Bemcentinib (BGB324) in Combination With Pembrolizumab in Patients With TNBC

Inclusion Criteria:

1. Provision of signed informed consent.
2. Male and non-pregnant females who are aged 18 years or older at the time of provisionof informed consent.
3. Histopathologically or cytologically documented TNBC or TN-IBC. Tumors must have beenconfirmed negative for ER and partial response (PR) by immunohistochemistry (IHC) (<1%positive tumor nuclei, as per ASCO-CAP guideline recommendations) and negative forhuman epidermal growth factor receptor 2 (HER2) by IHC or fluorescent or chromogenicin situ hybridization (FISH or CISH). Patients with equivocal HER2 results by IHCshould have their negativity status confirmed by FISH.
4. Locally advanced and unresectable or metastatic TNBC or triple negative inflammatorybreast cancer.
5. Received one or more prior therapies for TNBC or inflammatory breast cancer in themetastatic setting, and prior treatment (metastatic or (neo) adjuvant) must haveincluded a prior taxane and/or anthracycline-based therapy.
6. Has measurable disease as defined by RECIST 1.1 on computed tomography (CT) ormagnetic resonance imaging (MRI) and as determined by the site study team. Tumorlesions situated in a previously irradiated area are considered measurable ifprogression has been demonstrated in such lesions.
7. Provision of suitable tumor tissue for the analysis of Axl kinase expression and PD-L1expression.
8. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.
9. Life expectancy of at least 3 months.
10. Adequate organ function confirmed at Screening and within 10 days of initiatingtreatment, as evidenced by:

• Platelet count ≥100,000 /mm3;
• Hemoglobin ≥9.0 g/dL (≥5.6 mmol/L);.
• Absolute neutrophil count (ANC) >1,500 /mm^3;
• Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 timesthe upper limit of normal (ULN), or ≤5 times the ULN for patients with livermetastases;
• Total bilirubin ≤1.5 times the ULN, or direct bilirubin <ULN for patients withtotal bilirubin levels >1.5xULN;
• Creatinine ≤1.5 times the ULN and calculated creatinine clearance >60 mL/min (byCockcroft Gault formula);
• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times the ULNand Activated Partial Thromboplastin Time (aPTT) ≤1.5 times the ULN. Note: Ifpatient is receiving anticoagulant therapy, then PT or PTT must be withintherapeutic range of intended use of anticoagulants;
• Lactate dehydrogenase (LDH) ≤2.5 times the ULN.

11. Female patients of childbearing potential must have a negative pregnancy test (eitherurine or serum pregnancy test) within 72 hours prior to the first dose of studytreatment. If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required.
12. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 orless (except alopecia). If the patient received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from theintervention.
13. Patients of reproductive potential must be willing to practice highly effectivemethods of contraception throughout the study and for 120 days after the last dose ofstudy medication. Abstinence is acceptable if this is the usual lifestyle of thepatient.

Exclusion Criteria:

1. Has disease that is suitable for local therapy administered with curative intent.
2. More than 3 previous lines of therapy in the metastatic setting.
3. Has received prior therapy with an immunomodulatory agent.
4. Has a known additional malignancy that is progressing or requires active treatment.Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma ofthe skin that has undergone potentially curative therapy or in situ cervical cancer.
5. Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis.
6. History of the following cardiac conditions:

• Congestive cardiac failure of >Grade II severity according to the New York HeartAssociation (NYHA);
• Ischemic cardiac event including myocardial infarction within 3 months prior tofirst dose;
• Uncontrolled cardiac disease, including unstable angina, uncontrolledhypertension (i.e. sustained systolic BP >160 mmHg or diastolic BP >90 mmHg), orneed to change medication due to lack of disease control within 6 weeks prior tothe provision of consent;
• History or presence of sustained bradycardia (≤55 BPM), left bundle branch block,cardiac pacemaker or ventricular arrhythmia. Note: Patients with asupraventricular arrhythmia requiring medical treatment, but with a normalventricular rate are eligible;
• Family history of long QTc syndrome; personal history of long QTc syndrome orprevious drug-induced QTc prolongation of at least Grade 3 (QTc >500 ms).

7. Abnormal left ventricular ejection fraction on echocardiography or Multi GatedAcquisition Scan (MUGA) (less than the lower limit of normal for a patient of that ageat the treating institution or <45%, whichever is lower).
8. Current treatment with any agent known to cause Torsades de Pointes which cannot bediscontinued at least five half-lives or two weeks prior to the first dose of studytreatment.
9. Screening 12-lead ECG with a measurable QTc interval according to Fridericia'scorrection >450 ms.
10. Is currently participating and receiving study therapy or has participated in a studyof an investigational agent and received study therapy or used an investigationaldevice within 4 weeks of the first dose of study treatment.
11. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapywithin 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤Grade 1 or atbaseline) from AEs due to a previously administered agent.
12. Received an anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the firstdose of study treatment or who has not recovered (i.e. ≤Grade 1 or baseline) from AEsdue to agents administered more than 4 weeks earlier.
13. Major surgery within 28 days prior to start of study treatment and failure to haverecovered adequately from the toxicity and/or complications from the interventionprior to the first dose of study treatment.
14. Received transfusion of blood products (including platelets or red blood cells) oradministration of colony stimulating factors (including granulocyte-colony stimulatingfactor [G-CSF], Granulocyte-macrophage colony-stimulating factor [GM-CSF] orrecombinant erythropoetin) within 4 weeks prior to the first dose of study treatment.
15. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or anyother form of immunosuppressive therapy within 7 days prior to the first dose of studytreatment.
16. Active autoimmune disease that has required systemic treatment in past 2 years (i.e.with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
17. Known history of human immunodeficiency virus (HIV 1/2 antibodies)
18. Has known active infection with Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., Hepatitis C virus (HCV) RNA (qualitative) is detected).
19. 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.
20. Has a history of (non-infectious) pneumonitis that required steroids or currentpneumonitis.
21. Has a history of interstitial lung disease.
22. Inability to swallow or tolerate oral medication.
23. Existing gastrointestinal disease affecting drug absorption such as celiac disease orCrohn's disease, or previous bowel resection which is considered to be clinicallysignificant or could interfere with absorption.
24. Known lactose intolerance.
25. Requires vitamin K antagonists. Note: Patients receiving low doses prescribed tomaintain the patency of venous access devices may be included. Factor Xa antagonistsare permitted.
26. Treatment with any of the following: histamine receptor 2 inhibitors, proton pumpinhibitors or antacids within 7 days of start of study treatment.
27. Treatment with any medication which is predominantly metabolized by CYP3A4 and has anarrow therapeutic index.
28. Known severe hypersensitivity (≥Grade 3) to bemcentinib, pembrolizumab, and/or any oftheir excipients.
29. Has an active infection requiring systemic therapy (apart from cutaneous infections).
30. Has a history or current evidence of any condition, therapy, or laboratory abnormalitythat, in the opinion of the Investigator, might confound the results of the trial,interfere with the patient's participation and compliance in the trial, or means it isnot in the best interests of the patient to participate.
31. Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting from Screening through to 120 days after thelast dose of study treatment.
32. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.