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

Study Overview
=================
Brief Summary
-----------------
A Phase I/2 multi-center open-label study of BGB324 (bemcentinib) in combination with erlotinib in participants with Stage IIIb or Stage IV non-small cell lung cancer. 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.

Detailed Description
-----------------
This is a multi-center, multi-arm open-label Phase I/2 study that will be conducted at up to 10 clinical sites in the US. Up to approximately 40 participants with histologically- or cytologically-confirmed Stage IIIb or Stage IV non-small cell lung cancer will receive bemcentinib( BGB324) as a single agent (Run-in Cohort(mono therapy)) or in combination with erlotinib (Arms A, B, C). Run-in Arm to establish the safety and tolerability of bemcentinib(BGB324) administered as a single agent bemcentinib will be 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) will be opened to confirm the bemcentinib dose to be used in combination with erlotinib. In Arm A the dose of bemcentinib (BGB324) will be escalated in a standard 3+3 fashion until an maximum tolerated dose (MTD) of the combination (bemcentinib + erlotinib) is established. The dose of bemcentinib to be investigated in arm B and C will be confirmed upon recommendation of a Safety Review Committee. Arm B and C will open in parallel and will investigate bemcentinib in combination with erlotinib.

Official Title
-----------------
A Multi-Center Open-Label Phase I/2 Study of BGB324(Bemcentinib) in Combination With Erlotinib in Patients With Stage IIIb or Stage IV Non-Small Cell Lung Cancer

Conditions
-----------------
Non-Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: erlotinib
* Drug: bemcentinib


Participation Criteria
=================
Eligibility Criteria
-----------------
General Criteria Provision of written informed consent to participate in this investigational study. Histological or cytological confirmation of Stage IIIb or Stage IV (unresectable) NSCLC. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Age 18 years or older at the time of consent. 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 Has received previous systemic therapy for unresectable NSCLC. Has exhausted existing licensed therapies, or is unsuitable for treatment with existing licensed therapies for NSCLC. Additional Inclusion Criteria for Arm A 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 BGB324 (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 BGB324 (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). Additional Inclusion Criteria for Arm B 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. 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 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. Participants must have completed afatinib and/or gefitinib treatment at least 1 week before the first dose of BGB324. Toxicity from other prior therapy has resolved to <=Grade 1 (previous treatment with bevacizumab and other licensed antibody therapies is permitted). 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 Known EGFR mutation status: Presence of an activating EGFR mutation (including exon 19 deletion or exon 21 [L858R] substitution mutation or other rearrangement of the EGFR gene). Disease that is measurable or evaluable according to RECIST Version 1.1. 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). 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). 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 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 tachyarrythmias, as defined by the need for treatment. tachyarrythmias, 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 triplicate 12-lead 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 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >=2.5 times the ULN (up to 5 times the ULN in the presence of liver metastases). Inability to tolerate oral medication. Impaired coagulation as evidenced by: International normalized ratio (INR) >1.5 times ULN (or equivalent); or Activated partial thromboplastin time (aPTT) >1.5 times ULN. Existing gastrointestinal disease affecting drug absorption, such as celiac disease or Crohn's disease. Previous bowel resection that may impair study drug absorption. Impaired renal function as demonstrated by creatinine clearance of <=50 mL/min determined by Cockcroft Gault formula. 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. 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. Treatment with any medication which is predominantly metabolized by CYP3A4 and has a narrow therapeutic index. 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. 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. 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. 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. 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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>designed to determine the maximum dose of bemcentinib that can be safely administered in combination with erlotinib administered at the approved oral dose level of 150 mg daily. It is anticipated that a maximum of three bemcentinib dose levels will be evaluated, with up to approximately 18 participants enrolled. In the absence of unacceptable toxicity, participants will be allowed to continue receiving bemcentinib in combination with erlotinib until disease progression.- (Arm completed) | Drug: erlotinib<br>* erlotinib is used to treat non-small cell lung cancer (NSCLC), pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).<br>* Other names: Tarceva;Drug: bemcentinib<br>* 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.<br>* Other names: BGB324;|
| Active Comparator: Arm B<br>will incorporate a Simon-like two-stage design with relaxed stopping for futility to evaluate the safety, pharmacokinetics and clinical activity of bemcentinib in combination with erlotinib in participants with an activating EGFR mutation who have progressed after receiving prior EGFR TKI inhibitors or who have progressed after osimertinib. | Drug: erlotinib<br>* erlotinib is used to treat non-small cell lung cancer (NSCLC), pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).<br>* Other names: Tarceva;Drug: bemcentinib<br>* 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.<br>* Other names: BGB324;|
| Active Comparator: Arm C<br>will evaluate the safety, pharmacodynamics and clinical activity of bemcentinib when administered in combination with erlotinib in participants with an activating EGFR mutation who have received at least twelve weeks of erlotinib without disease progression (Open to enrolment). | Drug: erlotinib<br>* erlotinib is used to treat non-small cell lung cancer (NSCLC), pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).<br>* Other names: Tarceva;Drug: bemcentinib<br>* 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.<br>* Other names: BGB324;|
| Other: Run in Arm<br>The primary goal of the Run-in Cohort is to establish the safety and tolerability of bemcentinib administered as a single agent. Eligible participants will have either exhausted existing licensed therapies or be unsuitable for treatment with existing licensed therapies for NSCLC. bemcentinib will be administered at a loading dose of 600 mg on Day 1 and Day 2 of Cycle 1, followed by 200 mg daily thereafter (Arm completed) | Drug: bemcentinib<br>* 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.<br>* Other names: BGB324;|

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. | 5 years | 
| Number of Participants with Clinically Significant Clinical Laboratory, Physical examination, Vital Signs, Echocardiogram or Multi-gated Acquisition (MUGA) Scan and Electrocardiogram (ECG) Abnormalities | Number of participants with clinical laboratory (haematology, chemistry, coagulation and urinalysis), physical examination, vital signs, echocardiogram or multi-gated acquisition (MUGA) scan and ECG abnormalities will be reported. | 5 years | 
| Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status | ECOG: 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. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics Parameter: Area Under The Curve Within A Dosing Interval (AUC0-t) of Bemcentinib |  | 6 weeks | 
| Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) of Bemcentinib |  | 6 weeks | 
| Pharmacokinetics Parameter: Time to Reach Maximum Plasma Concentration (Tmax) of Bemcentinib | Tmax defined as the time to reach Cmax. | 6 weeks | 
| Pharmacodynamic Parameter: Changes in the Phosphorylation Status of Signaling Proteins | A tumor tissue sample for analysis will be taken using a core needle biopsy to evaluate changes in the phosphorylation status of signaling proteins. | 5 years | 
| Pharmacodynamic Parameter: Change from Baseline in Circulating Markers Levels | Change from baseline in circulating markers in the blood including sAxl, Gas6, cytokines and cell-free nucleic acids will be reported. | Baseline to 5 years | 
| Pharmacodynamic Parameter: Changes in Gene Expression of Tumor Tissue or Circulating Nucleic Acids | A tumor tissue sample for analysis will be taken using a core needle biopsy to evaluate changes in gene expression of tumor tissue or circulating nucleic acids. | 5 years | 
| Pharmacodynamic Parameter: Spectrum of Mutations (Including EGFR Mutations) Within Cancer Cell Population or In Circulating Nucleic Acids | A tumor tissue sample for analysis will be taken using a core needle biopsy to evaluate the spectrum of mutations (including EGFR Mutations) within cancer cell population or In circulating nucleic acids. | 5 years | 
| Pharmacodynamic Parameter: Number of Participants with Epithelial-Mesenchymal Transition Gene Signature | Number of participants with epithelial-mesenchymal transition gene signature will be reported. | 5 years | 
| Time To Progression | Time to Progression (Arm C) | 5 years |