A Phase 1/2 multi-center open-label study of BGB324 (bemcentinib) as a single agent (Run-in Cohort) and in combination with erlotinib (Arms A, B, and C) in participants with Stage IIIb or Stage IV non-small cell lung cancer (NSCLC). Bemcentinib is a potent selective small molecule inhibitor of AXL, a surface membrane protein kinase receptor which is connected with poor prognosis and acquired resistance to therapy.

This is a multi-center, multi-arm open-label Phase 1/2 study that was conducted at 10 clinical sites in the United States and in Europe.

Total 40 participants with histologically- or cytologically-confirmed Stage IIIb or Stage IV NSCLC received bemcentinib (BGB324) as a single agent (Run-in Cohort) or in combination with erlotinib (Arms A, B, and C).

Run-in Arm to establish the safety and tolerability of bemcentinib (BGB324) administered as a single agent; bemcentinib was administered at a loading dose of 600 mg on Day 1 and Day 2 of Cycle 1, followed by 200 mg daily thereafter. After 6 participants have been dosed and safety established; Arm A (dose escalation arm) was opened to confirm the bemcentinib dose to be used in combination with erlotinib.

In Arm A the dose of bemcentinib (BGB324) was escalated in a standard 3+3 fashion until a maximum tolerated dose (MTD) of the combination (bemcentinib + erlotinib) was established. The dose of bemcentinib to be investigated in Arm B and C was confirmed upon recommendation of a Safety Review Committee.

Arm B and C was open in parallel to investigate bemcentinib in combination with erlotinib.

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 bemcentinib. 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 bemcentinib. 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 bemcentinib (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 bemcentinib (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 (the 28-day screening period could be extended to allow for confirmation of the T790M status. Other assessments including computed tomography were conducted in the 28-day screening period).

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 bemcentinib (Cycle 1, Day 1). Toxicities associated with other EGFR inhibitors to be <Grade 2 in severity at the time of first dose of bemcentinib.

16. Participants must have completed afatinib and/or gefitinib treatment at least 1 week before the first dose of bemcentinib.

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 bemcentinib (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 bemcentinib (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 tachyarrhythmias, as defined by the need for treatment.

   tachyarrhythmias, 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 12-lead triplicate 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 bemcentinib 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 bemcentinib, 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 bemcentinib (Cycle 1, Day 1) with the exception of treatment with other EGFR inhibitors which must be completed 1 week prior to commencing treatment with bemcentinib. 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 bemcentinib (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 bemcentinib (Cycle 1, Day 1). Note prior treatment with an alternative EGFR inhibitor and/or programmed cell death protein 1 (PD-1) blockade is permitted.

Individual participant data that underlie the results reported in the article, after deidentification [text, tables, figures and appendices].

Beginning 3 months and ending 5 years following article publication

Proposal should be directed to HYPERLINK mail to: registry.postings@bergenbio.com. To gain access, data requestors will need to sign a data access agreement.