Clinical trial NCT01449461
Conditions: Lymphoma, Large-Cell, Anaplastic Carcinoma, Non-Small-Cell Lung
Sponsor: Ariad Pharmaceuticals
Start date: 2011-09-20; Completion date: 2020-02-18
Enrollment: 137 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is 2-fold: initially, in the dose escalation phase, the goal is to determine the safety profile of orally administered brigatinib, including: the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile. Then, once the RP2D is established, an expansion phase will assess the preliminary anti-tumor activity of brigatinib, both in non-small cell lung cancer (NSCLC) with ALK gene rearrangement (including participants with active brain metastases) or mutated EGFR, and in other cancers with abnormal targets against which brigatinib is active.

Detailed description:
The drug being tested in this study is called brigatinib (AP26113). Brigatinib is being tested to treat people with NSCLC. This study will look at the safety, tolerability and efficacy of brigatinib.

The study enrolled 137 patients. Participants were assigned to one of the following treatment groups:

* Brigatinib 30 mg once daily (QD)/60 mg QD
* Brigatinib 90 mg QD
* Brigatinib 120 mg QD/60 mg twice daily (BID)
* Brigatinib 90 mg QD-180 mg QD
* Brigatinib 180 mg QD/90 mg BID
* Brigatinib 240 mg QD/120 mg BID/300 mg QD

This multi-center trial will be conducted worldwide. The overall expected time to participate in this study is approximately 4 years. Participants will make multiple visits to the clinic, and 30 days after the End-of-Treatment visit. Follow-up is intended to continue for at least 2 years after the initial dose.

Arms: arm 1: Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years). arm 2: Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years). arm 3: Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years). arm 4: 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. arm 5: Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years). arm 6: Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).
Interventions: intervention 1: Brigatinib
Intervention descriptions: intervention 1: Brigatinib tablets and capsules.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-
Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113
NCT Number: NCT01449461
Protocol Approve Date: 20 March 2017
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.
AP26113-11-101
Version 8.0  20 March 2017
Page 1 of 83
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1/2 Study of the Safety, Tolerability, 
Pharmacokinetics and Preliminary Anti-Tumor Activity of 
the Oral ALK/EGFR Inhibitor AP26113
Protocol Number:
AP26113-11-101
Study Phase:
Phase 1/2
Product Name:
AP26113
IND Reference Number:
IND 110,935
EudraCT Number:
2011-005718-12
Sponsor:
ARIAD Pharmaceuticals, Inc.
125 Binney Street
Cambridge, MA 01242
Telephone: +1 (617) 494-0400
Original Protocol Issue Date:
27 June 2011
Protocol Amendment 1 Date:
22 July 2011
Protocol Amendment 2 Date:
21 February 2012
Protocol Amendment 3 Date:
17 September 2012
Protocol Amendment 4 Date:
30 November 2012
Protocol Amendment 5 Date:
22 May 2013
Protocol Amendment 6 Date:
20 December 2013
Protocol Amendment 7 Date:
20 March 2017
Version Number:
8.0
PROTOCOL REVISION HISTORY:
Amendment Number
Protocol Version Number
Date
Version 1.0
27 June 2011
Amendment 1
Version 2.0
22 July 2011
Amendment 2
Version 3.0
21 February 2012
Amendment 3
Version 4.0
17 September 2012
Amendment 4
Version 5.0
30 November 2012
Amendment 5
Version 6.0
22 May 2013
Amendment 6
Version 7.0
20 December 2013
Amendment 7
Version 8.0
20 March 2017
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Property of Takeda: For Non-Commercial Use Only a


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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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ARIAD Pharmaceuticals, Inc.
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Version 8.0  20 March 2017
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PROTOCOL SYNOPSIS
Sponsor
ARIAD Pharmaceuticals, Inc.
125 Binney St.
Cambridge, MA 01242
Study Treatment
AP26113
Study Title
A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and 
Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor 
AP26113
Phase
Phase 1/2
Summary and Study 
Rationale
Specific genetic lesions that drive the proliferation of cancer cells, such 
as those causing activation of certain tyrosine kinases, render some 
cancers highly sensitive to therapeutic agents that inhibit the kinase.  
However, the efficacy of such agents is often limited by the 
development of mutations in the target kinase domain that confer 
resistance by reducing inhibitor binding.  For example, the ABL kinase 
inhibitor imatinib has revolutionized treatment for patients with chronic 
myeloid leukemia (CML), whose disease is driven by an activated 
BCR-ABL fusion oncoprotein.  Over time, however, development of 
mutations in the ABL kinase domain confers resistance in a substantial 
proportion of patients.  The second-generation ABL inhibitors dasatinib 
and nilotinib, by virtue of being more potent inhibitors of ABL, 
demonstrate superior efficacy, and are able to overcome much of the 
mutation-based resistance exhibited by imatinib.  More recently, genetic 
lesions in 2 other tyrosine kinases, anaplastic lymphoma kinase (ALK) 
and the epidermal growth factor receptor (EGFR) have been identified 
that show a similar pattern of sensitivity to first-generation inhibitors 
and susceptibility to mutation-based resistance.
Activating gene rearrangements or mutations in ALK have been 
identified as driver mutations in some patients with non-small cell lung 
cancer (NSCLC), anaplastic large cell lymphoma (ALCL), diffuse 
large-cell lymphoma (DLCL), inflammatory myofibroblastic tumors 
(IMT), neuroblastoma, and other cancers.  Crizotinib, an ALK kinase 
inhibitor, has demonstrated promising clinical activity in NSCLC, 
ALCL, and IMT patients harboring ALK translocations (Butrynski, 
2010; Kwak, 2010; Gambacorti-Passerini, 2011).  However, emerging 
data suggest that mutations in the kinase domain of ALK, including at 
the gatekeeper residue (L1196M), can confer resistance to crizotinib 
(Choi, 2010).  Therefore, an ALK inhibitor that is more potent than 
crizotinib may be required to overcome such resistance.
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Activating mutations in EGFR have been identified in 10% to 20% of 
patients with NSCLC—the EGFR kinase inhibitors gefitinib and 
erlotinib have demonstrated activity in these patients.  However, the 
clinical efficacy of gefitinib and erlotinib is ultimately limited by the 
development of resistance, such as by mutation in the EGFR kinase 
domain gatekeeper residue (T790M), which occurs in 50% of patients 
(Yun, 2008; Suda, 2010).  Second-generation agents capable of 
inhibiting the T790M mutant form are in development, but can exhibit 
toxicity due to co-inhibition of native (endogenous) EGFR, suggesting 
that a T790M-selective agent will be required.
To address limitations of existing inhibitors of ALK and EGFR, ARIAD 
is developing AP26113, a novel, synthetic, orally-active tyrosine kinase 
inhibitor (TKI).  AP26113 potently inhibits activated forms of ALK and 
EGFR, as well as mutated resistant forms of both proteins, including the 
respective L1196M and T790M gatekeeper variants.  Notably, AP26113 
does not inhibit native EGFR. In addition, its spectrum of kinase 
inhibitory activity includes other targets potentially important in 
oncogenesis.  In in vitro assays, AP26113 also inhibits the activity of 
ROS1, FAK, and CHK2 kinases.
Based on the promising activity profile of AP26113 in vitro and in vivo, 
as well as its pharmacologic profile, this phase 1/2 clinical trial of the 
agent is the first assessment of AP26113 in patients.  The trial will be 
conducted in 2 parts: a dose escalation phase, followed by an expansion 
phase.
The patient population of the initial dose escalation phase of the trial 
will include patients with advanced malignancies, all histologies other 
than leukemia, refractory to available therapies or for whom no standard 
or available curative treatments exist.  The objectives will be to 
determine the safety, tolerability, pharmacokinetic profile, and 
recommended phase 2 dose (RP2D) of orally administered AP26113 in 
these patients. The RP2D is the maximum tolerated dose (MTD) or 
less.  An RP2D less than the MTD may be chosen if aspects of 
tolerability not encompassed by the MTD determination suggest 
utilizing a lower dose.  
The expansion phase will include 5 histologically and molecularly 
defined cohorts, with cohort 5 being limited to patients with active brain 
metastases.  The dose and schedule for the expansion cohorts will be 
determined based on the RP2D and schedule determined in the dose 
escalation phase of the trial.  The decision to open the expansion cohorts 
will be based on an assessment of safety and preliminary anti-tumor 
activity from the dose escalation cohort.  The 5 expansion cohorts are as 
follows:
1. NSCLC patients with ALK rearrangements who are naive to 
prior ALK inhibitor therapy;
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1.
Histologically confirmed advanced malignancies.  All 
histologies except leukemia;
2.
Refractory to available therapies or for whom no standard or 
available curative treatments exist;
3.
Tumor tissue available for analysis.  Patients with less tissue 
than required can be enrolled only with prior approval from 
the Sponsor.  
Part 2: Expansion cohorts (5 additional cohorts):
1.
Expansion cohort 1: NSCLC patients whose tumors exhibit 
ALK rearrangements and who have not been treated with 
previous ALK inhibitors:
i.
Histologically or cytologically confirmed 
NSCLC;
ii.
Tumor tissue available for analysis (see General 
Eligibility Criterion 1);
iii.
History of ALK rearrangement by FISH;
iv.
No prior ALK inhibitor therapy.
2.
Expansion cohort 2: NSCLC patients whose tumors exhibit 
ALK rearrangements and who are resistant to crizotinib:
i.
Histologically or cytologically confirmed 
NSCLC;
ii.
Tumor tissue available for analysis (see General 
Eligibility Criterion 1);
iii.
History of ALK rearrangement by FISH;
iv.
Resistant to crizotinib (and have not received any 
other prior ALK inhibitor therapy).
3.
Expansion cohort 3: NSCLC patients whose tumors exhibit 
an EGFR-T790M mutation and who are resistant to 1 prior 
EGFR TKI:
i.
Histologically or cytologically confirmed 
NSCLC;
ii.
Previous treatment with only 1 EGFR TKI for 
which the last administration was within 30 days 
of the initiation of AP26113;
iii.
Documented evidence of an EGFR-T790M
mutation following disease progression on the 
most recent EGFR TKI therapy;
iv.
No intervening systemic therapy between 
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cessation of the EGFR TKI and initiating
AP26113;
v.
Tumor tissue available for analysis (see General 
Eligibility Criterion 1). 
4.
Expansion cohort 4: Patients with any cancers with 
abnormalities in ALK or other AP26113 targets.  Examples 
include, but are not limited to, ALCL, DLCL, IMT, and other 
cancers with ALK abnormalities, or tumors with ROS1
fusions:
i.
Histologically confirmed lymphomas and other 
cancers, with the exception of leukemias;
ii.
Tumor tissue available for analysis (see General 
Eligibility Criterion 1).
5.
Expansion cohort 5: NSCLC patients whose tumors exhibit 
ALK rearrangements and who have active, measurable brain 
metastases:
i.
Histologically or cytologically confirmed 
NSCLC;
ii.
Tumor tissue available for analysis (see General 
Eligibility Criterion 1);
iii.
History of ALK rearrangement by FISH;
iv.
Either crizotinib naive or resistant;
v.
Have at least one measurable brain lesion (≥10 
mm by contrast enhanced, T1 weighted magnetic 
resonance imaging [cMRI]).  Previously treated 
brain lesions by stereotactic radiosurgery (SRS) 
or surgical resection should not be included as a 
target or non-target lesion;
vi.
Previously untreated brain metastases or 
previously treated brain metastases with 
radiologically documented new or progressing 
brain lesions.  Unequivocal progression of 
previously treated lesions (non-SRS and non-
surgically treated lesions) at least 3 months after 
the last treatment; 
vii.
Neurologically stable.  Patients must be on a 
stable or decreasing dose of corticosteroids 
and/or have no requirement for anticonvulsants 
for 5 days prior to the baseline MRI and for 5 
days prior to initiating AP26113. 
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General Eligibility Criteria
All patients must meet all the following eligibility criteria for study 
entry.
1.
All patients must have tumor tissue available for analysis.  If 
sufficient tissue is not available, patients must undergo a 
biopsy to obtain adequate samples.  For patients in expansion 
cohorts 2, 3, and 5, for whom failure of prior therapy is 
specified (crizotinib for cohorts 2 and 5, one EGFR-TKI for 
cohort 3), tumor tissue must be available following failure of 
the prior therapy.  Requirements are provided in Section 5.1.  
Patients with less tissue than required can be enrolled only
with prior approval from the Sponsor.
2.
Must have measurable disease by RECIST.
3.
Male or female patients ≥18 years old.
4.
Eastern Cooperative Oncology Group (ECOG) performance 
status 0 or 1.
5.
Minimum life expectancy of 3 months or more.
6.
Adequate renal and hepatic function as defined by the 
following criteria:
i.
Total serum bilirubin ≤2 x upper limit of normal (ULN);
ii.
Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤2.5 x ULN (or ≤5 x ULN if 
liver function abnormalities are due to underlying 
malignancy);
iii.
Serum creatinine < 2 x ULN;
iv.
Serum albumin ≥2 g/dL.
7.
Adequate bone marrow function as defined by the following 
criteria:
i.
Absolute neutrophil count (ANC) ≥1500/µL;
ii.
Platelets ≥75,000/µL;
iii.
Hemoglobin ≥9.0 g/dL.
8.
Normal QT interval on screening electrocardiogram (ECG) 
evaluation, defined as QTcF of ≤450 ms in males or 
≤470 ms in females.
9.
For females of childbearing potential, a negative pregnancy 
test must be documented prior to enrollment.
10.
Female patients who are of childbearing potential and fertile 
male patients must agree to use an effective form of 
contraception with their sexual partners throughout study 
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participation.
11.
Signed and dated informed consent indicating that the patient 
has been informed of all pertinent aspects of the study.
12.
Willingness and ability to comply with scheduled visits and 
study procedures.
Main Exclusion 
Criteria
1.
Received an investigational agent ≤14 days prior to initiating 
AP26113.
2.
Received systemic anticancer therapy (including monoclonal 
antibodies and irreversible TKIs such as afatinib or 
dacomitinib) or radiation therapy ≤14 days prior to initiating 
AP26113.
a.
Except for a reversible EGFR TKI (ie, erlotinib or 
gefitinib) or crizotinib, which are allowed up to 72 hours 
prior to initiating AP26113, provided that the patient is 
free of treatment-related toxicity that might confound 
the safety evaluation of AP26113. 
3.
Received any prior agents targeted against ALK, with the 
exception of crizotinib, or received more than 1 prior EGFR 
TKI. 
a.
Re-challenge with the same TKI is allowed. 
4.
Major surgery within 28 days prior to initiating AP26113.
5.
Brain metastases that are neurologically unstable or require
anticonvulsants or an increasing dose of corticosteroids.   
a.
Patients with previously treated brain metastases without 
evidence of disease or recurrence are allowed for 
cohorts 1-4.
b. Patients with evaluable but non-measurable, active brain
lesions who otherwise meet the criteria for cohort 5 for 
CNS disease can be enrolled in other cohorts. 
6.
Significant uncontrolled or active cardiovascular disease, 
specifically including, but not restricted to:
a.
Myocardial infarction or unstable angina within 
3 months prior to first dose of AP26113;
b.
Any history of congestive heart failure within 3 months 
prior to first dose of AP26113;
c.
History of clinically significant (as determined by the 
treating physician) atrial arrhythmia or any ventricular 
arrhythmia.
7.
Uncontrolled hypertension (Diastolic blood pressure [BP] 
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> 100 mm Hg; Systolic > 150 mm Hg).
8.
Prolonged QTcF interval, or being treated with medications
known to cause Torsades de Pointes (refer to Attachment 4).
9.
History or presence of pulmonary interstitial disease or drug-
related pneumonitis.
10.
Ongoing or active infection.  The requirement for intravenous 
(IV) antibiotics is considered active infection.
11.
Known history of human immunodeficiency virus (HIV).  
Testing is not required in the absence of history.
12.
Pregnant or breastfeeding.
13.
Malabsorption syndrome or other gastrointestinal illness that 
could affect oral absorption of AP26113.
14.
Any condition or illness that, in the opinion of the 
Investigator, would compromise patient safety or interfere 
with the evaluation of the safety of the drug.
15.
Leptomeningeal carcinomatosis and spinal cord compression.  
In the case of suspected meningeal involvement, a negative 
lumbar puncture prior to study entry is required.  
Approximate Number 
of Patients
Approximately 110 to 175 patients total study
1.
Dose escalation cohort

Approximately 6 dose levels = 30 to 70 patients
2.
Expansion cohorts

1 = NSCLC ALK inhibitor naive = approximately 
20 patients

2 = NSCLC ALK inhibitor resistant = approximately 
50 patients

3 = NSCLC EGFR-T790M and resistant to 1 prior 
EGFR TKI = approximately 20 patients

4 = Other cancers with ALK and/or ROS1 positivity = 
approximately 20 patients

5 = ALK+ NSCLC with active brain metastases = 
approximately 25 patients
Approximate 
Duration of Patient 
Participation
The expected total duration of patient participation is approximately 
2 years, including a 2- to 3-week screening period, an estimated average 
of 10 to 12 cycles (28 days each) of AP26113 in responding patients 
(participation for patients who do not respond will most likely be of 
shorter duration), and the 30-day after treatment discontinuation 
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assessments.  Overall survival (OS) will also be measured at least every 
3 months, for up to 2 years following the first dose.
Approximate 
Duration of Study
The total estimated duration of the study is 4 years, including 24 months 
to accrue patients with 2 years for treatment and follow-up for the last 
patient.  Patients who are still on study at 2 years will be allowed to 
receive study drug beyond 2 years until disease progression or they 
discontinue treatment for other reasons.
Approximate Number 
of Study Centers
Approximately 10 centers
Dosage and 
Administration
Based on preclinical 28-day toxicity data generated in rodents and 
non-human primates, the proposed starting dose of AP26113 in this 
phase 1/2 trial is 30 mg administered orally once daily.
The dose escalation phase of this phase 1/2 trial will employ sequential 
dose escalation of oral AP26113 using a standard 3+3 design, starting at 
30 mg administered orally once daily, and increasing in increments until 
the MTD is identified.  The initial planned dose level cohorts are 30 mg, 
60 mg, 90 mg, and 120 mg once daily oral doses of AP26113.  Further 
dose escalation will involve increments of no more than 50% of the 
previous dose depending on safety findings.  Multiple doses (eg, twice 
daily) may be administered daily based on PK findings (eg, half-life 
[t1⁄2]) for the initial patients.
The number of patients in each dose level cohort may vary depending 
on the events of the study, but cohorts will have a minimum of 
3 patients enrolled.  At each dose level, 3 patients will be enrolled 
initially and followed for 28 days.  Increasing to the next dose level will 
depend on the safety findings of the previous cohort.  If no DLTs are 
observed, the next higher cohort will begin enrollment.  Expansion of a 
cohort from 3 to 6 patients will occur if 1 of 3 patients experiences a 
DLT at a given dose. Expansion may also occur at any dose to confirm 
safety observations.  Standard definitions of DLT and MTD will be 
employed.  The maximum administered dose in the trial will likely 
exceed the MTD.  Intermediate doses between the MTD and the next 
lower dose may be explored.  Schedules for single or multiple dosing of 
AP26113 in a given period may be explored depending on PK findings.  
Intra-patient dose escalation will be allowed according to the following 
scheme.  All patients will have the option to increase dose while on 
study if the following conditions are met: 1) the patient tolerated his/her
starting dose without a DLT and s/he remains on study without disease 
progression, 2) the Cycle 2 PK samples have been drawn per protocol, 
and 3) the proposed next dose level has been evaluated and it has been 
shown that it does not exceed the MTD.
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Concomitant 
Treatment
Palliation and supportive care are permitted during the course of the 
trial for management of symptoms and underlying medical conditions 
that may develop during the study.  The inclusion and exclusion criteria 
should be used to determine which medications a patient is allowed to 
be on at the time of screening and study entry.  Once a patient has 
begun treatment, a condition may arise that requires the initiation of a 
new concomitant treatment.  After a patient has begun the study, the 
addition of the following concurrent medications are prohibited:
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);
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 Attachment 4).  
Medications that prolong the QT interval, but are not known to 
be associated with Torsades, should be avoided, but are not 
prohibited;
4. Herbal preparations or related over-the-counter preparations 
containing herbal ingredients;
5. Extensive surgery requiring in-patient care (patients may have 
an interruption in therapy for 14 days should emergency surgery 
be required).
Patients should avoid using AP26113 in combination with other agents 
known to cause bradycardia (eg, beta-blockers, non-dihydropyridine 
calcium channel blockers, clonidine, and digoxin).  The investigator or 
qualified designee should also educate patients not to start on any over-
the-counter (OTC) medications, herbal or prescription medications that 
may affect heart rate, and to consult with the investigator prior initiating 
any therapy.
Medications that are potent inhibitors or inducers of p450 cytochromes, 
in particular CYP2C8 and CYP3A4, should be avoided.
Safety Evaluation
Safety assessments will include physical and laboratory examinations, 
vital signs, and ECGs.  Adverse events (AEs) will be graded according 
to the National Cancer Institute (of the United States) Common 
Terminology Criteria for Adverse Events (NCI CTCAE v 4.0; see 
Attachment 1).  Periodic meetings with study investigators will be held 
to assess safety throughout the trial.
All patients receiving at least 1 dose of AP26113 will be considered 
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evaluable for safety.  The AE incidence rates, as well as the frequency 
of occurrence of overall toxicity, categorized by toxicity grades 
(severity), will be described.  Listings of laboratory test results will also 
be generated, and descriptive statistics summarizing the changes in 
laboratory tests over time will be presented.
Maximum Tolerated Dose (MTD)
The MTD is defined as the highest dose at which ≤1 of 6 evaluable 
patients experience a DLT within the first 28 days of treatment (end of 
cycle 1).  Evaluable patients must complete at least 75% of their 
planned doses, unless missed doses are due to AEs.  The cohort may be 
expanded to better define the safety profile for confirmation of the 
MTD.  The maximum administered dose in the trial will likely exceed 
the MTD.
Dose-Limiting Toxicities (DLTs)
Standard AEs will be considered DLTs that count for the determination 
of the MTD of AP26113.  A DLT is a drug-related toxicity that is 
observed to occur within the first 28 days of treatment (end of cycle 1) 
as defined below.  Drug-related toxicities include any toxicity that is
possibly, probably, or definitely drug-related.  Toxicity grades will be 
defined by the NCI CTCAE v 4.0.  DLTs are defined by the following:

Non-hematologic toxicities:
i.
Any grade ≥3 non-hematologic toxicity, with the 
exception of self-limiting or medically controllable 
toxicities (eg, nausea, vomiting, fatigue, electrolyte 
disturbances, hypersensitivity reactions) lasting < 3 days, 
and excluding alopecia. 

Hematologic toxicities:
i.
Febrile neutropenia not related to underlying disease 
(fever, > 101°F [> 38.3°C]; ANC < 500);
ii.
Prolonged grade 4 neutropenia (> 7 days);
iii.
Neutropenic infection: ≥grade 3 neutropenia with 
≥grade 3 infection;
iv.
Thrombocytopenia ≥grade 3 with bleeding or grade 4 
lasting ≥7 days.

Missed ≥25% of planned doses of AP26113 over 28 days due to 
treatment-related AEs in the first cycle.
QT Interval 
Evaluation
The following ECG assessments will be required.  Triplicate ECGs at 
Cycle 1, Day 1 before the first dose of AP26113.  Triplicate ECGs on 
Cycle 2, Day 1 (Day 29) prior to administration of the Cycle 2, Day 1 
dose, and at 1, 2, 4, and 6 hours after dosing of AP26113.  ECGs will be 
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this design, the estimate of the rate of DLT at the MTD is in the range 
of 0.17 to 0.26.  The estimate of the rate of DLT at the highest dose, 
which is 1 step above the MTD, is 0.33 (Ting, 2006).
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TABLE OF CONTENTS
PROTOCOL REVISION HISTORY:.........................................................................................1
DISCLOSURE STATEMENT .....................................................................................................2
PROTOCOL APPROVAL PAGE ...............................................................................................3
Investigator Signature .......................................................................................................4
Sponsor Representative Signature ...................................................................................5
PROTOCOL SYNOPSIS..............................................................................................................7
LIST OF ABBREVIATIONS .....................................................................................................26
DEFINITIONS OF TERMS .......................................................................................................29
1
INTRODUCTION.......................................................................................................35
1.1
Background......................................................................................................35
1.2
AP26113 ...........................................................................................................35
1.2.1
Preclinical Pharmacology...................................................................35
1.2.2
Preclinical Absorption, Distribution, Metabolism and 
Excretion (ADME) ..............................................................................36
1.2.3
Preclinical Toxicology.........................................................................37
1.2.4
Starting Dose Rationale......................................................................38
1.2.5
Clinical .................................................................................................39
1.3
Study Rationale ...............................................................................................39
2
STUDY OBJECTIVES...............................................................................................39
3
STUDY DESIGN.........................................................................................................40
3.1
Overall Study Design and Plan......................................................................40
4
SELECTION OF STUDY POPULATION...............................................................41
4.1
Inclusion Criteria ............................................................................................42
4.1.1
Cohort Eligibility Criteria..................................................................42
4.1.2
General Eligibility Criteria ................................................................43
4.2
Exclusion Criteria ...........................................................................................44
5
STUDY PROCEDURES.............................................................................................45
5.1
Study Procedure Descriptions........................................................................46
5.2
Screening Period..............................................................................................51
5.3
Screen Failures ................................................................................................51
5.4
Active Study Period ........................................................................................51
5.5
End of Treatment............................................................................................51
5.6
30 Days after End of Treatment ....................................................................52
5.7
Follow-up Period.............................................................................................52
5.8
Study Duration ................................................................................................52
5.9
Patient Discontinuation ..................................................................................52
5.10
Study or Site Termination..............................................................................53
5.11
Sample Collection, Storage, and Shipping....................................................54
6
STUDY TREATMENT(S) .........................................................................................54
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6.1
Study Drug.......................................................................................................54
6.2
Selection of Starting Dose...............................................................................54
6.3
Treatment Administration .............................................................................54
6.4
Dose Escalation................................................................................................54
6.4.1
Intra-Patient Dose Escalation ............................................................56
6.4.2
Maximum Tolerated Dose (MTD).....................................................56
6.4.3
Dose-Limiting Toxicities (DLTs) .......................................................56
6.5
Dose Modification(s) .......................................................................................57
6.5.1
Dose Re-escalation...............................................................................58
6.6
Initiation of Expansion Phase Enrollment....................................................58
6.7
Prior and Concomitant Medications.............................................................58
6.8
Prohibited Treatment(s)/Therapy .................................................................58
6.9
Treatment Compliance...................................................................................59
6.10
Treatment(s) Supply .......................................................................................59
6.10.1
Formulation, Packaging, and Labeling.............................................59
6.10.2
Preparation and Dispensing...............................................................60
6.10.3
Treatment(s) Storage and Accountability.........................................60
7
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .................................60
7.1
Definitions........................................................................................................60
7.1.1
Adverse Event......................................................................................60
7.1.2
Serious Adverse Event........................................................................61
7.1.2.1
Progression of the malignancy under study (including 
signs and symptoms of progression)........................................62
7.1.2.2
Hospitalizations........................................................................62
7.1.3
Abnormal Test Findings.....................................................................63
7.1.4
Expectedness........................................................................................63
7.2
Evaluation of Adverse Events and Serious Adverse Events .......................63
7.2.1
Adverse Event Severity.......................................................................63
7.2.2
Causality ..............................................................................................64
7.3
Serious Adverse Event Reporting Procedures .............................................65
7.3.1
Serious Adverse Event Reporting Period .........................................65
7.3.2
Reporting Serious Adverse Events ....................................................65
7.3.3
Information to be Provided by the Investigator for a Serious 
Adverse Event......................................................................................66
7.3.4
Follow-up Information on a Serious Adverse Event........................66
7.3.5
Required Follow-up for Serious Adverse Events.............................66
7.4
Sponsor Responsibility for Expedited Safety Reports.................................66
7.5
Other Safety Issues..........................................................................................67
7.5.1
Pregnancy ............................................................................................67
8
PLANNED STATISTICAL METHODS..................................................................67
8.1
General Considerations ..................................................................................67
8.1.1
Termination of Study..........................................................................68
8.2
Study Endpoint(s) ...........................................................................................68
8.2.1
Primary Endpoint(s)...........................................................................68
8.2.2
Secondary Endpoint(s) .......................................................................68
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8.2.3
Other Endpoints..................................................................................69
8.3
Determination of Sample Size........................................................................69
8.4
Definition of Analysis Populations.................................................................69
8.5
Efficacy Analysis .............................................................................................69
8.6
Safety Analysis.................................................................................................70
8.6.1
Pharmacokinetic Analysis ..................................................................70
8.6.2
QTcF Analysis .....................................................................................70
8.7
Protocol Deviations/Violations.......................................................................70
9
QUALITY CONTROL AND QUALITY ASSURANCE........................................71
9.1
Investigators and Study Administrative Structure......................................71
9.2
Study Monitoring ............................................................................................71
10
ETHICAL CONDUCT OF THE STUDY ................................................................72
10.1
Institutional Review Board (IRB) or Ethics Committee (EC) Approval...72
10.2
Patient Information and Consent ..................................................................72
10.3
Patient Confidentiality....................................................................................72
11
DATA HANDLING AND RECORD KEEPING.....................................................73
11.1
Case Report Forms and Study Records........................................................73
11.2
Access to Source Documentation...................................................................73
11.3
Retention of Data.............................................................................................73
12
PUBLICATION AND DISCLOSURE POLICY .....................................................73
13
REFERENCES............................................................................................................75
TABLE OF TABLES
Table 1
Schedule of Events ......................................................................................................32
Table 2
Dose Modifications for Non-hematologic/Hematologic Toxicity or Pneumonitis 
Events ...........................................................................................................................57
Table 4.1 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.............................................................................................................................79
TABLE OF FIGURES
Figure 1 Schematic of AP26113 Phase 1/2 Trial Design – Dose Escalation and Expansion 
Phases ...........................................................................................................................41
Figure 2 Schematic of AP26113 Phase 1/2 Trial Design – Dose Escalation Phase ...............55
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LIST OF ATTACHMENTS
ATTACHMENT 1
NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (NCI 
CTCAE) ....................................................................................................76
ATTACHMENT 2
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS ...................................................................77
ATTACHMENT 3
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST VERSION 1.1).........................................................................78
ATTACHMENT 4
DRUGS WITH A RISK OF TORSADES DE POINTES ....................79
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LIST OF ABBREVIATIONS
Abbreviation
Term
ADME
absorption, distribution, metabolism, excretion
AE
adverse event
ALCL
anaplastic large cell lymphoma
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ARIAD
ARIAD Pharmaceuticals, Inc.
AST
aspartate aminotransferase
AUC
area under the curve
ß-HCG
beta-human chorionic gonadotropin
BP
blood pressure; blast phase
BUN
blood urea nitrogen
CBC
complete blood count
cDNA
complementary deoxyribonucleic acid
cGMP
current Good Manufacturing Practice
CI
confidence interval
Cmax
maximum concentration
CML
chronic myeloid leukemia
CNS
central nervous system
CPK
creatine phosphokinase
CR
complete response
CT
computed tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DDI
drug-drug interaction
DLCL
diffuse large-cell lymphoma
DLT
dose-limiting toxicity
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDTA
ethylenediaminetetraacetic acid
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
FFPE
FISH
Fixed-formalin paraffin-embedded 
Fluorescence In Situ Hybridization
FDA
Food and Drug Administration (United States)
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HDPE
high density polyethylene
HIV
human immunodeficiency virus
HPFB
Canadian Health Products and Food Branch
IC50
50% inhibitory concentration
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Abbreviation
Term
IND
Investigational New Drug
ICH
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (formerly known as
International Conference on Harmonisation)
ICJME
International Committee of Medical Journal Editors
IMT
inflammatory myofibroblastic tumors
INR
International Normalized Ratio
IRB
Institutional Review Board
IV
intravenous
LD50
lethal dose, 50%; dose required to kill half of the tested population
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
ms
millisecond
MTD
maximum tolerated dose
NCI
National Cancer Institute (of the United States)
NCI CTCAE, v.4
NCI Common Terminology Criteria for Adverse Events, version 4.0
NSCLC
non-small cell lung cancer
OS
overall survival
PCR
PD
polymerase chain reaction
progressive disease
PDGFR
platelet-derived growth factor receptor
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
QD
every day
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
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SD
standard deviation, stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
SRS
serum glutamic pyruvic transaminase
stereotactic radiosurgery
STD10
dose that is severely toxic to 10% of tested rodents
t1/2
half-life
TGA
Australian Therapeutic Goods Administration
TKI
tyrosine kinase inhibitor
Tmax
time of maximum concentration
TTP
time-to-progression
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Abbreviation
Term
ULN
upper limit of normal
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DEFINITIONS OF TERMS
Term
Definition
Active Study 
Period
The Active Study Period for a patient begins with administration of the 
first dose of study drug and continues through 30 days following 
discontinuation of study drug.
Suspected Adverse 
Reaction
A Suspected Adverse Reaction is any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  For the 
purposes of Investigational New Drug (IND) safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship 
between the drug and the adverse event.
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
The 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.
30 Days After End 
of Treatment
At 30 Days After End of Treatment, a patient completes all post-treatment 
discontinuation assessments.
End of Trial
The End of Trial (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.
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Term
Definition
Follow-up Period
The Follow-up Period for a patient begins after the last completed 
assessment during the active study period 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.
On-Study Period
The On-Study Period for a patient begins with the signing of the informed 
consent form and concludes 30 days following the last dose of study drug.
Patient
Throughout this document the term Patient refers to a patient in this 
clinical research study.
QTcF
For the purposes of this study, the corrected (Fridericia) QT interval is 
calculated using the following formula: 
QTcF = QT interval/3√RR interval.
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), the Good Clinical Practice: 
Consolidated Guideline (Canada), the International Conference on 
Harmonisation Guideline for Good Clinical Practice, the Therapeutic 
Goods Administration Annotated International Conference on 
Harmonisation Guidelines (Australia), 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 
appropriate health and regulatory agencies. These may be international, 
national, or local and may include but not be limited to the Australian 
Therapeutic Goods Administration (TGA), the Canadian Health Products 
and Food Branch (HPFB), the 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 appropriate 
research departments within ARIAD Pharmaceuticals, Inc., or its designee.
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Term
Definition
Study 
Administrative 
Manual
In the context of this study, Study Administrative Manual is a general term 
for the information provided to sites on technical aspects of the trial. 
Study Drug
A Study Drug is any drug, device, biological agent, or comparator 
(including placebo) used in the Sponsor’s clinical research and 
development studies. 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.
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1
INTRODUCTION
1.1
Background
Specific genetic lesions that drive the proliferation of cancer cells, such as those causing 
activation of certain tyrosine kinases, render some cancers highly sensitive to therapeutic agents 
that inhibit the kinase.  However, the efficacy of such agents is often limited by the development 
of mutations in the target kinase domain that confer resistance by reducing inhibitor binding.  For 
example, the ABL kinase inhibitor imatinib has revolutionized treatment for patients with 
chronic myeloid leukemia (CML), whose disease is driven by an activated BCR-ABL fusion 
oncoprotein.  Over time, however, development of mutations in the ABL kinase domain confers 
resistance in a substantial proportion of patients.  The second-generation ABL inhibitors 
dasatinib and nilotinib, by virtue of being more potent inhibitors of ABL, demonstrate superior 
efficacy, and are able to overcome much of the mutation-based resistance exhibited by imatinib.  
More recently, genetic lesions in 2 other tyrosine kinases, anaplastic lymphoma kinase (ALK) 
and the epidermal growth factor receptor (EGFR) have been identified that show a similar 
pattern of sensitivity to first-generation inhibitors and susceptibility to mutation-based resistance.
Activating gene rearrangements or mutations in ALK have been identified as driver mutations in 
some patients with non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma 
(ALCL), diffuse large-cell lymphoma (DLCL), inflammatory myofibroblastic tumors (IMT), 
neuroblastoma, and other cancers.  Crizotinib, an ALK kinase inhibitor, has demonstrated 
promising clinical activity in NSCLC, ALCL, and IMT patients harboring ALK translocations 
(Butrynski, 2010; Kwak, 2010; Gambacorti-Passerini, 2011).  However, emerging data suggest 
that mutations in the kinase domain of ALK, including at the gatekeeper residue (L1196M), can 
confer resistance to crizotinib (Choi, 2010).  Therefore, an ALK inhibitor that is more potent 
than crizotinib may be required to overcome such resistance.
Activating mutations in EGFR have been identified in 10% to 20% of patients with NSCLC—the 
EGFR kinase inhibitors gefitinib and erlotinib have demonstrated activity in these patients.  
However, the clinical efficacy of gefitinib and erlotinib is ultimately limited by the development 
of resistance, such as by mutation in the EGFR kinase domain gatekeeper residue (T790M), 
which occurs in 50% of patients (Yun, 2008; Suda, 2010).  Second-generation agents capable of 
inhibiting the T790M mutant form are in development, but can exhibit toxicity due to 
co-inhibition of native (endogenous) EGFR, suggesting that a T790M-selective agent will be 
required.
1.2
AP26113
AP26113 is a novel, synthetic, orally-active tyrosine kinase inhibitor (TKI), discovered and 
developed by ARIAD Pharmaceuticals Inc (the Sponsor).  AP26113 will be developed in cancers 
that carry molecularly defined targets against which the agent is shown to have activity.
1.2.1
Preclinical Pharmacology
A series of in vitro and in vivo studies have been performed to characterize the 
pharmacodynamic profile of AP26113.  These studies have demonstrated that the compound 
potently inhibits activated variants of ALK and EGFR such as EML4-ALK and EGFR-L858R.  
Moreover, AP26113 potently inhibits variants of ALK and EGFR that contain additional 
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ARIAD Pharmaceuticals, Inc.
AP26113-11-101
Version 8.0 20 March 2017
Page 39 of 83
rodents, the starting dose in humans would be somewhat higher than 30 mg/day.  Therefore, the 
selected initial dose of 30 mg/day (approximately 18 mg/m2) represents a conservative and 
reasonably safe starting dose for the phase 1/2 clinical trial.  In addition, this 30 mg/day dose is 
5 times lower than the well tolerated dose of 90 mg/m2/day (7.5 mg/kg/day) in the 28-day study 
in cynomolgus monkeys.
1.2.5
Clinical
There is no previous investigational or marketed product human experience with AP26113.
1.3
Study Rationale
To address limitations of existing inhibitors of ALK and EGFR, initial development focus for 
AP26113 will be in NSCLC with ALK gene rearrangements or EGFR gene activating and 
resistance mutations.  AP26113 potently inhibits activated forms of ALK and EGFR, as well as 
mutated resistant forms of both proteins, including the respective L1196M and T790M 
gatekeeper variants.  Notably, AP26113 does not inhibit native EGFR.  In addition, its spectrum 
of kinase inhibitory activity includes other targets potentially important in oncogenesis.  In in 
vitro assays, AP26113 also inhibits the activity of ROS1, FAK, and CHK2 kinases.
Based on the promising activity profile of AP26113 in vitro and in vivo, as well as its 
pharmacologic profile, this phase 1/2 clinical trial of the agent will be conducted in 2 parts: a 
dose escalation phase, followed by an expansion phase.  The dose escalation phase will establish 
the safety, tolerability, and pharmacokinetic profile of AP26113, along with a recommended 
phase 2 dose (RP2D) and schedule of orally administered AP26113 for use in the expansion 
phase.  The expansion phase will include 5 histologically and molecularly defined cohorts based 
on the known preclinical activity profile of AP26113, with emphasis on its ALK and EGFR 
inhibitory properties in the NSCLC setting. 
Activity of AP26113 in patients with brain metastases is an important consideration for this 
therapy, given the critical unmet medical need CNS progression represents in patients treated 
with crizotinib (Camidge et al., 2012). Patients with brain metastases from NSCLC typically do 
not respond to crizotinib due to low penetration of the drug into the CNS (Camidge et al., 2012). 
Furthermore, prognosis for these patients is poor (survival of less than one year).  Preliminary 
clinical CNS activity has been observed in patients with ALK+ disease with brain metastases in 
the phase 1 portion of this study.  Thus, the fifth cohort will assess AP26113 activity in ALK+ 
NSCLC patients with active, measurable brain metastases.   
2
STUDY OBJECTIVES
The objectives of this study are:
1. To determine the safety profile of orally administered AP26113 including identification 
of the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs).
2. To determine the RP2D of orally administered AP26113.
3. To examine the pharmacokinetic (PK) profile of AP26113.
4. To describe the preliminary anti-tumor activity of AP26113 in NSCLC with ALK gene 
rearrangement or mutant EGFR activity, and other cancers with abnormal targets.
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CCI


ARIAD Pharmaceuticals, Inc.
Version 8.0 20 March 2017
Figure 1
Schematic
Expansion
4
SELECTION OF ST
An estimated 135 to 175 patients
approximately 30 to 70 patients i
20 patients each in expansion coh
cohort 5.
Part 1
Dose Escalation Phase
c of AP26113 Phase 1/2 Trial Design – Dose E
n Phases
TUDY POPULATION
s are anticipated to enroll at approximately 10 ce
in the dose escalation part of the study, and appr
horts 1, 3, and 4; 50 patients in cohort 2; and 25 
Part 2
Expansion Phase
AP26113-11-101
Page 41 of 83
Escalation and 
enters, including 
roximately 
patients in 
e
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4.1
Inclusion Criteria
4.1.1
Cohort Eligibility Criteria
Patients must meet all the criteria for the cohort for which their entry is proposed.
Part 1: Dose escalation cohort (initial cohort):
1. Histologically confirmed advanced malignancies.  All histologies except 
leukemia;
2. Refractory to available therapies or for whom no standard or available curative 
treatments exist;
3. Tumor tissue available for analysis.  Patients with less tissue than required can be 
enrolled only with prior approval from the Sponsor.  
Part 2: Expansion cohorts (5 additional cohorts)
1. Expansion cohort 1: NSCLC patients whose tumors exhibit ALK rearrangements 
and who have not been treated with previous ALK inhibitors:
i. Histologically or cytologically confirmed NSCLC;
ii. Tumor tissue available for analysis (see General Eligibility Criterion 1);
iii. History of ALK rearrangement by fluorescence in situ hybridization 
(FISH);
iv. No prior ALK inhibitor therapy.
2. Expansion cohort 2: NSCLC patients whose tumors exhibit ALK rearrangements 
and who are resistant to crizotinib:
i. Histologically or cytologically confirmed NSCLC;
ii. Tumor tissue available for analysis (see General Eligibility Criterion 1);
iii. History of ALK rearrangement by FISH;
iv. Resistant to crizotinib (and have not received any other prior ALK 
inhibitor therapy).
3. Expansion cohort 3: NSCLC patients whose tumors exhibit an EGFR-T790M
mutation and who are resistant to 1 prior EGFR TKI:
i.
Histologically or cytologically confirmed NSCLC;
ii.
Previous treatment with only 1 EGFR TKI for which the last 
administration was within 30 days of the initiation of AP26113;
iii.
Documented evidence of an EGFR-T790M mutation following disease 
progression on the most recent EGFR TKI therapy;
iv.
No intervening systemic therapy between cessation of the EGFR TKI 
and initiating AP26113;
v.
Tumor tissue available for analysis (see General Eligibility Criterion 1). 
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4. Expansion cohort 4: Patients with any cancers with abnormalities in ALK or other 
AP26113 targets.  Examples include, but are not limited to, ALCL, DLCL, IMT,
and other cancers with ALK abnormalities, or tumors with ROS1 fusions:
i.
Histologically confirmed lymphomas and other cancers, with the
exception of leukemias;
ii.
Tumor tissue available for analysis (see General Eligibility Criterion 1).
5. Expansion cohort 5: NSCLC patients whose tumors exhibit ALK rearrangements 
and who have active, measurable brain metastases:  
i.
Histologically or cytologically confirmed NSCLC;
ii.
Tumor tissue available for analysis (see General Eligibility Criterion 1);
iii.
History of ALK rearrangement by FISH;
iv.
Either crizotinib naive or resistant;
v.
Have at least one measurable brain lesion (≥ 10 mm by contrast enhanced, 
T1 weighted magnetic resonance imaging [cMRI]).  Previously treated 
brain lesions by stereotactic radiosurgery (SRS) or surgical resection 
should not be included as a target or non-target lesion;
vi.
Previously untreated brain metastases or previously treated brain 
metastases with radiologically documented new or progressing brain
lesions. Unequivocal progression of previously treated lesions (non-SRS
and non-surgically treated lesions) at least 3 months after the last 
treatment;  
vii.
Neurologically stable.  Patients must be on a stable or decreasing dose of 
corticosteroids and/or have no requirement for anticonvulsants for 5 days 
prior to the baseline MRI and for 5 days prior to initiating AP26113. 
4.1.2
General Eligibility Criteria
All patients must meet all the following eligibility criteria for study entry.
1.
All patients must have tumor tissue available for analysis.  If sufficient tissue is not 
available, patients must undergo a biopsy to obtain adequate samples.  For patients in 
expansion cohorts 2, 3, and 5, for whom failure of prior therapy is specified (crizotinib 
for cohorts 2 and 5, one EFGR-TKI for cohort 3), tumor tissue must be available
following failure of the prior therapy.  Requirements are provided in Section 5.1.
Patients with less tissue than required can be enrolled only with prior approval from 
the Sponsor.  
2.
Must have measurable disease by RECIST.
3.
Male or female patients ≥ 18 years old.
4.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5.
Minimum life expectancy of 3 months or more.
6.
Adequate renal and hepatic function as defined by the following criteria:
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i.
Total serum bilirubin ≤ 2 x upper limit of normal (ULN);
ii.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤2.5 x ULN (or ≤ 5 x ULN if liver function abnormalities are due to underlying 
malignancy);
iii.
Serum creatinine < 2 x ULN;
iv.
Serum albumin ≥ 2 g/dL.
7.
Adequate bone marrow function as defined by the following criteria:
i.
Absolute neutrophil count (ANC) ≥ 1500/µL;
ii.
Platelets ≥ 75,000/µL;
iii.
Hemoglobin ≥ 9.0 g/dL.
8.
Normal QT interval on screening electrocardiogram (ECG) evaluation, defined as 
QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
9.
For females of childbearing potential, a negative pregnancy test must be documented 
prior to enrollment.
10.
Female patients who are of childbearing potential and fertile male patients must agree 
to use an effective form of contraception with their sexual partners throughout study 
participation.
11.
Signed and dated informed consent indicating that the patient has been informed of all 
pertinent aspects of the study.
12.
Willingness and ability to comply with scheduled visits and study procedures.
4.2
Exclusion Criteria
Patients are not eligible for participation in the study if they meet or have any of the following 
exclusion criteria:
1.
Received an investigational agent ≤14 days prior to initiating AP26113.
2.
Received systemic anticancer therapy (including monoclonal antibodies and 
irreversible TKIs such as afatinib or dacomitinib) or radiation therapy ≤14 days prior 
to initiating AP26113.
a.
Except for a reversible TKI (ie, erlotinib or gefitinib) or crizotinib, which are
allowed up to 72 hours prior to initiating AP26113, provided that the patient is 
free of treatment-related toxicity that might confound the safety evaluation of 
AP26113. 
3.
Received any prior agents targeted against ALK, with the exception of crizotinib, or 
received more than 1 prior EGFR TKI. 
a.
Re-challenge with the same TKI is allowed. 
4.
Major surgery within 28 days prior to initiating AP26113.
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5.
Brain metastases that are neurologically unstable or require anticonvulsants or an
increasing dose of corticosteroids.   
a.
Patients with previously treated brain metastases without evidence of disease or 
recurrence are allowed for cohorts 1-4. 
b. Patients with evaluable but non-measurable, active brain lesions who otherwise 
meet the criteria for cohort 5 for CNS disease can be enrolled in other cohorts. 
6.
Significant uncontrolled or active cardiovascular disease, specifically including, but 
not restricted to:
a.
Myocardial infarction or unstable angina within 3 months prior to first dose of 
AP26113;
b.
Any history of congestive heart failure within 3 months prior to first dose of 
AP26113;
c.
History of clinically significant (as determined by the treating physician) atrial 
arrhythmia or any ventricular arrhythmia.
7.
Uncontrolled hypertension (Diastolic blood pressure [BP] > 100 mm Hg; Systolic 
> 150 mm Hg).
8.
Prolonged QTcF interval, or being treated with medications known to cause Torsades 
de Pointes (refer to Attachment 4).
9.
History or presence of pulmonary interstitial disease or drug-related pneumonitis.
10.
Ongoing or active infection.  The requirement for IV antibiotics is considered active 
infection.
11.
Known history of human immunodeficiency virus (HIV).  Testing is not required in 
the absence of history.
12.
Pregnant or breastfeeding.
13.
Malabsorption syndrome or other gastrointestinal illness that could affect oral 
absorption of AP26113.
14.
Any condition or illness that, in the opinion of the Investigator, would compromise 
patient safety or interfere with the evaluation of the safety of the drug.
15.
Leptomeningeal carcinomatosis and spinal cord compression.  In the case of suspected 
meningeal involvement, a negative lumbar puncture prior to study entry is required.  
5
STUDY PROCEDURES
The on-study period begins with the signing of the informed consent form and ends 30 days
following the last dose of study drug.  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 active study period begins with administration of the 
first dose of AP26113 and continues through 30 days following discontinuation of AP26113.  
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The follow-up period begins after the last completed assessment during the active study period 
and continues until patient contact discontinues.
5.1
Study Procedure Descriptions
See the Schedule of Events for the required assessments at each visit.  The following list 
describes the procedures/tests required for this study.
1.
Informed consent
Informed consent, documented by a signed consent form, must be obtained prior to any 
screening activities not otherwise part of the patient’s care.
2.
Demographics
Demographic information consists of the patient’s age, gender, race, and ethnicity (as 
allowed by local law and regulations).
3.
Medical and Surgical History
Medical and surgical history includes diagnoses, procedures, smoking history, medical and 
surgical treatments, and current medications.
4.
Prior Cancer Therapy
Prior cancer therapy history consists of the specific oncologic regimens a patient has 
received, the dates of the regimen and the best response to the regimen, and the reason for 
failure or intolerance to each regimen.  Stem cell transplant or experimental or 
investigational therapy history must also be recorded.
5.
Diagnosis
The initial cancer diagnosis and the current cancer diagnosis at the time of screening (if 
different), along with dates of diagnosis and tumor histology, need to be recorded.  
6.
Mutation Status
Regarding current and past ALK and EGFR 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 IHC, ALK point 
mutations, activating or resistance mutations or deletions of EGFR, and other mutations).  
For patients entering cohort 3, documentation of the EGFR-T790M mutation is required,
following progression on the most recent EGFR-TKI treatment course. 
7.
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.  Subsequent physical examinations may be 
directed to relevant findings.  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.
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8.
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.
9.
Pulse Oximetry
Pulse oximetry assessments will be taken at screening, prior to the first dose, and 
approximately 4 and 24 hours after the first dose.  Pulse oximetry will only be performed 
on patients enrolled in the dose escalation portion (phase 1) of the study.
10.
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 Attachment 2.
11.
Hematology
Hematology measurements include complete blood count (CBC) with differential and 
platelet count.
12.
Serum Chemistry
Serum chemistry (fasting) consists of a peripheral blood draw with the following 
assessments: sodium, potassium, chloride, bicarbonate (or total carbon dioxide [CO2]), 
blood urea nitrogen (BUN, or urea), albumin and total protein, creatinine, total bilirubin 
(both direct and indirect), ALT (SGPT), AST (SGOT), alkaline phosphatase, magnesium, 
phosphorous, calcium, lactate dehydrogenase (LDH), uric acid, amylase and lipase,
creatine phosphokinase (CPK), and glucose. If non-fasting serum chemistry blood draws 
are taken, this should be noted, along with the time the patient last ate and the reason the 
patient did not fast.
13.
Urinalysis
Urinalysis will include pH, specific gravity, protein, ketones, glucose, urobilinogen, and 
occult blood.
14.
Insulin
Serum insulin and glucose should be measured concurrently. If non-fasting insulin blood 
draws are taken, this should be noted, along with the time the patient last ate and the reason 
the patient did not fast.
15.
Testosterone Level (males only)
In male patients, serum testosterone should be measured at Cycle 1, Day 1 and per the 
Schedule of Events throughout the study.
16.
Thyroid-Stimulating Hormone 
Thyroid-stimulating hormone should be measured at Cycle 1, Day 1 and per the Schedule 
of Events throughout the study.
17.
Prothrombin Time (PT) and Partial Thromboplastin Time (PTT)
PT and PTT will be expressed as an International Normalized Ratio (INR) or in seconds.
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18.
Electrocardiogram (ECG)
All ECGs must be 12-lead ECGs.  An ECG is required at screening to determine 
eligibility – this may be a single ECG.  Triplicate ECGs must be taken on Cycle 1, Day 1
before the first dose of AP26113.  Triplicate ECGs must be taken on Cycle 2, Day 1 (Day 
29) prior to administration of the Cycle 2, Day 1 dose, and at 1, 2, 4, and 6 hours after 
dosing of AP26113.  Triplicate ECGs should be taken 1 to 2 minutes apart over a 5 minute 
timeframe.  ECG measurements should coincide with the PK measurements that have the 
same time points.  As such, triplicate ECGs should be taken directly before obtaining the 
PK sample at the allotted time points on Cycle 1, Day 1 and Cycle 2, Day 1.  Subsequent 
ECGs (after Cycle 2, Day 1) only need to be done once.
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).
ECGs will be recorded electronically and will be evaluated centrally.  For consistency, the 
Fridericia correction – QTcF – method must be used for all calculating of QTc intervals.
19.
Safety Assessments – Adverse Events
Patients must be followed for all adverse events (AEs) from the date the informed consent 
is signed until at least 30 Days After the End of Treatment, and for all serious or study 
drug-related toxicities until the AEs are resolved or are considered chronic or stable or until
patient contact discontinues.  Serious adverse events (SAEs) should be monitored and 
reported as described in Section 7.
Type, incidence, severity (graded in accordance with the National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.0, see 
Attachment 1), timing, seriousness and relatedness, outcome, action taken with study drug, 
and treatment will be assessed and documented by the investigator throughout the study 
(see Section 7).
Malignancy-related signs and symptoms noted at study entry will be recorded as AEs 
during the trial if they worsen in severity or increase in frequency.
20.
Concomitant Medications
Concomitant medications for all ongoing medical history conditions or AEs must be 
reported from the date the informed consent is signed until at least 30 Days After the End 
of Treatment, and for all concomitant medications related to 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 
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within 7 days prior to first study drug administration. Women of childbearing potential at 
study start must also complete the pregnancy test at the End of Treatment.
22.
Disease Assessment
At screening, disease assessment must include imaging of the chest, abdomen, pelvis and 
brain using appropriate radiological procedures (computed tomography [CT] scan, MRI 
scan) and physical examination (for palpable lesions).  A contrast enhanced brain MRI
(such as gadolinium) is required for all patients at baseline and for patients who have CNS 
metastases at follow-up visits. Target and non-target lesions must be selected at study start 
and followed throughout the course of treatment for response assessment according to 
RECIST guidelines (provided in Attachment 3).  CNS lesions previously treated with SRS 
are not evaluable and should not be selected as either target or non-target lesions. All 
radiographic images (eg, CT scan, MRI) performed during the trial will be submitted to and 
stored by an imaging core lab for future independent evaluation as appropriate. 
Disease assessment will be performed at screening, and at 8-week intervals through Cycle 
15, and at 12-week intervals from Cycle 16 through End of Treatment, for all cohorts, and 
may be limited to sites of disease.  The allowable window for the tumor imaging screening 
assessment is 21 days prior to Day 1.  However, whenever feasible, baseline imaging 
should be performed as close as possible to Cycle 1, Day 1.  Imaging assessment is also 
required to be performed at the End of Treatment.  
Note: RECIST-defined responses will be confirmed with an imaging assessment at a 
4-week interval. For patients in cohort 5, cMRI must reveal at least one measurable brain 
lesion (≥10 mm at the longest diameter) at screening as the target lesion.  All imaging
scans should include a slice thickness of 1 mm, ideally, and up to 5 mm as a maximum.   
23.
Survival
All patients should be followed-up for survival at least every 3 months, up to 2 years after 
the initial dose of AP26113.
24.
Tissue and Research Blood Samples
Screening:
At entry, all patients must provide tumor tissue for analysis of genetic alterations, a blood 
sample as a normal comparator (approximately 3 mL), and a blood sample for analysis of 
circulating tumor DNA in plasma (approximately 20 mL).  Both screening blood samples
may be taken at the same time as the blood samples drawn for screening serum chemistry 
and hematology.  If tumor tissue is not available, the patient must undergo a biopsy to 
obtain an adequate sample.  
Patients entering the study into cohorts for whom failure of a prior TKI therapy is an 
eligibility requirement (expansion cohorts 2, 3, and 5) must have available tumor tissue 
taken after the time of progression on the most recent TKI treatment course. 
Formalin-fixed, paraffin-embedded (FFPE) tumor tissue must be provided as a paraffin 
block or as slide sections. The minimum amount of tumor tissue required is 1 cubic mm, 
with at least 20% nucleated tumor cellularity. Patients with less tissue than required can be 
enrolled only with prior approval from the Sponsor.  
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Active Study Period:
All patients must provide a blood sample (approximately 20 mL) concomitant with each 
disease assessment (ie, at every 8 weeks through Cycle 15, and every 12 weeks from Cycle 
16 through End of Treatment).  Plasma derived from the blood samples will be used to 
quantitatively assess tumor mutations in circulating DNA. 
Post-treatment:
An optional post-treatment biopsy at time of progression (for patients whose best response 
was not progressive disease) will be taken. As at screening, the minimum amount of FFPE
tissue required is 1 cubic mm, with at least 20% nucleated tumor cellularity.
Post-progression tissue will be analyzed at Foundation Medicine to identify mutations that 
may inform treatment decisions following progression on AP26113. The results of these 
tests will be provided to the Investigator and the Sponsor immediately after analysis per the 
testing procedures. 
25.
Cerebrospinal Fluid Sampling
If lumbar puncture (LP) is performed as part of the standard of care, remaining CSF 
samples should be analyzed to determine the concentration of AP26113 (≥ 500 μL is 
sufficient), and these samples should have matched blood samples (for PK analyses) when 
possible. 
26.
PK Sampling
To determine AP26113 and AP26123 (a metabolite of AP26113) plasma levels, 3 mL of 
whole blood will be collected into an EDTA K2 tube (lavender top) as described below and
in the Schedule of Events.
Dose Escalation Phase:
Cycle 1 PK: During Cycle 1, blood samples will be collected immediately prior to the first 
dose (time 0), and 0.5, 1, 2, 4 (± 10 minutes), 6, 8 (± 20 minutes), and 24 hours (± 60 
minutes) after the first dose. The 24-hour sample will be collected prior to drug 
administration on Cycle1, Day 2.  Blood samples will also be collected prior to dosing on 
Cycle 1, Days 8, 15, and 22.
Cycle 2 PK: During Cycle 2, samples will be collected before dosing and 0.5, 1, 2, 4 
(± 10 minutes), 6, 8 (± 20 minutes), 24, and 48 hours (± 60 minutes) after administration of 
AP26113 on Cycle 2, Day 1.  No drug will be administered on Cycle 2, Day 2.  If multiple 
daily doses (eg, BID dosing) are employed, only the first dose on Cycle 2, Day 1 will be 
administered. The 48-hour sample will be collected before administration of the dose on 
Cycle 2, Day 3.  
Cycle 3 PK: A single PK sample will also be collected pre-dose on Cycle 3, Day 1.
Expansion Phase PK: 
PK evaluation will also be performed for the expansion cohorts to obtain cohort-specific 
single-dose and trough PK at the recommended dose established in the dose escalation 
phase of the trial.  PK sampling time points will be the same as the sampling time points in 
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the dose escalation phase; however, adjustments may be made based on the PK findings in 
the dose escalation phase.
5.2
Screening Period
The screening period begins when the informed consent form is signed, and continues until the 
first dose of AP26113 is administered.  Screening assessments should 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.  Screening physical examination, vital signs, ECOG 
Performance Status assessments, hematology, chemistry, insulin, urinalysis and PT/PTT, and 
pregnancy test assessments can each also be used as the Day 1 assessment, without the need for 
having to repeat the tests, if these screening assessments are accomplished within 7 days prior to 
Day 1 AND, in the opinion of the investigator, there is no reason to believe they have 
substantially changed.
Assessments required at screening are shown on the Schedule of Events.  A detailed description 
of procedures and timing is provided in Section 5.1.  In addition, all patients must provide tumor 
tissue for analysis.  If tumor tissue is not available, the patient must undergo a biopsy to obtain 
adequate samples.
5.3
Screen Failures
Patients who have signed informed consent and subsequently fail to meet the inclusion and/or 
exclusion criteria are defined as screen failures.  For all screen failures, the Investigator is to 
maintain a screening log that documents the patient initials and reason(s) for screen failure.  A 
copy of the log should be retained in the Investigator’s study files.
5.4
Active Study Period
The active study period begins when the patient receives the first dose of AP26113.
Assessments required during the active study period are shown on the Schedule of Events.  A 
detailed description of procedures and timing is provided in Section 5.1.  In summary, physical
examination, vital signs, ECOG Performance Status, clinical laboratory assessments 
(hematology, chemistry, urinalysis, insulin, coagulation [PT/PTT]), and ECGs will be performed 
at Cycle 1 Day 1, Cycle 2 Day 1, every 28 days from Cycle 3 onwards (at Day 1 of each cycle), 
at End of Treatment, and at 30 Days After End of Treatment.  Disease assessment will be 
performed at Cycle 1 Day 1, and at every 8 weeks through Cycle 15, then at every 12 weeks
from Cycle 16 through End of Treatment.  In addition, at Cycle 1, Day 15 additional clinical 
laboratory assessments are required (hematology, chemistry, insulin, and PT/PTT only).
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.
5.5
End of Treatment
The End of Treatment is defined as the point when the patient receives the last dose of AP26113 
or the patient discontinues taking AP26113.  Study procedures at the End of Treatment must be 
conducted within 14 days following the last dose of study drug.
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Assessments required at the End of Treatment are shown on the Schedule of Events.  A detailed 
description of procedures and timing is provided in Section 5.1.
5.6
30 Days after End of Treatment
A patient is required to complete all post treatment discontinuation assessments 30 Days After 
End of Treatment.  Study procedures at 30 Days After End of Treatment must be conducted 
within 30 days (± 7 days) following the last dose of study drug.
Assessments required at 30 Days After End of Treatment are shown on the Schedule of Events.  
A detailed description of procedures and timing is provided in Section 5.1.
5.7
Follow-up Period
The follow-up period for a patient begins after the last completed assessment during the active 
study period and continues until patient contact ceases.  All patients should be followed for 
survival at least every 3 months (± 14 days), up to 2 years after the initial dose of AP26113.  For 
patients who discontinue the study treatment due to a reason other than progressive disease, 
additional tumor assessments should be documented, if available, until disease progression or 
start of another systemic anti-cancer therapy.
5.8
Study Duration
The expected total duration of patient participation is approximately 2 years, including a 2- to 
3-week screening period, an estimated average of 10 to 12 cycles (28 days each) of AP26113 in 
responding patients (participation for patients who do not respond will most likely be of shorter 
duration), and the 30-day after treatment discontinuation assessments.  In addition, patients 
should be followed-up for survival at least every 3 months, up to 2 years after the initial dose.
The total estimated duration of the study is 4 years, including 24 months to accrue patients with 
2 years for treatment and follow-up for the last patient.  Patients who are still on study at 2 years 
will be allowed to receive study drug beyond 2 years until disease progression or they 
discontinue treatment for other reasons.
5.9
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;
In some cases, despite progression by RECIST, patients and investigators may have 
the opinion that continued study drug administration is beneficial, and in these cases, 
therapy may continue with the Sponsor’s agreement.

Entry into another therapeutic clinical trial or start of additional 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;
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
Pregnancy;

Patient withdrawal of consent and decision to discontinue participation;

Termination of the trial 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 trial for any reason, every effort must be made to perform all 
End of Treatment and 30 Days After End of Treatment assessments per the schedule of events.  
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 the active study period will be followed-up for 
survival for at least 3 months and up to 2 years after initial dose of AP26113. For patients who 
discontinue the study treatment due to a reason other than progressive disease, additional tumor 
assessments should be documented, if available, until disease progression or start of another 
systemic anti-cancer therapy.
5.10
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), and International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
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5.11
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 and CSF samples must be 
stored at -20ºC until shipment.  Specific instructions regarding the handling and shipment of 
these specimens will be provided in the Study Reference Manual.
6
STUDY TREATMENT(S)
6.1
Study Drug
AP26113 is a novel, synthetic, orally active TKI that potently inhibits activated, mutant forms of 
ALK and EGFR.
6.2
Selection of Starting Dose
The starting dose of AP26113 in the initial phase 1/2 clinical trial is 30 mg/day.  This dose level 
was selected on the basis of data obtained from the 28-day oral toxicology studies in rats and 
monkeys (see Section 1.2.4 for more details on the rationale for starting dose selection).
6.3
Treatment Administration
AP26113 will be administered orally in capsules or tablets, each consisting of 30 mg of AP26113 
active pharmaceutical ingredient. Changes to the strength and composition of the tablets and 
capsules may be made during the course of AP26113 development. Study drug (AP26113) will 
be self-administered by the patient.  The starting dose will be 30 mg taken orally once daily.  
Each 28-day dosing period is referred to as 1 cycle. Patients will take the prescribed dose with 
water approximately 2 hours after a light meal.  Patients will be instructed not to eat or drink 
anything other than water for 2 hours after taking their dose.  Patients who forget to take their 
scheduled dose of study drug should be instructed not to make up the missed dose.  Missed doses 
should be recorded in an appropriate source record (eg, clinic chart), patient diary card, and study 
drug administration eCRF. 
6.4
Dose Escalation
The dose escalation phase of this phase 1/2 trial will employ sequential dose escalation of oral 
AP26113 using a standard 3+3 design, starting at 30 mg administered orally once daily, and 
increasing in increments until the MTD is identified.  Figure 2 provides a schematic 
representation of the dose escalation phase of the study.  The following guidelines are provided; 
however, decisions for dose escalation will be made in conference with the Investigator and 
Sponsor.  Doses in between or higher than those shown in the following guidance may be 
explored.
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Figure 2
Schematic of AP26113 Phase 1/2 Trial Design – Dose Escalation Phase
Key: DLT=Dose Limiting Toxicities.  MTD=Maximum Tolerated Dose.  RP2D=Recommended Phase 2 Dose.  
QD=once daily.
Initially, 3 patients will be enrolled, will take 30 mg of AP26113 administered orally once daily, 
and will be followed for 28 days.  The next scheduled dose is 60 mg, followed by the 90 and 
120 mg dose level cohorts.  Further dose escalation will involve increments of no more than 50% 
of the previous dose depending on safety findings.  Multiple doses (eg, twice daily) may be 
administered daily based on PK findings (eg, t1⁄2) for the initial patients.
The number of patients in each dose level cohort may vary depending on the events of the study, 
but cohorts will have a minimum of 3 patients enrolled.  At each dose level, 3 patients will be 
enrolled initially and followed for 28 days.  Increasing to the next dose level will depend on the 
safety findings of the previous cohort.  If no DLTs are observed, the next higher cohort will 
begin enrollment.  Expansion of a cohort from 3 to 6 patients will occur if 1 of 3 patients 
experiences a DLT at a given dose.  If this occurs, 3 more patients will be enrolled at that dose 
level.  If 1 or more patients exhibit a DLT, the dose level will be designated to have exceeded the 
MTD.  If none experience a DLT, dose escalation will continue.  Expansion of the cohort size 
may also occur at any dose to confirm safety observations.
Starting Dose
Dose
Time
Cohort 1 (n=3)
30 mg QD
Cohort 6 (n=3)
X mg QD
DLT
Cohort 8 (n=3)
X mg QD
MTD/RP2D
Part 2
Molecularly 
Defined 
Cohorts
Expansion 
Phase
Cohort 2 (n=3)
60 mg QD
Cohort 3 (n=3)
90 mg QD
Cohort 4 (n=3)
120 mg QD
Cohort 5 (n=3)
X mg QD
Cohort 6 (n=3)
X mg QD
DLT
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Further dose escalation, multiple doses, and dose modifications may occur as described in 
Section 6.5.
The maximum administered dose in the trial will likely exceed the MTD.  Intermediate doses 
between the MTD and the next lower dose may be explored.  Schedules for single or multiple 
dosing of AP26113 in a given period may be explored depending on PK findings.
6.4.1
Intra-Patient Dose Escalation
Intra-patient dose escalation will be allowed according to the following scheme.  All patients will 
have the option to increase dose while on study if the following conditions are met: 1) the patient 
tolerated his/her starting dose without a DLT and s/he remains on study without disease 
progression, 2) the Cycle 2 PK samples have been drawn per protocol, and 3) the proposed next 
dose level has been evaluated and it has been shown that it does not exceed the MTD.
6.4.2
Maximum Tolerated Dose (MTD)
The MTD is defined as the highest dose at which ≤ 1 of 6 evaluable patients experience a DLT 
within the first 28 days of treatment (end of Cycle 1).  Evaluable patients must complete at least 
75% of their planned doses, unless missed doses are due to related AEs.  The cohort may be 
expanded to better define the safety profile or for confirmation of the MTD.  The maximum 
administered dose in the trial will likely exceed the MTD.
6.4.3
Dose-Limiting Toxicities (DLTs)
DLTs will be summarized by category (hematologic and non-hematologic) and by Medical 
Dictionary for Regulatory Activities (MedDRA) Preferred Term.  Standard AEs will be 
considered DLTs that count for the determination of the MTD of AP26113.  A DLT is a 
drug-related toxicity that is observed to occur within the first 28 days of treatment (end of cycle 
1) as defined below.  Drug-related toxicities include any toxicity that is possibly, probably, or 
definitely drug-related.  Toxicity grades will be defined by the NCI CTCAE v 4.0.  DLTs are 
defined by the following:
●
Non-hematologic toxicities
i.
Any grade ≥ 3 non-hematologic toxicity, with the exception of self-limiting 
or medically controllable toxicities (eg, nausea, vomiting, fatigue, electrolyte 
disturbances, hypersensitivity reactions) lasting < 3 days, and excluding 
alopecia.
●
Hematologic toxicities
i.
Febrile neutropenia not related to underlying disease (fever, > 101°F; ANC 
< 500)
ii.
Prolonged grade 4 neutropenia (> 7 days)
iii.
Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection
iv.
Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days
●
Missed ≥ 25% of planned doses of AP26113 over 28 days due to treatment-related 
AEs in the first cycle.
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6.5
Dose Modification(s)
Dose delays or reductions will be implemented as indicated in Table 2 for patients who 
experience adverse drug reactions due to non-hematologic (excluding pneumonitis events) or 
hematologic toxicity.  After dose reduction, patients should continue therapy at the reduced dose.  
Dose reductions may be implemented a second time if additional toxicity ensues.  If study drug 
is held for more than 2 weeks, resumption of therapy must be discussed with the Sponsor.  In 
general, re-escalation of doses will occur only in consultation with the Sponsor, as stipulated in 
Section 6.5.1 below.  If Grade 3 or 4 toxicity requiring dose reduction occurs in the first dose 
cohort, reduce dose by 50%.
For patients with pneumonitis events, dose delays or reductions will be implemented as indicated
in Table 2. If a patient has a pneumonitis event Grade 1 or 2, AP26113 dosing should be 
withheld until patient recovers to baseline status; dosing should then be resumed as outlined in 
below. If a patient has an event of pneumonitis event Grade 3 or 4, dosing of AP26113 should be 
permanently discontinued.
Table 2
Dose Modifications for Non-hematologic/Hematologic Toxicity or 
Pneumonitis Events 
Toxicity Grade
Action 
Non-Hematologic Toxicity (excluding Pneumonitis Events)
Grade 1
Continue therapy at same dose level.
Grade 2
Continue therapy at same dose level. If symptoms are intolerable, recurrent or not 
controlled by supportive care, withhold therapy until symptoms remit and reduce to next 
lower dose level.
Grade 3
Withhold therapy until toxicity is grade ≤1or has returned to baseline, then resume therapy. 
Therapy may be resumed at the same dose, or at the next lower dose level, based on the 
investigator’s judgment.
Grade 4
Withhold therapy until toxicity is grade ≤1or has returned to baseline, then resume therapy 
at the next lower dose level. Therapy may also be discontinued based on the investigator’s 
judgment.
Hematologic Toxicity
Grade 1
Continue therapy at same dose level.
Grade 2
Continue therapy at same dose level.
Grade 3
Withhold therapy until toxicity is grade ≤2 or has returned to baseline, then resume 
therapy. Therapy may be resumed at the same dose, or at the next lower dose level, based 
on the investigator’s judgment.
Grade 4
Withhold therapy until toxicity is grade ≤2 or has returned to baseline, then resume therapy 
at the next lower dose level. Therapy may also be discontinued based on the investigator’s 
judgment.
Pneumonitis Events
Grade 1 
Withhold the dose until recovery to baseline, then resume at the same dose. 
If pneumonitis recurs, permanently discontinue treatment.
Grade 2 
Withhold the dose until recovery to baseline, then resume at the next lower dose level
(eg, 240 mg QD to 180 mg QD, 180 mg QD to 120 mg QD, 120 mg QD to 90 mg QD, or 
90 mg QD to 60 mg QD).
If pneumonitis recurs, permanently discontinue treatment.
Grade 3 or 4 
Permanently discontinue treatment
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6.5.1
Dose Re-escalation
Dosing reduced for toxicity may be re-escalated to the original dose only after discussion with 
the Sponsor.  For dose re-escalation, the escalation dose must not exceed the MTD, and the 
patient must have recovered from the adverse event.  For patients who continue the treatment 
despite radiologic disease progression (see Section 5.9), the dose may be escalated to a higher 
dose that is determined not to exceed the MTD, following discussion with the Sponsor.  
6.6
Initiation of Expansion Phase Enrollment
The decision to proceed from the dose-escalation portion of the study and to open the expansion 
cohorts will depend on establishing that AP26113 can be administered safely.  Enrollment in 
expansion cohorts will be dependent on observing evidence of disease response in the dose 
escalation cohort.  Once the RP2D is identified, patients will be enrolled into the molecularly 
defined expansion cohorts comprising Part 2 of the study design (Figure 1).  The expansion 
phase will include 5 additional histologically and molecularly defined cohorts, with cohort 5 
being limited to patients with active brain metastases (Figure 1).  The dose and schedule for the 
expansion cohorts will be determined based on the RP2D and schedule determined in the dose 
escalation phase of the trial. Additional dosing strategies may be evaluated in the expansion 
cohorts to gather additional safety and efficacy data at a dose below the current RP2D. 
6.7
Prior and Concomitant Medications
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 course of the trial for underlying medical 
conditions and management of symptoms.  Patients with CNS lesions requiring SRS are allowed 
to continue the study treatment after appropriate interruption; however, for analysis purposes, 
these patients will be considered to have progressive disease.
Concomitant medications for all ongoing medical history conditions or AEs must be reported 
from the date the informed consent is signed until at least 30 Days After the End of Treatment, 
and for all concomitant medications related to serious or study drug-related toxicities until the 
medication is no longer taken or until patient contact discontinues.
6.8
Prohibited Treatment(s)/Therapy
The following concurrent medications 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);
2.
Use of any other investigational drug or device;
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3.
Medications that are known to be associated with the development of Torsades de 
Pointes (see Attachment 4).  Medications that prolong the QT interval, but are not 
known to be associated with Torsades, should be avoided, but are not prohibited;
4.
Herbal preparations or related over-the-counter preparations containing herbal 
ingredients;
5.
Extensive surgery requiring in-patient care (patients may have an interruption in 
therapy for 14 days should emergency surgery be required).
Medications that are potent inhibitors or inducers of P450 cytochromes, in particular CYP2C8 
and CYP3A4, should be avoided.
Patients should avoid using AP26113 in combination with other agents known to cause 
bradycardia (eg, beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and 
digoxin).  The investigator or qualified designee should also educate patients not to start on any 
over-the-counter (OTC) medications, herbal or prescription medications that may affect heart 
rate, and to consult with the investigator prior initiating any therapy.
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.
6.9
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.
6.10
Treatment(s) Supply
Upon receipt of clinical trial 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.
6.10.1
Formulation, Packaging, and Labeling
AP26113 drug product is supplied as either capsules or tablets, containing 30 mg of AP26113 
active pharmaceutical ingredient.  Any excipients used to manufacture the drug product will be 
of pharmaceutical grade.  The drug product is manufactured under Current Good Manufacturing 
Practice (CGMP) during the course of the trial.  AP26113 will be supplied in white high density 
polyethylene (HDPE) bottles with child-resistant caps with liner.
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Bottle 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 capsules or 
tablets, and lot number.
6.10.2
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 approved by the Sponsor.  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.
6.10.3
Treatment(s) Storage and Accountability
The recommended storage condition for AP26113 is controlled room temperature.
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 of study drug must be 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 trial 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 trial, a final study drug 
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.
7
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
7.1
Definitions
7.1.1
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
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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.
AEs include:
●
Abnormal test findings
●
Changes in physical examination findings
●
Other untoward medical events, regardless of their relationship to the study drug, such as 
injury, events that require surgery, accidents, or apparently unrelated illnesses
●
Hypersensitivity
Additionally, AEs may include signs or symptoms resulting from:
●
Drug overdose
●
Drug withdrawal
●
Drug abuse
●
Drug misuse
●
Drug interactions
●
Drug dependency
●
Exposure in utero
7.1.2
Serious Adverse Event
The Investigator or Sponsor will determine the seriousness of an AE based on the following:
An AE is considered a SAE if at least one (1) of the following conditions applies:

Death:  An AE that results in death is any patient death within 30 days of the last dose of 
study drug administration.  The cause of death or AE that resulted in a fatal outcome is 
the SAE.

Life-threatening AE:  An AE that places the patient, in the view of the Investigator or 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 is defined as any substantial disruption of a person’s ability 
to conduct normal life functions.

Inpatient hospitalization or prolongation of existing hospitalization:  Hospitalization 
refers to admission of a patient into a hospital for any length of time.

A congenital anomaly/birth defect:  A fixed, permanent impairment established at or 
before birth.
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
Cancer:  Occurrence or diagnosis of a new cancer during the trial is considered a SAE.  A 
new cancer is a cancer that is histopathologically different than the cancer under study in 
the trial (ie, does not include metastatic or progressive disease).

Overdose:  Any AE associated with an overdose of study drug.  An overdose of study 
drug is defined as an occurrence of administered dose exceeding that which is prescribed 
by the investigator per protocol.

Important medical event:  Medical and scientific judgment should be exercised in 
determining whether an event is an important medical event.  An important medical event 
may not result in death, be life-threatening, or require hospitalization.  However, if it is 
determined that the event may jeopardize the patient and/or may require intervention to 
prevent one of the other outcomes listed in the definition above, the important medical 
events should be reported as serious.  Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization; or the development of drug dependency 
or drug abuse.
7.1.2.1
Progression of the malignancy under study (including signs and symptoms of 
progression)
Worsening of signs and symptoms of the malignancy under trial 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 unless the progression 
requires inpatient hospitalization or results in death.  In that case, the event should be reported as 
an SAE.
7.1.2.2
Hospitalizations
AEs reported from clinical trials that require hospitalization or prolongation of hospitalization 
are considered serious.  Any initial admission (even if less than 24 hours) to a health care facility 
meets these criteria.  Adverse events that require emergency room care that do not result in 
hospital admission are not SAEs unless assessed by the investigator to be an important medical 
event.  Hospitalization does not include the following: 

Hospice facilities

Respite care

Skilled nursing facilities

Nursing homes

Routine emergency room admissions

Same day surgeries (as outpatient/same day/ambulatory procedure)
Hospitalization or prolongation of hospitalization in the absence of a precipitating AE is not in 
itself a SAE.  Examples include:

Social admission (eg, patient has no place to sleep)
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
Protocol-specified admission during a clinical trial (eg, for a procedure required by the 
trial protocol)

Optional admission not associated with a precipitating AE (eg, for elective cosmetic 
surgery that was planned prior to study enrollment [appropriate documentation is 
required for these cases])

Hospitalization or prolongation of hospitalization for scheduled therapy of the target 
malignancy of the study is not considered an SAE.
7.1.3
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.
●
Test result leads to a change in study drug dosing or discontinuation from the trial, 
significant additional concomitant drug treatment, or other therapy.
●
Test result is considered to be an AE by the investigator or sponsor.
7.1.4
Expectedness
The expectedness of a SAE is assessed by the Sponsor in the overall classification of SAEs for 
regulatory reportability.  The current Investigator’s Brochure section “Summary of Data and 
Guidance for the Investigator” will be used as the reference for determination of expectedness
and risk assessment.
7.2
Evaluation of Adverse Events and Serious Adverse Events
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 criteria for classification as a SAE (see Section 
7.1.2) requiring immediate notification to ARIAD or its designated representative.
The investigator will document the following assessments for all adverse events and serious 
adverse events in accordance with applicable guidelines for completion of the eCRF and the 
Serious Adverse Event Report form.
7.2.1
Adverse Event Severity
The severity of AEs will be assessed according to the NCI CTCAE, Version 4.0.  If the AE is not 
defined in the CTCAE, the Investigator will determine the severity of the AE based on the 
following definitions:

Mild (Grade 1):  The AE is noticeable to the patient, but does not interfere with routine 
activity.  The AE does not require discontinuing administration or reducing the dose of 
the study drug.
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
Moderate (Grade 2):  The AE interferes with routine activity, but responds to 
symptomatic therapy or rest.  The AE may require reducing the dose, but not 
discontinuing administration of the study drug.

Severe (Grade 3):  The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy.  In addition, the AE leads to discontinuing 
administration or reducing the dose of the study drug.

Life Threatening (Grade 4):  The AE requires discontinuing administration of the study 
drug.  The patient is at immediate risk of death.

Death (Grade 5):  The patient dies as a direct result of the complication or condition 
induced by administration of the study drug.
7.2.2
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.
In addition, if the investigator determines a SAE is associated with trial procedures, the 
investigator must record this causal relationship in the source documents and on the SAE form, 
and report such an assessment in accordance with the SAE reporting requirements.
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 study 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 study 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 (study 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
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
The AE could have been due to another equally likely cause

Dechallenge (if performed) is positive
Probably Related (study 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 (study 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

Rechallenge (if feasible) is positive

The AE shows a pattern consistent with previous knowledge of the test drug or a test drug 
class.
7.3
Serious Adverse Event Reporting Procedures
7.3.1
Serious Adverse Event Reporting Period
All AEs (serious and non-serious) should be reported on the AE eCRF for all patients beginning 
at the time of signing the informed consent form and concluding 30 days following the last dose 
of the assigned study treatment in the study or the investigator/patient decision to discontinue 
treatment, whichever occurs later. 
Once a patient is deemed a screen failure, AE collection is no longer required (see Section 5.3
Screen Failures). 
Any AEs (serious and non-serious) ongoing at the end of the reporting period should be followed 
until they resolve to baseline, stabilize, or are considered to be chronic/irreversible. 
There is no requirement to monitor subjects for SAEs after end of study. Investigators in the 
European Economic Area (EEA) are obligated to report SAEs that they become aware of to the 
Sponsor even after the reporting period (reference European Commission CT-3 section 4.4). 
Investigators outside the jurisdiction of the EEA are encouraged to report SAEs after the 
reporting period.
7.3.2
Reporting Serious Adverse Events
The investigator or investigator’s designee must notify ARIAD Pharmacovigilance and Risk 
Management or its designated representative immediately (within 24 hours) after becoming 
aware of an SAE. This timeframe also applies to additional new information (follow-up) on 
previously reported SAEs.
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7.3.3
Information to be Provided by the Investigator for a Serious Adverse Event
Information should be provided on the Serious Adverse Event Report form signed and dated by 
the Investigator.  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
7.3.4
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 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.
7.3.5
Required Follow-up for Serious Adverse Events
There should be routine follow-up for 30 days after permanent discontinuation of study drug in 
all patients in order to monitor for the occurrence of SAEs.  If an SAE continues after the 30-day 
evaluation period, then the patient must be followed until the event resolves or stabilizes.  The 
medical monitor may specify a longer period of time, if required to assure the safety of the 
patient.
7.4
Sponsor Responsibility for Expedited Safety Reports
ARIAD, as study sponsor, is responsible for reporting suspected, unexpected and serious adverse 
reactions involving the study drug to all regulatory authorities and participating investigators in 
accordance with ICH Guidelines and/or local regulatory requirements, as applicable. In addition, 
ARIAD, or authorized designee, will be responsible for the submission of safety letters to central 
independent ECs (IECs). 
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The sponsor 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 IRB/EC will determine whether 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 will be reported by the sponsor or its designated 
representative, either as expedited safety reports and/or in aggregate reports, to the relevant 
competent health authorities in all concerned countries.
7.5
Other Safety Issues
7.5.1
Pregnancy
Females of childbearing potential and fertile males will be informed as to the potential risk of 
conception while participating in this study and will be advised that they must use effective 
contraception during the dosing period and for a period of at least 30 days thereafter for females 
and 120 days for males.  A pregnancy test will be performed on each pre-menopausal female of 
childbearing potential immediately prior to the first dose of study drug, 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 trial, 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.
8
PLANNED STATISTICAL METHODS
8.1
General Considerations
The dose escalation phase of this phase 1/2 trial will employ sequential dose escalation of oral 
AP26113 using a standard 3+3 design, starting at 30 mg administered orally once daily, and 
increasing in increments until the MTD is identified. 
Descriptive statistics and analyses will be provided for each dose level, and for patients 
combined across dose levels where applicable.
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Data from patients in the expansion phase cohorts will be summarized together with data from 
patients in the dose escalation cohorts, as appropriate.  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, treatment administration/compliance, 
efficacy, safety, and pharmacokinetic parameters.  Data will also be displayed graphically, where 
appropriate.
8.1.1
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;
●
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.
8.2
Study Endpoint(s)
8.2.1
Primary Endpoint(s)
The primary endpoint of the dose escalation component of the study is the RP2D of orally 
administered AP26113.  The primary endpoint of expansion cohorts 1-4 is the overall response 
rate (using RECIST).  The primary endpoint of expansion cohort 5 is CNS response rate (using 
RECIST). 
8.2.2
Secondary Endpoint(s)
Secondary endpoints of the dose escalation component of the study include:
1.
MTD of orally administered AP26113
2.
Safety, tolerability, and DLTs of AP26113
3.
Plasma PK parameters of single-dose and steady state AP26113
Secondary endpoints of the expansion cohort component of the study include:
1.
Safety and tolerability of AP26113
2.
Plasma PK parameters
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Kaplan-Meier estimate.  The PFS, TTP and OS will be analyzed using the Kaplan-Meier method.  
Median time to progression and progression rates at 6 months and 12 months will be computed
along with CIs. The OS rates at 12 and 24 months and associated CIs will be computed.  Best 
target lesion response will be displayed using a “waterfall” plot.
Patients’ molecular genetic status will be characterized by both mutation history and central 
testing results obtained from the tumor tissue sample provided at study entry in order to explore 
molecular genetic features that are associated with the anti-tumor activity of AP26113.  Data 
obtained from the central laboratory will be used to support the development of a well-validated 
test that can be used in future studies to prospectively identify patients with tumors with such 
features.  
8.6
Safety Analysis
Safety assessments will include physical and laboratory examinations, vital signs, and ECGs.  
Adverse events will be graded according to the NCI CTCAE v 4.0.  Periodic meetings with study 
investigators will be held to assess safety throughout the trial.
All patients receiving at least 1 dose of AP26113 will be considered evaluable for safety.  The 
AE incidence rates, as well as the frequency of occurrence of overall toxicity, categorized by 
toxicity grades (severity), will be described.  Listings of laboratory test results will also be 
generated, and descriptive statistics summarizing the changes in laboratory tests over time will 
be presented.
8.6.1
Pharmacokinetic Analysis
Parameters: maximum concentration (Cmax), time of maximum concentration (Tmax), area under 
the curve (AUC; over the first 24 hours), and drug elimination half-life (t1⁄2), will be estimated 
from plasma concentration data using non-compartmental methods.  The geometric mean and 
95% CIs will be reported.  Accumulation for Cmax, and AUC will be estimated from plasma 
concentration levels on Cycle 1, Day 1 (Day 1) and Cycle 2, Day 1 (Day 29), using the 
geometric mean ratio and 95% CI.  Dose linearity for Cmax and AUC will be assessed using 
regression methods.
8.6.2
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 1 on-drug QTcF value 
>450 ms, 480 ms, and 500 ms; and the proportion of treated patients with a maximum change in 
QTcF from baseline >30 ms and >60 ms.  The Fridericia correction (QTcF) will be used 
throughout.  QTcF change from baseline and blood concentration will be analyzed using mixed 
effects models.
8.7
Protocol Deviations/Violations
To be protocol-compliant, a patient must not have any major protocol deviations during the study 
period.  Protocol deviations will be identified prior to study closure and will be listed by dosing 
cohort in the clinical study report.
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9
QUALITY CONTROL AND QUALITY ASSURANCE
The Sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors.  Before enrolling any patients into this study, the Sponsor personnel or its designee and 
the Investigator will review the protocol, the Clinical Investigator's Brochure, the eCRFs and 
instructions for their completion, the procedure for obtaining informed consent, and the 
procedure for reporting AEs.  A qualified representative of the Sponsor will monitor the conduct 
of the study by visiting the site and by contacting the site by telephone.  During the visits, 
information recorded in the eCRFs will be verified against source documents.  The Sponsor’s 
medical monitor will review the data for safety information.  The Sponsor’s clinical data 
associates or designees will review the data for legibility, completeness, and logical consistency.  
Additionally, the Sponsor’s clinical data associates will use automated validation programs to 
help identify missing data, selected protocol violations, out-of-range data, and other data 
inconsistencies.  Requests for data clarification or correction will be added to the electronic 
database and reviewed by the investigational site for resolution.  The Sponsor may visit the 
investigational site and perform a quality check of the eCRFs against source documents.
9.1
Investigators and Study Administrative Structure
The Investigator must provide the Sponsor with the following documents BEFORE enrolling any 
patients:
●
An executed Clinical Trial Agreement,
●
FDA Form 1572,
●
Documentation of financial disclosure,
●
Principal Investigator’s Curriculum Vitae,
●
IRB/EC approval of the protocol,
●
IRB/EC approved 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 will accept 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 and 
the FDA for any changes in the study personnel reported in the current FDA Form 1572.
9.2
Study Monitoring
This study will be monitored by a representative 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).
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●
Compliance with regulations (the verification will require comparison of the source 
documents to the eCRFs).
10
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 Good Clinical Practice (GCP) guidelines and 
the applicable regulatory requirements.
10.1
Institutional Review Board (IRB) or Ethics Committee (EC) Approval
The protocol and the informed consent document must have the initial and at least 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 also should be 
reviewed by the IRB/EC.  The Sponsor will not ship clinical supplies until a signed approval 
letter from the IRB/EC has been received and a Clinical Trial Agreement has been signed by the 
Sponsor and the clinical site.
10.2
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 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.
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.
10.3
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.
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11
DATA HANDLING AND RECORD KEEPING
11.1
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 trial.  All 
pertinent data records are to be submitted to the Sponsor during and/or at completion or 
termination of the study.
11.2
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.
11.3
Retention of Data
Trial 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 
discontinuation of clinical development of the product). Trial 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.
12
PUBLICATION AND DISCLOSURE POLICY
The Investigator must notify the IRB/EC of the conclusion of the clinical trial.  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, 
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 trials of drugs (including biological products) and medical devices subject to 
FDA regulations for any disease or condition.  The International Committee of Medical Journal 
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Editors (ICMJE) requires trial registration as a condition for publication of research results 
generated by a clinical trial. (http://www.icmje.org [Accessed: 18 December 2013]).
The Institution and Principal Investigator acknowledge that the study is a 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 forty-five (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 the Institution and/or Principal Investigator publishes the 
results of the Study, the Institution and/or Principal Investigator hereby grant(s) 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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13
REFERENCES
Butrynski JE, D'Adamo DR, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic 
tumor. N Engl J Med 2010;363(18):1727-1733.
Camidge DR, Doebele RC. Treating ALK-positive lung cancer—early successes and future 
challenges. Nat Rev Clin Oncol 2012;9(5):268-77.
Choi YL, Soda M, et al. EML-ALK mutations in lung cancer that confer resistance to ALK 
inhibitors. N Engl J Med 2010;363(18):1734-1739.
DeGeorge J, Ahn C-H, Andres P, Brower M, Giorgio D, Goheer M, et al. Regulatory 
considerations for preclinical development of anticancer drugs. Cancer Chemotherapy and 
Pharmacology 1998;41:173-185.
Gambacorti-Passerini C, Messa C, et al. Crizotinib in anaplastic large-cell lymphoma. N Engl J 
Med 2011;364(8):775-776.
Kwak EL, Bang YJ, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. 
N Engl J Med 2010;363(18):1693-1703.
Le Tourneau C, Lee JJ, Siu LL. Dose Escalation Methods in Phase I Cancer Clinical Trials. J 
Natl Cancer Inst 2009;101(10):708–720.
Suda KI, Murakami, 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.
Ting N. ed. Dose Finding in Drug Development, Springer 2006 pg 53.
Yun C.H, Mengwasser KE, et al. The T790M mutation in EGFR kinase causes drug resistance 
by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008;105(6):2070-2075.
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ATTACHMENT 1
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, v.4.0) can be found on the following website.
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 [Accessed: 
18 December 2013]
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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ATTACHMENT 2
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, Horton J, Davis TE, McFadden ET, Carbone PP. 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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ATTACHMENT 3
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST VERSION 1.1)
Eisenhauer, E. A., Therasse P., Bogaerts J., Schwartz L. H., Sargent D., Ford R., Dancey J., 
Arbuck S., Gwyther S., Mooney M., Rubinstein L., Shankar L., Dodd L., Kaplan R., Lacombe 
D., & Verweij J. (2009). New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). European Journal of Cancer, 45, 228-247.
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ATTACHMENT 4
DRUGS WITH A RISK OF TORSADES DE POINTES
The website http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/ [Accessed: 
15 February 2017] 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 4.1
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
Anagrelide
Agrylin, Xagrid
Phosphodiesterase 3 inhibitor / Thrombocythemia
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
Cilostazol
Pletal
Phosphodiesterase 3 inhibitor / Intermittent claudication
Ciprofloxacin
Cipro, Cipro-XR, 
Neofloxin
Antibiotic / Bacterial infection
Cisapride
Propulsid®
GI stimulant / heartburn
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Generic Name
Brand Name
Class/Clinical Use
Citalopram
Celexa®
Antidepressant / depression
Clarithromycin
Biaxin®, Prevpac®
Antibiotic / bacterial infection
Cocaine
Cocaine
Local anesthetic / topical anesthetic
Disopyramide 
Norpace®
Antiarrhythmic / abnormal heart rhythm
Dofetilide 
Tikosyn®
Antiarrhythmic / abnormal heart rhythm
Domperidone
Motilium®, 
Motillium®, Motinorm 
Costi®, Nomit®
Antinausea / nausea
Donepezil
Aricept
Cholinesterase inhibitor / Dementia (Alzheimer's Disease)
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
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Generic Name
Brand Name
Class/Clinical Use
Flecainide
Tambocor®, 
Almarytm®, 
Apocard®, Ecrinal®, 
Flécaine®
Antiarrhythmic / abnormal heart rhythm
Fluconazole
Diflucan, Trican
Antifungal / Fungal infection
Gatifloxacin 
(Removed from 
Market)
Tequin
Antibiotic / Bacterial infection
Grepafloxacin 
(Removed from 
Market)
Raxar
Antibiotic / Bacterial infection
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
Ibogaine
(Only on Non US 
Market)
None
Psychedelic / Narcotic addiction, unproven
Ibutilide
Corvert®
Antiarrhythmic / abnormal heart rhythm
Levofloxacin
Levaquin, Tavanic
Antibiotic / Bacterial infection
Levomepromazine 
(Only on Non US 
Market)
Nosinan, Nozinan, 
Levoprome
Antipsychotic / Schizophrenia
Levomethadyl
Orlaam®
Opiate agonist / pain control, narcotic dependence
Levosulpiride 
(Only on Non US 
Market)
Lesuride, Levazeo, 
Enliva (with
rabeprazole)
Antipsychotic / Schizophrenia
Mesoridazine
Serentil®
Antipsychotic / schizophrenia
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Generic Name
Brand Name
Class/Clinical Use
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
Oxaliplatin
Eloxatin
Antineoplastic Agent / cancer
Papaverine HCl 
(Intra-coronary)
none
Vasodilator, Coronary / Diagnostic adjunct
Pentamidine 
Pentam®, NebuPent®
Anti-infective / pneumocystis pneumonia
Pimozide
Orap® 
Antipsychotic / Tourette's tics
Probucol
Lorelco®
Antilipemic / Hypercholesterolemia
Procainamide 
Pronestyl®, Procan®
Antiarrhythmic / abnormal heart rhythm
Propofol
Diprivan,  Propoven
Anesthetic, general / Anesthesia
Quinidine
Quinaglute®, 
Duraquin®, Quinact®, 
Quinidex®, 
Cin-Quin®, Quinora®  
Antiarrhythmic / abnormal heart rhythm
Roxithromycin 
(Only on Non US 
Market)
Rulide, Xthrocin, 
Roxl-150, Roxo, 
Surlid, Rulide, 
Biaxsig, Roxar, 
Roximycinv, 
Roxomycin, 
Rulid, Tirabicin, 
Coroxin
Antibiotic / Bacterial
Sevoflurane
Ulane®, Sojourn®
Anesthetic, general / anesthesia
Sotalol 
Betapace®, Sotalex®, 
Sotacor® 
Antiarrhythmic / abnormal heart rhythm
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Version 8.0 20 March 2017
Page 83 of 83
Generic Name
Brand Name
Class/Clinical Use
Sparfloxacin 
Zagam® 
Antibiotic / bacterial infection
Sulpiride 
(Only on Non US 
Market)
Dogmatil, Dolmatil, 
Eglonyl, Espiride, 
Modal, Sulpor
Antipsychotic, atypical / Schizophrenia
Sultopride 
(Only on Non US 
Market)
Barnetil,  Barnotil, 
Topral
Antipsychotic, atypical / Schizophrenia
Terfenadine
(Removed from 
Market)
Seldane®
Antihistamine / allergic rhinitis
Terlipressin 
(Only on Non US 
Market)
Teripress,  Glypressin, 
Terlipin,  Remestyp, 
Tresil, Teriss and 
others
Vasoconstrictor / Septic shock
Terodiline 
(Only on Non US 
Market)
Micturin, Mictrol (not 
bethanechol)
Muscle relaxant / Bladder
Thioridazine
Mellaril®, 
Novoridazine®, 
Thioril® 
Antipsychotic / schizophrenia
Vandetanib
Caprelsa®
Anticancer / thyroid cancer
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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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 Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-
Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113
NCT Number: NCT01449461
SAP Approve Date: 14 April 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.
AP26113-11-101
AP26113
Statistical Analysis Plan
 
Page 1
STATISTICAL ANALYSIS PLAN
STUDY TITLE: A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and 
Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113
PROTOCOL NUMBER:
AP26113-11-101
PROTOCOL DATE:
27 June 2011
PROTOCOL AMENDMENT DATE:
20 December 2013
SAP VERSION:
Version 1.0
DATE:
14 April 2016
SPONSOR:
ARIAD Pharmaceuticals, Inc. 
26 Landsdowne Street 
Cambridge, MA 02139-4234
PROTOCOL REVISION HISTORY:
Amendment Number
Protocol Version Number
Date
Version 1.0
27 June 2011
Amendment 1
Version 2.0
22 July 2011
Amendment 2
Version 3.0
21 February 2012
Amendment 3
Version 4.0
17 September 2012
Amendment 4
Version 5.0
30 November 2012
Amendment 5
Version 6.0
22 May 2013
Amendment 6
Version 7.0
20 December 2013
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AP26113
Statistical Analysis Plan
 
Page 2
TABLE OF CONTENTS
PROTOCOL REVISION HISTORY:...................................................................................1
1
INTRODUCTION...................................................................................................6
1.1
Purpose.........................................................................................................6
1.1.1
Study Design ....................................................................................6
1.1.2
Study Objectives..............................................................................7
1.1.3
Changes from analyses planned in the protocol: .........................7
1.2
Analysis Endpoints......................................................................................9
1.2.1
Dose Escalation Phase.....................................................................9
1.2.1.1
Primary Endpoint(s)..............................................................9
1.2.1.2
Secondary Endpoint(s)..........................................................9
1.2.2
Efficacy Analysis .............................................................................9
1.2.2.1
Primary Endpoint(s)..............................................................9
1.2.2.2
Secondary Endpoint(s)..........................................................9
1.2.2.3
Safety Endpoints .................................................................10
1.2.2.4
Pharmacokinetic Analysis...................................................10
2
STATISTICAL CONSIDERATIONS ................................................................10
2.1
Sample Size ................................................................................................10
2.2
Randomization and Masking ...................................................................10
2.3
Handling of Data .......................................................................................10
2.3.1
Baseline Values..............................................................................11
2.3.2
Collapsed Treatment Group ........................................................11
2.3.3
Mutation History...........................................................................11
2.3.4
Prior Exposure to Crizotinib........................................................12
2.3.5
CNS Metastases.............................................................................12
3
POPULATIONS FOR ANALYSIS .....................................................................12
3.1
All Patients.................................................................................................12
3.2
Pharmacokinetic (PK) population...........................................................12
4
STATISTICAL METHODS ................................................................................12
4.1
Demographics, Baseline Characteristics, and Patient Disposition.......12
4.2
Study Drug Exposure................................................................................12
4.3
Efficacy Analysis .......................................................................................13
4.3.1
Primary Efficacy Analysis............................................................13
4.3.1.1
Determination of Intracranial CNS Response and 
Associated Endpoints..........................................................13
4.3.1.2
Data Handling Rules for Response Contemporaneous 
Scans. ..................................................................................14
4.4
Secondary Efficacy Analyses....................................................................14
4.4.1
Best Overall Response (BOR). .....................................................14
4.4.2
Confirmed Response.....................................................................14
4.4.3
Best Confirmed Response.............................................................15
4.4.4
Progression-Free Survival............................................................15
4.4.5
Duration of Response....................................................................17
4.4.6
Overall Survival ............................................................................17
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AP26113
Statistical Analysis Plan
 
Page 3
4.4.7
Health-Related Quality of Life (HRQoL) Measurement...........17
4.4.8
Patient-Reported Outcomes (PRO).............................................17
4.5
Safety Analyses..........................................................................................17
4.5.1
Adverse Events ..............................................................................17
4.5.1.1
Derivation of Treatment-Emergent Adverse Event Flag ....17
4.5.1.2
Synonym Recoding.............................................................18
4.5.1.3
AEs in Special Categories...................................................18
4.5.1.4
Analysis of Adverse Events ................................................18
4.5.2
Laboratory Data............................................................................19
4.5.3
Vital Signs ......................................................................................19
4.5.4
QTcF Analysis ...............................................................................19
4.5.5
Other Measures.............................................................................19
APPENDIX 1
NOTES FROM RECIST V1.1 .................................................................20
APPENDIX 2
ADVERSE EVENTS SYNONYMS*.......................................................24
APPENDIX 3
DATE HANDLING AND IMPUTATION..............................................28
Calculation of Study Day...........................................................................................28
Calculation of Months ...............................................................................................28
Imputation Rules for Missing Initial Cancer Diagnosis Date and Start Date and 
Stop Date for Selected Prior Anti-Cancer Therapies ............................28
Imputation Rules for Missing Onset Date and Resolution Date of Adverse 
Events .........................................................................................................29
TABLE OF TABLES
APPENDIX TABLE 1 SUMMARY OF THE OVERALL RESPONSE STATUS 
CALCULATION AT EACH TIME POINT FOR 
PATIENTS WHO HAVE TARGET +/- NON-TARGET 
DISEASE AT BASELINE..................................................................22
APPENDIX TABLE 2 SUMMARY OF THE OVERALL RESPONSE STATUS 
CALCULATION AT EACH TIME POINT FOR 
PATIENTS WHO HAVE NON-MEASURABLE 
(THEREFORE NON-TARGET) DISEASE ONLY AT 
BASELINE...........................................................................................22
APPENDIX TABLE 3 SUMMARY OF THE BEST OVERALL RESPONSE 
STATUS CALCULATION WHEN CONFIRMATION OF 
CR AND PR IS REQUIRED..............................................................23
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AP26113
Statistical Analysis Plan
 
Page 4
LIST OF ABBREVIATIONS (Excluding common laboratory tests)
Abbreviation
Term
AE
adverse event
ALCL
anaplastic large cell lymphoma
ALK
anaplastic lymphoma kinase
AP26113
brigatinib
ARIAD
ARIAD Pharmaceuticals, Inc.
AUC
area under the curve
BOR
best overall response
CAT
computerized axial tomography
Cmax
maximum plasma concentration
CMQ
Customized MedDRA Query
CNS
central nervous system
CR
complete response
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLCL
diffuse large-cell lymphoma
DLT
dose-limiting toxicity
DNA
Deoxyribonucleic acid
ECG
electrocardiogram
EGFR
epidermal growth factor receptor
FISH
fluorescence in situ hybridization
HRQoL
health-related quality-of-life
ICH
International Conference on Harmonisation
IMT
inflammatory myofibroblastic tumors
IRC
independent review committee
ITT
Intention-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
MMQ
Modified MedDRA query
MRI
magnetic resonance imaging
ms
milliseconds
MTD
maximum tolerated dose
NE
not evaluable – often reported for interpretable lab results
not evaluated – reported when disease assessment scans cannot be read
non-CR/non-PD
not complete response and not progressive disease; also denoted 
^CR/^PD
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
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AP26113
Statistical Analysis Plan
 
Page 5
Abbreviation
Term
PRO
patient-reported outcomes
PT
preferred term
QD
once-daily
QTcF
QT interval corrected (Fridericia)
RECIST
Response Evaluation Criteria in Solid Tumors 
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SMQ
Standardised MedDRA Query
SOC
System Organ Class
TKI
tyrosine kinase inhibitor
TTP
time to progression
ULN
upper limit of normal
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AP26113
Statistical Analysis Plan
 
Page 6
1
INTRODUCTION
1.1
Purpose
This statistical analysis plan (SAP) will describe the statistical analyses performed by ARIAD 
Pharmaceuticals, Inc. for protocol AP26113-11-101.Though this is an ongoing study a clinical 
study report (CSR) will be prepared for regulatory submission using the following data extracts:

The clinical database will be analyzed using a data cut dated 2015-11-16. The last date of 
patient contact included in this cut occurred on 2015-11-13. 

Intracranial central nervous system (CNS) response was assessed by an Independent 
Review Committee (IRC). IRC data are available from a data cut on 2016-01-28, from 
which the last observed scan was performed on 2015-10-08. 
Subsequent data cuts and analyses will be performed to allow monitoring of the study, to address 
requests for information from regulatory agencies, and to facilitate periodic updates of the CSR.
1.1.1
Study Design
AP26113-11-1 is an open-label, multi-center, dose escalation study (3+3 design initial dose 
escalation cohort) with expansion into 5 cohorts (histologically and molecularly defined) after 
the recommended phase 2 dose (RP2D) is established. 
The patient population of the initial dose escalation phase of the trial will include patients with 
advanced malignancies, all histologies other than leukemia, refractory to available therapies or 
for whom no standard or available curative treatments exist. The objectives will be to determine 
the safety, tolerability, pharmacokinetic profile, and the RP2D of orally administered AP26113
(brigatinib) in these patients. The RP2D is the maximum tolerated dose (MTD) or less. An RP2D 
less than the MTD may be chosen if aspects of tolerability not encompassed by the MTD 
determination suggest utilizing a lower dose.
The expansion phase will include 5 additional histologically and molecularly defined cohorts, 
with cohort 5 being limited to patients with active brain metastases. The dose and schedule for 
the expansion cohorts will be determined based on the RP2D and schedule determined in the 
dose escalation phase of the trial. The decision to open the expansion cohorts will be based on an 
assessment of safety and preliminary anti-tumor activity from the dose escalation cohort. The 5 
expansion cohorts are as follows:
1) NSCLC patients with ALK rearrangements who are naive to prior ALK inhibitor therapy.
2) NSCLC patients with ALK rearrangements who are resistant to crizotinib.
3) NSCLC patients who are resistant to 1 prior EGFR TKI and have a documented EGFR-
T790M mutation following disease progression on the most recent EGFR TKI therapy.
4) Patients with any cancers with abnormalities in ALK or other brigatinib targets (examples 
include, but are not limited to, ALCL, DLCL, IMT, and other cancers with ALK 
abnormalities, or tumors with ROS1 fusions).
5) NSCLC patients with ALK rearrangements who are either naive or resistant to crizotinib 
and who have active brain metastases.
The safety and tolerability of orally administered brigatinib will continue to be assessed in the 
expansion cohorts. However, the primary objective of the expansion component of the trial is to 
describe the preliminary efficacy of brigatinib in these patient populations. Overall response rate 
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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ARIAD Pharmaceuticals, Inc.
AP26113-11-101
AP26113
Statistical Analysis Plan
 
Page 8
treated as censored follow-up intervals. Interpretation of competing risks models is difficult 
in a small, non-randomized study with heterogeneous diagnoses, prior treatment histories, 
and on-study treatment experiences. 

The exploration of covariates on the safety and efficacy profiles of brigatinib will not be 
included in the main CSR. Very little inferential modeling is planned, even on an exploratory 
basis. Where sufficient data are available results will be broken out by important baseline 
disease characteristics such as diagnosis, mutation history, prior anti-cancer therapy, and 
presence of CNS (brain) metastases, but consideration of these characteristics will be 
accomplished through presentations on subsets of similar patients rather than model-building 
exercises. Exploration of covariates will be included in a separate exposure response report.

Separate primary endpoints were defined for the dose escalation cohort, expansion cohorts 1-
4, and expansion cohort 5 (See section 1.2 above). The determination of RP2D remains the 
primary endpoint of the dose escalation phase. However, it is more informative to group all
patients by important clinical characteristics such as tumor type and mutation history rather 
than the expansion cohort to which they were assigned in order to present primary efficacy 
estimates from the largest samples possible. Patients from the dose-escalation phase will be 
combined with those from across the expansion cohorts, according to starting dose regimen,
in order to provide the best possible characterizations of systemic and intracranial CNS 
response rates as well as other efficacy endpoints. Section 8.1 of the protocol states that data 
from patients in the expansion phase cohorts will be summarized together with data from
patients in the dose escalation cohorts, as appropriate. 

Time to progression (TTP) and time to treatment failure in patients who remain on brigatinib
after initial progression (both in protocol section 8.2.2) will not be estimated. The clinical 
relevance of TTP is better captured by estimation of progression-free survival, which will be 
presented in the CSR for all analysis populations of interest. Evaluation of endpoints 
following progression is not consistent with RECIST 1.1 guidelines.

Extra-CNS PFS will not be estimated in Cohort 5 patients (protocol section 8.2.2). The 
assessment of intracranial PFS was performed by an independent review committee (IRC) as 
defined by a charter, while no specific assessment was performed by the IRC to cover 
determination of extra-CNS disease burden. Robust analyses will be performed on 
investigator-performed whole-body disease assessments (RECIST 1.1) and the iCNS-specific 
assessments performed by the IRC. Investigation of progression excluding the CNS will best 
be accomplished by comparison of results of these analyses when performed as designed. 

A small number of patients were entered into the study without a measurable lesion at study 
entry, via a waiver of the relevant inclusion criteria. Such patients cannot be assessed as 
Partial Response (PR) or Stable Disease (SD) as defined by RECIST 1.1. They will be
assessed as CR, defined as complete clearance of all lesions observed at baseline, or PD, 
defined as progression of the baseline lesions or the appearance of new lesions. Evaluable 
assessments that do not meet either of these definitions are reported as non-Complete 
Response/non-Progressive Disease or non-CR/non-PD.
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AP26113
Statistical Analysis Plan
 
Page 9
1.2
Analysis Endpoints
1.2.1
Dose Escalation Phase
1.2.1.1
Primary Endpoint(s)
The primary endpoint of the dose escalation phase of the study is:

The primary endpoint of the dose escalation component of the study is the RP2D of 
orally administered brigatinib. 
1.2.1.2
Secondary Endpoint(s)
Secondary endpoints of the dose escalation component of the study include:
1.
MTD of orally administered brigatinib
2.
Safety, tolerability, and DLTs of brigatinib
3.
Plasma PK parameters of single-dose and steady state brigatinib
1.2.2
Efficacy Analysis
1.2.2.1
Primary Endpoint(s)
The primary efficacy endpoints of the study as stated in the protocol are:

The primary endpoint of expansion cohorts 1-4 is the overall response rate (using 
RECIST 1.1). 

The primary endpoint of expansion cohort 5 is CNS response rate (using RECIST 1.1). 
Note: The definitions for the 5 expansion cohorts were not entirely mutually exclusive and 
allowed patients to qualify for more than one expansion cohort. Also, many of the patients 
enrolled in the dose-escalation phase also met the qualifications for one or more of the expansion 
cohorts. RECIST 1.1 evaluations were performed for every patient when possible, and therefore 
disease assessment data for every patient enrolled can enhance the characterization of the anti-
tumor activity of brigatinib. Likewise, the intracranial CNS response was evaluated by 
independent review for every patient with available post-exposure brain scans. Therefore the 
analysis of efficacy endpoints has been simplified to present both systemic response using 
RECIST 1.1 (in all patients) and intracranial CNS response (in ALK+ NSCLC patients with 
intracranial CNS metastases at baseline), to the extent that data are available. 
1.2.2.2
Secondary Endpoint(s)
Secondary endpoints of the expansion cohort component of the study as stated in the protocol
include:
1.
Safety and tolerability of brigatinib
2.
Plasma PK parameters
3.
Efficacy assessments include: best target lesion response, PFS, TTP, and time to
treatment failure in patients who remain on study after RECIST 1.1 progression, but 
who continue to benefit according to the treating investigator. Overall survival (OS) 
will also be measured for up to 2 years following the first dose of brigatinib.

For cohort 5: additional efficacy assessments include: overall response rate using
RECIST 1.1, CNS PFS, and extra CNS PFS.
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AP26113
Statistical Analysis Plan
 
Page 10
Note: TTP and time to treatment failure will not be analyzed since they are not likely to make 
meaningful contributions beyond what is covered by PFS (see section 1.1.3 above). 
Progression free survival, duration of response and overall survival will be estimated using 
Kaplan-Meier methods.
1.2.2.3
Safety Endpoints
Safety will be characterized through the analysis of all relevant data including adverse events, 
laboratory measures, ECG, and vital signs as described starting in Section 4.4.9. 
1.2.2.4
Pharmacokinetic Analysis
A non-compartmental pharmacokinetic (PK) analysis will be performed on the concentration of 
brigatinib in blood samples drawn in both the escalation (phase 1) and expansion (phase 2) 
phases of the study. The following PK parameters single dose and at steady state will be 
determined: Cmax, AUC 0-tau, AUC 0-inf, Tmax, Thalf, Cl/F, V/F. Summary statistics will be 
produced by dose cohort. Dose proportionality for AUC and Cmax will be explored using 
regression.
2
STATISTICAL CONSIDERATIONS
2.1
Sample Size
This is a phase 1/2 study uses a 3+3 dose escalation design for the phase 1 component. The 
number of patients is consistent with phase 1 dose finding studies and depends on the number of 
dose cohorts needed to reach the maximum tolerated dose (MTD). With a 3+3 design, the 
estimate of the rate of DLT at the MTD is in the range of 0.17 to 0.26. The estimate of the rate of 
DLT at the highest dose, which is 1 step above the MTD, is 0.33 (Ting, 2006).
The sample size for the phase 2 component of the study is determined based on clinical rather 
than statistical considerations. The histologically and molecularly defined expansion cohorts will 
facilitate obtaining preliminary estimates of clinical activity and the cohort sizes are consistent 
with an early phase 2 study.
2.2
Randomization and Masking
This is a non-randomized open label study.
2.3
Handling of Data
Overall RECIST response at each evaluation will be used as recorded by the investigator and 
will not be determined by programmatic processing of the individual data from target, non-
target, and new lesions. Intracranial CNS response will be assessed by IRC and handled in the 
same way. 
Some adverse events are recoded to reduce the possibility of underreporting as described in 
4.4.8.
Date imputation is described in Appendix 3. Imputation of other data is not anticipated. 
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2.3.4
Prior Exposure to Crizotinib
Some analyses will be presented on patients who were, or were not, exposed to crizotinib prior to 
study entry. Subsets of patients based on crizotinib exposure will be drawn from the set of ALK+ 
NSCLC patients. 
2.3.5
CNS Metastases
Some tables and figures will be presented on subsets of patients selected on the basis of:

Presence or absence of CNS metastases at study entry

Presence of measurable CNS lesions at study entry

History of radiotherapy directed at CNS lesions
Subsets of patients based on CNS metastases criteria will be drawn from the set of ALK+ 
NSCLC patients unless otherwise specified. 
3
POPULATIONS FOR ANALYSIS
3.1
All Patients
Since treatment assignment in the study was not performed through an intention-to-treat method, 
such as randomization, the definition of an ITT population is not relevant. In addition, since all 
patients received at least 1 dose of brigatinib at the intended starting dose the standard definitions 
of Safety and Efficacy populations both select every patient who entered the study. Therefore 
analyses that do not specify subsets of patients will be reported under the All Patients heading. 
3.2
Pharmacokinetic (PK) population
All patients in the treated population with at least 1 PK concentration measurement.
4
STATISTICAL METHODS
4.1
Demographics, Baseline Characteristics, and Patient Disposition
Patient disposition will be tabulated by starting dose regimen and by categories as recorded by 
the investigator in the clinical database: ongoing, discontinued due to: Adverse Event, death, 
disease progression, lack of efficacy, physician decision, patient decision, and lost to follow up.
Demographic and baseline characteristics will be summarized overall and separately for each 
dose group. The following variables will be included: age, gender, race, weight, country/region, 
and disease characteristics (e.g., time since diagnosis, mutation status). Continuous variables will 
be summarized with descriptive statistics and categorical data will be presented in counts and 
percentages. 
Baseline disease characteristics will include ECOG performance status, time since diagnosis, 
diagnostic characteristics, prior therapies, and presence of CNS metastases. 
4.2
Study Drug Exposure
Study drug exposure will be summarized by number of doses, total cumulative dose, days from 
first dose to last dose), dose intensity (total dose/days from first to last dose) and maximum days 
of dose delay. Statistics will be produced for each starting dose regimen and overall. Compliance 
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will also be summarized, including percent compliance, and number of patients with a dose delay
of 3 or more days or dose reduction.
4.3
Efficacy Analysis
4.3.1
Primary Efficacy Analysis
Patients will be assessed with scans every 8 weeks. Objective Response Rate (ORR), defined as 
complete response (CR) or partial response (PR) by RECIST 1.1 prior to the first occurrence of 
PD, is the primary efficacy analysis endpoint.
Objective response rate with exact binomial 95% confidence intervals will be computed overall 
and by collapsed dose group. For patients with data from independent review of brain 
metastasizes a second objective response will be determined by restricting the RECIST 1.1 
criteria to brains lesions only (target, non-target and new lesions).
Time to first response will be analyzed using the Kaplan-Meier method. Patients who do not 
achieve response will be censored at the time of PD, if observed, or their last evaluable scan.
4.3.1.1
Determination of Intracranial CNS Response and Associated Endpoints
Assessment of anti-tumor activity in the brain has become an important aspect of TKI therapy in 
ALK+ NSCLC. Intracranial CNS response and progression will be evaluated for all patients 
determined to have brain metastases at baseline who have post-exposure CNS scans. Brain MRI 
scans were performed on all patients at Screening, but imaging assessments of the brain after 
initiating treatment with study drug were only performed for patients determined by the 
investigator to have brain metastases at Screening. All patients had their baseline MRI read by 
the IRC. Then, those who were identified as having baseline brain metastases had their on-study 
brain scans read. CT scans were not sent to the independent reviewers.
The assessment CNS response and progression requires special considerations that differ from 
RECIST 1.1. The first is that inclusion of target lesions in the brain is not required for RECIST 
1.1 if there is sufficient burden of disease elsewhere in the body to fulfill the limitation of 5 
target lesions. Another is that presence of measureable lesions outside the CNS combined with 
non-measurable lesions in the brain renders a patient evaluable by RECIST 1.1 but difficult to 
assess by the same standards when attempting a CNS-specific reading. 
MRI scans were sent to an Independent Review Committee (IRC) for blinded assessment of 
intracranial CNS response. The review methods followed a modification of RECIST 1.1. All
assessments for each patient were read by a single reader so no adjudication was employed. 
The principal modifications to RECIST 1.1 were: 
1) Reviewers only assessed MRI of the head, and no other body location were included in 
this review
2) Up to 5 target brain lesions were selected for following on subsequent scans. RECIST 1.1 
allows 5 total target lesions but limits the number of target lesions in a single body 
system to 2.
3) For this review, the reviewers were not given any history as to whether the subject had 
prior CNS radiation therapy or if there had been progression in the field since completion 
of therapy. Selection of Target and Non-target lesions selection was therefore not based 
on this clinical history. 
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4) Reviews were not provided with steroid dose information or the neurologic status of the 
subject.
Target CNS lesions had to meet the same definitions of measurability as used for RECIST 1.1 
response assessment. The process for selection of target, non-target and new lesions mirrored 
RECIST 1.1 as much as possible. Target lesions were to be measureable according to the same 
criteria as for systemic response and were tracked in the same way. Patients with no CNS lesions 
that could qualify as target lesions were tracked for progression or complete clearance of non-
target lesions. Evaluation of new lesions was performed consistently with systemic disease 
assessment. 
A special case in the selection of non-target lesions not described in RECIST 1.1 regards 
Leptomeningeal disease. It should be noted the presence of Leptomeningeal disease is an 
exclusion criteria for this study. However if in the opinion of the reviewer Leptomeningeal 
disease is present, it will be considered a non-target lesion.
Evaluation of response specific to target, non-target, and new lesions will proceed in the same 
manner as for RECIST, and the conversion of these three levels of response to time point 
response will also be the same. Conversion of timepoint response to other endpoints such as 
BOR or confirmed response will also be done in the same manner as for RECIST 1.1 response 
unless otherwise specified. 
4.3.1.2
Data 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. CAT scan and MRI). Scans within a +/- 2 day 
window scans will be “merged” lesion by lesion. If a lesion (target, non-target or new lesion) is 
on only 1 scan the evaluations of the multiple lesions will be 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 count as a new lesion. If a non-target lesion is present on multiple scans 
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.
The handling of contemporaneous scans was performed in the data management process prior to 
export for programming and analysis. 
4.4
Secondary Efficacy Analyses
Preliminary estimates of clinical activity including: progression free survival (PFS), duration of 
response, and time to response will be determined.
4.4.1
Best Overall Response (BOR).
Best overall response will be evaluated according to RECIST 1.1 criteria. For interim analyses 
patients who are still on study but have no follow up scans will be categorized as not evaluable.
Early, less than 26 days, scans showing stable disease (SD), PR or CR will not be evaluable for 
BOR. Early scans showing PD will be considered evaluable for BOR.
4.4.2
Confirmed Response
Patients who achieve PR or CR and who have subsequent RECIST 1.1 evaluations will be 
assessed for confirmation of response. To be considered the additional scans must be done on or 
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after Day 26 relative to the first scan showing response (defined as Day 1 in this context), with 
the exception that PD from a scan prior to Day 26 will define a response as unconfirmed. All 
scans after the first occurrence of PD will be excluded from consideration in the assessment of 
confirmed response.
Responses will be confirmed as follows:

PR can be confirmed by another PR or a CR

CR can only be confirmed by another CR
Scans assessed as Not Evaluated (NE) will not confirm a response. The first NE scan following
the initial response can be ignored, but more than one NE scan in a row will cause the first 
response to be unconfirmed. In this case even though the first response was unconfirmed later 
responses will still be eligible for confirmation. 
When confirming PR an assessment of SD will be treated as equivalent to NE. Therefore a single 
NE or SD will not cause failure to confirm the initial PR, but a subsequent scan of either type 
will render the initial PR to be unconfirmed. 
Analysis of confirmed response will be done in the same manner as for ORR. Time to response 
will count the first response for each patient for whom response was confirmed. Censoring for 
patients who never responded will be the same as for ORR. Followup for patients with 
unconfirmed response will also be censored at the first occurrence of PD (when observed) or the 
last evaluable scan.  
4.4.3
Best Confirmed Response
Best confirmed response is defined as the best response for each patient that met the definition of 
confirmed response. If a patient had scans of PR => CR => PD then:

The patient’s best overall response is CR

The patient’s best confirmed response is PR 
4.4.4
Progression-Free Survival
A key secondary endpoint for this trial is PFS. PFS is defined as the time from the date of first 
dose to the date of the first documented evidence of progressive disease (PD) or death 
(whichever occurs first). PFS time will be censored at the last date for which the tumor 
assessment resulted in the absence of PD for patients who have not demonstrated objective tumor 
progression and are still on trial. For patients who withdraw consent for any reason before 
demonstrating evidence of tumor progression or recurrence, PFS time will be censored at the last 
date for which the tumor assessment resulted in the absence of PD. Patients are censored at the 
date of first dose of study treatment if no additional follow-up data are obtained.
Included below is a table that summarizes the data handling rules for the analysis of PFS. The 
assumptions for the data handling conventions are as follows:

The assessment of tumor response will be based on the evaluations performed every 8 
weeks after first dose of trial treatment. Evidence of PD may be obtained at these 
scheduled visits, or obtained from disease evaluations conducted between scheduled 
visits, prompted by symptoms.
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
An adequate assessment will be defined as one where sufficiently clear radiological 
images are obtained so that changes in target lesions may be observed, or the presence of 
new lesions determined.

All events are based on well-documented and verifiable progression events or death. 
Patients not experiencing a PD event are censored at the last date that the patient was 
known to be progression-free. The progression dates are based only on radiographic 
assessments. Clinical progression is not considered a disease progression event and 
therefore is not part of the PFS analysis.

If one or more radiographic assessments are missing, the most recent date that a 
progression was documented will be used as the date of progression.

The date of progression is defined as the earliest date when tumor progression is noted.

For PFS, if PD is not documented, then the date of death will be defined as the date of 
progression.
Condition Date of progression or censoring
No progression
censored
One or more missed follow-up visits 
after which one of the following 
occurred:
• Patient withdrew consent
• Patient lost to follow-up
Date of last evaluable non-PD 
assessment
censored
New anticancer treatment started 
without evidence of PD prior to 
discontinuation of study treatment
Date of last evaluable non-PD 
assessment prior to starting new 
treatment 
censored
Progression documented between 
scheduled visits 
Date of radiographic assessment 
showing progression
progressed
Cancer-related surgery prior to 
documented progression
Date of surgery
censored
Treatment discontinuation for a 
reason other than documented disease 
progression or death
Follow patients until date of 
progression or death
If no event occurs, censor at last 
evaluable non-PD assessment, prior to 
initiation of subsequent anticancer 
therapy
progressed
censored
Death before first PD assessment
Or Death between adequate 
assessment visits
Date of death
progressed
Death or progression after last valid 
scan for assessment of disease burden
Patients will be followed until date of 
death or end of study participation. 
Death within 126 days of last valid scan
Death after 126 days of last valid scan
progressed
censored
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4.4.5
Duration of Response
The analysis of response duration will only include patients with confirmed CR or PR based on 
disease assessment by the investigator. 
Duration of response will be analyzed using the Kaplan-Meier method.The start of response will 
be the first date of observed response (PR or CR), and duration of response following response 
will use the censoring scheme described for PFS in the previous section. End of response will be 
observed if the response interval was ended by a PFS event, otherwise the response-time 
followup will be censored at the time of the last valid scan. The duration of response will be 
calculated as PFS Date – Response Date + 1.
4.4.6
Overall Survival
Overall survival (OS) will be determined by the number of days from first dose date to date of 
death. If the patient is lost to follow up, the time will be set to the last date that the patient was 
known to be alive and the observation will be censored. The same analytical methods will be 
applied to OS as were used for PFS. 
4.4.7
Health-Related Quality of Life (HRQoL) Measurement
Quality of life assessments are not being collected.
4.4.8
Patient-Reported Outcomes (PRO)
Patient-reported outcomes are not being collected.
4.5
Safety Analyses
4.5.1
Adverse Events
4.5.1.1
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.

In the case of missing onset date, impute using the rules defined in Appendix 3.
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4.5.1.2
Synonym Recoding
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 2. The lists of terms recoded through 
this process are subject to change as new events occur and/or MedDRA versions change.). Such 
events will be identified as “Treatment-Emergent 'Synonym Recoded' Preferred Term” in the 
titles of tables in which they are presented.
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 first be sorted in a 
descending order of incidence of any event in the SOC, then SOCs will be sorted alphabetically 
in case of tied incidence rates.
4.5.1.3
AEs in Special Categories
Custom groupings of adverse events have been created to facilitate the analysis of areas of 
concern specific to brigatinib. Some of these groupings are Standardized MedDRA queries 
(SMQ) or Modified MedDRA queries (MMQ). Others were created through medical review of 
existing PTs by the ARIAD Medical Monitor and/or other sponsor personnel. Presentations of 
this type are identified by inclusion of the phrase “in Special Categories” in the table titles. 
When more than one Special Category is presented in a table it is possible that a single PT will 
appear in more than one place on that table. 
4.5.1.4
Analysis of Adverse Events
Tables for AEs will be presented for all patients and for ALK+ NSCLC patients and will include:

A summary table with number of patients having any AE as well as any AE meeting 
criteria of interest such as relatedness, seriousness, severity, as well as combinations of 
these characteristics

A table by System Organ Class (SOC) and Preferred Term (PT) for each treatment-
emergent event, counting each patient once for each SOC and PT experienced, by:

All events

All serious events

All related events

All serious and related events

All Grade 3-5 events

All Grade 3-5 serious events

All Grade 3-5 related events

All Grade 3-5 serious and related events

AEs in special categories

Grade 3-5 AEs in special categories

Pulmonary AEs (pulmonary events are one of the special categories)

Grade 3-5 Pulmonary AEs 

Pulmonary AEs within 7 days of first dose

Pulmonary AEs within 14 days of first dose

Grade 3-5 Pulmonary AEs within 7 days of first dose
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
Grade 3-5 Pulmonary AEs within 14 days of first dose

Pulmonary AEs within 7 days of dose escalation – Dose escalation is defined as 
an increase in the total mg of brigatinib from the maximum dose received in the 
previous 7 days

Pulmonary AEs within 7 days of dose resumption – Dose resumption is defined as 
receipt of brigatinib after 7 or more days of no exposure to the drug
4.5.2
Laboratory Data
Laboratory data will be summarized as shift from baseline to highest on-study grade as defined 
by CTCAE 4.0. On-study grade will be defined using the minimum and/or maximum post-
exposure result as appropriate. For example, glucose will be evaluated for hypoglycemia using 
the patient’s minimum post-exposure value, and for hyperglycemia using the patient’s maximum 
post-exposure value. Testosterone, INR, and Insulin will get cross tabulated baseline, low, 
normal, high by highest and lowest value on study (low, normal, high).
4.5.3
Vital Signs
Systolic and diastolic blood pressure will be summarized as shift from baseline to highest on-
study grade as defined by CTCAE 4.0. On-study grade will be defined using the minimum 
and/or maximum post-exposure result as appropriate. Hypotension will be evaluated using the 
patient’s minimum post-exposure value SBP and DBP, and hypertension using the patient’s 
maximum post-exposure value. 
4.5.4
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 Fridericia correction (QTcF) will be used throughout.
QTcF change from baseline and blood concentration will be analyzed using mixed effects 
models. A detailed QT analysis will be specified in a separate analysis plan.
4.5.5
Other Measures
On-study assessments not covered by other sections of this document will be presented in 
summary tables of observed values and/or changes from baseline. 
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Appendix 1
Notes from RECIST v1.1
Appendix 1.1
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 1.2
Target Lesions vs. Non-target Lesions vs. New Lesions
1. Target lesions
a.
A maximum of five total (and two per organ, maximum) of lesions or 
pathological lymph nodes will be identified at baseline to follow up to assess 
tumor burden in target lesions for response determination.  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 1.3
Time Point Overall Response Status and Best Overall Response Status 
Calculation
Appendix Table 1
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.
Appendix Table 2
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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Appendix Table 3
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 2
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
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blood glucose 
decreased
Investigations
Hypoglycaemia
Metabolism and 
Nutrition Disorders
Hypoglycemia
Metabolism and Nutrition 
Disorders
Hypoglycaemia
Metabolism and 
Nutrition Disorders
blood glucose increased
Investigations
Hyperglycaemia
Metabolism and 
Nutrition Disorders
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
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Blood Phosphorus 
decreased
Investigations
Hypophosphataemia
Metabolism and 
Nutrition Disorders
blood phosphate 
decreased
Investigations
Hypophosphataemia
Metabolism and 
Nutrition Disorders
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
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
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Troponin I increased
Investigations
Troponin increased
Investigations
painful defaecation
Gastrointestinal Disorders
proctalgia
Gastrointestinal 
Disorders
blood pressure 
increased
Investigations
hypertension
Vascular disorders
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
Myocardial Infarction
Cardiac Disorders
Acute Myocardial 
Infarction/Myocardial 
Infarction
Cardiac Disorders
Acute Myocardial 
Infarction
Cardiac Disorders
Acute Myocardial 
Infarction/Myocardial 
Infarction
Cardiac 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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Appendix 3
Date Handling and Imputation
Calculation of Study Day
Study Day is defined as the date an event occurred – date of first dose of study drug +1.Unless 
otherwise specified other date calculations will be defined as the difference between the dates + 
1.
Calculation of Months
Intervals expressed in days will be converted to months by # days / 30.4375.
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
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.
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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.
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.
   
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