| Eligibility |
Inclusion Criteria:
1. Patients able to understand and willing to sign a written protocol specific informed
consent and 18 years or older at the time of consent
2. Histologically confirmed advanced cutaneous melanoma that is either non-resectable
(Stage IIIc) or metastatic (Stage IV) with:
1. At least one measurable lesion as defined by RECIST 1.1 on CT or MRI scan and
2. Documented progression of =1 measurable lesion
3. ECOG score 0 to 2 at screening
4. Availability of fresh or archival tumour tissue sample suitable for evaluation of
predictive biomarkers of response
5. Male patients with female partners of childbearing potential and female patients of
childbearing potential willing to practice highly effective birth control from
screening, throughout the study and for at least 3 months following the last dose of
study treatment (and if female of childbearing potential, has a negative serum
pregnancy test in the 7 days before the first dose of study treatment)
Exclusion Criteria:
1. Prior first line systemic treatment for the treatment of Stage IIIb or Stage IIIc
melanoma, including BRAF or MEK inhibitor (adjuvant immunomodulating agent treatment
more than 6 months prior to first dose of study treatment is allowed)
2. Symptomatic central nervous system metastatic lesions as determined by the
Investigator (patients with radiographically stable, asymptomatic lesions previously
irradiated or surgically resected are eligible provided there is no need for systemic
corticosteroids and treatment was completed at least 4 weeks before the first dose of
study treatment)
3. History of malignancy other than melanoma within the last 2 years (basal or squamous
cell carcinoma of the skin or carcinoma in situ of the cervix; isolated elevation in
prostate specific antigen in the absence of histological or radiographic evidence of
prostate cancer is allowed)
4. History of or current active autoimmune diseases, including but not limited to
inflammatory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis, autoimmune
hepatitis, systemic sclerosis (scleroderma and variants), systemic lupus
erythematosus, autoimmune vasculitis, autoimmune neuropathies (e.g. Guillain-Barré
syndrome). Patients with vitiligo, or other non-serious autoimmune diseases based on
the Investigator's assessment, are NOT excluded
5. ONLY FOR BRAF POSITIVE PATIENTS: History of retinal vein occlusion (RVO) or ongoing
retinal pigment epithelial detachment (RPED)
6. History of the following cardiac conditions:
1. Congestive cardiac failure of >Grade 2 severity (see Appendix 1) according to the
New York Heart Association (defined as symptomatic at less than ordinary levels
of activity)
2. Ischemic cardiac event including myocardial infarction within 3 months prior to
first dose of study treatment
3. Uncontrolled cardiac disease, including unstable angina, uncontrolled
hypertension (i.e. sustained systolic blood pressure >160 mmHg or diastolic blood
pressure >90 mmHg), or need to change medication within 6 weeks of provision of
consent due to lack of disease control
4. 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
5. Family history of long QTc syndrome; personal history of long QTc syndrome or
previous drug-induced QTc prolongation
7. Known abnormal left ventricular ejection fraction on echocardiography or Multi Gated
Acquisition (MUGA) scan (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 Torsade de Points which cannot be
discontinued at least five half-lives or two weeks prior to the first dose of study
treatment
9. Screening 12-lead ECG with a measurable QTc interval calculated according to
Fridericia's correction (QTcF) >450 ms
10. Inadequate organ function as defined by the following laboratory values:
1. Haematological: absolute neutrophil count =1.5 x 109/L, platelets =100 x 109/L,
haemoglobin =9.0 g/dL
2. Renal: serum creatinine =1.5 x institutional upper limit of normal (ULN) and
creatinine clearance =50 mL/minute
3. Hepatic: total bilirubin =1.5 x institutional ULN, alanine transaminase (ALT) and
aspartate transaminase (AST) =2.5 x institutional ULN or =5.0 x institutional ULN
if liver metastases are present
4. Coagulation: international normalised ratio or prothrombin time and activated
partial thromboplastin time =1.5 x institutional ULN if not using anticoagulants
(if patient is receiving anticoagulant therapy value must be within therapeutic
range for the condition being treated)
11. Ongoing infection requiring systemic treatment. Patients who are on prophylactic anti
infectives or who have been afebrile for 48 hours following the initiation of
treatment are eligible
12. Known active infection with human immunodeficiency virus (HIV), hepatitis B or C
viruses (screening not required)
- Patients who have a history of hepatitis B infection are eligible provided they
are hepatitis B surface antigen negative
- Patients 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
13. Any conditions which may have significant impact on absorption of BGB324 or dabrafenib
or trametinib from the gastrointestinal tract (including but not limited to, celiac
disease or Crohn's disease, gastric or bowel resection)
14. Any severe or uncontrolled medical conditions which may jeopardise patient safety,
compliance with the protocol, or interpretation of study results in the opinion of the
Investigator
15. Current or recent (within last year) systemic treatment with immunosuppressive or
immunomodulating agents (including systemic steroids intended for immunosuppressive
effect), or other medications known to have significant impact on the immune system.
Topical agents and inhaled steroids are permitted
16. Treatment with any medication with a narrow therapeutic index which is predominantly
metabolised by cytochrome P450 (CYP)3A4 and cannot be stopped before the first dose of
study treatment
17. Known hypersensitivity to pembrolizumab or BGB324 or excipients (including lactose
intolerance)
18. ONLY FOR BRAF POSITIVE PATIENTS: Known hypersensitivity to dabrafenib or trametinib
(including lactose intolerance)
19. Treatment with histamine receptor 2 inhibitors, proton pump inhibitors or antacids in
the 7 days before the first dose of study treatment
20. Treatment with more than 40 mg prednisolone (or equivalent dose of systemic
corticosteroid) which cannot be discontinued up to one week prior to starting BGB324.
During the study this exclusion criteria is only applicable for patients receiving
BGB324.
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