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

NCT02424617 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: BGBC004
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

Non-Small Cell Lung Cancer

Keywords

BGB324; Bemcentinib; Erlotinib; NSCLC

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (8)

• Area Under the Curve (AUC) Over 24 Hours at Steady State of Bemcentinib

  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

  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

  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

  At Day 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days)

• Cmax of Erlotinib

  At Day 1 and 8 (in Cycle 1): pre-dose, 2, 4, 6, 8 and 24 hours post-dose (cycle length=21 days)

Study Arms (4)

Phase 1- Run in Arm (Bemcentinib Monotherapy)

EXPERIMENTAL

Participants in this arm received bemcentinib as monotherapy. This was to determine the safety and tolerability of bemcentinib when administered alone.

Drug: Bemcentinib

Phase 1- Arm A (Bemcentinib + Erlotinib)

EXPERIMENTAL

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: Erlotinib; Drug: Bemcentinib

Phase 2- Arm B (Bemcentinib + Erlotinib)

EXPERIMENTAL

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: Erlotinib; Drug: Bemcentinib

Phase 2- Arm C (Bemcentinib + Erlotinib)

EXPERIMENTAL

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: Erlotinib; Drug: Bemcentinib

Interventions

Erlotinib DRUG

Participants received erlotinib 150 mg for the 21-day cycle.

Also known as: Tarceva

Phase 1- Arm A (Bemcentinib + Erlotinib); Phase 2- Arm B (Bemcentinib + Erlotinib); Phase 2- Arm C (Bemcentinib + Erlotinib)

Bemcentinib DRUG

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.

Also known as: BGB324

Phase 1- Run in Arm (Bemcentinib Monotherapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has received previous systemic therapy for unresectable NSCLC.
• Has exhausted existing licensed therapies, or is unsuitable for treatment with existing licensed therapies for NSCLC.
• Known EGFR mutation status.
• Either:
• 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:
• 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).
• Erlotinib-related toxicities being well-controlled and \<Grade 3 in severity at the time of the first dose of bemcentinib (Cycle 1, Day 1).
• Toxicity from other prior therapy has resolved to ≤ Grade 1 (previous treatment with bevacizumab and other licensed antibody therapies is permitted).
• 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).
• Disease that is measurable according to the response evaluation criteria in solid tumors (RECIST) Version 1.1.
• 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.
• 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.
• Participants must have completed afatinib and/or gefitinib treatment at least 1 week before the first dose of bemcentinib.
• Toxicity from other prior therapy has resolved to ≤ Grade 1 (previous treatment with bevacizumab and other licensed antibody therapies is permitted).

You may not qualify if:

• Pregnant or lactating.
• Abnormal left ventricular ejection fraction (less than the lower limit of normal for a participants of that age at the treating institution or \<45%).
• 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.
• History of an ischemic cardiac event, including myocardial infarction, within 3 months of consent.
• Pulmonary hemorrhage or hemoptysis \>2.5 mL blood within 6 weeks of consent unless cause has been addressed and is medically resolved.
• 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.
• 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.
• 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.
• 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.
• Known family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy.
• Previous history of ≥ Grade 3 drug-induced QTc prolongation.
• Screening 12-lead triplicate electrocardiogram (ECG) with an average measurable interval utilizing Fridericia's correction (QTcF) \>450 ms.
• Inadequate liver function as demonstrated by:
• Serum bilirubin ≥ 1.5 times the upper limit of normal range (ULN); or

Sponsors & Collaborators

• BerGenBio ASA: lead

Study Sites (10)

UC San Diego Moores Cancer Center

La Jolla, California, 92093-0698, United States

Location

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Horizon Oncology Research,

Lafayette, Indiana, 47905, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

The Sarah Cannon Research Institute Tennessee Oncology PLLC

Nashville, Tennessee, 37203, United States

Location

Mary Crowley Cancer Research Centers

Dallas, Texas, 75230, United States

Location

Southwestern Medical Center

Dallas, Texas, 75390-8852, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Oncology Consultants PA

Houston, Texas, 77030, United States

Location

Related Publications (10)

• 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.

  PMID: 20818175 BACKGROUND

• 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.

  PMID: 25136066 BACKGROUND

• 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.

  PMID: 23091115 BACKGROUND

• 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.

  PMID: 19097774 BACKGROUND

• 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.

  PMID: 23242819 BACKGROUND

• Korshunov VA. Axl-dependent signalling: a clinical update. Clin Sci (Lond). 2012 Apr;122(8):361-8. doi: 10.1042/CS20110411.

  PMID: 22187964 BACKGROUND

• 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.

  PMID: 19671800 BACKGROUND

• 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.

  PMID: 7165009 BACKGROUND

• 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.

  PMID: 22751098 BACKGROUND

• 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.

  PMID: 25120909 BACKGROUND

Related Links

• Please see BerGenBio's website for more information.

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Erlotinib Hydrochloride; bemcentinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: BerGenBio Clinical Team
• Organization: BerGenBio ASA

registry.postings@bergenbio.com

+ 47 55961159

Study Officials

• Dr. Lauren Byers, MD

  MD, Anderson Cancer Centre Houston, Texas

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 9, 2015
• First Posted: April 23, 2015
• Study Start: April 19, 2015
• Primary Completion: August 25, 2021
• Study Completion: August 25, 2021
• Last Updated: February 26, 2025
• Results First Posted: February 26, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months and ending 5 years following article publication
• 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.

Locations

US (10)