- Age 18 years
- Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma
(stage IIIC to IV per American Joint Committee on Cancer [AJCC])
- Documented evidence of BRAF V600 mutation.
- Newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at
the time of progression, if not medically contraindicated.
- Evidence of measurable disease, as determined by RECIST v1.1.
INCLUSION CRITERIA for triple combinations:
Progressive disease following prior treatment with LGX818/MEK162 combination. PRINCIPAL
EXCLUSION CRITERIA Symptomatic or untreated leptomeningeal disease.
- Symptomatic brain metastases. Patients previously treated or untreated for brain
metastases that are asymptomatic in the absence of corticosteroid therapy or on a
stable dose of steroids for four weeks are allowed to enroll. Brain metastases must
be stable at least 4 weeks with verification by imaging (e.g. brain MRI completed at
screening demonstrating no current evidence of progressive brain metastases).
Patients are not permitted to receive enzyme inducing anti-epileptic drugs.
- Patients who have developed brain metastases during Part I of the study may continue
to Part II upon discussion with Novartis Medical Monitor. The brain metastasis must
be either asymptomatic or treated and stable for at least 4 weeks and on a stable or
tapering dose of steroids for at least 2 weeks. Patients with brain metastasis are
not eligible for the combination with LEE011.
- Known acute or chronic pancreatitis.
- History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
or hypercoagulability syndromes);
- Clinically significant cardiac disease including any of the following:
- CHF requiring treatment (NYH grade 2),
- LVEF < 50% as determined by MUGA scan or ECHO
- History or presence of clinically significant ventricular arrhythmias or atrial
- Clinically significant resting bradycardia
- Unstable angina pectoris 3 months prior to starting study drug
- Acute Myocardial Infarction (AMI) 3 months prior to starting study drug,
- QTcF > 480 msec. Patients with any of the following laboratory values at
- Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]
- Platelets < 100,000/mm3 [100 x 109/L]
- Hemoglobin < 9.0 g/dL
- Serum creatinine >1.5 x ULN or calculated or directly measured CrCl < 50% LLN (lower
limit of normal)
- Serum total bilirubin >1.5 x ULN
- AST/SGOT or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present
Additional exclusion criteria for the triple combinations:
- Patients with fasting glucose > 120 mg/dL or 6.7 mmol/L, and HbA1c > 8 %.
- Patient has any of the following mood disorders as judged by the
Investigator or a Psychiatrist:
- Patient has a score 12 on the PHQ-9 questionnaire
- Patient has CTCAE grade 3 anxiety
- History and/or current evidence of significant ectopic mineralization/ calcification
with the exception of calcified lymph nodes and asymptomatic vascular calcification.
- Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/
band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits
etc., confirmed by ophthalmologic examination
- Patients with uncontrolled hypertension (please refer to WHO-ISHguidelines) are
excluded from study.
- QTcF >450 ms for males and >470 ms for females Congenital long QT syndrome or family
history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade 3 and
magnesium levels below the clinically relevant lower limits at study entry
- Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI
- PT/INR or aPTT > 1.5xULN
Other protocol-defined inclusion/exclusion criteria may apply.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
Incidence of adverse events
Incidence rate of Dose Limiting Toxicities (DLTs)
Plasma Pharmacokinetics (PK) parameters of LGX818 + MEK162 and triple combination partners
Overall Response Rate (ORR) (Part II)
Progression Free Survival (PFS)(Part I and II)
Duration Of Response (DOR) (Part I and II)
Overall Survival (OS) (Part II)
Time to Response (TTR) (Part I and II)
Disease Control Rate (DCR) (Part I and II)
Severity of adverse events