, and durability of response, all characteristics that cannot be studied well in a phase 1 
setting.  Thus, there is a rationale to further test higher doses as well.  Initially, 180 mg QD was 
selected as a RP2D, but the observed incidence of early pulmonary AEs precludes utilizing this 
dose.  The addition of a 90-mg QD 7-day lead-in to therapy with 180 mg QD appears to lessen 
the incidence of early pneumonitis and pulmonary symptoms.  Therefore, this dose will be tested 
as a RP2D as well.  In summary, AP26113 was generally safe at doses up to 180 mg QD in the 
phase 1/2 trial.  AP26113 exhibited substantial anticancer activity in patients with crizotinib-
resistant ALK+ NSCLC.  AP26113 is also active in ALK+ brain metastases with frequent 
responses of clinically meaningful duration.  Two RP2Ds have been determined for further 
study.   
7.4 
Rationale for the Phase 2 AP26113 Clinical Study  
There continues to be a need to explore new treatment options for patients who have experienced 
failure of crizotinib due to resistance or intolerance.  Chemotherapy is an approved treatment 
option for such patients although it is not specifically approved for use in ALK+ NSCLC 
patients.  In an unselected NSCLC population, first-line (doublet) chemotherapy typically yields 
ORRs of 30% (median PFS: 4 to 5 months) and second-line (single-agent) chemotherapy yields 
ORRs <11% (PFS: 2.9 months) (Shepherd et al, 2000; Fossella et al, 2000; Hanna et al, 2004; 
Shepherd et al, 2005; Kim et al, 2008; Shaw et al, 2012; Solomon et al, 2013).  New therapies 
are needed to improve response rates, to provide greater durability of response, and to overcome 
resistance to crizotinib.  Like all cancers, ALK+ NSCLC is a serious condition, and patients who 
have experienced failure of crizotinib likely have increased morbidity and mortality. 
Based on the promising activity profile of AP26113 in vitro and in vivo and the clinical activity 
demonstrated in the phase 1/2 study, this phase 2 study will evaluate AP26113 using two dosing 
regimens.  Patients with ALK+ NSCLC who have experienced failure of crizotinib therapy will 
be randomized 1:1 to receive either 90 mg QD continuously (in Arm A) or a lead-in dose of 90 
mg QD for 7 days followed by 180 mg QD continuously (in Arm B). 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is to determine the efficacy of AP26113, as evidenced by 
objective response rate, in patients with ALK-positive locally advanced or metastatic NSCLC 
whose disease has progressed on therapy with crizotinib.  Two dosing regimens will be tested.    
8.2 
Secondary Objectives 
The secondary objectives of the study (for each dosing regimen) are: 
1. To further characterize the efficacy of AP26113 in patients with ALK-positive, locally 
advanced or metastatic NSCLC whose disease has progressed on therapy with crizotinib, 
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1. Have histologically or cytologically confirmed locally advanced or metastatic NSCLC that is 
ALK+.  
2. Must meet one of the following two criteria: 
a. Have documented ALK rearrangement by a positive result from the Vysis® ALK Break-
Apart fluorescence in situ hybridization (FISH) Probe Kit; or   
b. Have documented ALK positivity by a different test and tissue available for the Vysis® 
FISH test.  Tissue should be derived preferably from a biopsy taken after progression 
with crizotinib.  If such a sample is not available, testing may be performed with archived 
tumor tissue. 
3. Had progressive disease while on crizotinib, as assessed by the investigator or treating 
physician. 
4. No longer a required criterion as of Amendment 2. 
5. Have at least 1 measurable lesion per RECIST v1.1 (see Appendix C).  Note: Previously 
irradiated lesions may not be used for target lesions, unless there is unambiguous radiological 
progression after radiotherapy.  Brain lesions may not be used as target lesions if they were: 
1) previously treated with whole brain radiation therapy (WBRT) within 3 months, or 2) 
previously treated by stereotactic radiosurgery (SRS) or surgical resection.  
6. No longer a required criterion as of Amendment 2. 
7. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0) grade ≤2 (see 
Appendix A). 
8. Are a male or female patient ≥18 years old.  
9. Have a life expectancy ≥3 months. 
10. Have adequate organ and hematologic function, as determined by: 
a. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x upper limit of 
normal (ULN; ≤5 x ULN is acceptable if liver metastases are present)  
b. Total serum bilirubin ≤1.5 x ULN (<3.0 x ULN for patients with Gilbert syndrome) 
c. Serum creatinine ≤1.5 x ULN 
d. Serum lipase/amylase ≤1.5 x ULN 
e. Absolute neutrophil count (ANC) ≥1500/µL 
f. Platelets ≥75000/µL 
g. Hemoglobin ≥10 g/dL 
11. Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (see 
Appendix B). 
12. Have normal QT interval on screening electrocardiogram (ECG) evaluation, defined as QT 
interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females.  
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13. For female patients of childbearing potential, a negative pregnancy test must be documented 
prior to enrollment.  
14. Female and male patients who are fertile must agree to use a highly effective form of 
contraception with their sexual partners throughout study participation (Section 14.3.1).   
15. Must provide a signed and dated informed consent indicating that the patient has been 
informed of all pertinent aspects of the study, including the potential risks, and is willingly 
participating.  
16. Have the willingness and ability to comply with scheduled visits and study procedures.  
10.2 
Exclusion Criteria 
Patients meeting any of the criteria below are ineligible for the study: 
1. Received any prior ALK-targeted TKI other than crizotinib.  
2. Received crizotinib within 3 days of the first dose of AP26113 (Day 1, Cycle 1). 
3. Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days, except 
SRS or stereotactic body radiosurgery. 
4. Received monoclonal antibodies or had major surgery within 30 days of the first dose of 
AP26113 (Day 1, Cycle 1). 
5. Have been diagnosed with another primary malignancy within the past 3 years (except for 
adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer, 
which are allowed within 3 years).  
6. Have symptomatic CNS metastases that are neurologically unstable or require an increasing 
dose of corticosteroids. 
7. Have current spinal cord compression.   
8. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but 
not restricted to: 
a. Myocardial infarction (MI) within 6 months prior to the first dose of AP26113 
b. Unstable angina within 6 months prior to first dose 
c. Congestive heart failure (CHF) within 6 months prior to first dose 
d. History of clinically significant (as determined by the treating physician) atrial 
arrhythmia 
e. Any history of ventricular arrhythmia 
f. Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose 
9. Have a history or the presence of pulmonary interstitial disease or drug-related pneumonitis. 
10. Have an ongoing or active infection.  The requirement for intravenous (IV) antibiotics is 
considered active infection. 
11. Have a known history of human immunodeficiency virus (HIV).  Testing is not required in 
the absence of history. 
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12. Have a history of or active significant gastrointestinal (GI) bleeding within 3 months of the 
first dose of AP26113. 
13. Have a known or suspected hypersensitivity to AP26113 or its excipients. 
14. Have malabsorption syndrome or other GI illness that could affect oral absorption of the 
study drug. 
15. Have any condition or illness that, in the opinion of the investigator, would compromise 
patient safety or interfere with evaluation of the drug study.  
16. Be pregnant or breastfeeding.  
11 
STUDY PROCEDURES 
Informed consent, documented by a signed consent form, must be obtained prior to any 
screening activities not otherwise part of the patient’s care.  The screening period begins when 
the informed consent form is signed, and continues until the first dose of study drug is 
administered.  The follow-up period begins after the last completed site visit and continues until 
patient contact discontinues.  
11.1 
Study Procedure Descriptions 
The study procedures to be performed at screening and throughout the study are listed in Table 3  
(Schedule of Events), which is meant to provide a convenient display of the timing and scope of 
required assessments expected at each visit, but does not provide a comprehensive description of 
each assessment.  A complete list of all study-related assessments as well as a detailed 
description of what is expected in the assessment is included below.  Investigators must be 
familiar with the details of this section and use it in conjunction with the table to adequately 
carry out the required study assessments.  All study assessments should occur within ±3 days of 
the scheduled study visit unless otherwise noted in the Schedule of Events descriptions or table.  
A cycle is defined as 28 days.   
The following list describes the procedures/tests required for this study. 
1. 
Screening 
Patients with known locally advanced or metastatic NSCLC, ALK+ status, and history of 
prior crizotinib treatment can be considered for screening.  Screening assessments must be 
performed no more than 14 days prior to Day 1, with the exception of tumor imaging 
assessment where the allowable window is 21 days prior to Day 1.  However, whenever 
feasible, baseline imaging should be performed as close as possible to Cycle 1, Day 1.   
Screening physical examination, ECOG Performance Status assessments, hematology, 
chemistry, insulin, testosterone (male patients), urinalysis and PT/PTT, and pregnancy test 
assessments do not need to be repeated on Day 1 if they were performed for screening 
within 7 days prior to Day 1 AND, in the opinion of the investigator, there is no reason to 
believe they have substantially changed.  The pregnancy test may be repeated at any time 
during the study if the patient or the investigator has cause to believe that the patient may 
be pregnant (refer to item 21 for further details).   
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2. 
Informed Consent 
Informed consent, documented by a signed and dated consent form, must be obtained prior 
to any screening activities that are not otherwise part of the patient’s care. 
3. 
Randomization 
Specific instructions for randomization will be supplied in the Study Reference Manual.  
Randomization procedures should be performed following complete eligibility assessments 
and prior to the initiation of assigned treatment.  
4. 
Demographics 
Demographic information consists of the patient’s age, sex, race, and ethnicity (as allowed 
by local law and regulations). 
5. 
Medical/Surgical History 
A complete medical history will be taken at screening.  Information to be documented 
includes relevant past illnesses, smoking history, ongoing medical conditions, and surgical 
procedures (not related to the primary diagnosis). 
6. 
Diagnosis and Cancer History 
The initial cancer diagnosis and the current cancer staging at the time of screening, along 
with tumor histology, and sites of primary and metastatic disease, should be recorded.   
7. 
Prior Cancer Therapy 
Prior cancer therapy history consists of cancer-related surgical procedures, radiation, and 
systemic therapies.  Surgical procedures include curative and diagnostic procedures (for 
example, biopsy).  Radiation will include both definitive and palliative treatment, and 
systemic therapy should include all regimens given and each drug name in a regimen, the 
start and stop dates of each drug and the best response to the regimen, and the reason for 
discontinuation.  Experimental or investigational therapy history must also be recorded.   
8. 
ALK Mutation Status 
Regarding current and past ALK mutation history, any previously identified mutations, and 
the dates of identification, must be recorded.  (This includes ALK rearrangements by FISH, 
ALK abnormalities by other methods including immunohistochemistry [IHC], and ALK 
point mutations).   
Patients entering the study must either have a history of a positive Vysis® ALK Break-
Apart FISH Probe Kit test, or must submit tissue samples for analysis using the Vysis® 
ALK Break-Apart FISH Probe Kit.  Specifications regarding handling and processing of 
tissue for this test are described under item 23 below (Tumor Tissue Samples) and in the 
Study Reference Manual.   
9. 
Physical Examination 
A complete physical examination must be performed at screening and/or on Cycle 1, Day 1 
prior to the first dose of AP26113, the extent of which should be consistent with medical 
history and the patient’s underlying disease.   
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Subsequent physical examinations may be directed to relevant findings.  Of note, due to the 
adverse reactions reported during treatment with crizotinib, investigators are cautioned to 
monitor patients treated with AP26113 for signs of vision dysfunction as well.  The End-of-
Treatment physical examination should be a complete physical examination.  The 30 day 
after treatment physical examination may be directed to any relevant findings. 
10. Vital Signs 
Vital signs include temperature, pulse, respiratory rate, and blood pressure (when patient is 
seated).  In addition, the screening assessment must include height and weight.  Vital signs 
should be repeated on Cycle 1, Day 1, prior to first dose, regardless of the time from 
screening.  
11. ECOG Performance Status 
The patient’s performance status must be assessed using the ECOG performance scale 
during screening and/or on Cycle 1, Day 1 prior to the first dose of AP26113.  The ECOG 
performance scale is provided in Appendix B. 
12. Hematology 
Hematology measurements include complete blood count (CBC) with differential and 
platelet count.  Cycle 1, Day 1 hematology blood draws should be performed prior to the 
first dose of AP26113.  
13. Chemistry 
Serum chemistry consists of a peripheral blood draw with the following assessments: 
sodium, potassium, chloride, bicarbonate (or total carbon dioxide), blood urea nitrogen 
(BUN, or urea), albumin and total protein, creatinine, bilirubin (at least total and direct or 
total and indirect), ALT (SGPT), AST (SGOT), alkaline phosphatase, magnesium, 
phosphorous, calcium, lactate dehydrogenase (LDH), creatine kinase (CK), uric acid, 
amylase and lipase, and glucose.  The serum chemistry blood draws at screening and on 
Cycle 2, Day 1 (and all blood draws for glucose) should be performed in a fasting state, 
which should be noted.  Cycle 1, Day 1 serum chemistry blood draws should be performed 
prior to the first dose of AP26113. 
14. Urinalysis 
Urinalysis will include pH, specific gravity, protein, ketones, glucose, urobilinogen, and 
occult blood.  Cycle 1, Day 1 urinalysis blood draws should be performed prior to the first 
dose of AP26113. 
15. Insulin 
Serum insulin and glucose should be measured concurrently.  All insulin and glucose blood 
draws should be performed in a fasting state, which should be noted.  Cycle 1, Day 1 
insulin blood draws should be performed prior to the first dose of AP26113. 
16. Testosterone Level (males only)  
In male patients, serum testosterone should be measured at screening or Cycle 1, Day 1 
(prior to the first dose of AP26113); and per the Schedule of Events throughout the study. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


ARIAD Pharmaceuticals, Inc. 
AP26113-13-201 
 
Version 4.0 24 August 2015 
Page 40 of 89 
 
17. Prothrombin Time/Partial Thromboplastin Time 
Prothrombin time (PT) will be expressed as an International Normalized Ratio (INR) or in 
seconds (the latter against control).  Partial thromboplastin time (PTT) will be expressed in 
seconds. 
18. Electrocardiogram  
All electrocardiograms (ECGs) must be 12-lead ECGs.   
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 has, during 
the study, been prescribed medication that can prolong the QT interval or medication that 
can potentially alter the QT interval (other than medications explicitly prohibited). 
For consistency, the Fridericia correction (QTcF = QT interval/3√RR interval) method 
must be used for all calculations of heart rate-corrected QT (calculated) (QTc) intervals.  
19. Adverse Events 
AEs are to be recorded continuously throughout the entire study and graded per NCI 
CTCAE version 4.0 (See Appendix A). 
20. Concomitant Treatments 
Concomitant treatments 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 Last Dose, and for 
all concomitant treatments related to serious or study drug-related toxicities until the 
medication is no longer taken or until patient contact discontinues. 
21. 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.  Women of childbearing potential at 
study start must also complete the pregnancy test once every 3 cycles thereafter and at the 
End-of-Treatment. 
22. Disease Assessment CT/MRI, Brain MRI 
At screening, disease assessment must include imaging of the chest and abdomen (covering 
adrenal glands), using appropriate radiological procedures (CT scans or magnetic 
resonance imaging [MRI] with contrast, unless contrast media is contraindicated).  
Contrast-enhanced MRI of the brain (such as gadolinium) is required at screening for all 
patients and will be repeated post-baseline for patients with CNS metastases.  All 
radiographic images (eg, CT scan, MRI) performed during the study will be submitted to 
the imaging core laboratory for central review.   
Disease assessment by CT or MRI scans will be performed at screening and at 8-week 
intervals thereafter (on Day 1 [±3 days] of every odd-numbered cycle) through 15 cycles 
after the initial dose of AP26113, and every 3 cycles thereafter until disease progression.  
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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ARIAD Pharmaceuticals, Inc. 
AP26113-13-201 
 
Version 4.0 24 August 2015 
Confidential and Proprietary 
Page 43 of 89 
 
Table 3 
Schedule of Events 
 
Screening 
Period 
Treatment through 30 Days After Last Dose 
Follow-up 
Period 
Assessment 
Screening1 
Cycle 1  
(28 Days) 
Every 4 
weeks (Day 
1 of each 
cycle from 
Cycle 2 
onwards) 
Every 8 
weeks (from 
Day 1 of 
Cycle 3 
through 
Cycle 15; 
every 3 
cycles 
thereafter) 
Every 12 
weeks (Day 
1 of every 
3rd cycle 
from Cycle 
4 onwards) 
End-of-
Treatment27 
30 Days 
After 
Last 
Dose28 
Follow-
up29 
Day (D) 
D-14 to D0 
D1 
D8 
D15 
 
 
 
 
 
 
Informed Consent2 
X 
 
 
 
 
 
 
 
 
 
Randomization3 
X 
 
 
 
 
 
 
 
 
 
Demographics4 
X 
 
 
 
 
 
 
 
 
 
Medical/Surgical History5 
X 
 
 
 
 
 
 
 
 
 
Diagnosis and Cancer 
History6 
X 
 
 
 
 
 
 
 
 
 
Prior Cancer Therapy7 
X 
 
 
 
 
 
 
 
 
 
ALK Mutation Status8 
X 
 
 
 
 
 
 
 
 
 
Physical Examination9 
X 
X 
X* 
X* 
X 
 
 
X 
X 
 
Vital Signs10 
X 
X 
X 
X 
X 
 
 
X 
X 
 
ECOG Performance 
Status11 
X 
X 
 
 
X 
 
 
X 
X 
 
Hematology12 
X 
X 
 
X 
X 
 
 
X 
X 
 
Chemistry (fasting, if 
possible)13 
X 
X 
 
X 
X 
 
 
X 
X 
 
Urinalysis14 
X 
X 
 
 
X 
 
 
X 
X 
 
Insulin (fasting, if 
possible)15 
X 
X 
 
X 
X 
 
 
X 
X 
 
Testosterone Level  
(males only)16 
X 
X 
 
 
X 
 
 
X 
X 
 
Prothrombin Time 
(PT)/Partial 
Thromboplastin Time 
(PTT)17 
X 
X 
 
X 
X 
 
 
X 
X 
 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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ARIAD Pharmaceuticals, Inc. 
 
 
AP26113-13-201 
 
Version 4.0 24 August 2015 
Page 45 of 89 
 
11.2 
Screening Period  
The screening period begins when the informed consent form is signed, and continues until the 
first dose of AP26113 is administered.  See Section 11.1 for further details. 
11.3 
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.  Patients who screen fail may 
later be re-screened with prior sponsor approval.   
11.4 
Treatment through 30 Days after Last Dose  
This period begins when the patient receives the first dose of AP26113. 
Assessments required during this period are shown in Table 3.  A detailed description of 
procedures and timing is provided in Section 11.1. 
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.  
11.5 
End-of-Treatment or Early Termination  
End-of-Treatment is defined as the point when or the patient and investigator decide to end study 
treatment (which may be after a dose interruption).   
Assessments required at End-of-Treatment are shown in Table 3.  A detailed description of 
procedures and timing is provided in Section 11.1. 
11.6 
30 Days After Last Dose 
Assessments required at 30 Days After Last Dose are shown in Table 3.  A detailed description 
of procedures and timing is provided in Section 11.1.  
11.7 
Follow-up Period Procedures 
The follow-up period for a patient begins after the last completed site visit and continues until 
patient contact ceases (for at least 2 years after the last patient has enrolled).   
Assessments required for the Follow-up Period are shown in Table 3.  A detailed description of 
procedures and timing is provided in Section 11.1.  
11.8 
Study Duration 
11.8.1 
Approximate Duration of Patient Participation 
Patients will continue to be dosed with AP26113 until they experience disease progression or 
intolerable toxicity.  Treatment may be continued after progression, at the discretion of the 
investigator.  On Arm A, at the time of progression, the patient may continue at the same dose or 
the patient’s dose may be escalated from 90 mg QD to 180 mg QD.  For patients on either arm 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


ARIAD Pharmaceuticals, Inc. 
 
 
AP26113-13-201 
 
Version 4.0 24 August 2015 
Page 46 of 89 
 
receiving 180 mg QD, at the time of progression, treatment may continue if there is still evidence 
of clinical benefit (see Section 13.1.2 for details on treatment continuation after progression).  
11.8.2 
Approximate Duration of Study 
The total estimated duration of the study is at least 3 years, including approximately 18 months 
to accrue patients, with 2 years for treatment and follow-up for the last patient.  Patients will be 
allowed to receive study drug beyond this period until disease progression or they discontinue 
treatment for other reasons.  
11.9 
Patient Discontinuation 
Patients will be discontinued from further study drug administration in the event of any of the 
following: 
 
Intolerable toxicity as determined by the investigator 
 
Progression of disease requiring an alternate therapy, in the opinion of investigator   
(Note: In some cases, despite progression by RECIST v1.1, patients and investigators 
may have the opinion that continued study drug administration is beneficial and, in 
these cases, therapy may continue). 
 
Entry into another therapeutic clinical study or start of new anticancer therapy 
 
Significant deviation from the protocol or eligibility criteria, in the opinion of the 
medical monitor or investigator 
 
Noncompliance with study or follow-up procedures 
 
Pregnancy 
 
Patient withdrawal of consent or decision to discontinue participation 
 
Termination of the study by the sponsor 
 
Any other reason that, in the opinion of the investigator, would justify removal of the 
patient from the study 
In the event that a patient is withdrawn from the study, every effort will be made by the 
Investigator to document and report the reasons for withdrawal as thoroughly as possible.  The 
reason(s) for withdrawal must be clearly reported on the appropriate page of the patient’s 
electronic case report form (eCRF).  An eCRF must be completed for any patient who receives 
study drug.  An End-of-Treatment reason must be recorded for any patient who receives study 
drug. 
If a patient is discontinued from the study for any reason, every effort must be made to perform 
all End-of-Treatment and 30 Days After Last Dose assessments per the schedule of events 
(Table 3).  In the event that the patient fails to return for the necessary visit(s), an effort must be 
made to contact the patient to determine the reason, and this information should be recorded in 
the appropriate source record and reported as a deviation. 
All patients who discontinue prematurely from study treatment will be followed-up for survival 
every 3 months after the last dose of AP26113.  
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11.10 
Study or Site Termination 
If the sponsor, investigator, medical monitor, or regulatory agencies discover conditions during 
the study that indicate that the study or site should be terminated, this action may be taken after 
appropriate consultation between the sponsor, investigator, and medical monitor.  Conditions that 
may warrant termination of the study include, but are not limited to: 
● 
The discovery of a serious, unexpected, or unacceptable risk to subjects enrolled in the 
study; 
● 
The decision on the part of the sponsor to suspend or discontinue testing, evaluation, 
or development of the study treatment; 
● 
Submission of knowingly false information from the research facility to the sponsor, 
medical monitor, or regulatory authorities; 
● 
Insufficient adherence to protocol requirements. 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the guidelines for Good Clinical Practice (GCP), International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).  
11.11 
Sample Collection, Storage, and Shipping 
All samples must be collected by appropriately trained individuals.  Use of Universal Precautions 
is recommended when collecting any biological specimen.  Plasma samples must be stored at or 
below -20ºC until shipment.  Specific instructions regarding the handling and shipment of these 
specimens will be provided in the Study Reference Manual.  
12 
EFFICACY AND SAFETY ASSESSMENTS 
12.1 
Efficacy Assessments 
Tumor response will be determined per RECIST v1.1 (see Appendix C) by the investigator, with 
a secondary independent radiological review.  Evaluation of efficacy will be by ORR (confirmed 
≥4 weeks after initial response), disease control rate (CR, PR, SD), time to/duration of response, 
PFS, OS, and time on treatment.  CNS response will be evaluated by ORR and PFS. 
12.2 
Safety Assessments 
Safety assessments will include physical and laboratory examinations, vital signs, and ECGs.  
AEs will be graded according to the NCI CTCAE, v4.0 (see Appendix A and the Study 
Reference Manual).  Safety assessments and their timing are outlined in Section 11.1. 
12.3 
Pharmacokinetic Assessments 
Sparse plasma AP26113 concentration data obtained from this study will be included in 
integrated population PK analyses, along with data from study AP26113-11-101, with the 
objective of further characterizing the plasma PK of AP26113 in the intended patient population, 
and to assess exposure-response (for efficacy) and exposure-safety relationships in patients 
receiving AP26113.  
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Study drug administration will continue until the patient dies, discontinues treatment, or the trial 
ends.  In some cases, despite progression by RECIST v1.1, patients and investigators may have 
the opinion that continued study drug administration is beneficial and, in these cases, therapy 
may continue. 
13.1.2 
Continued Treatment after Disease Progression 
Patients will continue to be dosed with AP26113 until they experience disease progression or 
intolerable toxicity.  In certain circumstances, at the discretion of the treating investigator, 
therapy may continue after progressive disease has been identified. 
Candidates for Dose Escalation on Arm A 
Patients on Arm A being treated at 90 mg QD who experience progressive disease will be 
allowed, at the discretion of the treating investigator, to escalate their dose to 180 mg QD.  
According to the investigator’s assessment, the risk posed to the patient by dose escalation must 
be acceptable, and must be outweighed by the potential benefit of continued treatment.  Patients 
who have undergone dose reduction for adverse events to 60 mg are not candidates for escalation 
to 180 mg QD.   
Continued Therapy at the Time of Disease Progression on Either Arm 
Patients in either arm who experience disease progression may continue to be treated at the same 
dose if in the opinion of the treating investigator they continue to experience benefit.   
13.1.3 
Dose Modification(s) 
13.1.3.1 Dose Modifications for Treatment-related Adverse Events   
The following sections provide recommended dose modification guidelines for treatment-related 
adverse events observed with AP26113 administration.  Dose modification guidelines specific to 
the management of early onset pulmonary syndrome and pneumonitis are provided in Sections 
13.1.4.1 and 13.1.4.2.  
Dose interruptions or reductions should be implemented for patients who experience treatment-
related AEs, upon clinical judgment of the investigator.  Study drug administration may be 
delayed for up to 28 days to allow for improvement or resolution of the event.  If a treatment-
related AE does not resolve to grade 1 or less after dose interruption for more than 28 days, the 
patient must be discontinued from study treatment.  Additionally, the sponsor’s Medical Monitor 
must be contacted if any AE deemed unrelated to treatment requires dose interruption for more 
than 28 days.   
13.1.3.1.1 Dose Modifications for Arm A (90 mg QD)  
Criteria for dose modifications of general treatment-related adverse events (excluding early onset 
pulmonary syndrome and pneumonitis) in patients initially treated with 90 mg QD are 
recommended in Table 4.   
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Table 4 
Arm A AP26113 Dose Modification Recommendations for Treatment-
related Adverse Events (Excluding Pneumonitis) 
Toxicity Grade per CTCAE v4.0 
Recommended Action 
Nonhematologic Toxicity 
Grade 1 
 
Manage the toxicity with supportive care while continuing at the same dose  
Grade 2 
Manage the toxicity with supportive care while continuing at the same dose  
 
Grade 3 
 
When the current dose is 90 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 90 mg or 60 mg QD at the discretion of the investigator  
 
Upon recurrence at 90 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 60 mg QD  
 
When the current dose is 60 mg QD: 
Consider discontinuing treatment 
Grade 4 
When the current dose is 90 mg QD:  
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 60 mg QD, or discontinue, at the discretion of the investigator 
 
When the current dose is 60 mg QD: 
Consider discontinuing treatment 
QTc Prolongation 
Grade 1 (QTcF 450-480 ms) 
Review concomitant medications and perform serum electrolyte analysis 
(including potassium, calcium, and magnesium). 
Manage the toxicity with supportive care and correct with supplements if 
electrolytes are below normal limits.  
Continue at the same dose.  
Grade 2 (QTcF 481-500 ms) 
First occurrence at any dose level: 
Hold treatment 
Perform serum electrolyte analysis (including potassium, calcium, and 
magnesium) and correct with supplements if below normal limits 
Review concomitant medications 
Repeat ECG as clinically indicated, but at least daily until QTcF returns to ≤ 
Grade 1 (480 ms) 
Resume at current dose after recovery to ≤ Grade 1 
If no contributing reason was identified for QTcF elevation, then weekly 
ECG monitoring is recommended for 4 weeks upon resumption of treatment, 
then monthly for 6 months, and then every 3 months for the remainder of the 
study, or more frequently as clinically indicated 
 
Upon recurrence at 90 mg QD: 
Repeat above 
Hold until event is ≤ Grade 1, or has returned to baseline 
Resume at 60 mg QD 
 
Upon recurrence at 60 mg QD: 
Consider discontinuing treatment 
Grade 3 (QTcF ≥ 501 ms on at 
least 2 separate ECGs) 
First occurrence at any dose level: 
Hold treatment 
Perform serum electrolyte analysis (including potassium, calcium, and 
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magnesium) and correct with supplements if below normal limits 
Review concomitant medications 
Repeat ECG as clinically indicated, but at least daily until QTcF returns to ≤ 
Grade 1 (480 ms) 
Resume at next lower dose level after recovery to ≤ Grade 1 
If no contributing reason was identified for QTcF elevation, then weekly 
ECG monitoring is recommended for 4 weeks upon resumption of treatment, 
then monthly for 6 months, and then every 3 months for the remainder of the 
study, or more frequently as clinically indicated 
 
Upon recurrence at 90 mg QD: 
Repeat above 
Hold until event is ≤ Grade 1, or has returned to baseline 
Resume at 60 mg QD 
 
Upon recurrence at 60 mg QD: 
Consider discontinuing treatment 
Grade 4 (QTc ≥501 or >60 ms 
change from baseline and Torsade 
de pointes or polymorphic 
ventricular tachycardia or 
signs/symptoms of serious 
arrhythmia)  
Consider discontinuing treatment  
Hematologic Toxicity 
Grade 1 
 
Continue at current dose 
Grade 2 
 
Continue at current dose 
Grade 3 
When the current dose is 90 mg QD: 
Hold until event is ≤Grade 2, or has returned to baseline 
Resume at 90 mg or 60 mg QD at the discretion of the investigator 
 
Upon recurrence at 90 mg QD: 
Hold until event is ≤Grade 2, or has returned to baseline 
Resume at 60 mg QD 
 
When the current dose is 60 mg QD: 
Consider discontinuing treatment 
Grade 4 
When the current dose is 90 mg QD: 
Hold until event is ≤Grade 2, or has returned to baseline 
Resume at 60 mg QD  
 
When the current dose is 60 mg QD: 
Consider discontinuing treatment 
13.1.3.1.2 Dose Modifications for Arm B (90 mg QD Day 1-7 Followed by 180 mg QD) 
Dose Modifications for Patients Prior to Dose Escalation  
Criteria for dose modifications for treatment-related AEs prior to dose escalation, in the first 7 
days of treatment (excluding early onset pulmonary syndrome and pneumonitis) are 
recommended in Table 5.   
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Table 5 
Arm B AP26113 Dose Modification Recommendations for Treatment-related 
Adverse Events (Excluding Pneumonitis) prior to Dose Escalation 
Toxicity Grade per 
CTCAE v4.0 
Action for Dose Modification 
Criteria for Dose Escalation  
Nonhematologic Toxicity 
Grade 1 
 
Manage the toxicity with supportive 
care while continuing at the same 
dose. 
Escalate to 180 mg QD on Day 8, as 
scheduled.  
Grade 2 (≤3 days) 
Manage the toxicity with supportive 
care while continuing at the same 
dose.  
If the event is controlled to no worse than 
Grade 1 at Day 8, escalate to 180 mg QD, as 
scheduled.  
Grade 2 (for >3 days, 
despite optimal supportive 
care)  
Hold until event is ≤Grade 1, or has 
returned to baseline, then resume at 
90 mg QD.  
If no recurrence of Grade 2 after 90 mg QD 
for 7 days, escalate to 120 mg QD.  Do not 
escalate to 180 mg QD.   
 
If recurrence of Grade 2 after 90 mg QD, no 
escalation.   
Grade 3 
Hold until event is ≤Grade 1, or has 
returned to baseline, then resume at 
90 mg QD.  
No dose escalation.  
Grade 4  
Hold until event is ≤Grade 1, or has 
returned to baseline, then resume at 
60 mg QD.  
No dose escalation.  
Hematologic Toxicity
Grade 1 or Grade 2 
Continue at 90 mg QD.  
Escalate to 180 mg QD on Day 8, as 
scheduled.  
Grade 3 
Hold until event is ≤Grade 2, or has 
returned to baseline, then resume at 
90 mg QD.  
No dose escalation. 
Grade 4 
Hold until event is ≤Grade 2, or has 
returned to baseline, then resume at 
90 mg QD.  
No dose escalation.  
13.1.3.1.3 Dose Modifications after Dose Escalation to 180 mg QD for Patients in Arm B 
For patients in Arm B, after the initial treatment period at 90 mg QD, the dose should be 
escalated to 180 mg QD after 7 days, or the dose modification guidelines above should be 
followed.   
Criteria for dose modifications for treatment-related AEs after dose escalation for patients in 
Arm B (excluding early onset pulmonary syndrome and pneumonitis) are recommended in Table 
6.   
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Table 6 
Arm B AP26113 Dose Modification Recommendations for Treatment-related 
Adverse Events (Excluding Pneumonitis) after Dose Escalation Period* 
Toxicity Grade per CTCAE v4.0 
Recommended Action 
Nonhematologic Toxicity 
Grade 1  
Manage the toxicity with supportive care while continuing at the same dose  
 
Grade 2  
Manage the toxicity with supportive care while continuing at the same dose 
 
Grade 3 
 
When the current dose is 180 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 180 mg QD or 120 mg QD at the discretion of the investigator   
 
Upon recurrence at 180 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 120 mg QD  
 
When the current dose is 120 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 90 mg QD after recovery  
 
When the current dose is 90 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 60 mg QD after recovery, or discontinue at the discretion of the 
investigator  
 
When the current dose is 60 mg QD: 
Consider discontinuing treatment 
Grade 4 
When the current dose is 180 mg QD:  
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 120 mg QD, or discontinue, at the discretion of the investigator 
 
When the current dose is 120 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 90 mg QD, or discontinue, at the discretion of the investigator 
 
When the current dose is 90 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 60 mg QD after recovery, or discontinue at the discretion of the 
investigator 
 
When the current dose is 60 mg QD: 
Consider discontinuing treatment 
QTc Prolongation 
Grade 1 (QTcF 450-480 ms) 
Manage the toxicity with supportive care such as reviewing concomitant 
medications and performing serum electrolyte analysis (including potassium, 
calcium, and magnesium) and correct with supplements if below normal  
while continuing at the same dose  
Grade 2 (QTcF 481-500 ms) 
First occurrence at any dose level: 
Hold treatment 
Perform serum electrolyte analysis (including potassium, calcium, and 
magnesium) and correct with supplements if below normal limits 
Review concomitant medications 
Repeat ECG as clinically indicated, but at least daily until QTcF returns to ≤ 
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Grade 1 (480 ms) 
Resume at current dose after recovery to ≤ Grade 1 
If no contributing reason was identified for QTcF elevation, then weekly 
ECG monitoring is recommended for 4 weeks upon resumption of treatment, 
then monthly for 6 months, and then every 3 months for the remainder of the 
study, or more frequently as clinically indicated 
 
Upon recurrence at 180 mg QD: 
Repeat above 
Hold until event is ≤ Grade 1, or has returned to baseline 
Resume at 120 mg QD 
 
Upon recurrence at 120 mg QD: 
Repeat above 
Hold until event is ≤ Grade 1, or has returned to baseline 
Resume at 90 mg QD 
 
Upon recurrence at 90 mg QD: 
Repeat above 
Hold until event is ≤ Grade 1, or has returned to baseline 
Resume at 60 mg QD 
 
Upon recurrence at 60 mg QD: 
Consider discontinuing treatment 
Grade 3 (QTcF ≥ 501 ms on at 
least 2 separate ECGs) 
First occurrence at any dose level: 
Hold treatment 
Perform serum electrolyte analysis (including potassium, calcium, and 
magnesium) and correct with supplements if below normal limits 
Review concomitant medications 
Repeat ECG as clinically indicated, but at least daily until QTcF returns to ≤ 
Grade 1 (480 ms) 
Resume at next lower dose level after recovery to ≤ Grade 1 
If no contributing reason was identified for QTcF elevation, then weekly 
ECG monitoring is recommended for 4 weeks upon resumption of treatment, 
then monthly for 6 months, and then every 3 months for the remainder of the 
study, or more frequently as clinically indicated 
 
Upon recurrence at 120 mg QD: 
Repeat above 
Hold until event is ≤ Grade 1, or has returned to baseline 
Resume at 90 mg QD 
 
Upon recurrence at 90 mg QD: 
Repeat above 
Hold until event is ≤ Grade 1, or has returned to baseline 
Resume at 60 mg QD 
 
Upon recurrence at 60 mg QD: 
Consider discontinuing treatment 
Grade 4 (QTc ≥501 or >60 ms 
change from baseline and Torsade 
de pointes or polymorphic 
ventricular tachycardia or 
signs/symptoms of serious 
arrhythmia)  
Consider discontinuing treatment  
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Hematologic Toxicity 
Grade 1  
Continue at current dose 
 
Grade 2 
Continue at current dose  
 
Grade 3 
When the current dose is 180 mg QD: 
Hold until event is ≤Grade 2, or has returned to baseline 
Resume at 180 mg or 120 mg QD at the discretion of the investigator 
 
Upon recurrence at 180 mg QD: 
Hold until event is ≤Grade 2, or has returned to baseline 
Resume at 120 mg QD 
 
When the current dose is 120 mg QD: 
Hold until event is ≤Grade 2, or has returned to baseline 
Resume at 90 mg QD 
 
When the current dose is 90 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 60 mg QD after recovery, or discontinue at the discretion of the 
investigator 
 
When the current dose is 60 mg QD: 
Consider discontinuing treatment 
Grade 4 
When the current dose is 180 mg QD: 
Hold until event is ≤Grade 2, or has returned to baseline 
Resume at 120 mg QD after recovery  
 
When the current dose is 120 mg QD,  
Hold until event is ≤Grade 2, or has returned to baseline 
Resume at 90 mg QD after recovery  
 
When the current dose is 90 mg QD: 
Hold until event is ≤Grade 1, or has returned to baseline 
Resume at 60 mg QD after recovery, or discontinue at the discretion of the 
investigator 
 
When the current dose is 60 mg QD 
Consider discontinuing treatment  
*Apply these recommendations either after dose escalation was accomplished, or after dose reduction for Grade 3 or 
4 toxicity was implemented resulting in no dose escalation.  
13.1.4 
Dose Modification and Management of Specific Treatment-related Adverse 
Events 
Comprehensive assessments of any study drug-related AEs (adverse drug reactions) experienced 
by the patient 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 patient for 
any AE experienced while participating in this study. 
Any medication, including those administered for therapy of symptoms considered to be 
associated with study drug administration, should be reported on the appropriate concomitant 
medication page of the patient’s eCRF.  The symptoms should be reported on the AE page. 
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13.1.4.1 Early Onset Pulmonary Syndrome 
An early onset pulmonary syndrome consistent in some cases with pneumonitis occurred shortly 
after treatment initiation in 15% of patients who had received AP26113 at 180 mg QD, and 
possibly in a patient at 120 mg.  The syndrome may include the acute onset of symptoms of 
dyspnea, cough, chest tightness, and fever.  It has been observed after a single dose of AP26113 
in patients.  It is possible that patients with pre-existing pulmonary interstitial disease, including 
lymphangitic involvement by tumor, may be at increased risk.  The syndrome is associated in 
more severe cases with hypoxia and chest CT findings of ground glass opacities consistent with 
pneumonitis, and in these cases constituted SAEs.  However, in some patients, the symptoms 
resolved without drug interruption, dose modification, or specific intervention.  This suggests 
that the pathogenesis and natural history of this condition may differ from later-onset 
pneumonitis, rarely observed with AP26113, but described with other TKIs.  Nonetheless, 
investigators must be aware that this pneumonitis-like syndrome may present within 24 hours of 
initial dosing.  
The occurrence of the early onset pneumonitis-like syndrome was not observed at doses of 90 
mg, and was more common at higher doses, suggesting a relationship to initial dose.  Similar 
pulmonary events have not been reported frequently after the first several days of treatment, at 
which time higher drug concentrations are attained in most patients as drug accumulates due to 
its long half-life.  The timing and the reversibility of the early onset pulmonary syndrome 
suggest that if a low initial dose was tolerated, the dose could be escalated to a higher dose 
without an increased risk of developing such events.  This is the rationale for a lead-in period at 
90 mg QD for the first 7 days before escalation to 180 mg QD.  
Early onset respiratory events, including but not limited to, dyspnea, hypoxia, dry cough, chest 
tightness, and presumptive lung infection (pneumonia) should be monitored and reported.  
Newly developed or worsening of pulmonary symptoms in the first week of study drug 
administration specifically with hypoxia and ground glass opacity in the chest CT indicative of 
interstitial lung disease or pneumonitis could suggest a relationship to AP26113.  Other 
etiologies, including pulmonary embolism and infectious pneumonia, should be ruled out if 
possible.  If no evidence of other etiology is identified, a causal relationship to AP26113 should 
be considered.  Such pulmonary events of hypoxia and radiographic evidence of pneumonitis 
occurring in patients in Arm B within the first 7 days of initial treatment should be evaluated 
before dose escalation.  Although the early onset syndrome has not been observed after dose 
escalation to 180 mg, it should also be considered in the period immediately following dose 
escalation from 90 mg to 180 mg.  
The management of early onset pulmonary symptoms should include drug interruption, 
monitoring of oxygen saturation, and radiographic evaluation, with high dose corticosteroids, 
supplemental oxygen therapy, and empiric antibiotics as indicated.  Dose modification should be 
accomplished according to the recommendations in Table 4 and Table 5.  If the symptoms 
include documented hypoxia and/or radiologic evidence of interstitial or ground glass changes, 
or result in an SAE, the early onset condition should be treated according to Table 7.  
13.1.4.2 Pneumonitis 
Pneumonitis, including interstitial lung disease, occurring later in the course of therapy, is a 
known side effect of TKIs used in NSCLC.  Crizotinib has been associated with severe, life-
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threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 
(1.6%) patients (XALKORI®, Pfizer, Inc.).  Other TKIs used in the treatment of NSCLC have 
similar adverse reactions.  Drug-related pneumonitis may be associated with signs and symptoms 
such as dyspnea, hypoxia, cough, hemoptysis, and fever as well as radiologic evidence of 
parenchymal or interstitial changes.  In the phase 1/2 study of AP26113, one case of drug-related 
grade 3 pneumonitis occurred (at 240 mg) 7.5 months after the first dose of AP26113, out of a 
total of 91 patients treated.    
The diagnosis of pneumonitis and determination of causal relationship to the drug is often 
confounded by the underlying disease (especially lymphangitic carcinomatosis) and other factors 
such as lung infection and radiation effect due to non-specific signs and symptoms as well as 
similar radiological appearance.  Pneumonitis should be suspected when such signs and 
symptoms develop or in asymptomatic patients when a new ground glass opacity or interstitial 
infiltration is noted in imaging studies.  If a patient is considered to have the potential diagnosis 
of drug-related pneumonitis, physical examination, assessment of O2 saturation, and evaluation 
for infectious etiologies, and thoracentesis, bronchoscopy, or open lung biopsy should be 
considered to reach a diagnosis.  If the causality is at least possibly related to the study drug, 
management of pneumonitis, including dose interruption and potentially discontinuation is 
required, as presented in Table 7. 
 
Table 7 
AP26113 Dose Modification Recommendations for Treatment-related 
Pneumonitis 
Toxicity Grade  
Dose Modification for Arm A 
Dose Modification for Arm B 
Grade 1  
 
Withhold the dose until pneumonitis returns to 
Grade 0 (baseline), then resume at the same 
dose.   
If pneumonitis recurs, permanently discontinue 
treatment 
Withhold the dose until pneumonitis returns 
to Grade 0 (baseline), then resume at the 
same dose.   
If occurs during 7-day lead-in at 90 mg QD, 
withhold dose until pneumonitis returns to 
grade 0, then resume at 90 mg and do not 
escalate.  
If pneumonitis recurs, permanently 
discontinue treatment.  
Grade 2 
 
Withhold the dose until pneumonitis returns to 
Grade 0.  Resume at 60 mg QD.  
If pneumonitis recurs, permanently discontinue 
treatment. 
Withhold the dose until pneumonitis returns 
to Grade 0.  Resume at 120 mg QD.   
If occurs during 7-day lead-in at 90 mg QD, 
withhold dose until pneumonitis returns to 
grade 0, then resume at 60 mg and do not 
escalate.. 
If pneumonitis recurs, permanently 
discontinue treatment. 
Grade 3 
Permanently discontinue treatment.  
Permanently discontinue treatment. 
Grade 4 
Permanently discontinue treatment. 
Permanently discontinue treatment. 
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13.1.4.3 Nausea and Emesis 
Treat with standard-of-care antiemetics.  Prophylactic antiemetics may be used. 
13.1.4.4 Diarrhea 
For grade 1 diarrhea, symptomatic care such as loperamide (Imodium®, McNEIL-PPC, Inc.) may 
be given, or no intervention may be undertaken, according to the investigator’s clinical 
judgment.  For grade 2 diarrhea, administer loperamide at 4 mg, then 2 mg every 2 to 4 hours 
until the patient is symptom-free for 12 hours.  No dose modification is necessary unless the 
patient does not tolerate AP26113 or the symptom recurs.  For grade ≥3 despite loperamide, 
treatment will be withheld until recovery to grade ≤1 (Table 6).  Other medications and 
supportive care may be added according to the institution’s standard of care.  
13.1.5 
Re-Escalation after Dose Modification 
Re-escalation after dose modification for adverse events is discouraged.  However, if in the 
opinion of the treating investigator re-escalation is warranted, this must be undertaken after 
consultation with the sponsor.  To be a candidate for re-escalation, the AE that led to dose 
modification must not have recurred, and no other AEs of Grade 3 or 4 must have been observed 
during the preceding 28 days.  
13.2 
Prior and Concomitant Treatment(s)/Therapy 
History of prior cancer therapy will be recorded at screening, and concomitant cancer therapy 
will be recorded during the study on the appropriate eCRF for each patient. 
Reasonable efforts will be made to collect information on all prior cancer therapy received by the 
patient (eg, chemotherapy, radiotherapy, immunotherapy, biologics).  The information must be 
obtained from the patient’s medical chart and recorded on the appropriate eCRF. 
Palliation and supportive care are permitted during the study for management of symptoms and 
underlying medical conditions that may develop during the study.  Once a patient has begun 
treatment, a condition may arise that requires the initiation of a new concomitant treatment.  
Patients with CNS lesions requiring SRS are allowed to continue study treatment after 
appropriate interruption, as determined by the investigator; however, for analysis purposes, these 
patients will be considered to have PD.   
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 Last Dose, and for all 
concomitant medications related to serious or study drug-related toxicities until the medication is 
no longer taken or until patient contact discontinues.   
13.3 
Prohibited Treatment(s)/Therapy 
The following concurrent medications or procedures are prohibited for the duration of the study:   
1. 
Any other anticancer therapy including, but not limited to: chemotherapeutic agents, 
immunotherapy, biological response modifiers (excluding growth factors), 
radiotherapy, and/or systemic hormonal therapy (with the exception of local 
therapies, including SRS, used for palliative or symptomatic control of existing 
lesions, with appropriate treatment interruption at the discretion of the investigator); 
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2. 
Use of any other investigational drug or device; 
3. 
Medications that are known to be associated with the development of Torsades de 
Pointes (see Appendix E).  Medications that prolong the QT interval, but are not 
known to be associated with Torsades de Pointes, should be avoided, but are not 
prohibited; 
4. 
Extensive surgery requiring in-patient care (patients may have an interruption in 
therapy for 14 days should emergency surgery be required). 
If a patient’s clinical condition requires treatment with one of the prohibited classes of 
medications specified above, the clinical details of the situation should be discussed with the 
medical monitor at the earliest possible time to determine whether it is safe for the patient to 
continue treatment with AP26113.  
13.4 
Potential Drug Interactions  
In vitro studies with human liver microsomes indicate that cytochrome 450 (CYP) 2C8 and 
CYP3A4 are involved in the human metabolism of AP26113.  Medications and dietary 
(grapefruit-containing products) or herbal products (St John’s Wort) that are strong inhibitors or 
inducers of P450 cytochromes, in particular, CYP2C8 or CYP3A4, should be avoided (see 
Appendix D). 
AP26113 is not a reversible inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5, with 
IC50s of >70 μM.  AP26113 is also not a metabolism-dependent or a time-dependent inhibitor of 
the CYPs tested.  Hence, drug-drug interactions (DDIs) due to inhibition of CYPs by AP26113 
are unlikely. 
13.5 
Treatment Compliance 
Patients will be provided a diary card or equivalent where the date of study drug administration 
will be recorded and complete instructions will be provided with the Study Reference Manual.  
Patients who forget to take their dose should not make up the missed dose.  Any missing doses 
must be recorded in an appropriate source record (eg, clinic chart), patient diary card, and study 
drug administration eCRF.  Training of patients should be documented in the appropriate source 
record (eg, clinic chart).  When possible, patients should take the study drug under observation 
during scheduled study visits to the clinic.  The investigator is responsible for ensuring that the 
patient diary card(s) are accounted for and noted in source documentation.  
13.6 
Treatment Supply 
Upon receipt of clinical study materials and/or study drug, the investigator or designee must 
verify that the shipment was received as stated on the clinical supply shipment form, enclosed 
within each shipment.  The form is then returned to the clinical supply distributor as instructed 
on the form.  If there are any discrepancies with the shipment the sponsor should be contacted 
immediately (contact information is listed on the clinical supply shipment form).  A copy of this 
form must be retained in the site files.  
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13.6.1 
Formulation, Packaging and Labeling 
AP26113 drug product is supplied as film-coated tablets, which may contain either 30 mg, 90 mg 
or 180 mg of AP26113 active pharmaceutical ingredient.  Other ingredients are typical 
pharmaceutical excipients (lactose monohydrate, microcrystalline cellulose, sodium starch 
glycolate, hydrophobic colloidal silica, and magnesium stearate).  The tablet coating is composed 
of typical pharmaceutical grade coating components (talc, polyethylene glycol, polyvinyl 
alcohol, and titanium dioxide).  The drug product is manufactured under Current Good 
Manufacturing Practice in accordance with approved procedures.  AP26113 will be supplied in 
white high density polyethylene bottles with induction sealed caps or blister packs. 
Bottle or blister pack labels will bear the appropriate label text as required by governing 
regulatory agencies.  At a minimum, such text will include product name, product strength, 
number of tablets, and lot number.  
13.6.2 
Preparation and Dispensing 
The study pharmacist or designee at the site will be responsible for handling and dispensing 
study drug, and completing associated documentary paperwork.  Supplies are shipped to the 
investigative site at appropriate intervals, depending on patient accrual.  The site must use an 
appropriate dispensing log/accountability form provided by the sponsor, or an acceptable 
substitute used by the site.  Each time study medication is dispensed for a patient, the following 
information must be recorded: the patient’s initials, the patient’s study number, drug product 
strength (30 mg), quantity dispensed with the corresponding lot number, and the initials of the 
person dispensing the drug.  These logs are to be maintained by the study pharmacist in the 
pharmacy throughout the duration of the study and will be periodically verified by a 
representative of the sponsor.  
13.6.3 
Treatment Storage and Accountability 
The recommended storage condition for AP26113 is under 30°C.  Do not refrigerate or freeze.  
The investigator is responsible for ensuring that the study drug provided to the patient and 
returned from the patient are accounted for and noted in source documentation. 
All used bottles or blister packs of study drug must be returned to the study sponsor or destroyed 
in an appropriate manner according to the standard practice at each study center.  Destruction of 
such supplies will be documented, and a representative of the sponsor will verify disposition 
records. 
During the study and at termination, patients must return all unused study drug supplies and the 
return of these unused study drug supplies must be recorded.  Returned supplies must not be 
re-dispensed. 
No other utilization of AP26113 intended for use in this study is authorized by the sponsor.  The 
principal investigator or his/her designee will be responsible for the appropriate handling and 
disposition of residual study drug.  Each site is responsible for proper and careful destruction of 
study drug returned by patients. 
Periodically, throughout and at the conclusion of the study, a representative of the sponsor will 
conduct an inventory of unused study drug.  At the completion of the study, a final study drug 
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accountability review will be conducted.  Any discrepancies must be investigated and all unused 
study drug must be destroyed on site per the standard operating procedures of the investigative 
site.  
14 
ADVERSE EVENT REPORTING 
14.1 
Adverse Events 
14.1.1 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.  An AE can be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product whether or not considered related to the medicinal product.  Any worsening of 
a preexisting condition, which is temporally associated with the use of the study drug (ie, occurs 
after the first dose of study drug), is also an AE. 
Adverse events include: 
 Abnormal test findings 
 Changes in physical exam findings 
 Other untoward medical events, regardless of their relationship to the study drug, such 
as injury, events that require surgery, accidents, or apparently unrelated illnesses, and 
 Hypersensitivity 
Additionally, AEs may include signs or symptoms resulting from: 
 Drug overdose 
 Drug withdrawal 
 Drug abuse 
 Drug misuse 
 Drug interactions 
 Drug dependency, and 
 Exposure in utero 
14.1.2 
Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE are as follows: 
 Test result is associated with accompanying symptoms that are considered clinically 
significant in the opinion of the investigator. 
 Test result requires additional diagnostic testing (other than merely repeating an 
abnormal test) or medical/surgical intervention. 
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 Test result leads to a change in study drug dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy. 
 Test result is considered to be an AE by the investigator or sponsor. 
14.1.3 
Performing Adverse Events Assessments 
All observed or volunteered AEs, regardless of treatment group or suspected causal relationship 
to the investigational product(s), will be reported, as described in the following sections.   
For all AEs, the investigator must pursue and obtain information adequate to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious AE 
(SAE; see Section 14.2.1) requiring immediate notification to ARIAD or its designated 
representative.    
14.1.4 
Reporting Adverse Events 
For all enrolled patients, AEs should be recorded on the eCRF beginning with signing of the 
informed consent form and concluding 30 days following the last dose of the assigned study 
treatment, or the investigator/patient decision to discontinue treatment, whichever occurs later.   
AEs ongoing after the reporting period:  Any ongoing AEs thought to be at least possibly 
study-drug related after this time should be followed and reported to the sponsor’s medical 
monitor at least every 4 weeks until they resolve to baseline (or CTCAE grade ≤1), stabilize, or 
are considered to be chronic/irreversible.  See Section 14.2.2 for reporting SAEs. 
14.1.5 
Adverse Event Severity 
The severity of AEs will be assessed according to the CTCAE, v4.0 (see Appendix A and the 
Study Reference Manual).  If the AE is not defined in the CTCAE, the investigator will 
determine the severity of the AE based on the following definitions: 
 Mild (grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity; 
 Moderate (grade 2): The AE interferes with routine activity but responds to 
symptomatic therapy or rest; 
 Severe (grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy; 
 Life-Threatening (grade 4): The patient is at immediate risk of death; 
 Death (grade 5): The patient dies as a direct result of the complication or condition 
induced by the AE. 
14.1.6 
Causality 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious).  An investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to the AE.   
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In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and on the SAE form 
and report such an assessment in accordance with the SAE reporting requirements.   
The investigator will use medical consideration and use the following categories of causality to 
determine the relatedness of an AE with the study drug based on the following definitions.  Not 
all criteria in each category of relatedness must be present.   
Definitely Not Related (not drug related) 
 The patient did not receive study drug 
OR 
 The temporal sequence of the AE onset relative to the administration of the study drug 
is not reasonable 
OR 
 There is another obvious cause of the AE 
Probably Not Related (not drug related) 
 There is evidence of exposure to study drug 
 There is another more likely cause of the AE 
 Dechallenge (if performed) is negative or ambiguous 
 Rechallenge (if performed) is negative or ambiguous 
Possibly Related (drug related) 
 There is evidence of exposure to study drug 
 The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable 
 The AE could have been due to another equally likely cause 
 Dechallenge (if performed) is positive 
Probably Related (drug related) 
 There is evidence of exposure to study drug 
 The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable 
 The AE is more likely explained by the study drug than by another cause 
Definitely Related (drug related) 
 There is evidence of exposure to study drug 
 The temporal sequence of the AE onset relative to administration of the study drug is 
reasonable 
 Dechallenge is positive 
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 Rechallenge (if feasible) is positive 
 The AE shows a pattern consistent with previous knowledge of the test drug or a test 
drug class 
14.1.7 
Expectedness 
The expectedness of an SAE is assessed by the sponsor in the overall classification of SAEs for 
regulatory reportability.  The Clinical Investigator Brochure section “Summary of Data and 
Guidance for the Investigator” will be used as the reference for determination of expectedness 
and risk assessment for AP26113.   
14.2 
Serious Adverse Events  
The definitions and reporting requirements of ICH Guidelines for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2A, will be followed.   
14.2.1 
Serious Adverse Event Definition 
The investigator or the sponsor may determine the seriousness of an AE based on the following: 
An AE is considered an SAE if at least one of the following conditions applies: 
 Death: An AE that results in death is any patient death within 30 days of the last dose 
of study drug administration.  The cause of death or AE that resulted in a fatal outcome 
is the SAE. 
 Life-threatening AE: An AE that places the patient, in the view of the investigator or 
the sponsor, at immediate risk of death from the event as it occurred (ie, this does not 
include an event that had it occurred in a more severe form might have caused death) 
 Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions: Any substantial disruption of a person’s ability to 
conduct normal life functions 
 Inpatient hospitalization or prolongation of existing hospitalization: Hospitalization 
refers to admission of a patient into a hospital for any length of time. 
 A congenital anomaly/birth defect: A fixed, permanent impairment established at or 
before birth 
 Cancer: Occurrence or diagnosis of a new cancer during the study is considered an 
SAE; a new cancer is a cancer that is histopathologically different than the cancer under 
study in the study (ie, does not include metastatic or progressive disease) 
 Important medical event: Medical and scientific judgment should be exercised in 
determining whether an event is an important medical event.  An important medical 
event may not result in death, be life-threatening, or require hospitalization.  However, 
if it is determined that the event may jeopardize the patient and/or may require 
intervention to prevent one of the other outcomes listed in the definition above, the 
important medical events should be reported as serious.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
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dyscrasias, or convulsions that do not result in hospitalization; or the development of 
drug dependency or drug abuse. 
14.2.1.1 Progression of the Malignancy Under Study (including signs and symptoms of 
progression) 
Worsening of signs and symptoms of the malignancy under study should be reported as AEs in 
the appropriate section of the eCRF.  Disease progression assessed by measurement of malignant 
lesions on radiographs or other methods should not be reported as an AE.   
14.2.1.2 Hospitalizations 
Adverse events (reported from clinical studies) that require hospitalization or prolongation of 
hospitalization are considered serious.  Any initial admission (even if less than 24 hours) to a 
health care facility meets these criteria.  Adverse events that require emergency room care that 
do not result in hospital admission are not SAEs unless assessed by the investigator to be an 
important medical event.  Hospitalization does not include the following: 
 Hospice facilities 
 Respite care 
 Skilled nursing facilities 
 Nursing homes 
 Routine emergency room admissions, and 
 Same day surgeries (as outpatient/same day/ambulatory procedure) 
Hospitalization or prolongation of hospitalization in the absence of a precipitating AE is not in 
itself an SAE.  Examples include: 
 Social admission (eg, patient has no place to sleep) 
 Protocol-specified admission during a clinical study (eg, for a procedure required by the 
study protocol) 
 Optional admission not associated with a precipitating AE (eg, for elective cosmetic 
surgery that was planned prior to study enrollment [appropriate documentation is 
required for these cases]) 
 Hospitalization or prolongation of hospitalization for scheduled therapy of the target 
malignancy of the study is not considered an SAE 
14.2.2 
Reporting Serious Adverse Events  
Serious AEs require immediate notification by the investigator or designee to ARIAD 
Pharmacovigilance and Risk Management, or its designated representative, beginning from the 
time the patient provides informed consent (ie, prior to undergoing any study-related procedure 
and/or receiving investigational product), through and including 30 days after the last 
administration of study treatment, or the investigator/patient decision to discontinue treatment, 
whichever occurs later.  Any SAE occurring any time after the reporting period must be 
promptly reported to ARIAD Pharmacovigilance and Risk Management or its designated 
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representative immediately after becoming aware of the SAE if a causal relationship to the 
investigational product is suspected.  All SAEs ongoing 30 days or more after last dose of study 
drug is administered should be followed at least every 4 weeks until they resolve to baseline (or 
CTCAE grade ≤1), stabilize, or are considered to be chronic/irreversible.   
Should the FDA or national regulatory authorities require that the sponsor submit additional 
event data, the investigator will be asked to provide those data to the sponsor in a timely fashion.   
14.2.3 
Information to be Provided by the Investigator for a Serious Adverse Event 
The sponsor or designee will require all of the following information about the patient and the 
event: 
 Investigator identification 
 Patient identification code (eg, sex, age, or date of birth) 
 Information on study drug (eg, start/stop date, dose and frequency of study drug 
administered) 
 Description of event 
In addition to the above information, the sponsor will require the investigator’s assessment of the 
following: 
 Severity of the SAE  
 Relationship of the SAE to the study drug 
 Outcome of the SAE  
14.2.4 
Follow-up Information on a Serious Adverse Event  
Appropriate diagnostic tests should be performed and therapeutic measures, as medically 
indicated, should be instituted.  Appropriate consultation and follow-up evaluations should be 
carried out until the event has resolved or is otherwise explained by the investigator.  For all 
SAEs, the investigator is obligated to pursue and provide information to ARIAD in a timely 
manner.  In addition, an investigator may be requested by ARIAD to obtain specific information 
in an expedited manner.  This information may be more detailed than that captured on the AE 
form.  In general, this will include a description of the AE in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible causality.  
Information on other possible causes such as concomitant medication and illnesses must be 
provided.   
Required Follow-up for Serious Adverse Events 
There should be routine follow-up through and including 30 days after the last administration of 
assigned study treatment or the investigator/patient decision to discontinue treatment, whichever 
occurs later, in all patients in order to monitor for the occurrence of SAEs.  If an SAE continues 
after the 30-day evaluation period, then the patient must be followed until the event resolves or 
returns to baseline.  The medical monitor may specify a longer period of time if required to 
assure the safety of the patient.   
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Sponsor Responsibility for Expedited Safety Reports 
ARIAD will notify investigators of all reportable SAEs.  This notification will be in the form of 
an expedited safety report.  Upon receiving such notices, the investigator must review and retain 
the notice with other study-related documentation.   
The investigator and Institutional Review Board (IRB)/Ethics Committee (EC) will determine if 
the informed consent requires revision.  The investigator should also comply with the IRB/EC 
procedures for reporting any other safety information.   
Suspected serious adverse reactions and other significant safety issues reported from the 
investigational product development program shall be reported to the relevant competent health 
authorities in all concerned countries according to local regulations (either as expedited safety 
reports and/or in aggregate reports), by the sponsor or its designated representative.   
14.3 
Other Safety Issues 
14.3.1 
Pregnancy 
Female patients of childbearing potential and fertile male patients will be informed as to the 
potential risk of conception while participating in this study and will be advised that they must 
use highly effective contraception (ie, results in a low failure rate when used consistently and 
correctly) during the dosing period and for a period of at least 4 months thereafter.  A pregnancy 
test will be performed on each pre-menopausal female patient of childbearing potential 
immediately prior to the first dose of study drug, once every three cycles while on treatment, and 
again at treatment discontinuation.  A negative pregnancy test must be documented prior to 
administration of study drug. 
If a patient is confirmed pregnant during the study, study drug administration must be 
discontinued immediately.  The investigator must immediately notify the ARIAD medical 
monitor of this event and record the pregnancy on a Pregnancy Form.  Initial information 
regarding a pregnancy must be immediately forwarded to ARIAD Pharmacovigilance and Risk 
Management or its designated representative. 
The investigator must immediately report follow-up information to the sponsor regarding the 
course of the pregnancy, including perinatal and neonatal outcome, regardless of whether the 
patient has discontinued participation in the study.  If the pregnancy results in the birth of a child, 
additional follow-up information may be requested.  If the pregnancy results in spontaneous 
abortion or stillbirth, the event should be reported as an SAE. 
Pregnancy outcomes must be collected for the female partners of any males who took study drug 
in this study.  Consent to report information regarding these pregnancy outcomes should be 
obtained from the female partner.  
14.3.2 
Overdose 
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of study 
treatment that exceeds the dose described in the protocol.  Overdoses are not considered AEs; 
however, all overdoses should be recorded on an Overdose Form and forwarded to ARIAD 
Pharmacovigilance and Risk Management, or its designated representative, within 24 hours.  An 
overdose should be reported even if it does not result in an AE.  Overdoses do not need to be 
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recorded on the CRF; dosing information is recorded on the CRF.  Throughout the course of the 
study, every effort must be made to remain alert to possible AEs.  If an AE occurs, the first 
concern should be for the safety of the patient.  If necessary, appropriate medical intervention 
should be provided.  At the signing of the ICF, each patient must be given the names and 
telephone numbers of study site staff for reporting AEs, medical emergencies, pregnancies, and 
overdoses.  Monitor AEs as instructed in the Schedule of Events (Section 11.1) and as clinically 
indicated.   
15 
PLANNED STATISTICAL METHODS 
15.1 
General Considerations 
Descriptive statistics (such as means, medians, standard deviations, and ranges for continuous 
data and percentages for categorical data) will be used to summarize patient characteristics, study 
treatment administration/compliance, efficacy, safety, pharmacokinetic parameters, and genetic 
status.  Data will also be displayed graphically, where appropriate.  Two-sided confidence 
intervals for all parameters to be estimated will be constructed using a significance level of 
alpha=0.05, with the exception of the primary endpoint, which will be tested at a two-sided alpha 
level of 0.025 to adjust for the multiplicity of having two treatment arms tested (with two-sided 
97.5% confidence intervals).  
Although this is a randomized study, inference will be made on each arm separately, and any 
comparisons will be purely descriptive.  The primary analysis is planned to be conducted when 
all ongoing patients have completed their Cycle 6 disease assessment. 
15.2 
Analysis Populations 
Intention to Treat (ITT) Population – The ITT population includes all patients randomized to 
each regimen regardless of whether they receive study drug or adhere to the assigned dose.  The 
primary analyses of efficacy will be based on the ITT population. 
Treated population – The treated population for each regimen includes all patients receiving at 
least one dose of study treatment.  This will include patients who have experienced failure of 
crizotinib but do not have a history of ALK status by the Vysis® FISH test at baseline regardless 
of the results of the subsequent Vysis® FISH test performed at that time, as patients may be 
treated before these results are available. 
Safety will be analyzed using the treated population. 
Per-protocol population – The per-protocol population will exclude all patients in the treated 
population who do not meet key entry criteria, have no measurable disease at baseline, or have 
no adequate post-baseline response assessment unless the reason is death or early discontinuation 
due to disease progression.  In particular, patients who have no history of an ALK rearrangement 
by the Vysis® FISH test at study entry and whose protocol-mandated test is negative for an ALK 
rearrangement will be excluded from the per-protocol analysis. 
Further criteria for the per-protocol population and the sensitivity analyses of the primary 
endpoint and selected secondary efficacy endpoints using this population will be detailed in the 
statistical analysis plan (SAP).  
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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ARIAD Pharmaceuticals, Inc. 
 
 
AP26113-13-201 
 
Version 4.0 24 August 2015 
Page 70 of 89 
 
the true rate is 35% or higher at two-sided alpha level of 0.025 using exact binomial test.  The 
treatment regimen will be considered to have achieved the primary objective when ORR 
assessed by the investigator is shown to be significantly higher than 20% at a two-sided alpha 
level of 0.025 at final analysis for that regimen.  
15.5 
Efficacy Analysis 
15.5.1 
Definitions of Efficacy Endpoints 
The primary endpoint, ORR assessed by the investigator, is defined as the proportion of the 
patients who are confirmed to have achieved CR or PR, per RECIST v1.1 (confirmed ≥4 weeks 
after initial response), after the initiation of study treatment in the ITT population. 
Secondary efficacy endpoints for this study are defined as follows: 
 Confirmed ORR assessed by IRC is defined as the proportion of the patients who are 
confirmed to have achieved CR or PR per IRC using RECIST v1.1 after the initiation of 
study treatment in the ITT population.   
 CNS ORR is defined as the proportion of the patients who have achieved CR or PR in the 
CNS per RECIST v1.1 after the initiation of study treatment in randomized patients with 
active CNS metastases at enrollment.  
 CNS PFS is defined as the time interval from the date of the first dose of the study 
treatment until the first date at which CNS disease progression is objectively 
documented, or death due to any cause, whichever occurs first, in randomized patients 
with active CNS metastases at enrollment.  It will be censored for patients without 
documented CNS disease progression. 
 Time to response is defined as the time interval from the date of the first dose of the study 
treatment until the initial observation of CR or PR.   
 Duration of response is defined as the time interval from the time that the measurement 
criteria are first met for CR/PR (whichever is first recorded) until the first date that the 
progressive disease is objectively documented.  
 Time on treatment is defined as the time from the first to the last dose of AP26113. 
 Disease control rate is defined as the proportion of randomized patients who have 
achieved CR, PR, or SD (in the case of SD, measurements must have met the SD criteria 
at least once after study entry at a minimum interval of 6 weeks) after the initiation of 
study treatment.  
 PFS is defined as the time interval from the date of the first dose of the study treatment 
until the first date at which disease progression is objectively documented, or death due 
to any cause, whichever occurs first, in the ITT population.  It will be censored for 
patients without documented disease progression. 
 OS is defined as the time interval from the date of the first dose of the study treatment 
until death due to any cause in the ITT population.  It will be censored on the date of last 
contact for those patients who are alive. 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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 Principal investigator’s Curriculum Vitae, 
 IRB/EC approval of the protocol, and 
 IRB/EC approved informed consent form. 
If any investigator retires, relocates, or otherwise withdraws from conducting the study, the 
responsibility for maintaining records may be transferred to another person (sponsor, IRB/EC, or 
other investigators) who accepts the responsibility.  The sponsor must be notified in writing and 
must agree to the change.  An updated FDA Form 1572 will be filed with the sponsor for any 
changes in study personnel reported in the current FDA Form 1572, and a disclosure of any 
financial interests in ARIAD or ARIAD products (as defined in 21 CFR part 54) will be required 
of any individual assuming the investigator’s responsibilities.   
16.2 
Study Monitoring 
This study will be monitored by representatives of the sponsor.  Site visits are made before the 
study begins, at regular intervals during the study, and at the study closeout.  Communication by 
telephone, mail, and e-mail may be used, as needed, to supplement site visits.  The investigator 
and study personnel will cooperate with the sponsor, provide all appropriate documentation, and 
be available to discuss the study.  The purpose of the site visits is to verify: 
 
Adherence to the protocol (the investigator should document and explain any 
deviation from the approved protocol). 
 
The completeness and accuracy of the eCRFs and the dispensing and inventory record 
(adequate time and space for these visits should be allocated by the investigator). 
 
Compliance with regulations (the verification will require comparison of the source 
documents to the eCRFs). 
17 
ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in accordance with the ethical standards that have their origin in the 
Declaration of Helsinki and that are consistent with ICH and GCP guidelines, the EMA guidance 
on “Ethical Considerations for Clinical Trials on Medicinal Products,” and other applicable 
regulatory requirements.   
Nothing in this protocol or the regulations is intended to limit the authority of a physician to 
provide emergency medical care under applicable regulations.  In addition, the investigator 
should be aware that some regulations require that he/she permit regulatory agencies to conduct 
inspections and review records pertaining to this clinical investigation.    
17.1 
Institutional Review Board or Ethics Committee Approval 
The protocol and the informed consent document must have the initial and at least annual or 
bi-annual (when required) approval of an IRB/EC.  The signed IRB/EC approval letter must 
identify the documents approved (ie, list the investigator’s name, the protocol number and title, 
the date of the protocol and informed consent document, and the date of approval of the protocol 
and the informed consent document).  Any advertisements used to recruit patients should also be 
reviewed by the IRB/EC.  The sponsor will not ship clinical supplies until a signed approval 
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letter from the IRB/EC has been received and a Clinical Trial Agreement has been signed by the 
sponsor and the clinical site.    
17.2 
Patient Information and Consent 
Regulatory agencies have issued regulations to provide protection for human patients in clinical 
investigations and to describe the general requirements for informed consent. 
A copy of your proposed informed consent document should be submitted to the sponsor for 
review and comment before submission to your IRB/EC.  The study should not begin until the 
document has been reviewed by the sponsor and must not begin until the document has been 
approved by the IRB/EC.  In some instances, the study must not begin until the document has 
been approved by a regulatory agency. The informed consent document shall contain all of the 
elements of the informed consent specified in the regulations.  Some regulations may require the 
disclosure of additional information to the patient and/or inclusion of additional information in 
an informed consent document.   
17.3 
Patient Confidentiality 
All unpublished information that the sponsor gives to the investigator, and all information 
generated in connection with the study, shall be kept confidential and shall not be disclosed to a 
third party without the prior written consent of the sponsor or published prior to the sponsor’s 
review in accordance with the terms of the Clinical Trial Agreement.  When the sponsor 
generates reports for presentations to regulatory agencies, one or more of the investigators who 
have contributed significantly to the study will be asked to endorse the final report.  The 
endorsement is required by some regulatory agencies.  The investigator shall not make a patent 
application based on the results of this study and shall not assist any third party in making such 
an application without the written authorization of the sponsor.    
17.4 
Study Committees 
17.4.1 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC), consisting of 3 to 5 members not 
associated with the conduct of the study, will be established for this study.  The committee will 
perform data review quarterly and meet at least twice yearly until the final analysis has been 
performed, as specified in the protocol.  Ad-hoc DMC meetings may also be held if a significant 
issue should arise.   
The DMC will be responsible for evaluating the results of safety analyses and will make 
recommendations to the sponsor.  Efficacy data can also be requested, if needed, to evaluate 
risk/benefit before making a recommendation; however, the trial will not be stopped early for 
positive efficacy.  The DMC will operate under the DMC charter, which specifies the data to be 
included in each review, rules related to study modification, and protection of the integrity of the 
data.  At each meeting, the DMC will make recommendations to either continue the study 
unchanged, to modify the study, or to discontinue the study.  The DMC will communicate the 
recommendations to the sponsor.  The final decision to act on the DMC recommendations will be 
made by the sponsor in consultation with the Study Steering Committee. 
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17.4.2 
Independent Review Committee 
A central IRC will evaluate all images collected during the study for the secondary endpoint of 
confirmed ORR by IRC.  An IRC charter defines the procedures used by the committee. 
17.4.3 
Steering Committee 
A steering committee will be constituted with initiation of the study.  Its purpose is to function in 
an advisory capacity to: 1) provide input on study conduct and progress; 2) ensure scientific and 
ethical integrity of the study; and 3) provide ongoing oversight of safety and efficacy in this 
open-label study.  The steering committee will include clinicians expert in the clinical care and 
investigation of the targeted patient population, and will also include sponsor representatives.  In 
addition to general study oversight, it will be responsible for periodic review of study data to 
evaluate the safety profile of AP26113, assess accumulating signals of efficacy, evaluate data 
quality, and provide input on operational aspects of the study.  The committee may make 
recommendations for the sponsor’s consideration based on periodic review.  
18 
DATA HANDLING AND RECORD KEEPING 
18.1 
Case Report Forms and Study Records 
Study-specific eCRFs will be made available to the Investigative site.  Study data, contained in 
source documentation, will be entered into the eCRFs for all patients enrolled in the study.  All 
pertinent data records are to be submitted to the sponsor during and/or at completion or 
termination of the study.   
18.2 
Access to Source Documentation 
The investigator agrees that qualified representatives of the sponsor and regulatory agencies will 
have the right, both during and after this study, to conduct inspections and to audit and review 
medical records pertinent to the clinical study as permitted by the regulations.  Patients will not 
be identified by name in any reports stemming from the study, and confidentiality of information 
in medical records will be preserved.  The confidentiality of the patient will be maintained unless 
disclosure is required by regulations. Accordingly, the following statement (or similar statement) 
that permits the release of the patient’s medical records will be included in the informed consent 
document: 
Representatives of regulatory agencies, IRB/EC, the sponsor, and the patient’s 
personal physician may review the patient medical records and all information 
related to this study as permitted by law. Patient identity will remain confidential 
unless disclosure is required by law. 
18.3 
Retention of Data 
Study documents (including correspondence related to this clinical study, patient records, source 
documents, eCRFs, study drug inventory records, and IRB/EC and sponsor correspondence 
pertaining to the study, original patient, laboratory, and study drug inventory records relating to 
the study) should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications in 
an ICH region (that is at least 15 years or at least 2 years have elapsed since the formal 
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discontinuation of clinical development of the product).  Study documents should be retained for 
a longer period if required by applicable regulatory requirements or by agreement with the 
sponsor.  Thereafter, records will not be destroyed without giving the sponsor prior written 
notice and the opportunity to further store such records, at the sponsor’s cost and expense.   
18.4 
Termination of Study 
The sponsor may terminate the study at any time for any of the following reasons: 
 
Failure to enroll patients 
 
Protocol violations 
 
Inaccurate or incomplete data 
 
Unsafe or unethical practices 
 
Questionable safety of the study drug 
 
Suspected lack of efficacy of the study drug; or 
 
Administrative decision 
In the event of the termination of the Study, by either the sponsor or an investigator: 
 
The investigator will return all study drugs, eCRFs, and related study materials to the 
sponsor. 
 
A written statement describing why the study was terminated prematurely will be 
provided by either the sponsor or the investigator. 
19 
FINANCING AND INSURANCE  
A clinical study agreement will be signed by the investigator (and/or, as appropriate, the hospital 
administrative representative) and the sponsor prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study.  Financial remuneration will 
cover the cost per included patient, based on the calculated costs of performing the study 
assessments in accordance with the protocol, and the specified terms of payment will be 
described in the contract.  The contract should describe whether costs for pharmacy, laboratory 
and other protocol-required services are being paid directly or indirectly.  Prior to the start of the 
study, investigators and sub-investigators will release sufficient and accurate information that 
permits the sponsor or sponsor-designated agent that an investigator has no personal or 
professional financial incentive regarding the future approval or non-approval of the study drug 
that his/her research might be biased by such financial incentives.  The financial information is 
exclusive of agreements directly related to fees associated with the study being conducted.  All 
information provided will be regarded as strictly confidential and will only be disclosed to the 
respective regulatory authority.   
20 
PUBLICATION AND DISCLOSURE POLICY  
The investigator must notify the IRB/EC of the conclusion of the clinical study.  This report 
should be made within 3 months of the completion or termination of the Study.  The final report 
sent to the IRB/EC should also be sent to the sponsor and, along with the completed eCRFs, 
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constitutes the final summary to the sponsor, thereby fulfilling the investigator’s regulatory 
responsibility.   
Section 801 of the FDA Amendments Act mandates the registration with ClinicalTrials.gov of 
certain clinical studies of drugs (including biological products) and medical devices subject to 
FDA regulations for any disease or condition.  The International Committee of Medical Journal 
Editors (ICMJE) requires study registration as a condition for publication of research results 
generated by a clinical study (http://www.icmje.org [Accessed: 13 January 2014]).  In addition, 
the EMA requires that clinical studies conducted in the European Union and other countries 
under their regulatory authority be registered (https://www.clinicatrialsregister.eu/ [Accessed: 
13 January 2014]).  
The institution and principal investigator acknowledge that the study is multi-center study, and, 
as such, agree that they will not publish a publication, abstract, poster or other disclosures 
(“Publication”) before a combined paper that identifies all the sites that participated in the study 
(“Multi-Center Publication”) is published.  If the Multi-Center Publication has not been 
completed within one (1) year from the date of the completion, termination, or abandonment of 
the multi-center study, the institution may publish or present its individual results in accordance 
with the provisions stated below.   
In order to balance the institution’s right to publish with ARIAD’s proprietary interests, the 
institution will submit to ARIAD material intended for publication, abstracts, posters and other 
disclosures (“Proposed Disclosures”) at least 45 days prior to submitting for publication or other 
disclosure to allow for expeditious review by ARIAD.  If ARIAD believes that any Proposed 
Disclosure contains any information relating to any patentable invention, the disclosure of such 
Proposed Disclosure shall be delayed for up to sixty (60) days from the date ARIAD receives the 
Proposed Disclosure to permit ARIAD to file patent applications.  If ARIAD believes that any 
Proposed Disclosure contains Confidential Information, ARIAD shall have the right to require 
that the institution delete any reference to Confidential Information, excluding the results of the 
study or other Permitted Research (as defined in Section 11).  If the institution and principal 
investigator choose not to publish, ARIAD reserves the right to publish the results of the study, 
and, if appropriate, to include its medical staff in the author list of such publication in accordance 
with academic publication standards.   
Subject to applicable copyright law, if an institution and/or principal investigator publishes 
results of the study, institution and/or principal investigator hereby grants ARIAD an irrevocable, 
royalty-free license to make and distribute copies of such publication under any copyright 
privileges that the institution and/or principal investigator may have.   
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21 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85(5):365-376. 
Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with 
previously untreated brain metastases from HER2-positive metastatic breast cancer 
(LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14(1):64-71. 
Bang YJ. Treatment of ALK-positive non–small cell lung cancer. Arch Pathology & Laboratory 
Med. 2012;136(10):1201-1204.  
Camidge DR, Kono SA, Flacco A, et al. Optimizing the detection of lung cancer patients 
harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK 
inhibitor treatment. Clin Cancer Res. 2010;16:5581-5590.   
Camidge DR, Doebele RC. Treating ALK-positive lung cancer—early successes and future 
challenges. Nat Rev Clin Oncol. 2012;9(5):268-277. 
Crino L, Kim D, Riely GJ, et al. Initial phase II results with crizotinib in advanced ALK-positive 
non-small cell lung cancer (NSCLC): PROFILE 1005 [abstract 7514]. Abstract presented at 
American Society of Clinical Oncology 2011. 
Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase 
inhibitor crizotinib. J Clin Oncol. 2011;29:e443–e445. 
Fayers PM, Aaronson NK, Bjordal K, et al. EORTC Scoring Manual. 3rd edition. Brussels: 
European Organisation for Research and Treatment of Cancer; 2001. 
Fossella FV. Second-line chemotherapy for non-small-cell lung cancer. Curr Oncol Rep. 
2000;2(1):96-101.   
Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus 
docetaxel in patients with non−small-cell lung cancer previously treated with chemotherapy. J 
Clin Oncol. 2004;22:1589-1597. 
Kaplan EL and Meier P. Nonparametric Estimation from Incomplete observations. J Am 
Statistical Assoc. 1958;53:457-481. 
Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-
rearranged lung Cancers. Sci Transl Med. 2012;4(120):120ra17. Epub 2012 Jan 25. 
Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell 
lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372(9652):1809-1818. 
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-
cell lung cancer. N Engl J Med. 2010;363(18):1693-1703. 
Perner S, Wagner PL, Demichelis F, et al. EML4-ALK fusion lung cancer: A rare acquired 
event. Neoplasia. 2008;10:298–302.  
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Pfizer Laboratories. XALKORI (crizotinib) prescribing information. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000Lbl.pdf. Accessed: 
January 13, 2014. 
Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies 
oncogenic kinases in lung cancer. Cell. 2007;131(6):1190-1203.   
Rivera VM, Anjum R, Wang F, et al. Efficacy and pharmacodynamic analysis of AP26113, a 
potent and selective orally active inhibitor of anaplastic lymphoma kinase (ALK). Poster 
presented at American Association for Cancer Research 2010. 
Shaw AT, Kim DW, Nakagawa K, et al. Phase 3 study of crizotinib vs pemetrexed or docetaxel 
chemotherapy in patients with advanced ALK-positive NSCLC (PROFILE 1007). In: 
Proceedings of the 37th European Society for Medical Oncology; 2012 Sep 28-Oct 2; Vienna, 
Austria: ESMO; 2012. Abstract nr 2862.   
Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best 
supportive care in patients with non-small-cell lung cancer previously treated with platinum-
based chemotherapy. J Clin Oncol. 2000;18(10):2095-2103. 
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-
cell lung cancer. N Engl J Med. 2005;353(2):123-132.   
Solomon BJ, Gettinger SN, Riely GJ, et al. Subgroup analysis of crizotinib versus either 
pemetrexed (PEM) or docetaxel (DOC) in the phase III study (PROFILE 1007) of advanced 
ALK-positive non-small cell lung cancer (NSCLC) [abstract 8105]. Abstract presented at 
American Society of Clinical Oncology 2013. 
Suda KI, Murakami I, Katayama T, et al. Reciprocal and complementary role of MET 
amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung 
cancer. Clin Cancer Res. 2010;16(22):5489-5498. 
Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an 
immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 
2009;15(9):3143-3149.   
Togashi Y, Masago K, Masuda S, et al. Cerebrospinal fluid concentration of gefitinib and 
erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 
2012;70(3):399-405.  
Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various 
histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 
2009;115:1723–1733. 
Zhang S, Wang F, Keats J, et al. AP26113, a potent ALK inhibitor, overcomes mutations in 
EML4-ALK that confer resistance to PF-02341066 (PF1066) [abstract]. Poster presented at 
American Association for Cancer Research 2010. 
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22 
APPENDICES 
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APPENDIX A 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE) 
The United States of America (USA) National Cancer Institute Common Terminology Criteria 
for Adverse Events, version 4.0 (NCI CTCAE, v4.0) can be found on the following website. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 [Accessed: 
13 January 2014] 
This version of CTCAE is compatible at the AE (Adverse Event) term level where each CTCAE 
term is a Medical Dictionary for Regulatory Activities Terminology (MedDRA) LLT (Lowest 
Level Term).  CTCAE v4.0 includes 764 AE terms and 26 'Other, specify' options for reporting 
text terms not listed in CTCAE.  Each AE term is associated with a 5-point severity scale.  
MedDRA v12.0.  
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APPENDIX B 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
ECOG Performance 
Status* 
Grade 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
*As published in Am J Clin Oncol: 
Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.  The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
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APPENDIX C 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST VERSION 1.1) 
Note: These criteria are adapted from Eisenhauer EA, Therasse P, Bogaerts J, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eu J 
Cancer 2009;45:228-247. 
 
Choosing Target Lesions 
• Select up to 5 lesions (up to 2 per organ) 
• Select largest reproducibly measurable lesions 
• If the largest lesion cannot be measured reproducibly, select the next largest lesion which can 
be 
• Add up longest diameters (LD) of non-nodal lesions (axial plane) 
• Add short axis diameters of nodes 
• This is the “sum of the longest diameters” (SLD) 
Non-Target Lesions 
• All other sites of disease present at baseline and not classified as target lesions will be classified 
as non-target lesions, including any measurable lesions that were not chosen as target lesions 
• It is possible to record multiple non-target lesions involving the same organ as a single item on 
the eCRF (eg, “multiple enlarged pelvic lymph nodes”) 
Determining Response 
• Assess at baseline and on study with consistent modalities (CT, MRI, PET/CT) 
- Measure target lesions and calculate SPD 
- Visually assess non-target lesions 
- Search for new lesions 
- Combine these assessments into the overall response 
Target Lesion Response 
Complete Response (CR) 
 
Disappearance of all extranodal target lesions. 
 
All pathological lymph nodes must have decreased to <10 mm in short 
axis 
Partial Response (PR) 
 
At least a 30% decrease in the SLD of target lesions, taking as reference 
the baseline sum diameters 
Progressive Disease (PD) 
 
SLD increased by at least 20% from the smallest value on study 
(including baseline, if that is the smallest) 
 
The SLD must also demonstrate an absolute increase of at least 5 mm. 
(Two lesions increasing from 2 mm to 3 mm, for example, does not 
qualify) 
Stable Disease (SD) 
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD 
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Non-evaluable (NE) 
 
One or more lesions cannot be evaluated due to missing data or poor 
image quality unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the 
assigned time point response (eg, PD based on other findings) 
Non-Target Lesion Response 
Complete Response (CR) 
 
Disappearance of all extranodal non-target lesions 
 
All lymph nodes must be non-pathological in size (<10mm short axis) 
 
Normalization of tumor marker level 
Non-CR/Non-PD 
 
Persistence of one or more non-target lesions(s) and/or maintenance of 
tumor marker level above the normal limits 
Progressive Disease (PD) 
 
Unequivocal progression of existing non-target lesions. (Subjective 
judgment by experienced reader) 
Unable to Evaluate (UE) 
 
One or more lesions cannot be evaluated due to missing data or poor 
image quality unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the 
assigned time point response (eg, PD based on other findings) 
New Lesions  
• Should be unequivocal and not attributable to differences in scanning technique or findings 
which may not be a tumor (does not have to meet criteria to be “measurable”)  
• If a new lesion is equivocal, continue to next time point.  If confirmed then, PD is assessed at 
the date when the lesion was first seen.  
• Lesions identified in anatomic locations not scanned at baseline are considered new  
• New lesions on ultrasound should be confirmed on CT or MRI 
Evaluation of Overall Time Point Response for Patients with Measurable Disease at 
Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE=Not Evaluable 
 
 
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APPENDIX D 
DRUGS THAT INTERACT WITH CYP450 ENZYMES 
 
The list of drugs that interact with CYP450 enzymes (notably, CYP2C8 and CYP3A4, 5, and 7) 
can be found online at http://medicine.iupui.edu/clinpharm/ddis/table.aspx [Accessed: 
13 January 2014].  Drugs listed should be avoided if possible.   
Note:  The website should be used as a guideline and is not necessarily comprehensive.  It is the 
investigator’s responsibility to ensure that any drugs under consideration have not been newly 
identified as CYP inhibitors.   
 
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APPENDIX E 
DRUGS WITH A RISK OF TORSADES DE POINTES 
The website http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/ [Accessed: 13 
January 2014] lists four categories of QT-prolonging drugs and may be used as a guide for this 
protocol.  Categories include “Drugs with Known TdP Risk,” “Drugs with Possible TdP Risk,” 
“Drugs with Conditional TdP Risk,” and “Drugs to be Avoided by Congenital Long QT 
Patients.”  The investigator site should register (under the “For Healthcare Providers” tab) to 
access these categories.  If the investigator site does not wish to register, a composite list, 
including all categories, is available.   
Drugs with a known risk of Torsades de Pointes are listed in the table below, and are the only 
category of QT-prolonging drugs that are prohibited in this study.  
Note: The website and table are only to be used as a guideline and are not comprehensive.  It is 
the investigator’s responsibility to ensure that any drugs under consideration have not been 
newly identified as causing Torsades de Pointes.   
Table 1.1 
Drugs Generally Accepted by the QTDrugs.org Advisory Board of the 
Arizona CERT to have a Known Risk of Causing Torsades de Pointes; Prohibited in this 
Study 
Generic Name 
Brand Name 
Class/Clinical Use 
Amiodarone  
Cordarone®, Pacerone®, 
Nexterone® 
Antiarrhythmic / abnormal heart 
rhythm 
Arsenic trioxide  
Trisenox® 
Anticancer / Leukemia 
Astemizole  
Hismanal® 
Antihistamine / Allergic rhinitis 
Azithromycin 
Zithromax®, Zmax® 
Antibiotic / bacterial infection 
Bepridil  
Vascor® 
Antianginal / heart pain 
Chloroquine 
Aralen® 
Antimalarial / malaria infection 
Chlorpromazine  
Thorazine®, Largactil®, 
Megaphen® 
Antipsychotic/ Antiemetic / 
schizophrenia/ nausea 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
Citalopram 
Celexa® 
Antidepressant / depression 
Clarithromycin 
Biaxin®, Prevpac® 
Antibiotic / bacterial infection 
Cocaine 
Cocaine 
Local anesthetic / topical anesthetic 
Disopyramide  
Norpace® 
Antiarrhythmic / abnormal heart 
rhythm 
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Dofetilide  
Tikosyn® 
Antiarrhythmic / abnormal heart 
rhythm 
Domperidone 
Motilium®, Motillium®, 
Motinorm Costi®, Nomit® 
Antinausea / nausea 
Dronedarone 
Multaq® 
Antiarrhythmic / atrial fibrillation 
Droperidol  
Inapsine®, Droleptan®, 
Dridol®, Xomolix® 
Sedative; Antinausea / anesthesia 
adjunct, nausea 
Erythromycin  
Erythrocin®, E.E.S.®, 
Robimycin®, Erymax®, Ery-
Tab®, Eryc Ranbaxy®, 
Erypar®, Eryped®, Erythrocin 
Stearate Filmtab®, 
Erythrocot®, E-Base®, 
Erythroped®, Ilosone®, MY-
E®, Pediamycin®, Zineryt®, 
Abboticin®, Abboticin-ES®, 
Erycin®, PCE Dispertab®, 
Stiemycine®, Tiloryth® 
Antibiotic; GI stimulant / bacterial 
infection; increase GI motility 
Escitalopram 
Cipralex®, Lexapro®, 
Nexito®, Anxiset-E®, 
Exodus®, Esto®, Seroplex®, 
Elicea®, Lexamil®, Lexam®, 
Entact®, Losita®, Reposil®, 
Animaxen®, Esitalo®, 
Lexamil® 
Antidepressant / major depression, 
anxiety disorder 
Flecainide 
Tambocor®, Almarytm®, 
Apocard®, Ecrinal®, 
Flécaine® 
Antiarrhythmic / abnormal heart 
rhythm 
Halofantrine  
Halfan® 
Antimalarial / malaria infection 
Haloperidol  
Haldol®, Aloperidin®, 
Bioperidolo®, Brotopon®, 
Dozic®, Duraperidol®, 
Einalon S®, Eukystol®, 
Halosten®, Keselan®, 
Linton®, Peluces®, 
Serenace®, Serenase®, 
Sigaperidol® 
Antipsychotic / schizophrenia, 
agitation 
Ibutilide 
Corvert® 
Antiarrhythmic / abnormal heart 
rhythm 
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Levomethadyl 
Orlaam® 
Opiate agonist / pain control, 
narcotic dependence 
Mesoridazine 
Serentil® 
Antipsychotic / schizophrenia 
Methadone 
Dolophine®, Symoron®, 
Amidone®, Methadose®, 
Physeptone®, Heptadone® 
Opiate agonist / pain control, 
narcotic dependence 
Moxifloxacin 
Avelox®, Avalox®, Avelon® 
Antibiotic / bacterial infection 
Ondansetron 
Zofran®, Anset®, Ondemet®, 
Zuplenz®, Emetron®, 
Ondavell®, Emeset®, 
Ondisolv®, Setronax® 
Somatostatin analog / nausea and 
vomiting 
Pentamidine  
Pentam®, NebuPent® 
Anti-infective / pneumocystis 
pneumonia 
Pimozide 
Orap®  
Antipsychotic / Tourette's tics 
Probucol 
Lorelco® 
Antilipemic / Hypercholesterolemia 
Procainamide  
Pronestyl®, Procan® 
Antiarrhythmic / abnormal heart 
rhythm 
Quinidine 
Quinaglute®, Duraquin®, 
Quinact®, Quinidex®, Cin-
Quin®, Quinora®   
Antiarrhythmic / abnormal heart 
rhythm 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, general / anesthesia 
Sotalol  
Betapace®, Sotalex®, 
Sotacor®  
Antiarrhythmic / abnormal heart 
rhythm 
Sparfloxacin  
Zagam®  
Antibiotic / bacterial infection 
Terfenadine 
Seldane® 
Antihistamine / allergic rhinitis 
Thioridazine 
Mellaril®, Novoridazine®, 
Thioril®  
Antipsychotic / schizophrenia 
Vandetanib 
Caprelsa® 
Anticancer / thyroid cancer 
 
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized Phase 2 Study of AP26113 in Patients with ALK-positive, Non-small Cell 
Lung Cancer (NSCLC) Previously Treated with Crizotinib 
NCT Number: NCT02094573
SAP Approve Date: 25 February 2016
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


ARIAD Pharmaceuticals, Inc.
AP26113-13-201
AP26113
Statistical Analysis Plan
08 February 2016 
 
Page 1
STATISTICAL ANALYSIS PLAN
STUDY TITLE: A Randomized Phase 2 Study of AP26113 in Patients with ALK-positive, 
Non-small Cell Lung Cancer (NSCLC) Previously Treated with Crizotinib
PROTOCOL NUMBER:
AP26113-13-201
PROTOCOL DATE:
27 June 2013
PROTOCOL AMENDMENT 
DATE:
29 July  2014
SAP VERSION:
Version 1.0
DATE:
25 February 2016
SPONSOR:
ARIAD Pharmaceuticals, Inc. 
26 Landsdowne Street 
Cambridge, MA 02139-4234
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ARIAD Pharmaceuticals, Inc.
AP26113-13-201
AP26113
Statistical Analysis Plan
08 February 2016 
 
Page 2
TABLE OF CONTENTS
1
INTRODUCTION..........................................................................................................4
2
STUDY DESIGN............................................................................................................5
2.1
Randomization ...................................................................................................5
2.2
Study Objectives.................................................................................................5
2.2.1
Primary Objective..................................................................................5
2.2.2
Secondary Objective ..............................................................................5
2.2.3
Exploratory Objective ...........................................................................6
2.3
Study Endpoints .................................................................................................6
2.3.1
Primary Endpoint ..................................................................................6
2.3.2
Secondary Endpoints .............................................................................6
2.3.3
Exploratory Endpoints ..........................................................................7
3
GENERAL CONSIDERATIONS ................................................................................7
3.1
Sample Size .........................................................................................................7
3.2
Analysis Populations..........................................................................................8
3.2.1
Intention to Treat (ITT) Population.....................................................8
3.2.2
Treated Population ................................................................................8
3.2.3
Per-protocol Population ........................................................................8
3.3
Demographics, Baseline Characteristics, and Patient Disposition................9
3.3.1
Imputation Rules for Missing Initial Cancer Diagnosis Date 
and Start Date and Stop Date for Selected Prior Anti-Cancer 
Therapies................................................................................................11
3.4
Efficacy Analysis ...............................................................................................12
3.4.1
Disease Assessment ...............................................................................12
3.4.2
Definitions of Efficacy Endpoints ........................................................12
3.4.3
Primary Efficacy Endpoints Analysis .................................................13
3.4.4
Secondary Efficacy Endpoint Analyses...............................................14
3.4.5
Specifications for Efficacy Endpoint Analyses...................................15
3.4.5.1
Data Handling Rules for ORR ..................................................15
3.4.5.2
Determination of Disease Progression......................................16
3.4.5.3
Data handling Rules Specifically for the Primary Analysis 
of PFS.........................................................................................16
3.4.5.4
Data handling Rules Specifically for the Sensitivity 
Analyses of PFS .........................................................................20
3.4.5.5
Data handling Rules Specifically for the Primary Analysis 
of Intracranial CNS PFS...........................................................20
3.4.5.6
Data Handling Rules Specifically for the Analysis of 
Duration of Response.................................................................20
3.4.5.7
Data Handling Rules Specifically for the Analysis of OS........20
3.4.5.8
Handling Rules for Response Contemporaneous Scans ..........20
3.5
Safety Analysis...................................................................................................21
3.5.1
Adverse Events ......................................................................................21
3.5.1.1
Imputation Rule for Missing Causal Relationship of 
Treatment-Emergent Adverse Events........................................22
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AP26113
Statistical Analysis Plan
08 February 2016 
 
Page 3
3.5.1.2
Imputation Rules for Missing Onset Date and Resolution 
Date of Adverse Events ..............................................................22
3.5.1.3
Derivation of Treatment-Emergent Adverse Event Flag..........23
3.5.1.4
Calculation Specifications for Treatment-Emergent 
Adverse Events ...........................................................................23
3.5.1.5
Specifications for the Analyses Outputs....................................24
3.5.2
Laboratory and Vital Signs Data.........................................................24
3.5.3
QTcF Analysis .......................................................................................24
3.5.4
Extent of Exposure................................................................................24
3.6
Quality of Life Measurement...........................................................................25
3.6.1
Analyses of Quality of Life Measurements.........................................26
3.6.2
Handling Rule of Missing Quality of Life Measurements.................26
3.7
Pharmacokinetic Analysis ................................................................................26
4
REFERENCES..............................................................................................................28
5
APPENDICES ...............................................................................................................29
TABLE OF TABLES
Table 1
Demographics and Baseline Characteristics .......................................................10
Table 2
The Scheme of Progression and Censoring for the Primary Analysis of PFS .18
Table 3
Summary of the Overall Response Status Calculation at each Time Point for 
Patients Who have Target +/- Non-target Disease at Baseline ..........................35
Table 4
Summary of the Overall Response Status Calculation at each Time Point for 
Patients Who Have Non-measurable (Therefore Non-target) Disease only at 
Baseline ...................................................................................................................35
Table 5
Summary of the Best Overall Response Status Calculation when 
Confirmation of CR and PR is Required.............................................................36
LIST OF APPENDICES
Appendix 1
Schedule of Events .................................................................................................30
Appendix 2
Notes from RECIST v1.1.......................................................................................33
Appendix 3
Adverse Events Synonyms* ..................................................................................37
Appendix 4
Adverse Events in Special Categories ..................................................................41
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AP26113
Statistical Analysis Plan
08 February 2016 
 
Page 4
LIST OF ABBREVIATIONS
Abbreviation
Term
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ARIAD
ARIAD Pharmaceuticals, Inc.
AST
aspartate aminotransferase
AUC
area under the curve
CBC
complete blood count
Cmax
maximum plasma concentration
CNS
central nervous system
CR
complete response
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organisation for Research and Treatment of Cancer
HRQoL
health-related quality-of-life
IRC
independent review committee
ITT
Intention-to-treat
MRI
magnetic resonance imaging
ms
milliseconds
NE
not evaluable
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcomes
QD
once-daily
QLQ
Quality of Life Questionnaire
QTcF
QT interval corrected (Fridericia)
RECIST
Response Evaluation Criteria in Solid Tumors 
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SRS
stereotactic radiosurgery
TKI
tyrosine kinase inhibitor
ULN
upper limit of normal
1
INTRODUCTION
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AP26113-13-201
AP26113
Statistical Analysis Plan
08 February 2016 
 
Page 5
This statistical analysis plan (SAP) describes the study design and statistical analyses for study
protocol AP26113-13-201, entitled “A Randomized Phase 2 Study of AP26113 in Patients with 
ALK-positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated with Crizotinib” by 
ARIAD Pharmaceuticals, Inc.
2
STUDY DESIGN
This is a phase 2, open-label, randomized, multicenter, international study.  The patient 
population will include patients with ALK-positive, locally advanced or metastatic non-small 
cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib. An 
estimated 218 patients will be enrolled at approximately 100 centers. Patient will be randomized 
1:1 to receive AP26113 in one of two different dosing regimens. In Arm A, AP26113 will be 
administered at a dose of 90 mg orally QD, continuously. In Arm B, AP26113 will be 
administered at a dose of 90 mg orally QD for 7 days, then 180 mg orally QD, continuously. A 
cycle of therapy will comprise 28 days of treatment, regardless of dose. Patients will remain on 
treatment until they meet one or more criteria for withdrawal as listed in Section 11.9 of the 
protocol. Patients will be evaluated according to the Schedule of Events in Appendix 1 
(Section 11.1 of the protocol).
2.1
Randomization
Patients will be allocated in a 1:1 ratio to each dosing regimen using a randomized block design 
stratified by the following factors:
1.
Presence of brain metastases at baseline (Yes vs. No)
2.
Best prior response to crizotinib therapy as assessed by the investigator (CR/PR vs. 
Any other response or status unknown)
A stratified permuted block randomization design has been determined for this study.  The 
randomization schedule will be created using SAS® procedure PROC PLAN at ARIAD.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of the study is to determine the efficacy of AP26113, as evidenced by 
objective response rate, in patients with ALK-positive locally advanced or metastatic NSCLC 
whose disease has progressed on therapy with crizotinib. Two dosing regimens will be tested.
2.2.2
Secondary Objective
Secondary objectives for each dosing regimen are as follows:
1.
To further characterize the efficacy of AP26113 in patients with ALK-positive, 
locally advanced or metastatic NSCLC whose disease has progressed on therapy 
with crizotinib, as shown by disease control rate, time to/duration of response, 
progression-free survival (PFS), overall survival (OS), and time on treatment
2.
To assess intracranial CNS response and PFS, per a modification of RECIST v1.1, in 
patients who have active brain metastases
3.
To assess the safety and tolerability of AP26113 in study patients
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Statistical Analysis Plan
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35%.  A sample size of at least 218 eligible patients (109 per treatment regimen) will provide 
approximate 90% power to rule out an uninteresting rate of 20% when the true rate is 35% or 
higher at two-sided alpha level of 0.025 using exact binomial test.  The treatment regimen will be 
considered to have achieved the primary objective when ORR assessed by the investigator is 
shown to be significantly higher than 20% at a two-sided alpha level of 0.025 at final analysis for 
that regimen.
3.2
Analysis Populations
3.2.1
Intention to Treat (ITT) Population
The ITT population includes all patients randomized to each regimen regardless of whether they 
receive study drug or adhere to the assigned dose. 
The primary analyses of efficacy will be based on the ITT population.
3.2.2
Treated Population
The treated population for each regimen includes all patients receiving at least one dose of study 
treatment.
Safety will be analyzed using the treated population. In the case that more than 3 patients have 
been randomized and are not treated with study treatment, the primary efficacy analyses will be 
repeated using the treated population.
3.2.3
Per-protocol Population
The sensitivity analyses of the primary endpoint and selected secondary efficacy endpoints will 
be performed using the per-protocol population.
The per-protocol population will exclude all patients in the treated population who do not meet 
key entry criteria, have no measurable disease at baseline, or have no adequate post-baseline 
radiographic response assessment. To specify, the per-protocol population will be the treated 
patients who also meet all of the following criteria:

Histologically or cytologically confirmed locally advanced or metastatic NSCLC

Confirmed baseline ALK rearrangement by Vysis® FISH test either locally or by 
central confirmation

Previously progressed on crizotinib

At least one measurable a target lesion as assessed by the investigator

At least two adequate post-baseline radiographic response assessments unless the 
reason for no post-baseline radiographic response assessment is one of the following:
o
Death
o
Discontinuation due to documented disease progression per RECIST v1.1 
o
Discontinuation due to AE
In cases where the investigator and IRC have different opinions regarding whether a patient has 
measurable disease at baseline, two types of per-protocol populations will be defined, one based 
on the investigator’s assessment, and the other based on IRC’s assessment.  Analyses of the ORR 
will be performed for both populations.
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3.3
Demographics, Baseline Characteristics, and Patient Disposition
Demographics and baseline characteristics to be summarized using descriptive statistics are 
listed in Table 1. Continuous prognostic factors will be summarized by means, medians, 
standard deviations, and ranges; categorical prognostic factors will be summarized by 
counts/percentages. Other prognostic factors (e.g., by categorizing the continuous prognostic 
factors and re-categorizing the categorical prognostic factors) may also be included in the 
analysis.
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Table 1
Demographics and Baseline Characteristics
Parameters
Categories for categorical parameters
Age (continuous)
Age (categorized in reference to age in whole 
years)
18 – 64, > = 65 
18-49, 50-64, 65-75, and > = 75 years
Gender
Male, Female
Race
White, Black/African American, Asian, Native Hawaiian or 
other Pacific Islander, Other
Ethnicity
Hispanic or Latino, Not Hispanic or Latino
Geographic region/investigative sites
North America, Europe, Asia-Pacific
Strata as randomized
Brain metastases at baseline/Best response to prior crizotinib of 
CR or PR, Brain metastases at baseline/Best response to prior 
crizotinib of any other response status or unknown, No brain 
metastases at baseline/Best response to prior crizotinib of CR or 
PR, No brain metastases at baseline/Best response to prior 
crizotinib of any other response status or unknown
Current strata
Brain metastases at baseline/Best response to prior crizotinib of 
CR or PR, Brain metastases at baseline/Best response to prior 
crizotinib of any other response status or unknown, No brain 
metastases at baseline/Best response to prior crizotinib of CR or 
PR, No brain metastases at baseline/Best response to prior 
crizotinib of any other response status or unknown
Stage at diagnosis
IA, IB, IIA, IIB, IIIA, IIIB, IV, Unknown or not staged
Stage at study entry
IIIB, IV, Other
Time since initial diagnosis (continuous)
Histopathological classification at study entry
Adenosquamous Carcinoma, Squamous, Large cell, Unknown, 
Other
Metastatic sites at study entry
Lung, brain, liver, bone, and number
Measureable intracranial CNS metastases as 
assessed by intracranial CNS IRC
Yes, No
Active intracranial CNS metastases at baseline 
Yes, No
Cigarette smoking history
Never, Former, Current
Current cigarette smoking amount
Less than 20 per Day, 20 To 60 per Day, More Than 60 per Day
broken out by status as current or former smoker                            
Weight (continuous)
Height (continuous)
BMI (continuous)
ECOG Performance Status
0, 1, 2
ALK mutation method of assessment
FISH-Vysis, FISH-non Vysis, IHC, RT-PCR, Sequencing, 
Unknown, Other
If other, specify
ALK+ by FISH-Vysis – Yes or No
ALK mutation type
L1152R, G1269A, S1206Y, F1174L, L1196M, D1203N, 
C1156Y, T1151Tins, G1202R, V1180L, I1171N, Unknown, 
Other
Overall Best response to prior crizotinib 
regimen(s)
Complete Response, Partial Response, Stable Disease, 
Progressive Disease, Unable to Assess, Unknown, Other
Best response to most recent crizotinib regimen
Complete Response, Partial Response, Stable Disease, 
Progressive Disease, Unable to Assess, Unknown, Other
Reason for stopping most recent crizotinib 
regimen
Resistant, Intolerant, Unknown, Other
Total duration of crizotinib (continuous)
Time from the stop date of most recent crizotinib 
regimen to first dose date (continuous)
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Parameters
Categories for categorical parameters
Most recent systemic therapy
Crizotinib, chemotherapy, other
Prior anticancer therapies
Top 10 therapies used (e.g., pemetrexed, carboplatin)
Number of patients who had received any chemotherapy
Number of patients who had received any platinum-based 
therapy
Number of patients who had received any other TKI
Any prior radiotherapy
Yes, No
Prior radiotherapy to the brain
Yes, No
Number of prior systemic anticancer 
therapies/regimens
0, 1, 2, etc.
Patient disposition will be tabulated by reasons leading to study treatment discontinuation 
including adverse event, death, documented disease progression (RECIST), clinical progressive 
disease, withdrawal by subject, physician decision, pregnancy, non-compliance with study drug, 
protocol violation, lost to follow-up, study terminated by sponsor, or other reason.
The list of characteristics described in the table above will also be used as the basis for subgroup 
analyses as described in Sections 3.4.3 and 3.4.4 below. 
3.3.1
Imputation Rules for Missing Initial Cancer Diagnosis Date and Start Date and 
Stop Date for Selected Prior Anti-Cancer Therapies
In general, a diagnosis date will be imputed first and then used to adjust the imputation of the 
corresponding prior treatment start date when necessary.
Initial Diagnosis Dates

If day is missing but month and year are non-missing (UU-MMM-YYYY), impute as 
earliest of: 01-MMM-YYYY, randomization date.

If day and month are missing (UU-UUU-YYYY), impute as earliest of: 01-JAN-YYYY, 
randomization date.

No imputation for a completely missing date (UU-UUU- UUUU)

Additional adjustment(s) may be applied depending on ARIAD medical’s review on the 
prior anti-cancer therapies data
Prior Anti-Cancer Therapies Dates
Start Date

If day is missing but month and year are non-missing (UU-MMM-YYYY), impute as 
earliest of: 01-MMM-YYYY, randomization date.

If day and month are missing (UU-UUU-YYYY), impute as earliest of: 01-JAN-YYYY, 
randomization date.

No imputation for a completely missing date (UU-UUU- UUUU)

If an imputed prior treatment start date is before diagnosis date, re-impute as diagnosis 
date.
Stop Date

If day is missing but month and year are non-missing (UU-MMM-YYYY), impute as the 
earliest of
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Page 12
o
30-MMM-YYYY if month is April, June, September or November, 
28-MMM-YYYY if month is February, 31-MMM-YYY otherwise
o
Randomization date

If day and month are missing (UU-UUU-YYYY), impute as earliest of: 31-DEC-YYYY, 
randomization date.
If after applying above rules, any prior treatment stop dates are prior to corresponding prior 
treatment start date, impute as start date.
Duration of a selected prior anti-cancer therapy will be calculated using the following formula: 
duration = stop date – start date +1. Duration will be calculated with imputed dates when 
necessary. Total duration will be the sum of the individual durations.
Time since the stop date of a selected prior anti-cancer therapy to the first dose of study 
treatment will be calculated using the following formula: time since stop date = stop date – first 
dose date +1. Time since the stop date to the first dose date will be missing in the case of a
completely missing stop date.
3.4
Efficacy Analysis
3.4.1
Disease Assessment
Disease assessment by CT or MRI scans will be performed at screening and at 8 week intervals 
thereafter (on Day 1 [±3 days] of every odd-numbered Cycle) through 15 cycles after the initial
dose of AP26113, and every 3 cycles thereafter until disease progression per RECIST v1.1 as 
assessed by the investigator.  More frequent imaging is permitted at any time, if clinically 
indicated; confirmation of CR or PR should be performed 4 weeks (allowing a minus 3-day time 
window) or more after initial response.  Imaging assessment will also be performed at the End of 
Treatment visit if more than 4 weeks have passed since the last imaging assessment.
For patients who continue the study treatment beyond documented progressive disease per 
RECIST v1.1 at the investigator’s discretion, imaging will continue with the same assessment 
schedule.  If the patient experiences symptomatic deterioration in the absence of radiologic 
progression, it is strongly recommended that additional imaging studies be performed to confirm 
progressive disease.
3.4.2
Definitions of Efficacy Endpoints
The primary endpoint, ORR assessed by the investigator, is defined as the proportion of the 
patients who are confirmed to have achieved CR or PR, per RECIST v1.1, after the initiation of 
study treatment in the ITT population. Confirmed responses are those that persist on repeat 
imaging 4 weeks (allowing a minus 3-day time window) or more after initial response.
Secondary efficacy endpoints for this study are defined as follows:

Confirmed ORR assessed by IRC is defined as the proportion of the patients who are 
confirmed to have achieved CR or PR per IRC using RECIST v1.1 after the initiation of 
study treatment in the ITT population.  Confirmed responses are those that persist on 
repeat imaging 4 weeks (allowing a minus 3-day time window) or more after initial 
response.

For randomized patients with active brain metastases at enrollment, intracranial CNS 
ORR is defined as the proportion of the patients who have achieved CR or PR in the 
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intracranial CNS per a modification of RECIST v1.1 as evaluated by IRC after the 
initiation of study treatment.  

For randomized patients with active brain metastases at enrollment, intracranial CNS PFS 
as evaluated by IRC is defined as the time interval from the date of the first dose of the 
study treatment until the first date at which intracranial CNS disease progresses, an 
increase of 20% or more in the sum of diameters of intracranial CNS target lesions, 
unequivocal progression of non-target lesions, or the appearance of new lesions in the 
intracranial CNS, is objectively documented by a scan, or death due to any cause, 
whichever occurs first. Intracranial CNS PFS will be censored according to the scheme 
specified in Section 3.4.5.3.

Unless otherwise stated, secondary efficacy endpoints will use investigator assessments 
with sensitivity analyses performed using the IRC assessments.

Disease control rate is defined as the proportion of the randomized patients who are 
confirmed to have achieved CR or PR or have a best overall response as SD for 6 weeks 
(allowing a minus 3-day time window) or more after initiation of the study drug using 
RECIST v1.1

Time to response is defined as the time interval from the date of the first dose of the study 
treatment until the initial observation of CR or PR for patients with confirmed CR/PR.  

For patients with a confirmed CR/PR, duration of response is defined as the time interval 
from the time that the measurement criteria are first met for CR/PR (whichever is first 
recorded) until the first date that the progressive disease is objectively documented or 
death. Duration of response will be censored according to the scheme specified in 
Section 3.4.5.3.

Time on treatment is defined as the time interval from the first dose to the last dose of 
AP26113.  For patients who have not discontinued, time on treatment will be censored as 
of the last dose of drug.

PFS is defined as the time interval from the date of the first dose of the study treatment 
until the first date at which disease progression is objectively documented, or death due 
to any cause, whichever occurs first, in the ITT population.  PFS will be censored 
according to the scheme specified in Section 3.4.5.3.

OS is defined as the time interval from the date of the first dose of the study treatment 
until death due to any cause in the ITT population.  OS will be censored on the date of 
last contact for patients who are still alive.
3.4.3
Primary Efficacy Endpoints Analysis
The best response (CR, PR, SD, or PD) according to RECIST v1.1 will be derived for each 
patient who receives at least one dose of study treatment.  Patients with no measurable disease at 
baseline or no adequate post-baseline radiographic response assessment will be included as non-
responders in the primary efficacy endpoint analysis.  The ORR is calculated as the proportion of 
the randomized patients who are confirmed to have achieved CR or PR after the initiation of 
study treatment using the following formula: ORR = (#confirmed Investigator-based CR or PR) 
/(#Randomized patients)*100%.  Confirmed responses are those that persist on repeat imaging 
4 weeks (allowing a minus 3-day time window) or more after initial response.  Exact 2-sided 
97.5% confidence intervals for the ORR will be calculated based on the binomial distribution.  
The primary analysis will be performed on ORR assessed by the investigator among all the 
randomized patients.  
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The best response in target lesions (including pathological lymph nodes) per RECIST v1.1 will 
be calculated as the maximum unsigned decrease (or the minimum increase if no decrease) in 
percentage in the sum of the longest dimensions of the target lesions at a single assessment as 
compared with baseline.  The best response will be displayed using a waterfall plot.
Sensitivity analysis I will be performed for ORR assessed by the investigator in the ITT 
population and using all responses (including unconfirmed responses).
Supportive sensitivity analysis II will be performed for confirmed ORR assessed by the 
investigator in the per-protocol population.
Subgroup analyses of the investigator-based ORR in the ITT population will be performed in all 
patient groups shown in Table 1 that have at least 10 patients. The difference in ORR between 
subgroups will be examined by Fisher’s exact test or logistic regression.  
Relationships between pharmacological findings and both safety and efficacy findings will be 
analyzed in a separate exposure-response report. Analyses for the exposure-response report will 
be conducted under an analytical plan specific to that report. 
The primary endpoint ORR will also be summarized by study center (small centers will be 
combined by region). Due to the small number of patients expected in most of the centers, it has 
been decided that study center will not be used as an additional randomization stratification 
factor or in logistic regression analyses.
3.4.4
Secondary Efficacy Endpoint Analyses
ORR per IRC will be used to assess the robustness of the primary analysis of the primary 
endpoint.  The IRC-based ORR in the ITT population will be calculated using the following 
formula: ORR per IRC = (#confirmed IRC-based CR or PR) / (#Randomized patients)*100%.  
The calculation of the IRC-based ORR in the per-protocol population will be as follows: ORR 
per IRC = (#confirmed IRC-based CR or PR) / (#Per-protocol patients)*100%.  The exact 2-
sided 97.5% binomial confidence intervals will be calculated.
Disease control rate will be assessed by the investigator and IRC in the ITT population and the 
exact 2-sided 95% binomial confidence intervals will be calculated.  The calculation formulas of 
the disease control rate will be as follows: disease control rate per investigator = (#Investigator-
based confirmed CR or PR or SD) / (#Randomized patients)*100%; disease control rate per IRC 
= (# IRC-based confirmed CR or PR or SD) / (#Randomized patients)*100%.
In general, the calculation of time-to-event efficacy endpoints will be as follows: 

PFS = progression/death/censoring date – first dose date + 1

OS = death/last contact date – first dose date + 1

time to response = response/censoring date – first dose date +1

Duration of confirmed response = PFS event/censoring date – date of the first response 
that was confirmed + 1.  

Duration of response = PFS event/censoring date – date of first response + 1.  
Median values and 2-sided 95% confidence intervals will be estimated using Kaplan-Meier 
(KM) method (Kaplan and Meier, 1958) in the ITT population.  The KM-estimated PFS rates 
and OS rates at 12 and 24 months and the associated 2-sided 95% confidence intervals will be 
computed.  Time to response will be summarized only for confirmed responders and all 
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responders (including confirmed and un-confirmed responders) using descriptive statistics, and 
time to both types of response will be estimated by the MK method in which followup for non-
responders will be censored.  Duration of response will also be summarized with descriptive 
statistics for patients with confirmed CR or PR and the Kaplan-Meier method in which followup
for patients without PFS events will be censored.
An additional IRC assessment will be performed to assess efficacy endpoints in the intracranial 
CNS in randomized patients with active brain metastases assessed by MRI at enrollment (see 
Imaging Services Review Charter). Intracranial CNS ORR assessed by the IRC and the exact 2-
sided 95% binomial confidence intervals will be calculated; median intracranial CNS PFS will 
be estimated using the Kaplan-Meier method.  The calculation formulas for intracranial CNS
ORR will be as follows: intracranial CNS ORR per IRC = (#IRC-assessed confirmed intracranial
CNS CR or PR) / (#Randomized patients with active brain metastasis)*100%.
Subgroup analyses of selected secondary efficacy endpoints will be performed in the same
manner as described for the primary endpoint above.  
The correlation of ALK and other biomarkers with time-to-event endpoints will be evaluated 
using Cox proportional hazard regression.
3.4.5
Specifications for Efficacy Endpoint Analyses
3.4.5.1
Data Handling Rules for ORR
Data handling rules for the primary endpoint are as follows:

Baseline disease evaluations should be performed as close as possible to the study 
treatment start and never more than 21 days before the beginning of the study treatment.

An adequate radiographic disease assessment will be defined as one where sufficiently 
clear radiological images are obtained so that changes in all the target lesions, non-target 
lesions and pathological lymph nodes may be observed and/or measured, or the presence 
of new lesions may be determined.  A patient will be considered as not evaluable for 
response at a protocol-specified time point if no imaging/measurement is done or the 
assessment is not adequate (e.g., only a subset of lesion measurements are made) unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned time point response.

The best overall response is the best response recorded across all time points from the 
start of the study treatment until the end-of-treatment disease assessment taking into 
account any requirement for confirmation (i.e., in the determination of best confirmed 
overall response versus best overall response). Response assessed after disease 
progression will not be considered in determination of the best overall response. Post-
study-treatment radiographic assessments including those after a new anticancer 
treatment has started will not be considered in determination of the best overall response.

Time point overall response and the best overall response will be calculated according to 
Table 3 – 5 in Appendix 2 (RECIST v1.1).  A patient will be considered to have a 
response if the criteria for response have been met at the protocol-specified time points 
immediately before and after the time point of inevaluable response, e.g., a patient with 
time point overall responses of PR-NE-PR as a confirmed PR. A single occurrence of SD 
in the same pattern will also be defined as a confirmed PR. However, a PR followed by 
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more than one occurrence of either NE or SD will not be considered as confirmed. In 
such cases subsequent responses can be confirmed. 

If SD is the best time point overall response however the interval from baseline to the 
radiographic assessment is less than 6 weeks (allowing a minus 3-day time window), the 
best overall response will depend on the subsequent assessments. A patient who has SD 
at first radiographic assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD.  A patient lost to follow-up after the first 
radiographic assessment which is SD however the duration of SD is less than 6 weeks 
(allowing a minus 3-day time window) from the first dose date, would be considered 
inevaluable.

All patients will be assigned to one of the following best overall response categories: CR, 
PR, SD, PD, early death, or unknown (including no measureable disease at baseline,
inevaluable post-baseline response because of early discontinuation due to adverse events 
or other reasons, and no exposure to study drug after randomization).  Symptomatic 
deterioration is not a descriptor of an objective response. All patients whose best response 
is not CR or PR will be considered as non-responders in the calculation of ORR.

For the analysis of intracranial CNS ORR and PFS: If a patient progresses due to lesions 
outside the intracranial CNS and continues on study treatment, this patient will continue 
to be evaluated as SD, PR, or CR in the intracranial CNS until progression in the
intracranial CNS or discontinuation from the study treatment.
3.4.5.2
Determination of Disease Progression
Disease progression will be determined to have occurred based on:

The appearance of one or more new lesions.

An increase in the size of target measurable lesions (greater than or equal to 20% of the 
sum of the longest diameters and at least 5 mm absolute increase per RECIST v1.1).

A clear, unequivocal increase in non-target disease, an overall level of substantial 
worsening in non-target disease (whether measurable or non-measurable) of a magnitude, 
even in the presence of SD or PR in target disease. A simple increase in one or more non-
target lesions alone is not considered ‘unequivocal progression’.

In patients with no measurable disease at baseline, disease progression is defined as the 
appearance of new lesions or substantial worsening in non-target disease.
3.4.5.3
Data handling Rules Specifically for the Primary Analysis of PFS
Data handling rules for the primary PFS analyses will be as follows:

All PFS events are based on well-documented and verifiable progression events or death.

Disease progression dates are based on adequate radiographic assessments by the 
investigator. The date of progression is defined as the date at which disease progression 
was first evident. For progression based on a new lesion, the progression date is the date 
of the first observation that the new lesion was detected. If multiple assessments based on 
the sum of target lesion measurements are done at different times, the progression date is 
the date of the last observation or radiological assessment of target lesions that shows a 
predefined increase in the sum of the target lesion measurements. Patients may continue 
the study treatment beyond documented progressive disease per RECIST v1.1 at the 
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investigator’s discretion. Among these patients, only the date of the first documented 
evidence of progressive disease will be used to define the PFS.

If a patient experiences only symptomatic progression or clinical deterioration in the 
absence of radiologic progression, symptomatic deterioration or clinical progression will 
not be considered as a disease progression event and therefore is not a PFS event.

In any efficacy evaluation, PFS for patients still being followed for progression will be 
censored at the last adequate radiographic progression-free assessment date before the 
clinical cut-off date.

The detailed scheme of progression and censoring for the primary analysis of PFS is 
specified in Table 2.
These rules are defined consistently with FDA Guidance: “FDA Guidance for Industry, Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics” (May 2007).
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Table 2
The Scheme of Progression and Censoring for the Primary Analysis of PFS
#Rule
Situation
Date of progression or censoring
Outcome
1
Patient randomized but untreated due to death 
or any other reason
Censored, PFS=1 day
2
No baseline disease assessment
Censored , PFS=1 day
3
No measurable disease at baseline
Date of new lesion(s) or substantial worsening in non-
target disease
Date of last adequate progression-free radiographic 
assessment 
Progressed
Censored
4
No progression or death
Date of last radiological assessment of measured 
lesions
Censored
5
Death before first PD assessment
Date of death
Progressed
6
Death between adequate assessment visits
Date of death
Progressed
7
Death after one missed radiographic 
assessment
Date of death
Progressed
8
Death after two of more missed radiographic 
assessments 
Date of last adequate radiographic assessment
Censored
9
Treatment discontinuation prior to documented 
disease progression or death
Date of last adequate radiographic assessment
Censored
10
New anticancer treatment started without 
documented disease progression and lead to 
treatment discontinuation
Date of last adequate progression-free radiographic 
assessment prior to initiation of new anticancer 
treatment
Censored
11
Cancer-related surgery prior to documented 
disease progression
Date of last adequate progression-free radiographic 
assessment prior to surgery
Censored
12
Disease progression documented between 
scheduled visits
Earliest of the following:
Date of radiological assessment showing new 
lesion (if progression is based on new lesion); 
Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions)
Progressed
13
Disease progression after 1 missed follow-up 
disease assessment
Date of progression
Progressed
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#Rule
Situation
Date of progression or censoring
Outcome
14
Disease progression after 2 or more missed 
follow-up disease assessments (death at any 
time)
Date of last adequate progression-free radiographic 
assessment
Censored
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3.4.5.4
Data handling Rules Specifically for the Sensitivity Analyses of PFS
Sensitivity Analysis I of PFS will be based on disease progression verified by IRC and use the 
progression and censoring scheme in Table 2, Section 3.4.5.3.  In an interim evaluation, for a 
patient who has progressed per investigator but has not been evaluated by the IRC, PFS will be 
censored at the last progression-free assessment date as assessed by IRC. 
Sensitivity Analysis II of PFS will be performed to assess the impact of missed scheduled 
disease assessment based on disease progression determined by the investigator.  This analysis 
will use the progression and censoring scheme in Table 2, Section 3.4.5.3 except for Rule #6, #7, 
#13, and # 14. In this analysis, the death date or the date at which disease progression was first 
evident will be used as disease progression date no matter how many scheduled disease 
assessments are missed prior to the death or documented disease progression.
3.4.5.5
Data handling Rules Specifically for the Primary Analysis of Intracranial CNS PFS
In patients with active brain metastases in the intracranial CNS at enrollment, intracranial CNS 
objective response (PD, SD, PR, CR) will be determined by restricting the RECIST v1.1 criteria 
to lesions in the intracranial CNS only (target, non-target, and new lesions).  A new lesion in the 
intracranial CNS will be scored as PD in the intracranial CNS.  If a patient progresses due to 
lesions outside the intracranial CNS and continues on study treatment, the patient will continue 
to be evaluated as SD, PR, or CR in the intracranial CNS until disease progression in the
intracranial CNS or the patient discontinues study treatment. Confirmation of CR or PR should 
be performed 4 weeks (allowing a minus 3-day window) or more after initial response.
The primary analysis of intracranial CNS PFS will be based on radiographic assessments in the 
intracranial CNS by the IRC.  The primary analysis will only include randomized patients with 
active brain metastases at baseline.  In all the analyses, the progression and censoring scheme in 
Table 2, Section 3.4.5.3 will be used except that the radiographic assessments are restricted to 
the disease in the CNS.
3.4.5.6
Data Handling Rules Specifically for the Analysis of Duration of Response
The analysis of response duration will be based on disease assessment by the investigator and 
use the progression and censoring scheme in Table 2, Section 3.4.5.3. The analysis of response 
duration will only include randomized patients with confirmed CR or PR. An additional analysis 
of duration of response will be performed using disease assessment performed by the IRC.
Censoring in the analysis of duration of response will be the same as for PFS. 
3.4.5.7
Data Handling Rules Specifically for the Analysis of OS
All the randomized patients will be included in the primary analysis. For patients who have been 
randomized and are not treated, the OS will be defined as the time interval from randomization 
date to death date or date of the last contact if available. In the case that at least 3 patients are 
randomized and untreated, a sensitivity analysis will be performed for treated patients only.
3.4.5.8
Handling Rules for Response Contemporaneous Scans
Two or more scans may be taken within a few days. The scans may cover multiple anatomical 
regions and can be of different modalities (e.g. CT scan and MRI).  Scans within a 2-day window 
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will be “merged” lesion by lesion. If a lesion (target, non-target, or new lesion) is on only 1 scan, 
evaluations of the multiple lesions will be simply combined.  
If a single target lesion appears on 2 or more scans, the lesion measurements will be averaged.  
Any new lesion on any of the multiple scans will be counted as a new lesion. If a non-target 
lesion is present on multiple scans, the assessment should be the ‘worst’ of the multiple 
evaluations, e.g. non-CR/non-PR and absent counts as non-CR/non-PR, progression and non-
CR/non-PR counts as progression etc.
3.5
Safety Analysis
Throughout the study, safety assessments will include physical and laboratory examinations, 
vital signs, and ECGs according to the Schedule of Events.  Adverse events will be assessed and 
categorized by the US National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), v 4.0 (see protocol Appendix A).  Patients will remain on treatment until 
they meet one or more criteria for withdrawal.  Patients will be supplied with study treatment 
until they discontinue from the study.
All safety analyses will be performed using the treated population, which will include all patients 
who have received at least one dose of study treatment.
3.5.1
Adverse Events
All adverse events (AEs) starting/worsening on or after the first dose of study treatment and no 
later than 30 days after the last dose date will be considered as treatment-emergent.  Treatment-
emergent AEs also include those with partially or completely missing start date since there is not
enough evidence that the event started before the first dose of study treatment.
All AEs entered in the clinical database (including treatment-emergent and non-treatment-
emergent AEs) will be listed in by-patient listings or available for review in appropriate datasets.  
The incidence rates of treatment-emergent AEs, as well as the frequency of occurrence of overall 
toxicity categorized by maximum toxicity grades (severity), will be described.  In addition, 
treatment-emergent AEs will be summarized by causal relationship to study treatment (in the 
opinion of the investigator) and action taken on study treatment, including dose modifications, 
interruptions and discontinuation.  Serious treatment-emergent AEs, both overall and by causal 
relationship to study treatment, will also be summarized.  Treatment-emergent AEs will also be 
summarized using cumulative incidence rate by cycles for all treated patients and among treated 
patients still at risk.  Incidence rate for treatment-emergent AEs and AE groups in special 
categories, e.g., pulmonary adverse events overall and within first 7 days, will be summarized 
and also be adjusted with patients’ entire exposure to study treatment and exposure through the 
AE initial onset.  AEs in special categories will also be summarized in terms of number of 
occurrences, by time to initial onset and duration of events. The special categories to be 
analyzed will include at minimum those listed in Appendix 4.  All deaths occurring during a 
period of exposure to AP26113 or within a period of up to 30 days following discontinuation 
from AP26113, and all deaths occurring later but resulting from treatment related adverse 
event(s) will be summarized by AEs leading to death and causal relationship to study treatment.
The incidence rates and cumulative incidence rate of treatment-emergent AEs will also be 
summarized in subgroups based on selected demographic and baseline characteristics, 
randomization stratification factors, and the mutation type in ALK and other selected 
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biomarkers. The correlation of ALK and other biomarkers with the incidence rates of selected 
treatment-emergent AEs will be evaluated using logistic regression.
3.5.1.1
Imputation Rule for Missing Causal Relationship of Treatment-Emergent Adverse 
Events
Missing causal relationship to the study treatment will be imputed as the least possible related for 
treatment-emergent AEs.
3.5.1.2
Imputation Rules for Missing Onset Date and Resolution Date of Adverse Events
In general the imputation will be conservative such that onset dates will be imputed to be as early 
as possible and resolution dates will be imputed to be as late as possible. Resolution date will be 
imputed first and then used to impute onset date.
Imputation for Resolution Date:

If day is missing but month and year are non-missing (UU-MMM-YYYY), impute as the 
earliest of:
o
Last day of the month (28, 29, 30 or 31 depending on in which month the adverse 
event resolved)
o
Data cutoff date
o
Death date

If day and month are missing (UU-UUU-YYYY), impute as the earliest of:
o
December 31 (31-DEC-YYYY)
o
Data cutoff date
o
Death date

If date is completely missing (e.g., AE is ongoing), impute as earliest of:
o
Data cutoff date
o
Treatment discontinuation date + 30 days
o
Death date
Imputation for Onset Date:

If day is missing but month and year are non-missing (UU-MMM-YYYY), impute as 
follows:
o
If year and month are the same as year and month of first dose date:

If resolution date (or imputed resolution date) is on or after first dose date, 
impute as first dose date

If resolution date (or imputed resolution date) is prior to first dose date, 
impute as latest of first day of the month or informed consent date
o
If year is the same as year of first dose date and month is after month of first dose 
date, impute as first date of month
o
If year is the same as year of first dose date and month is before month of first 
dose date, impute as latest of first day of the month or informed consent date
o
If year is after year of first dose date, impute as first day of month
o
If year is before year of first dose date, impute as latest of first day of the month 
or informed consent date

If day and month are missing and year is non-missing (UU-UUU-YYYY), impute as 
follows:
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o
If year is the same as year of first dose date:

If resolution date (or imputed resolution date) is on or after first dose date, 
impute as first dose date

If resolution date (or imputed resolution date) is prior to first dose date, 
impute as latest of first day of the month or informed consent date
o
If year is after year of first dose date, impute as January 1 (01-JAN-YYYY)
o
If year is before year of first dose date, impute as latest of first day of the year 
(01-JAN-YYYY) or informed consent date

If date is completely missing:
o
If resolution date (or imputed resolution date) is on or after first dose date, impute 
as first dose date
o
If resolution date (or imputed resolution date) is prior to first dose date, impute as 
informed consent date.
3.5.1.3
Derivation of Treatment-Emergent Adverse Event Flag
Sites are instructed to “split” AEs that are ongoing as of first dose date into two records: one that 
ends as of first dose date and one that begins on first dose date.  Therefore in some cases, what 
may at first appear as an AE that begins on first dose date is really a continuation of an AE that 
began prior to first dose date.  If all of the following criteria are true for any two AE records then 
the two records should be considered as one event:

The preferred term of the first AE = the preferred term of the second AE.

The start date of the first AE is before the date of first dose.

The end date of the first AE is one day before the date of first dose or equal to the date of 
first dose.

The start date of the second AE = the date of first dose.

The severity of the second AE <= the severity of the first AE.

The relatedness of both the first and the second AEs is “Not Related”.
After determining which records should be treated as a single event, the treatment-emergent flag 
can be determined as follows:

All AEs with an onset date on or after the first dose date and no later than 30 days after 
the last dose date.

In the case of missing onset date, impute using the rules defined in Section 3.5.1.2
3.5.1.4
Calculation Specifications for Treatment-Emergent Adverse Events
Time to onset is defined as the time interval from the first dose date until the onset date of a 
treatment-emergent AE. In case of a missing onset date, a date imputed with the rules in 
Section 3.5.1.2 will be used.  Time to onset will be computed with the following formula: time to 
onset= AE onset date – first dose date + 1.
Time to initial onset of an individual treatment-emergent AE is defined as the time interval from 
the first dose date until the earliest onset date of the treatment-emergent AEs of the same nature.  
In case of a missing onset date, a date imputed with the rules in Section 3.5.1.2 will be used. 
Time to initial onset will be computed with the following formula: time to initial onset = earliest 
AE onset date – first dose date + 1.
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Age at onset will be computed by the following formula and rounding down to the nearest 
integer: age at onset = floor ((AE start date – birth date + 1)/365.25).
Dose at onset will be defined as the dose received by patients on AE onset date, regardless of 
treatment arm.  Dose at onset will not be defined if the occurrence of a treatment-emergent AE is 
post treatment discontinuation.
Dose by onset will be defined as the last non-zero dose received by AE onset date.
3.5.1.5
Specifications for the Analyses Outputs
Adverse events will be coded with MedDRA dictionary. The version of the dictionary will be 
specified in the output listings or tables. Some preferred terms coding manifestations of similar 
medical conditions will be re-coded and re-grouped based on the synonym infrastructure 
determined through sponsor medical review (An example of such an infrastructure is provided in
Appendix 3). In the summary tables, MedDRA preferred terms will be sorted in a descending 
order of incidence rate first then alphabetically in case of tied incidence rates. In the tables of 
treatment emergent AEs grouped by MedDRA System Organ Class (SOC), SOCs will be put in 
the internationally agreed order.
3.5.2
Laboratory and Vital Signs Data
Laboratory and vital signs data in standard units will be summarized using summary statistics 
and graphically at baseline and at each cycle for which adequate data are available. Laboratory 
and blood pressures data will also be graded according to the NCI CTCAE, v.4.0 when 
applicable.  Change from baseline to the worst on-study result will be summarized using the 
changes from baseline values in standard units.  Change from baseline to the worst on-study 
result will also be summarized by shift in CTCAE grade for selected laboratories and blood 
pressures. Changes in Testosterone and Insulin will be summarized by cross-tabulations of 
baseline (low, normal, high) and the highest/lowest value on study (low, normal, high).
Laboratory measurements of ALT, AST, Alkaline phosphate (ALP), and total bilirubin (TBL) 
will be evaluated for the potential risk of drug-induced liver failure. 
Possible Hy’s Law cases (Zimmerman 1999) are defined as patients with ALT or AST > 3 × 
ULN, with ALP < 2 × ULN and total bilirubin (TBL) ≥2 × ULN with no other etiology to 
explain these liver-function test results.  Changes in ALT, AST, ALP, and TBL over time will 
also be graphically displayed for possible Hy’s law patients.
3.5.3
QTcF Analysis
Descriptive statistics of maximum QTcF and change from baseline will be calculated following 
the ICH-E14 guidelines: the proportion of treated patients with at least one on-drug QTcF value 
> 450 ms, 480 ms, and 500 ms; proportion of treated patients with a maximum change in QTcF 
from baseline > 30 ms and > 60 ms. The mean change in QTcF from baseline to maximum on 
study value will be calculated along with 95% confidence intervals.
3.5.4
Extent of Exposure
Exposure to AP26113 will be summarized using the following measures:

Time (days) on study treatment
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
Total cumulative dose of AP26113 administered

Dose intensity (mg/day)

Relative dose intensity (%)

Total person years

Dose interruption of at least 3 days
o
Number of patients with at least one occurrence
o
Number of patients who returned to dosing after interruption
o
Number of patients who returned to target dose after interruption
o
Total duration (days) of time off study drug prior to treatment discontinuation

Dose reduction of at least 3 days
o
Number of patients with at least one occurrence
o
Number of patients who returned to dosing after interruption
o
Number of patients who returned to target dose after interruption
o
Total duration (days) of time off study drug prior to treatment discontinuation
Time on treatment will be defined as the time interval from the first dose date to the last dosing 
date and computed with the following formula: Time (days) on treatment= last non-zero dose 
date – first dose date  + 1
Dose intensity will be calculated with the following formula: Dose intensity = Total cumulative 
dose/ Time (days) on study treatment.  Relative dose intensity will be defined as the proportion 
of the planned dose received by patients.  In treatment arm A, daily planned dose will be 90 mg 
and change to the escalated dose since the day 1 of escalation.  In treatment arm B, daily planned 
dose will be 90 mg in the 7-day lead-in period and 180 mg from day 8 onward.  Relative dose 
intensity will be calculated as follows: Relative dose intensity = Total cumulative dose 
administered / Total dose planned x 100%.
Total person years for a treated patient will be calculated using the following formula:
Total person years = Time (days) on study treatment / 365.25. The total person years in an 
analysis population will be the sum of the total person years of all the patients in this population.
Dose modifications will be summarized by dose interruption and dose reduction.  A patient will 
be identified as having dose interruption if this patient had no exposure to study drug for at least 
3 consecutive days. A patient will be identified as having dose reduction if this patient had a 
period of reduced dosage of at least 3 consecutive days, as long as the dose received was less 
than the target dose but greater than 0 mg on some of the days in this period. Periods of time in 
which a patient alternates between reduced dosing and dose interruptions will be handled in the 
following manner:

The entire period of time between the last receipt of the target dose and either resumption 
at the target dose or discontinuation of treatment will be considered as a single dose 
reduction period.

Any period of 3 or more days with no receipt of study drug within that dose reduction 
period will also be treated as a dose interruption.
3.6
Quality of Life Measurement
Patient-reported symptoms and HRQoL will be collected by administering the EORTC QLQ 
C30 (v.3.0, Aaronson et al., 1993) questionnaire at pre-specified scheduled visits, and at the visit 
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30 days after the last dose of AP26113.  The PRO questionnaire will be administered to patients 
when they arrive for their scheduled visits, prior to any clinical measurements, assessments, 
evaluations, or procedures being performed.
The EORTC QLQ-C30 will be scored for 5 functional scales (physical, role, cognitive, 
emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and a 
global health status/QoL scale.  Six single item scales also are included (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties).
3.6.1
Analyses of Quality of Life Measurements
For HRQoL measures, raw scores for multi-item scales will be calculated by averaging items 
within scales first.  Raw scores will be summarized by time point with descriptive statistics for 
each scale.  Raw scores for multi-item scales and single-item measures will be linearly 
transformed to obtain the score ranging from 0 to 100 according to EORTC QLQ-C30 (V3) 
Scoring Manual (Fayers et al., 2001).  The global health status / QoL scale based upon Q29 and 
Q30 will be used as the overall summary measure.
The HRQoL scores including the overall summary measure will be summarized at baseline and 
by time point in evaluable patients overall and by treatment group.  The changes from baseline 
over time will be summarized with descriptive statistics and explored using mixed effects 
models.
Information collected in the EORTC QLQ-C30 will be analyzed on its own, and findings such as 
dyspnea collected as part of the EORTC QLQ-C30 will not be considered as AEs.
3.6.2
Handling Rule of Missing Quality of Life Measurements
Handling rules for missing QoL measurement are as follows:

Missing items will be imputed as the average of the items which are present for a multi-
item scale if at least half of the items from the scale have been answered.

A missing single-item measure will not be imputed.

Missing forms will not be imputed.

Patients with missing baseline scores will be excluded from the analysis for a scale when 
the change from baseline is analyzed or the baseline score is used as a covariate.
3.7
Pharmacokinetic Analysis
All patients must provide a blood sample (approximately 3 mL per sample) for analysis of 
steady-state AP26113 plasma concentration. Samples will be collected on Day 1 of Cycles 2, 3, 
4, and 5. Cycle 2 requires sampling at pre-dose, and at 1 hour (±10 minutes), 4 hours (±15 
minutes) and 6-8 hours (±15 minutes) post-dose. During Cycles 3, 4, and 5, samples will be 
collected at two time points from each patient (a pre-dose sample and a second sample anytime 
between 1 to 8 hours post-dose). The AP26113-13-201 study samples will be analyzed with 
population PK modeling in combination with data from the “AP26113-11-101” study. PK data 
will also be used in an exposure-response analysis for safety and efficacy. The exposure-
response relationship between the simulated concentration (AUC and C-24hr) and ORR and PFS 
will be analyzed with stepwise logistic regression and stepwise Cox proportional regression 
models with adjusting potential confounding factors. The exposure-response analysis for 
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Page 27
selected adverse events and/or laboratory assessments will be analyzed in a similar manner. PK 
analyses will be detailed in a statistical analysis plan specifically developed for this purpose.
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4
REFERENCES
Aaronson NK, Ahmedzai S, Bergman, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85(5):365-376.
Kaplan EL and Meier P. Nonparametric Estimation from Incomplete observations. J Am 
Statistical Assoc. 1958;53:457-481.
Fayers PM, Aaronson NK, Bjordal K, et al. EORTC Scoring Manual. 3rd edition. Brussels: 
European Organisation for Research and Treatment of Cancer; 2001.
“FDA Guidance for Industry, Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics” (May 2007) available at 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071590.pdf.
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5
APPENDICES
The final SAP will include the following Appendices
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Appendix 1
Schedule of Events
Screening 
Period
Treatment through 30 Days After Last Dose
Follow-up 
Period
Assessment
Screening1
Cycle 1
(28 Days)
Every 4 weeks 
(Day 1 of each 
cycle from 
Cycle 2 
onwards)
Every 8 weeks
(from Day 1 of 
Cycle 3 through 
Cycle 15; every 3 
cycles thereafter)
Every 12 
weeks
(from Day 
1 of 3rd
Cycle from
Cycle 4 
onwards)
End-of-
Treatment27
30 Days 
After 
Last 
Dose28
Follow-
up29
Day (D)
D-14 to D0
D1
D8
D15
Informed Consent2
X
Randomization3
X
Demographics4
X
Medical/Surgical 
History5
X
Diagnosis and 
Cancer History6
X
Prior Cancer 
Therapy7
X
ALK Mutation 
Status8
X
Physical 
Examination9
X
X
X*
X*
X
X
X
Vital Signs10
X
X
X
X
X
X
X
ECOG Performance 
Status11
X
X
X
X
X
Hematology12
X
X
X
X
X
X
Chemistry (fasting, 
if possible)13
X
X
X
X
X
X
Urinalysis14
X
X
X
X
X
Insulin (fasting, if 
possible)15
X
X
X
X
X
X
Testosterone Level 
(males only)16
X
X
X
X
X
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Screening 
Period
Treatment through 30 Days After Last Dose
Follow-up 
Period
Assessment
Screening1
Cycle 1
(28 Days)
Every 4 weeks 
(Day 1 of each 
cycle from 
Cycle 2 
onwards)
Every 8 weeks
(from Day 1 of 
Cycle 3 through 
Cycle 15; every 3 
cycles thereafter)
Every 12 
weeks
(from Day 
1 of 3rd
Cycle from
Cycle 4 
onwards)
End-of-
Treatment27
30 Days 
After 
Last 
Dose28
Follow-
up29
Day (D)
D-14 to D0
D1
D8
D15
Patient-Reported 
Outcomes 
Assessment26
X
X
X
X
X
Subsequent 
Anticancer 
Therapy/Survival27
X
*Assessment for early pulmonary symptoms must be performed during the visit on Day 8 and Day 15.
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Appendix 2
Notes from RECIST v1.1
Appendix 2.1
Measureable disease vs. Non-measureable disease
Measurable disease is defined by the presence of at least one lesion with a longest diameter 
> = 10 mm or a pathological lymph node with a short axis of > = 15 mm.  Lesions with prior 
local treatment are usually not considered measurable unless there has been demonstrated 
progression in the lesion.
Non-measurable disease is defined as small lesions (longest diameter <10mm or pathological 
lymph nodes with > = 10 to < 15 mm short axis) or lesions truly non-measurable by reproducible 
imaging techniques.
Appendix 2.2
Target lesions vs. Non-target lesions vs. New lesions
1. Target lesions
a.
In the systemic assessment of disease, a maximum of five total (and from the five, 
up to two per organ, maximum) lesions or pathological lymph nodes will be 
identified at baseline for follow up to assess tumor burden in target lesions for 
response determination (see Section 3.4.4 for discussion of intracranial CNS 
assessment) .  The sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated as baseline or on-study 
sum diameters.
b. Measurement of target lesions:

“Too small to measure” - In case that target lesions become very faint on CT 
scan and are reported as ‘too small to measure’: if it is the opinion of the 
radiologist that a lesion has likely disappeared, the measurement should be 
recorded as 0mm; if a lesion or lymph node is believed to be present and is 
faintly seen but too small to measure, a default value of 5mm should be 
assigned.  This default value is derived from the 5mm CT slice thickness (but 
should not be changed with varying CT slice thickness).  If the radiologist is 
able to provide an actual measure, that should be recorded, even if it is below 
5mm.

Lesions that split or coalesce on treatment - When non-nodal lesions 
‘fragment’, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum. Similarly, as lesions coalesce, a 
plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest 
diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
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c.
Response criteria for target lesions:

Complete Response (CR): Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum diameters.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note: the unequivocal appearance of one or more new lesions is 
also considered progression).

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.
2. Non-target lesions
a.
All other lesions or pathological lymph nodes (or sites of disease) after the target 
lesions are chosen will be identified as non-target lesions and should also be 
recorded at baseline.
b. Measurements are not required and these lesions will be assessed only 
qualitatively as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow).  In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form 
(e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
c.
Response criteria for 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 (<10mm short axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumormarker level above the normal limits.

Progressive Disease (PD): Unequivocal progression of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
d. Assessment of progression of non-target lesions

When the patient has measurable disease at baseline, the designation of 
overall progression solely on the basis of change in non-target disease in the
face of SD or PR of target disease is extremely rare. To achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased 
sufficiently and requires discontinuation of treatment.
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
When the patient has only non-measurable disease at baseline, there is no 
measurable disease assessment to factor into the interpretation of an increase 
in non-measurable disease burden. An unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-
measurable disease is substantial and comparable in magnitude to the increase 
that would be required to declare PD form measurable disease: e.g., an 
increase in tumor burden representing an additional 73% increase in ‘volume’ 
(which is equivalent to a 20% increase diameter in a measurable lesion).
3. New lesions
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. If a new lesion 
is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial 
scan.
Appendix 2.3
Time point overall response status and best overall response status 
calculation
Table 3
Summary of the Overall Response Status Calculation at each Time Point 
for Patients Who have Target +/- Non-target Disease at Baseline
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable.
Table 4
Summary of the Overall Response Status Calculation at each Time Point 
for Patients Who Have Non-measurable (Therefore Non-target) Disease only at Baseline
Non-target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease, and NE = inevaluable.
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised.
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Table 5
Summary of the Best Overall Response Status Calculation when 
Confirmation of CR and PR is Required
Overall response
First time point
Overall response
Subsequent time point
Overall Response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable.
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
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Appendix 3
Adverse Events Synonyms*
MedDRA Dictionary 
Preferred Term
MedDRA Dictionary 
System Organ Class
Recoded Preferred 
Term
Recoded System 
Organ Class
Thrombocytopaenia
Blood and Lymphatic 
System Disorders
platelet count 
decreased
Investigations
Thrombocytopenia
Blood and Lymphatic 
System Disorders
platelet count 
decreased
Investigations
Thrombocytosis
Blood and Lymphatic 
System Disorders
platelet count 
increased
Investigations
Thrombocythaemia
Blood and Lymphatic 
System Disorders
platelet count 
increased
Investigations
Thrombocythemia
Blood and Lymphatic 
System Disorders
platelet count 
increased
Investigations
Anemia
Blood and Lymphatic 
System Disorders
Anaemia
Blood and Lymphatic 
System Disorders
Haemoglobin decreased
Investigations
Anaemia
Blood and Lymphatic 
System Disorders
Hemoglobin decreased
Investigations
Anaemia
Blood and Lymphatic 
System Disorders
Haematocrit decreased
Investigations
Anaemia
Blood and Lymphatic 
System Disorders
Erythrocytosis
Blood and Lymphatic 
System Disorders
Hemoglobin increased
Investigations
Erythrocythemia
Blood and Lymphatic 
System Disorders
Hemoglobin increased
Investigations
Leukopenia
Blood and Lymphatic 
System Disorders
white blood cell count 
decreased
Investigations
white blood cell count 
increased
Investigations
Leukocytosis
Blood and Lymphatic 
System Disorders
Neutropenia
Blood and Lymphatic 
System Disorders
Neutrophil count 
decreased
Investigations
Lymphopaenia
Blood and Lymphatic 
System Disorders
Lymphocyte count 
decreased
Investigations
Lymphopenia
Blood and Lymphatic 
System Disorders
Lymphocyte count 
decreased
Investigations
eosinophil count 
increased
Investigations
Eosinophilia
Blood and Lymphatic 
System Disorders
basophil count increased
Investigations
Basophilia
Blood and Lymphatic 
System Disorders
blood glucose decreased
Investigations
Hypoglycaemia
Metabolism and 
Nutrition Disorders
Hypoglycemia
Metabolism and Nutrition 
Disorders
Hypoglycaemia
Metabolism and 
Nutrition Disorders
MedDRA Dictionary 
Preferred Term
MedDRA Dictionary 
System Organ Class
Recoded Preferred 
Term
Recoded System 
Organ Class
blood glucose increased
Investigations
Hyperglycaemia
Metabolism and 
Nutrition Disorders
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MedDRA Dictionary 
Preferred Term
MedDRA Dictionary 
System Organ Class
Recoded Preferred 
Term
Recoded System 
Organ Class
Hyperglycemia
Metabolism and Nutrition 
Disorders
Hyperglycaemia
Metabolism and 
Nutrition Disorders
blood sodium decreased
Investigations
Hyponatraemia
Metabolism and 
Nutrition Disorders
Hyponatremia
Metabolism and Nutrition 
Disorders
Hyponatraemia
Metabolism and 
Nutrition Disorders
blood sodium increased
Investigations
Hypernatraemia
Metabolism and 
Nutrition Disorders
Hypernatremia
Metabolism and Nutrition 
Disorders
Hypernatraemia
Metabolism and 
Nutrition Disorders
blood potassium 
decreased
Investigations
Hypokalaemia
Metabolism and 
Nutrition Disorders
Hypokalemia
Metabolism and Nutrition 
Disorders
Hypokalaemia
Metabolism and 
Nutrition Disorders
blood potassium 
increased
Investigations
Hyperkalaemia
Metabolism and 
Nutrition Disorders
Hyperkalemia
Metabolism and Nutrition 
Disorders
Hyperkalaemia
Metabolism and 
Nutrition Disorders
blood calcium decreased
Investigations
Hypocalcaemia
Metabolism and 
Nutrition Disorders
Hypocalcemia
Metabolism and Nutrition 
Disorders
Hypocalcaemia
Metabolism and 
Nutrition Disorders
Hypercalcemia
Metabolism and Nutrition 
Disorders
Hypercalcaemia
Metabolism and 
Nutrition Disorders
blood calcium increased
Metabolism and Nutrition 
Disorders
Hypercalcaemia
Metabolism and 
Nutrition Disorders
blood magnesium 
decreased
Investigations
Hypomagnesaemia
Metabolism and 
Nutrition Disorders
Hypomagnesemia
Metabolism and Nutrition 
Disorders
Hypomagnesaemia
Metabolism and 
Nutrition Disorders
blood magnesium 
increased
Investigations
Hypermagnesaemia
Metabolism and 
Nutrition Disorders
Hypermagnesemia
Metabolism and Nutrition 
Disorders
Hypermagnesaemia
Metabolism and 
Nutrition Disorders
Blood Phosphorus 
decreased
Investigations
Hypophosphataemia
Metabolism and 
Nutrition Disorders
blood phosphate 
decreased
Investigations
Hypophosphataemia
Metabolism and 
Nutrition Disorders
MedDRA Dictionary 
Preferred Term
MedDRA Dictionary 
System Organ Class
Recoded Preferred 
Term
Recoded System
Organ Class
Hypophosphatemia
Metabolism and Nutrition 
Disorders
Hypophosphataemia
Metabolism and 
Nutrition Disorders
blood phosphorous 
increased
Investigations
Hyperphosphataemia
Metabolism and 
Nutrition Disorders
Hyperphosphatemia
Metabolism and Nutrition 
Disorders
Hyperphosphataemia
Metabolism and 
Nutrition Disorders
blood triglycerides 
increased
Investigations
Hypertriglyceridaemia
Metabolism and 
Nutrition Disorders
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MedDRA Dictionary 
Preferred Term
MedDRA Dictionary 
System Organ Class
Recoded Preferred 
Term
Recoded System 
Organ Class
Hypertriglyceridemia
Metabolism and Nutrition 
Disorders
Hypertriglyceridaemia
Metabolism and 
Nutrition Disorders
Hypercholesterolemia
Metabolism and Nutrition 
Disorders
Blood cholesterol 
increased
Investigations
Hypercholesterolaemia
Metabolism and Nutrition 
Disorders
Blood cholesterol 
increased
Investigations
blood albumin decreased
Investigations
Hypoalbuminaemia
Metabolism and 
Nutrition Disorders
Hypoalbuminemia
Metabolism and Nutrition 
Disorders
Hypoalbuminaemia
Metabolism and 
Nutrition Disorders
Hyperbilirubinaemia
Hepatobiliary Disorders
blood bilirubin 
increased
Investigations
Hyperbilirubinemia
Hepatobiliary Disorders
blood bilirubin 
increased
Investigations
Blood Lipase increased
Investigations
Lipase Increased
Investigations
Lipase
Investigations
Lipase Increased
Investigations
Blood Amylase
Investigations
Blood Amylase 
Increased
Investigations
Pancreatitis Acute
Gastrointestinal disorders
Pancreatitis
Gastrointestinal 
disorders
Rash erythematous
Skin and Subcutaneous 
Tissue Disorders
Rash
Skin and 
Subcutaneous Tissue 
Disorders
Rash Macular
Skin and Subcutaneous 
Tissue Disorders
Rash
Skin and 
Subcutaneous Tissue 
Disorders
Rash papular
Skin and Subcutaneous 
Tissue Disorders
Rash
Skin and 
Subcutaneous Tissue 
Disorders
rash maculo-papular
Skin and Subcutaneous 
Tissue Disorders
Rash
Skin and 
Subcutaneous Tissue 
Disorders
Troponin I increased
Investigations
Troponin increased
Investigations
painful defaecation
Gastrointestinal Disorders
proctalgia
Gastrointestinal 
Disorders
blood pressure increased
Investigations
hypertension
Vascular disorders
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MedDRA Dictionary 
Preferred Term
MedDRA Dictionary 
System Organ Class
Recoded Preferred 
Term
Recoded System 
Organ Class
blood pressure 
decreased
Investigations
hypotension
Vascular disorders
escherichia bacteraemia
Infections and Infestations
bacteraemia
Infections and 
Infestations
staphylococcal 
bacteraemia
Infections and Infestations
bacteraemia
Infections and 
Infestations
abdominal pain upper
Gastrointestinal Disorders
abdominal pain
Gastrointestinal 
Disorders
abdominal pain lower
Gastrointestinal Disorders
abdominal pain
Gastrointestinal 
Disorders
stomach discomfort
Gastrointestinal Disorders
abdominal discomfort
Gastrointestinal 
Disorders
*This list will be updated as new events occur and/or MedDRA versions change over the course of the study.
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ARIAD Pharmaceuticals, Inc.
AP26113-13-201
AP26113
Statistical Analysis Plan
08 February 2016 
 
Page 41
Appendix 4
Adverse Events in Special Categories
Selection of AEs for special categories will be performed through the use of Standardised MedDRA Queries 
(SMQs), Modified MedDRA Queries (MMQs), or Customized MedDRA Queries (SMQs). The adverse events in 
special categories will be listed and updated as new events occur and/or MedDRA versions change over the course 
of the study. The final versions of these query sets will be provided as an appendix to the final CSR. 
The following special categories of adverse events will be analyzed:

Pulmonary: early onset pulmonary events and later onset pneumonitis-like events

Hypertension events

Bradycardia events

Gastrointestinal events

Hepatic events

Pancreatic events 

Insulin level elevation/hyperglycemia events

Skin and soft tissue SOC events
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