- - Signed written informed consent.
- - Histologically confirmed advanced melanoma that is either stage III (unresectable) or
stage IV (metastatic).
- - Absence of a BRAF V600 mutation as determined by a validated test.
- - In case of mucosal or acral melanoma, absence of a cKIT (proto-oncogene c-Kit)
mutation as determined by a validated test.
- - Presence of archival melanoma tissue of possibility of new biopsy for mutational
- - Subjects must have failed at least one prior systemic treatment with immune checkpoint
inhibitors: CTLA-4 (cytotoxic T-lymphocyt antigen 4) blocking immune checkpoint
inhibitors (ipilimumab or other experimental anti-CTLA-4 antibodies), PD-1 (programmed
cell death 1) blocking immune checkpoint inhibitors (pembrolizumab, nivolumab or other
experimental anti-PD-1 antibodies) and/or PD-L1 (programmed cell death ligand 1)
blocking immune checkpoint inhibitors (avelumab, atezolizumab, durvalumab or other
experimental anti-PD-L1 antibodies).
Progression of disease per Response Evaluation
Criteria In Solid Tumors (RECIST), version 1.1, or per immune related response
criteria (irRC) must have been documented during this treatment. Patients who are not
able to undergo such treatment are also eligible.
- - The presence of at least one measurable lesion per RECIST, version 1.1
- Interval between the date of the last administration of prior therapy for melanoma and
the date of recruitment: a.
≥12 weeks following the date of the first administration
and ≥4 weeks following the date of the last administration of CTLA-4, PD-1 or PD-L1
blocking immune checkpoint inhibitor; b. ≥4 weeks following the date of the last
administration of chemotherapy (≥ 6 weeks in case of a nitrosurea or mitomycin C
containing regimen); c. ≥4 weeks following major surgery or extensive radiotherapy.
- - All prior anti-cancer treatment-related toxicities (except alopecia) must be ≤ grade 1
according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE
version 4.03; National Cancer Institute [NCI] 2010) at the time of recruitment.
- - Able to swallow and retain oral medication and must not have any clinically
significant gastrointestinal abnormalities that may alter absorption such as
malabsorption syndrome or major resection of the stomach or bowels.
- - Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to recruitment and agree to use effective contraception throughout the
treatment period, and for 16 weeks after the last dose of study treatment.
- - Men with a female partner of childbearing potential must have either had a prior
vasectomy or agree to use effective contraception from 14 days prior to administration
of the first dose of study treatment, throughout the treatment period, and for 16
weeks after the last dose of study treatment.
- - An Eastern Cooperative Oncology Group (ECOG) performance status
- Adequate baseline organ function as defined as follows: Absolute neutrophil count: ≥
1.2 x 103/mm3; Hemoglobin: ≥ 9.0 g/dL; Platelet count: ≥ 75 x 103/mm3; prothrombin
time/international normalized ratio and activated partial thromboplastin time: ≤ 1.5 x
ULN (upper limit of normal); Albumin: ≥ 2.5 g/dL; Total bilirubin: ≤ 1.5 x ULN;
aspartate aminotransferase and alanine aminotransferase: ≤ 2.5 x ULN; Calculated
creatinine clearance: ≥ 50 mL/min (by use of the Cockroft-Gault formula); LVEF (left
ventricular ejection fraction) ≥ LLN (lower limit of normal) by transthoracic
- Subjects with uveal melanoma.
- - Prior treatment with MAPK-pathway inhibitors
- Subjects with clinically active brain metastases (lesions should be stable and have
been definitely treated with stereotactic radiation therapy, surgery or gamma knife
therapy with no evidence of disease progression prior to enrollment.
- - Any contra-indication for evaluation by whole body 18FDG-PET/CT (18-fluorodeoxyglucose
positron emission tomography/computed tomography) and MRI (magnetic resonance imaging)
of the brain.
- - History of another malignancy.
Exception: subjects who have been disease-free for 3
years, (i.e. subjects with second malignancies that are indolent or definitively
treated at least 3 years ago) or subjects with a history of completely resected
non-melanoma skin cancer.
- - Current use of any prohibited medication.
- - Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days),
whichever is shorter, prior to recruitment.
- - Any serious or unstable pre-existing medical conditions (aside from malignancy
exceptions specified above), psychiatric disorders, or other conditions that could
interfere with the subject's safety, obtaining informed consent, or compliance with
- - Known Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), or hepatitis C
virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV
infection will be permitted).
- - No enzyme inducing anticonvulsants for ≥4 weeks prior to recruitment
- A history or evidence of cardiovascular risk including any of the following:
Current LVEF < LLN; b. A QT interval corrected (QTc) for heart rate using the
Bazett's formula (QTcB) ≥ 480 milliseconds; c. A history or evidence of current
clinically significant uncontrolled arrhythmias. Exception: subjects with atrial
fibrillation controlled for > 30 days prior to recruitment are eligible. d. A history
(within 6 months prior to recruitment) of acute coronary syndromes (including
myocardial infarction or unstable angina), or coronary angioplasty; e. A history or
evidence of current ≥ Class II congestive heart failure as defined by the New York
Heart Association (NYHA) guidelines; f. Treatment refractory hypertension defined as a
blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be
controlled by antihypertensive therapy; g. Patients with intra-cardiac defibrillators
or permanent pacemakers; h. Known cardiac metastases; i. Abnormal cardiac valve
morphology (≥ grade 2) documented by echocardiogram (subjects with grade 1
abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects
with moderate valvular thickening should not be entered on study.
- - Uncorrectable electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia,
hypocalcemia), long QT syndrome or taking medicinal products known to prolong the QT
- - A history or current evidence/risk of retinal vein occlusion (RVO) or central serous
retinopathy (CSR) including: a.
Presence of predisposing factors to RVO or CSR (e.g.,
uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled
diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
b. Visible retinal pathology as assessed by ophthalmic examination that is considered
a risk factor for RVO or CSR such as: i. Evidence of new optic disc cupping; ii.
Evidence of new visual field defects on automated perimetry; iii. Intraocular pressure
>21 mmHg as measured by tonography.
- - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study treatments, their excipients, and/or dimethyl
- - Females who are nursing.