This is an open label, single arm, multi-centre phase II study to assess the anti-tumour
activity and safety of BGB324 in combination with pembrolizumab in up to 56 patients with
previously treated, locally advanced and unresectable, or metastatic TNBC or TN-IBC. The
study will utilise an extension of Simon's 2-stage design. The primary objective is
objective response rate.
1. Provision of signed informed consent.
2. Male and non-pregnant females who are aged 18 years or older at the time of provision
of informed consent.
3. Histopathologically or cytologically documented TNBC or TN-IBC. Tumors must have been
confirmed negative for ER and PR by IHC (<1% positive tumor nuclei, as per ASCO-CAP
guideline recommendations) and negative for HER2 by IHC or fluorescent or chromogenic
in situ hybridization (FISH or CISH). Patients with equivocal HER2 results by IHC
should have their negativity status confirmed by FISH.
4. Locally advanced and unresectable or metastatic TNBC or triple negative inflammatory
5. Received one or more prior therapies for TNBC or inflammatory breast cancer in the
metastatic setting, and prior treatment (metastatic or (neo) adjuvant) must have
included a prior taxane and/or anthracycline-based therapy.
6. Has measurable disease as defined by RECIST 1.12 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.
7. Provision of suitable tumor tissue for the analysis of Axl kinase expression and
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 initiating
treatment, 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 patients with liver
- Total bilirubin ≤1.5 times the ULN, or direct bilirubin <ULN for patients with
total bilirubin levels >1.5xULN;
- Creatinine ≤1.5 times the ULN and calculated creatinine clearance >60 mL/min (by
Cockcroft Gault formula; see Appendix B);
- 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
patient is receiving anticoagulant therapy, then PT or PTT must be within
therapeutic range of intended use of anticoagulants;
- LDH ≤2.5 times the ULN.
11. Female patients of childbearing potential must have a negative pregnancy test (either
urine or serum pregnancy test) within 72 hours prior to the first dose of study
treatment. If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required.
12. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1
or less (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 the
13. Patients 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 of the
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 of
the skin that has undergone potentially curative therapy or in situ cervical cancer.
5. Has known active central nervous system (CNS) metastases and/or carcinomatous
6. History of the following cardiac conditions:
- Congestive cardiac failure of >Grade II severity according to the NYHA;
- Ischemic cardiac event including myocardial infarction within 3 months prior to
- 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: Patients 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 >500 ms).
7. Abnormal left ventricular ejection fraction on echocardiography or MUGA (less than
the lower limit of normal for a patient of that age at the treating institution or
<45%, whichever is lower).
8. Current treatment with any agent known to cause Torsades de Pointes which cannot be
discontinued at least five half-lives or two weeks prior to the first dose of study
9. Screening 12-lead ECG with a measurable QTc interval according to Fridericia's
correction >450 ms.
10. 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.
11. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤Grade 1 or at
baseline) from AEs due to a previously administered agent.
12. 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 AEs
due to agents administered more than 4 weeks earlier.
13. 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.
14. Received transfusion of blood products (including platelets or red blood cells) or
administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant
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 any
other form of immunosuppressive therapy within 7 days prior to the first dose of
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., 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 current
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 or
Crohn's disease, or previous bowel resection which is considered to be clinically
significant or could interfere with absorption.
24. Known lactose intolerance.
25. Requires vitamin K antagonists. Note: Patients receiving low doses prescribed to
maintain the patency of venous access devices may be included. Factor Xa antagonists
26. Treatment with any of the following: histamine receptor 2 inhibitors, proton pump
inhibitors or antacids within 7 days of start of study treatment.
27. Treatment with any medication which is predominantly metabolized by CYP3A4 and has a
narrow therapeutic index.
28. Known hypersensitivity to BGB324, pembrolizumab, or any of their 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
abnormality that, 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 is not in the best interests of the patient to participate.
31. 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.
32. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.