Trial of Dose Escalated BGB324 in Previously Treated Non-small Cell Lung Cancer.

Lung cancer remains the leading cause of cancer-related deaths worldwide with an estimated
incidence of 1.6 million cases resulting in 1.4 million deaths in annually. Non-small-cell
lung cancer (NSCLC) represents 80-85% of cases, and adenocarcinoma is the most common
histology.2 The majority of NSCLC patients present with advanced or metastatic disease that
is not amenable to surgical resection. Platinum-based combination chemotherapy has reached a
therapeutic plateau with a median overall survival (OS) of 7.4 to 9.9 months.

BGB324 is a potent selective small molecule inhibitor of Axl, a surface membrane protein
kinase receptor that is over-expressed in many metastatic solid tumors and has been
identified as a marker of a poor prognosis in patients with non-small cell lung cancer
(NSCLC).

Inclusion Criteria:

A patient is eligible for the study if the following criteria are met:

1. Provision of written informed consent to participate in this investigational study

2. Histologically or cytologically confirmed advanced (stage 4, according to the American
Joint Committee on Cancer [AJCC] Staging manual) NSCLC

3. Up to three previous lines of therapy, of which one must have been a platinum-based
doublet therapy and no more than two were cytotoxic chemotherapy.

4. Radiographic disease recurrence or progression during or after the last line of
chemotherapy

5. Patients with known activating EGFR mutations or ALK rearrangements should have
progressed after appropriate targeted treatment in addition to progressing during or
after platinum-based doublet chemotherapy

6. European Cooperative Oncology Group (ECOG) performance status 0 or 1

7. Age 18 years or older

8. Measurable or evaluable disease according to RECIST v1.1

9. Previously treated brain metastases (surgery and/or radiation therapy) are eligible,
provided that patients are asymptomatic and not requiring corticosteroids

10. The following minimum intervals are required between prior treatment and initiation of
study therapy:

Cytotoxic chemotherapy: 3 weeks Molecularly targeted therapy or immunotherapy: 2 weeks
Conventional fractionated radiation therapy: 2 weeks Stereotactic radiation therapy: 1
week Major surgery: 3 weeks

11. Adequate hematologic function (absolute neutrophil count [ANC] ≥ 1500 cells/µL;
hemoglobin ≥ 9 g/dL; platelets ≥ 100,000/µL

12. Adequate renal function (serum creatinine ≤ 1.5 mg/dL or calculated creatinine
clearance ≥ 50 mL/min using the Cockcroft-Gault equation)

13. Adequate hepatic function: total bilirubin ≤ upper limit of normal [ULN], alanine
aminotransferase [ALT] ≤ 1.5 x ULN, aspartate aminotransferase [AST] ≤ 1.5 x ULN). ALT
and AST ≤ 5x ULN if documented liver metastases

14. Previous treatment-associated toxicities resolved to CTCAE grade ≤2 (except alopecia)

15. Adequate archival tissue (10-15 slides, or 5 slides with 3 sections per slide) for
biomarker analysis

16. Female patients of childbearing potential must have a negative serum pregnancy test
within 7 days prior to taking their first dose of BGB324. Male patients and female
patients of reproductive potential must agree to practice highly effective methods of
contraception (such as hormonal implants, combined oral contraceptives, injectable
contraceptives, intrauterine device with hormone spirals, total sexual abstinence,
vasectomy) throughout the study and for ≥3 months after the last dose of BGB324.
Female patients are considered NOT of childbearing potential if they have a history of
surgical sterility, including tubal ligation, or evidence of post-menopausal status
defined as any of the following:

- Natural menopause with last menses >1 year ago

- Radiation induced oophorectomy with last menses >1 year ago

- Chemotherapy induced menopause with last menses >1 year ago

Exclusion Criteria

A patient is excluded from the study if any of the following criteria are met:

1. Pregnant or lactating

2. Abnormal left ventricular ejection fraction on echocardiography (less than the lower
limit of normal for a patient of that age at the treating institution or <45%)

3. History of an ischemic cardiac event including myocardial infarction within 3 months
of study entry

4. NSCLC with evidence of a centrally cavitating lesion

5. Peripheral neuropathy NCI CTCAE ≥Grade 2 at baseline

6. Pulmonary hemorrhage or hemoptysis > 2.5 mL blood within 6 weeks (or within 2 weeks if
source definitively treated [eg, radiation therapy or bronchoscopic procedure])

7. Congestive cardiac failure of >Grade 2 severity according to the NYHA defined as
symptomatic at less than ordinary levels of activity

8. Unstable cardiac disease, including unstable angina or unstable hypertension, as
defined by the need for change in medication for lack of disease control within the
last three months

9. History or presence of sustained bradycardia (less than or equal to 60 BPM) or history
of symptomatic bradycardia, left bundle branch block, cardiac pacemaker or significant
atrial tachyarrhythmias , as defined by the need for treatment

10. Previous treatment with docetaxel or an Axl inhibitor

11. Current treatment with agents that may prolong QT interval and may cause Torsade de
Points which cannot be discontinued at least five half-lives prior to treatment.
Please see Appendix J for list of relevant medications

12. Known family or personal history of long QTc syndrome or ventricular arrhythmias
including ventricular bigeminy

13. Previous history of Grade 3 or worse drug-induced QTc prolongation requiring treatment
withdrawal

14. Screening 12-lead ECG with a measurable QTc interval according to Fridericia's
correction >450 ms

15. Ongoing infection requiring systemic treatment

16. Inability to tolerate oral medication

17. Impaired coagulation as evidenced by:

- INR >1.5 times ULN, or

- aPTT > 1.5 times ULN

18. Clinically active existing gastrointestinal disease affecting drug absorption, such as
celiac disease or Crohn's disease

19. Previous bowel resection anticipated to affect drug absorption

20. Any evidence of severe or uncontrolled systemic conditions (e.g., severe hepatic
impairment) or current unstable or uncompensated respiratory or cardiac conditions
which makes it undesirable for the patient to participate in the study or which could
jeopardize compliance with the protocol

21. Treatment with any medication which is predominantly metabolized by CYP3A4 and has a
narrow therapeutic index

22. Active, uncontrolled central nervous system (CNS) disease

23. Known active infection with human immunodeficiency virus (HIV), hepatitis B or C
viruses (screening not required)

24. Major surgery within 28 days prior to the start of BGB324, excluding skin biopsies and
procedures for insertion of central venous access devices