A Phase 2, Multicenter, Randomized Study of AP26113

This is a randomized, phase 2, open-label, multicenter, international study to evaluate the
efficacy and safety of two different dosing regimens of AP26113 in patients with
ALK-positive, locally advanced or metastatic NSCLC who have previously been treated with
crizotinib.

The primary objective of the study is to determine the efficacy of AP26113, as evidenced by
confirmed objective response rate (ORR), as assessed by the investigator, per Response
Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two dosing regimens will be
tested. The secondary objectives of the study (for each dosing regimen) include confirmed
ORR, as assessed by a central independent review committee (IRC), per RECIST v1.1; CNS
response (ORR and progression free survival [PFS]), per RECIST v1.1, in patients with active
brain metastases); time to/duration of response; time on treatment; disease control rate,
per RECIST v.1.1; PFS; overall survival (OS); safety and tolerability; population
pharmacokinetics (PK); and patient-reported symptoms of lung cancer and health-related
quality of life (HRQoL). Exploratory objectives (for each dosing regimen) include
correlation of AP26113 exposure with both efficacy and safety and correlation of tumor and
plasma biomarkers with AP26113 efficacy and safety. It is estimated that accrual will be
completed within 18 months; the total estimated duration of the study is 3 years.

Inclusion Criteria:

1. Have histologically or cytologically confirmed locally advanced or metastatic NSCLC
that is ALK+.

2. Must meet one of the following two criteria:

1. Have documented ALK rearrangement by a positive result from the Vysis® ALK
Break-Apart fluorescence in situ hybridization (FISH) Probe Kit; or

2. Have documented ALK positivity by a different test and tissue available for the
Vysis® FISH test. Tissue should be derived preferably from a biopsy taken after
progression with crizotinib. If such a sample is not available, testing may be
performed with archived tumor tissue.

3. Had progressive disease while on crizotinib, as assessed by the investigator or
treating physician.

4. Have at least 1 measurable lesion per RECIST v1.1. Note: Previously irradiated
lesions may not be used for target lesions, unless there is unambiguous radiological
progression after radiotherapy. Brain lesions may not be used as target lesions if
they were: 1) previously treated with whole brain radiation therapy (WBRT) within 3
months, or 2) previously treated by stereotactic radiosurgery (SRS) or surgical
resection.

5. Recovered from toxicities related to prior anticancer therapy to National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, v4.0) grade
≤2.

6. Are a male or female patient ≥18 years old.

7. Have a life expectancy ≥3 months.

8. Have adequate organ and hematologic function, as determined by:

1. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 x upper
limit of normal (ULN; ≤5 x ULN is acceptable if liver metastases are present)

2. Total serum bilirubin ≤1.5 x ULN (<3.0 x ULN for patients with Gilbert syndrome)

3. Serum creatinine ≤1.5 x ULN

4. Serum lipase/amylase ≤1.5 x ULN

5. Absolute neutrophil count (ANC) ≥1500/µL

6. Platelets ≥75000/µL

7. Hemoglobin ≥10 g/dL

9. Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

10. Have normal QT interval on screening electrocardiogram (ECG) evaluation, defined as
QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females.

11. For female patients of childbearing potential, a negative pregnancy test must be
documented prior to enrollment.

12. Female and male patients who are fertile must agree to use a highly effective form of
contraception with their sexual partners throughout study participation.

13. Must provide a signed and dated informed consent indicating that the patient has been
informed of all pertinent aspects of the study, including the potential risks, and is
willingly participating.

14. Have the willingness and ability to comply with scheduled visits and study
procedures.

Exclusion Criteria:

1. Received any prior ALK-targeted TKI other than crizotinib.

2. Received crizotinib within 3 days of the first dose of AP26113 (Day 1, Cycle 1).

3. Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days,
except SRS or stereotactic body radiosurgery.

4. Received monoclonal antibodies or had major surgery within 30 days of the first dose
of AP26113 (Day 1, Cycle 1).

5. Have been diagnosed with another primary malignancy within the past 3 years (except
for adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate
cancer, which are allowed within 3 years).

6. Have symptomatic CNS metastases that are neurologically unstable or require an
increasing dose of corticosteroids.

7. Have current spinal cord compression.

8. Have significant, uncontrolled, or active cardiovascular disease, specifically
including, but not restricted to:

1. Myocardial infarction (MI) within 6 months prior to the first dose of AP26113

2. Unstable angina within 6 months prior to first dose

3. Congestive heart failure (CHF) within 6 months prior to first dose

4. History of clinically significant (as determined by the treating physician)
atrial arrhythmia

5. Any history of ventricular arrhythmia

6. Cerebrovascular accident or transient ischemic attack within 6 months prior to
first dose

9. Have a history or the presence of pulmonary interstitial disease or drug-related
pneumonitis.

10. Have an ongoing or active infection. The requirement for intravenous (IV) antibiotics
is considered active infection.

11. Have a known history of human immunodeficiency virus (HIV). Testing is not required
in the absence of history.

12. Have a history of or active significant gastrointestinal (GI) bleeding within 3
months of the first dose of AP26113.

13. Have a known or suspected hypersensitivity to AP26113 or its excipients.

14. Have malabsorption syndrome or other GI illness that could affect oral absorption of
the study drug.

15. Have any condition or illness that, in the opinion of the investigator, would
compromise patient safety or interfere with evaluation of the drug study.

16. Be pregnant or breastfeeding.