A Study of BGB324 (Bemcentinib) in Combination With Erlotinib in Patients With Non-Small Cell Lung Cancer

A Multi-Center Open-Label Phase 1/2 Study of BGB324 in Combination With Erlotinib in Patients With Stage IIIb or Stage IV Non-Small Cell Lung Cancer

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.

Study Overview

• Status: Completed
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Bemcentinib; Drug: Bemcentinib; Drug: Bemcentinib; Drug: Erlotinib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093-0698
      • UC San Diego Moores Cancer Center
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Indiana
    • Lafayette, Indiana, United States, 47905
      • Horizon Oncology Research,
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • The Sarah Cannon Research Institute Tennessee Oncology PLLC
  • Texas
    • Dallas, Texas, United States, 75230
      • Mary Crowley Cancer Research Centers
    • Dallas, Texas, United States, 75390-8852
      • Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Oncology Consultants PA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1- Run in Arm (Bemcentinib Monotherapy); Participants in this arm received bemcentinib as monotherapy. This was to determine the safety and tolerability of bemcentinib when administered alone.	Drug: Bemcentinib; Participants received bemcentinib 600 mg on Days 1 and 2 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.; Other Names: BGB324; Drug: Bemcentinib; Participants received starting loading dose of bemcentinib 600 mg (200 mg on Days 1, 2 and 3) and bemcentinib 100 mg as daily maintenance dose for the 21-day cycle. Depending on tolerability and DLT, the loading dose of bemcentinib was escalated to 800mg (400 mg on Days 1 and 2) and bemcentinib 100 mg as daily maintenance for the 21- day cycle and to 1200 mg daily (600 mg on Days 1 and 2, or 400 mg on Days 1, 2 and 3) and bemcentinib 200 mg as daily maintenance for the 21- day cycle).; Other Names: BGB324; Drug: Bemcentinib; Participants received bemcentinib 400 mg on Days 1, 2 and 3 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.; Other Names: BGB324
Experimental: Phase 1- Arm A (Bemcentinib + Erlotinib); Participants in this arm received erlotinib with bemcentinib. A standard 3+3 design to determine the dose of bemcentinib that could be safely administered in combination with erlotinib in participants who had received prior treatment with erlotinib. This was to determine the maximum tolerated dose of bemcentinib that could be safely administered with erlotinib.	Drug: Bemcentinib; Participants received bemcentinib 600 mg on Days 1 and 2 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.; Other Names: BGB324; Drug: Bemcentinib; Participants received starting loading dose of bemcentinib 600 mg (200 mg on Days 1, 2 and 3) and bemcentinib 100 mg as daily maintenance dose for the 21-day cycle. Depending on tolerability and DLT, the loading dose of bemcentinib was escalated to 800mg (400 mg on Days 1 and 2) and bemcentinib 100 mg as daily maintenance for the 21- day cycle and to 1200 mg daily (600 mg on Days 1 and 2, or 400 mg on Days 1, 2 and 3) and bemcentinib 200 mg as daily maintenance for the 21- day cycle).; Other Names: BGB324; Drug: Bemcentinib; Participants received bemcentinib 400 mg on Days 1, 2 and 3 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.; Other Names: BGB324; Drug: Erlotinib; Participants received erlotinib 150 mg for the 21-day cycle.; Other Names: Tarceva
Experimental: Phase 2- Arm B (Bemcentinib + Erlotinib); Participants in this arm received erlotinib with bemcentinib in participants with an activating epidermal growth factor receptor (EGFR) mutation who are T790M negative and who had progressed after receiving treatment with an approved EGFR tyrosine kinase inhibitor (TKI) [osimertinib, afatinib, or gefitinib].	Drug: Bemcentinib; Participants received bemcentinib 600 mg on Days 1 and 2 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.; Other Names: BGB324; Drug: Bemcentinib; Participants received starting loading dose of bemcentinib 600 mg (200 mg on Days 1, 2 and 3) and bemcentinib 100 mg as daily maintenance dose for the 21-day cycle. Depending on tolerability and DLT, the loading dose of bemcentinib was escalated to 800mg (400 mg on Days 1 and 2) and bemcentinib 100 mg as daily maintenance for the 21- day cycle and to 1200 mg daily (600 mg on Days 1 and 2, or 400 mg on Days 1, 2 and 3) and bemcentinib 200 mg as daily maintenance for the 21- day cycle).; Other Names: BGB324; Drug: Bemcentinib; Participants received bemcentinib 400 mg on Days 1, 2 and 3 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.; Other Names: BGB324; Drug: Erlotinib; Participants received erlotinib 150 mg for the 21-day cycle.; Other Names: Tarceva
Experimental: Phase 2- Arm C (Bemcentinib + Erlotinib); Participants in this arm received erlotinib daily along with bemcentinib in participants with an activating EGFR mutation (including exon 19 deletion or exon 21 [L858R] substitution or other rearrangement of the EGFR gene mutation) who had received greater than or equal to (≥) 12 weeks of erlotinib without disease progression.	Drug: Bemcentinib; Participants received bemcentinib 600 mg on Days 1 and 2 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.; Other Names: BGB324; Drug: Bemcentinib; Participants received starting loading dose of bemcentinib 600 mg (200 mg on Days 1, 2 and 3) and bemcentinib 100 mg as daily maintenance dose for the 21-day cycle. Depending on tolerability and DLT, the loading dose of bemcentinib was escalated to 800mg (400 mg on Days 1 and 2) and bemcentinib 100 mg as daily maintenance for the 21- day cycle and to 1200 mg daily (600 mg on Days 1 and 2, or 400 mg on Days 1, 2 and 3) and bemcentinib 200 mg as daily maintenance for the 21- day cycle).; Other Names: BGB324; Drug: Bemcentinib; Participants received bemcentinib 400 mg on Days 1, 2 and 3 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.; Other Names: BGB324; Drug: Erlotinib; Participants received erlotinib 150 mg for the 21-day cycle.; Other Names: Tarceva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAE)	An adverse event (AE) is any untoward medical occurrence in participants, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as AEs that occurred from the first dose of study drug administration up to 28-days post last dose of study drug.	First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Number of Participants With Clinically Significant Laboratory Abnormalities	Laboratory evaluation: assessment of hematology, clinical chemistry, coagulation, and urinalysis. Hematology assessment: full blood count including differential white cell count, hemoglobin, hematocrit and platelets. Clinical chemistry assessment: potassium, calcium, uric acid, electrolytes, blood urea nitrogen, total protein, total bilirubin, alanine aminotransferase, aspartate aminotransferase, creatinine, creatine phosphokinase, alkaline phosphatase, albumin, phosphorus, glucose, magnesium plus amylase and lipase. Coagulation assessment: prothrombin time and/or international normalized ratio, activated partial thromboplastin time. Urinalysis: dipstick measurement of blood, nitrite, glucose, ketones, leukocytes, protein, and pH. Clinical significance was determined based on investigator's decision. In this outcome measure number of participants with clinically significant abnormalities in assessment of hematology, clinical chemistry, coagulation, and urinalysis are reported.	First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at End of Study	The ECOG performance status was scored on a scale of Grade 0 to 5, where: 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, e.g. 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. Higher scores indicated worse condition. Number of participants with each ECOG Grade were reported.	End of study visit was 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Number of Participants With Clinically Significant Change From Baseline in Physical Examination, Vital Signs, and 12- Lead Triplicate Electrocardiogram (ECG) Parameters up to End of Study	Number of participants with clinically significant change from baseline in physical examination, vital signs (including blood pressure, pulse, respiratory rate and oral temperature) and 12-lead triplicate ECG parameters was reported. Clinically significant abnormalities were based on the investigator's decision.	Baseline up to end of the study (28 days post last dose; maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Number of Participants With Clinically Significant Abnormalities in Echocardiogram and Multi-gated Acquisition (MUGA) Scan	Number of participants with clinically significant abnormalities in echocardiogram and MUGA scan was reported. MUGA scan is used to measure the ejection fraction, which reports how well heart is functioning. Clinically significant abnormalities were based on the investigator's decision.	First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) Over 24 Hours at Steady State of Bemcentinib	The AUC is defined as the area under the curve over 24 hours at steady state. The AUC 0- 24 hours using the linear trapezoidal method was summarized using the predicted plasma concentrations at steady state.	Arm A only: Cycle(C)1 Day(D)1: Predose, 2, 4, 6, 8 & 24h post-dose; Arm B only: C1D1 & D2: Predose; Arms A&B: C1D8: Predose, 2, 4, 6, 8 & 24h post-dose: C1D15, C2D1,8 & 15, C3D1: Predose and End of Study
Maximum Observed Plasma Concentration (Cmax) of Bemcentinib	Cmax was defined as the observed maximum plasma concentration after single dose administration. Cmax was summarized using the predicted plasma concentrations at steady state.	Arm A only: Cycle(C)1 Day(D)1: Predose, 2, 4, 6, 8 & 24h post-dose; Arm B only: C1D1 & D2: Predose; Arms A&B: C1D8: Predose, 2, 4, 6, 8 & 24h post-dose: C1D15, C2D1,8 & 15, C3D1: Predose and End of Study
Time to Reach Maximum Plasma Concentration (Tmax) of Bemcentinib	The Tmax defined as the time taken to reach Cmax. The Tmax was summarized using the predicted plasma concentrations at steady state.	Arm A only: Cycle(C)1 Day(D)1: Predose, 2, 4, 6, 8 & 24h post-dose; Arm B only: C1D1 & D2: Predose; Arms A&B: C1D8: Predose, 2, 4, 6, 8 & 24h post-dose: C1D15, C2D1,8 & 15, C3D1: Predose and End of Study
AUC Over 24 Hours at Steady State of Erlotinib	The AUC 0-24 is defined as the area under the curve over 24 hours at steady state. The AUC 0- 24 hours using the linear trapezoidal method was summarized using the predicted plasma concentrations at steady state.	At Day 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days)
Cmax of Erlotinib	Cmax was defined as the observed maximum plasma concentration after single dose administration. Cmax was summarized using the predicted plasma concentrations at steady state.	At Day 1 and 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days)
Tmax of Erlotinib	The Tmax defined as the time taken to reach Cmax. The Tmax was summarized using the predicted plasma concentrations at steady state.	At Day 1 and 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days)
Dose Limiting Toxicity (DLT) Assessment	DLTs included any non-hematological toxicity ≥ Grade 3 except Grade 3 nausea, vomiting or diarrhea that resolved within 72 hours with optimal therapy: Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. Grade 4 neutropenia persisting for ≥ 5 days or Grade 3 or 4 febrile neutropenia. Treatment discontinuation or dose reduction for greater than (>) 72 hours during the first cycle as a result of treatment-related toxicity. DLTs were evaluated using National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03. Number of participants that reported DLTs were reported in this outcome measure.	First dose of study drug to 28 days post last dose (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)
Time To Progression (TTP)	TTP was calculated as the duration from the date of first administration of bemcentinib to the date of radiological progression of disease first observed, according to the overall response evaluation (progressive disease, measurement proven or progressive disease, symptomatic deterioration). If a participant died without any radiological assessment, the progressive disease date was date of death. Progression was assessed using the Response evaluation criteria in solid tumors (RECIST) version 1.1 criteria.	First dose of bemcentinib to first radiological progression (maximum study treatment exposure was 1554 days; maximum follow-up = 1582 days)

Collaborators and Investigators

• Sponsor: BerGenBio ASA
• Investigators: Principal Investigator: Dr. Lauren Byers, MD, MD, Anderson Cancer Centre Houston, Texas

Publications and helpful links

General Publications

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
• 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 Dec;5(6):649-55. No abstract available.
• Korshunov VA. Axl-dependent signalling: a clinical update. Clin Sci (Lond). 2012 Apr;122(8):361-8. doi: 10.1042/CS20110411.
• Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel-Rahman M, Wang X, Levine AD, Rho JK, Choi YJ, Choi CM, Kim SW, Jang SJ, Park YS, Kim WS, Lee DH, Lee JS, Miller VA, Arcila M, Ladanyi M, Moonsamy P, Sawyers C, Boggon TJ, Ma PC, Costa C, Taron M, Rosell R, Halmos B, Bivona TG. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012 Jul 1;44(8):852-60. doi: 10.1038/ng.2330.
• Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, Nilsson MB, Gudikote J, Tran H, Cardnell RJ, Bearss DJ, Warner SL, Foulks JM, Kanner SB, Gandhi V, Krett N, Rosen ST, Kim ES, Herbst RS, Blumenschein GR, Lee JJ, Lippman SM, Ang KK, Mills GB, Hong WK, Weinstein JN, Wistuba II, Coombes KR, Minna JD, Heymach JV. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res. 2013 Jan 1;19(1):279-90. doi: 10.1158/1078-0432.CCR-12-1558. Epub 2012 Oct 22.
• Hector A, Montgomery EA, Karikari C, Canto M, Dunbar KB, Wang JS, Feldmann G, Hong SM, Haffner MC, Meeker AK, Holland SJ, Yu J, Heckrodt TJ, Zhang J, Ding P, Goff D, Singh R, Roa JC, Marimuthu A, Riggins GJ, Eshleman JR, Nelkin BD, Pandey A, Maitra A. The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma. Cancer Biol Ther. 2010 Nov 15;10(10):1009-18. doi: 10.4161/cbt.10.10.13248. Epub 2010 Nov 15.
• Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Luthar N, Toulany M, Gill PS, Salgia R, Kimple RJ, Wheeler DL. AXL mediates resistance to cetuximab therapy. Cancer Res. 2014 Sep 15;74(18):5152-64. doi: 10.1158/0008-5472.CAN-14-0294. Epub 2014 Aug 18.
• Ishikawa M, Sonobe M, Nakayama E, Kobayashi M, Kikuchi R, Kitamura J, Imamura N, Date H. Higher expression of receptor tyrosine kinase Axl, and differential expression of its ligand, Gas6, predict poor survival in lung adenocarcinoma patients. Ann Surg Oncol. 2013 Dec;20 Suppl 3(Suppl 3):S467-76. doi: 10.1245/s10434-012-2795-3. Epub 2012 Dec 16.
• Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, Halsey W, Sathe GM, Martin AM, Gilmer TM. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009 Sep 1;69(17):6871-8. doi: 10.1158/0008-5472.CAN-08-4490. Epub 2009 Aug 11.
• Thiele S, Baschant U, Rauch A, Rauner M. Instructions for producing a mouse model of glucocorticoid-induced osteoporosis. Bonekey Rep. 2014 Jul 2;3:552. doi: 10.1038/bonekey.2014.47. eCollection 2014.

Helpful Links

• Please see BerGenBio's website for more information.

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2015
• Primary Completion (Actual): August 25, 2021
• Study Completion (Actual): August 25, 2021

Study Registration Dates

• First Submitted: April 9, 2015
• First Submitted That Met QC Criteria: April 20, 2015
• First Posted (Estimated): April 23, 2015

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; Erlotinib; BGB324; Bemcentinib
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: BGBC004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in the article, after deidentification [text, tables, figures and appendices].
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication
• IPD Sharing Access Criteria: 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No