Bemcentinib (BGB324) in Combination With Pembrolizumab in Patients With Advanced NSCLC

Study Overview
=================
Brief Summary
-----------------
This is an open-label, multi-center, single arm, phase II study to assess the anti-tumor activity and safety of bemcentinib when given in combination with pembrolizumab in up to 106 participants with previously treated, advanced adenocarcinoma of the lung. The study will enroll three cohorts of participants with previously treated, advanced adenocarcinoma of the lung: Cohort A will consist of participants who received a maximum of 1 prior line of platinum-containing chemotherapy and no prior immunotherapy of any kind. Cohort B will consist of participants who received a maximum of one prior line of an anti-programmed death receptor (PD)-(L)1 therapy (monotherapy). Cohort C will consist of participants who received a maximum of one prior line of therapy with an anti-PD-(L)1 therapy in combination with a platinum-containing chemotherapy.The primary objective is to assess the anti-tumor activity of bemcentinib and pembrolizumab when given in combination.

Official Title
-----------------
A Phase II Multi Center Study of BGB324 in Combination With Pembrolizumab in Patients With Previously Treated Advanced Adenocarcinoma of the Lung

Conditions
-----------------
Lung Cancer Metastatic, NSCLC Stage IV, Adenocarcinoma of Lung

Intervention / Treatment
-----------------
* Drug: Bemcentinib; pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of signed informed consent. Male and non-pregnant females who are aged 18 years or older at the time of provision of informed consent. Histopathologically or cytologically documented Stage IV adenocarcinoma non-small cell lung cancer (NSCLC). Note: participants with a mixed histology including a significant area of adenocarcinoma histology are eligible. Cohort A only: Has disease progression on or after a prior platinum-containing chemotherapy. Note: participants with Epidermal growth factor receptor (EGFR) mutations or Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK) genomic rearrangements must have documented disease progression on at least one licensed therapy for these indications and may not have received platinum-containing chemotherapy. Cohort B only: Has received a maximum of one prior line of an anti-PD-(L)1 therapy (monotherapy). Must have had disease control (SD, PR or CR) for at least 6 months on most recent treatment containing at least 2 doses of anti-PD-(L)1-therapy. Has disease progression when entering screening and this must be within 12 weeks of last dose of most recent treatment containing an anti-PD-(L)1 therapy. Progression should have been confirmed in one of the following ways: (i) Having had two scan assessments completed at least 4 weeks apart, both showing progression according to RECIST 1.1 or (ii) having had one scan assessment completed showing disease progression according to standards used for previous therapy combined with rapid disease progression / clinical progression. Cohort C: Only Has received a maximum of one prior line of an anti-PD-(L)1 therapy in combination with a platinum-containing chemotherapy. Must have had disease control containing at least 2 doses of anti-PD-(L)1 therapy. Disease control is defined as; (i) Stable disease (SD) for at least 12 weeks (date of first progression on anti-PD-(L)1 therapy) Or (ii). Confirmed partial response or complete response (PR/CR) - confirmatory scan must be performed >4 weeks from initial scan c) Has disease progression when entering screening (first date of progression of disease is taken as end date of response to previous anti-PD-(L)1 therapy) and this must be within 12 weeks of last dose of treatment containing an anti-PD-(L)1 therapy. Progression should have been confirmed in one of the following ways: (i) Having had two scan assessments completed at least 4 weeks apart, both showing progression according to RECIST 1.12 or (ii) Having had one scan assessment completed showing disease progression according to standards used for previous therapy combined with rapid disease progression / clinical progression. Measurable disease as defined by RECIST 1.1 on computed tomography (CT) or magnetic resonance imaging (MRI) and as determined by the site study team. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Provision of suitable tumor tissue for the analysis of Axl kinase expression and PD-L1 expression. Suitable tumor tissue must consist of a minimum of newly acquired (fresh) tumor tissue sample (as a Formalin fixed paraffin embedded [FFPE] block), together with either further newly acquired tumor tissue (i.e. further FFPE block) or an archival tumor tissue sample (as a further FFPE block or further 10 unstained slides). See Section 5.3.13 for further details. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. Life expectancy of at least 3 months. Adequate organ function confirmed at Screening within 10 days of treatment initiation - as evidenced by: Platelet count ≥100,000 /mm3; Hemoglobin ≥9.0 g/dL (≥5.6 mmol/L); Absolute neutrophil count (ANC) >1,500 /mm3; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal (ULN), or ≤5 times the ULN for participants with liver metastases; Total bilirubin ≤1.5 times the ULN or direct bilirubin <=ULN for participants with total bilirubin levels >1.5 ULN. Creatinine ≤1.5 times the ULN or calculated creatinine clearance 60 mL/min (by Cockcroft Gault formula); International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times the ULN and Activated Partial Thromboplastin Time (aPTT) ≤1.5 times the ULN. Note: If participants is receiving anticoagulant therapy, then PT or Partial thromboplastin time (PTT) must be within therapeutic range of intended use of anticoagulants; Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to the first dose of study treatment. If urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. participants (both male and female) of reproductive potential must be willing to practice highly effective methods of contraception throughout the study and for 120 days after the last dose of study medication. Abstinence is acceptable if this is the usual lifestyle for the participants. Female participants are considered NOT of childbearing potential if they have a history of surgical sterility or evidence of post-menopausal status defined as any of the following: ≥45 years of age and has not had menses for more than 1 year; Amenorrheic for >2 years without a hysterectomy and oophorectomy and a follicle stimulating hormone (FSH) value in the postmenopausal range upon Screening evaluation; Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If the participants received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention. Exclusion Criteria: Has disease suitable for local therapy administered with curative intent. Has received more than 1 prior line of chemotherapy for advanced or metastatic adenocarcinoma of the lung. Cohort A: Has received prior therapy with an immunomodulatory agent; Cohort B: Has received prior chemotherapy alone or in combination with immunotherapy in the metastatic setting Has a known additional malignancy that is progressing or requires active treatment. Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging (using the identical modality for each assessment, either MRI or CT scan) for at least 4 weeks prior to the first dose of trial treatment and any neurological symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. History of the following cardiac conditions: Congestive cardiac failure of >Grade II severity according to the New York Heart Association (NYHA) (Appendix C: defined as symptomatic at less than ordinary levels of activity). Ischemic cardiac event including myocardial infarction within 3 months prior to first dose. Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension (i.e. sustained systolic BP >160 mmHg or diastolic BP >90 mmHg), or need to change medication due to lack of disease control within 6 weeks prior to the provision of consent. History or presence of sustained bradycardia (≤55 BPM), left bundle branch block, cardiac pacemaker or ventricular arrhythmia. Note: participants with a supraventricular arrhythmia requiring medical treatment, but with a normal ventricular rate are eligible. Family history of long QTc syndrome; personal history of long QTc syndrome or previous drug-induced QTc prolongation of at least Grade 3 (QTc >500ms). Abnormal left ventricular ejection fraction on echocardiography or Multi Gated Acquisition Scan (MUGA) (less than the lower limit of normal for a participants of that age at the treating institution or <45%, whichever is lower). Current treatment with any agent known to cause Torsades de Pointes which cannot be discontinued at least five half-lifes or two weeks prior to the first dose of study treatment. Screening 12-lead ECG with a measurable QTc interval according to Fridericia's correction >450 ms. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment. Has participated in a study involving any immune check point inhibitor other than currently approved immune check point inhibitors for their lung cancer. Received chemotherapy or targeted small molecule therapy or radiation therapy within 2 weeks prior to starting study treatment or who has not recovered (i.e. ≤Grade 1 at baseline) from AEs due to a previously administered agent. Note: Participants with ≤Grade 2 alopecia are an exception to this criterion. If the participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Received an anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of study treatment or who has not recovered (i.e. ≤Grade 1 or baseline) from adverse events (AEs) due to agents administered more than 4 weeks earlier. Major surgery within 28 days prior to start of study treatment and failure to have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of study treatment. Note: Major surgery does not include procedures for insertion of venous catheters or biopsies. Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including Granulocyte-colony stimulating factor [G-CSF], Granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoetin) within 4 weeks prior to the first dose of study treatment. Note: Participants receiving stable dose of growth factors with a haemoglobin value that meets Inclusion Criterion 9b may be included. Note: Participants receiving stable dose of growth factors with a hemoglobin value that meets Inclusion Criterion 9b may be included. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Note: The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Has known active infection with Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., Hepatitis C virus (HCV) Ribonucleic acid (RNA) [qualitative] is detected). Note: i) Participants with a history of hepatitis B infection are eligible provided they are hepatitis B surface antigen negative ii) Participants with a history of hepatitis C infection are eligible provided they have no evidence of hepatitis C RNA using a quantitative polymerase chain reaction (qPCR) at least 6 months after completing treatment for hepatitis infection. Has received a live-virus vaccination within 30 days of planned treatment start. Note: Seasonal flu vaccines that do not contain live virus are permitted. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has a history of interstitial lung disease. Inability to swallow or tolerate oral medication. Existing gastrointestinal disease affecting drug absorption such as celiac disease or Crohn's disease, or previous bowel resection which is considered to be clinically significant or could interfere with absorption. Known lactose intolerance. Requires vitamin K antagonists. Note: Participants receiving low doses prescribed to maintain the patency of venous access devices may be included. Note: Factor Xa antagonists are permitted. Treatment with any of the following: histamine receptor 2 inhibitors, proton pump inhibitors or antacids within 7 days of start of study treatment. Treatment with any medication which is predominantly metabolized by CYP3A4 and has a narrow therapeutic index. Known hypersensitivity (>=Grade 3) to bemcentinib, pembrolizumab, or any of their excipients. Any evidence of severe or uncontrolled systemic conditions (e.g. severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions, or ongoing. Has active infection requiring systemic therapy (apart from cutaneous infections). Has received radiation to the lung of >30 Gy within 6 months of first dose. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participants participation for the full duration of the trial, or means it is not in the best interest of the participants to participate, in the opinion of the Investigator Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting from Screening through to 120 days after the last dose of study treatment. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Cohort B only: Has an EGFR mutation or ALK genomic rearrangement.

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
Intervention Model: Single Group Assignment
Interventional Model Description: Extension to Simon's 2-stage design allowing termination at the end of Stage 1 for either futility or efficacy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bemcentinib + pembrolizumab<br>Cohort A enrols participants who received a maximum of 1 prior line of platinum-containing chemotherapy and no prior immunotherapy of any kind to receive bemcentinib (BGB324) in combination with pembrolizumab. Cohort B enrolls participants who received a maximum of one prior line of an anti-PD-(L)1 therapy (monotherapy) to receive bemcentinib (BGB324) in combination with pembrolizumab. Cohort C enrolls participants who received a maximum of one prior line of therapy with an anti-PD-(L)1 therapy in combination with a platinum-containing chemotherapy. Bemcentinib capsules are administered at 400mg for days 1-3, and 200mg thereafter. Pembrolizumab is an IV infusion, administered at a dose of 200mg every 3 weeks. | Drug: Bemcentinib; pembrolizumab<br>* Bemcentinib is a selective Axl kinase inhibitor; pembrolizumab is a PD-1 inhibitor<br>* Other names: BGB324; Keytruda;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Objective Response Rate includes all participants who have a partial or complete response. | The disease response is the best improvement or change in a participants cancer burden, as measured from baseline (screening) and then measured again at regular intervals over the whole period of the study, an average of 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate | Disease Control Rate includes all participants who have a partial or complete response, or who maintain stable disease. | Disease response is assessed every 9 weeks for the first 45 weeks and then every 12 weeks until disease progression (worsens) or study completion, an average of 24 months. | 
| Duration of Response | Duration of response includes participants with a partial or complete response and is measured from the date of response until the cancer progresses (worsens). | Disease response is assessed every 9 weeks for the first 45 weeks and then every 12 weeks until disease progression or study completion, an average of 24 months. | 
| Progression-free Survival (PFS) | PFS is measured from the date of the 1st dose of the 1st cycle until the date of progression (the date on which the progression is initially observed) or the date of death (whichever is earlier). | Disease assessments are conducted at screening and then every 9 weeks for the first 45 weeks and then every 12 weeks until disease progression or death, whichever comes first, up to study completion (an average of 24 months) | 
| Overall survival | Time to death is measured from the date of first dose until the date of death or the date the participants is last known to be alive. It includes all participants. | Survival visits are conducted every 12 weeks after disease progression until death or until study completion (an average of 24 months). | 
| Number of participants with Adverse Events (as assessed by CTCAE v4.03) | The number of participants with each adverse event will be summarized. | Adverse events are collected from the date of consent until up to 120 days after cessation of both treatments. | 
| Pharmacokinetic (PK) Parameters: Maximum observed concentration (Cmax) | Cmax defined as the maximum observed concentration. | Up to 106 weeks | 
| PK Parameters: Area Under the Curve (AUC) | AUC defined as the area under the concentration versus time curve. | Up to 106 weeks | 
| PK Parameters: Elimination Half-life (T½) | T½ defined as the elimination half-life. | Up to 106 weeks | 
| Number of Participants with Clinical Laboratory, Vital Signs, and Electrocardiogram (ECG) Abnormalities | Number of participants with clinical laboratory (hematology, including coagulation, urinalysis), vital signs (temperature, systolic blood pressure, diastolic blood pressure, heart rate, and respiratory rate), and ECG abnormalities will be reported. | 106 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
bemcentinib, NSCLC, pembrolizumab, Keytruda, BGB324