| Eligibility |
General Criteria
1. Provision of written informed consent to participate in this investigational study.
2. Histological or cytological confirmation of Stage IIIb or Stage IV (unresectable)
NSCLC.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
4. Age 18 years or older at the time of consent.
5. Female participants of childbearing potential must have a negative serum pregnancy
test within 7 days prior to taking their first dose of BGB324. Male participants and
female participants 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 participants are considered NOT to be 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.
Additional Inclusion Criteria for Run-in Cohort
6. Has received previous systemic therapy for unresectable NSCLC.
7. Has exhausted existing licensed therapies, or is unsuitable for treatment with
existing licensed therapies for NSCLC.
Additional Inclusion Criteria for Arm A
8. Known EGFR mutation status.
9. Either:
1. Has received >=6 weeks historical treatment with erlotinib. Erlotinib treatment
must be re started >=1 week before the first dose of BGB324 (Cycle 1, Day 1).
Or:
2. Is currently receiving erlotinib treatment for NSCLC and will have received >=6
weeks treatment at the time of the first dose of bemcentinib (Cycle 1, Day 1).
10. Erlotinib related toxicities being well-controlled and <Grade 3 in severity at the
time of the first dose of BGB324 (Cycle 1, Day 1).
11. Toxicity from other prior therapy has resolved to <=Grade 1 (previous treatment with
bevacizumab and other licensed antibody therapies is permitted).
Additional Inclusion Criteria for Arm B
12. Participants must have documented EGFR mutation (including exon 19 deletion or exon 21
L85R substitution or other rearrangement of the EGFR gene). EGFR mutation may be
confirmed historically (prior to study entry) and during the 28 day screening period
confirmation of negative T790M status (confirmed with blood test or biopsy from a
progressing tumor). Participants who have previously been treated with a T790M
inhibitor (i.e., osimertinib) and have progressed will not require T790M testing.
13. Disease that is measurable according to the response evaluation criteria in solid
tumors (RECIST) Version 1.1.
14. Has progressed after receiving erlotinib or any other an approved EGFR inhibitor
(i.e., afatinib, or gefitinib) at any time during therapy for advanced disease.
15. Erlotinib related toxicities being well-controlled and <Grade 3 in severity at the
time of the first dose of BGB324 (Cycle 1, Day 1). Toxicities associated with other
EGFR inhibitors to be <Grade 2 in severity at the time of first dose of BGB324.
16. Participants must have completed afatinib and/or gefitinib treatment at least 1 week
before the first dose of BGB324.
17. Toxicity from other prior therapy has resolved to <=Grade 1 (previous treatment with
bevacizumab and other licensed antibody therapies is permitted).
18. Participants who have an activating EGFR mutation may have up to 4 lines of previous
treatment in the advanced setting. Additional chemotherapy may also have been given
for treatment of limited stage disease in the adjuvant setting provided this was
completed at least 6 months prior to study treatment.
Additional Inclusion Criteria for Arm C
19. Known EGFR mutation status:
20. Presence of an activating EGFR mutation (including exon 19 deletion or exon 21 [L858R]
substitution mutation or other rearrangement of the EGFR gene).
21. Disease that is measurable or evaluable according to RECIST Version 1.1.
22. Is currently receiving erlotinib for NSCLC and will have received >=12 weeks'
treatment at the time of the first dose of BGB324 (Cycle 1, Day 1).
23. Have erlotinib related toxicities that are well controlled and <Grade 3 in severity
the time of the first dose of BGB324 (Cycle 1, Day 1).
24. No prior treatment for advanced NSCLC except erlotinib and/or previous surgery
(participants who have received treatment for their NSCLC while awaiting confirmation
of EGFR status, may be eligible to participate and the inclusion of such participants
should be discussed with the Medical Monitor).
Exclusion Criteria
1. Pregnant or lactating.
2. Abnormal left ventricular ejection fraction (less than the lower limit of normal for a
participants of that age at the treating institution or <45%).
3. Treatment with any of the following; histamine receptor 2 inhibitors, proton pump
inhibitors or antacids within 3 days or 5 half-lives, whichever is longer. The
Investigator may initiate rescue treatment with these medications during the study,
providing they are taken in the evening.
4. History of an ischemic cardiac event, including myocardial infarction, within 3 months
of consent.
5. Pulmonary hemorrhage or hemoptysis >2.5 mL blood within 6 weeks of consent unless
cause has been addressed and is medically resolved.
6. Congestive cardiac failure of >Class II severity according to the New York Heart
Association (NYHA) defined as symptomatic at less than ordinary levels of activity.
7. Unstable cardiac disease, including unstable angina or unstable hypertension, as
defined by the need for change in medication for lack of disease control within 3
months of consent.
8. History or presence of sustained bradycardia (<=60 bpm) or history of symptomatic
bradycardia, left bundle branch block, cardiac pacemaker or significant atrial
tachyarrythmias, as defined by the need for treatment.
tachyarrythmias, as defined by the need for treatment.
9. Current treatment with agents that may prolong QT interval and may cause Torsade de
Points which cannot be discontinued at least 2 weeks prior to treatment.
10. Known family or personal history of long QTc syndrome or ventricular arrhythmias
including ventricular bigeminy.
11. Previous history of >=Grade 3 drug-induced QTc prolongation.
12. Screening triplicate 12-lead electrocardiogram (ECG) with an average measurable
interval utilizing Fridericia's correction (QTcF) >450 ms.
13. Inadequate liver function as demonstrated by:
- Serum bilirubin >=1.5 times the upper limit of normal range (ULN); or
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >=2.5 times
the ULN (up to 5 times the ULN in the presence of liver metastases).
14. Inability to tolerate oral medication.
15. Impaired coagulation as evidenced by:
1. International normalized ratio (INR) >1.5 times ULN (or equivalent); or
2. Activated partial thromboplastin time (aPTT) >1.5 times ULN.
16. Existing gastrointestinal disease affecting drug absorption, such as celiac disease or
Crohn's disease.
17. Previous bowel resection that may impair study drug absorption.
18. Impaired renal function as demonstrated by creatinine clearance of <=50 mL/min
determined by Cockcroft Gault formula.
19. Absolute neutrophil count <1.5 x 109/L, hemoglobin <9.0 g/dL, platelet count <100 x
109/L in the absence of blood product support.
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 participant 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; (previously-treated CNS
metastases that are asymptomatic and do not require steroid treatment are allowed).
Note: Participants with known CNS metastases who have completed radiotherapy at least
2 weeks prior to BGB324 treatment are eligible.
23. Known active infection with human immunodeficiency virus (HIV), hepatitis B or C
viruses (screening not required):
- Participants who have a history of hepatitis B infection are eligible provided
they are hepatitis B surface antigen negative.
- Participants who have a history of hepatitis C infection are eligible provided
they have no evidence of hepatitis C ribonucleic acid using a quantitative
polymerase chain reaction assay at least 6 months after completing treatment for
hepatitis C infection.
24. Major surgery requiring general anesthesia within 28 days prior to the start of
BGB324, excluding biopsies and procedures for insertion of central venous access
devices.
25. Treatment with cytotoxic chemotherapy, within the 3 weeks prior to the first dose of
BGB324 (Cycle 1, Day 1) with the exception of treatment with other EGFR inhibitors
which must be completed 1 week prior to commencing treatment with BGB324. There is no
requirement to discontinue ongoing treatment with erlotinib.
26. Treatment with other non-cytotoxic agents for NSCLC in the 10 days or 4 half-lives,
prior to the first dose of BGB324 (Cycle 1, Day 1) whichever is shorter.
27. Prior biological therapies in the 4 weeks (or 5 half lives, whichever is shorter)
before the first dose of BGB324 (Cycle 1, Day 1). Note prior treatment with an
alternative EGFR inhibitor and/or programmed cell death protein 1 (PD-1) blockade is
permitted.
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