PRIMARY OBJECTIVES:
I. One year progression free survival (PFS) rate.
SECONDARY OBJECTIVES:
I. Obtain biopsy samples from patients treated with an intermittent schedule of LGX818 and
MEK162 to study adaptive and acquired resistance as well as melanoma evolutionary patterns.
II. Study molecular changes of adaptive resistance and acquired resistance to LGX818 and
MEK162 in circulating melanoma cells.
III. Study plasma samples for circulating deoxyribonucleic acid (DNA), microribonucleic acid
(microRNA) and protein signatures of adaptive resistance and acquired resistance.
IV. Explore the median progression free survival and overall survival of patients receiving
an intermittent schedule of LGX818 and MEK162.
OUTLINE:
Patients receive LGX818 orally (PO) once daily (QD) and MEK162 PO twice daily (BID)
continuously for 8 weeks, followed by intermittent dosing in subsequent cycles (3 weeks off
therapy, 5 weeks on therapy). Cycles repeat every 8 weeks in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 6
months thereafter.
Inclusion Criteria:
- Signed written informed consent
- Histologically confirmed diagnosis of metastatic melanoma with the presence of the
B-Raf proto-oncogene, serine/threonine kinase (BRAFV600) mutation
- Eastern Cooperative Oncology Group (ECOG) performance status < 3
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- Hemoglobin (Hgb) >= 9 g/dL without transfusions
- Platelets (PLT) >= 90 x 10^9/L without transfusions
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 x upper
limit of normal (ULN); patient with liver metastases =< 5 x ULN
- Total bilirubin =< 2 x ULN, or < 5 ULN if Gilbert’s disease
- Creatinine =< 1.5 mg/dL, or calculated creatinine clearance (determined as per
Cockcroft-Gault) >= 50 mL/min
- Left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated
acquisition (MUGA) scan or echocardiogram (ECHO)
- Corrected QT (QTc) interval =< 480 ms
- Able to take oral medications
- Patient is deemed by the Investigator to have the initiative and means to be compliant
with the protocol (treatment and follow-up)
- Negative serum beta (β) human chorionic gonadotropin (HCG) test (female patient of
childbearing potential only) within 72 hours prior to first dose
Exclusion Criteria:
- Prior exposure to BRAF or MEK inhibitors
- Any active central nervous system (CNS) lesion (i.e., those with radiographically
unstable, symptomatic lesions) and/or leptomeningeal metastases; however, patient
treated with stereotactic radiotherapy, whole brain radiation or surgery are eligible
if patient remained without evidence of CNS disease progression >= 4 weeks; patients
must be off corticosteroid therapy for >= 2 weeks
- History or current evidence of retinal vein occlusion (RVO) or predisposing factors to
RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
hypercoagulability syndromes)
- History of retinal degenerative disease
- History of Gilbert’s syndrome
- Previous or concurrent malignancy is not an exclusion provided that the other
malignancy is considered under control and target lesions from melanoma are clearly
defined for response assessment
- Impaired cardiovascular function or clinically significant cardiovascular diseases,
including any of the following:
- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6
months prior to screening,
- Symptomatic chronic heart failure, history or current evidence of clinically
significant cardiac arrhythmia and/or conduction abnormality < 6 months prior to
screening except atrial fibrillation and paroxysmal supraventricular tachycardia
- Uncontrolled arterial hypertension despite medical treatment
- Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
and/or active hepatitis C infection
- Patients who have neuromuscular disorders that are associated with elevated creatine
kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
sclerosis, spinal muscular atrophy)
- Patients who are planning on embarking on a new strenuous exercise regimen after first
dose of study treatment; muscular activities, such as strenuous exercise, that can
result in significant increases in plasma CK levels should be avoided while on MEK162
treatment
- Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel
resection)
- Patients taking non-topical medication known to be a strong inhibitor of cytochrome
P450, family 3, subfamily A, polypeptide 4 (CYP3A4); however patients who either
discontinue their treatment or switch to another medication at least three days prior
to randomization are eligible
- Any other condition that would, in the Investigator’s judgment, contraindicate the
patient’s participation in the clinical study due to safety concerns or compliance
with clinical study procedures, e.g., infection/inflammation, intestinal obstruction,
unable to swallow medication, social/psychological issues, etc.
- Patients who have undergone major surgery =< 3 weeks prior to starting study drug or
who have not recovered from side effects of such procedure
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test
- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
throughout the study and for 8 weeks after study drug discontinuation; highly
effective contraception methods include:
- Total abstinence when this is in line with the preferred and usual lifestyle of
the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception
- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment;
in case of oophorectomy alone, only when the reproductive status of the woman has
been confirmed by follow up hormone level assessment
- Male sterilization (at least 6 months prior to screening); for female patients on
the study, the vasectomized male partner should be the sole partner for that
patient
- Combination of any of the two following (a+b or a+c or b+c)
- a. Use of oral, injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy (failure
rate < 1%), for example hormone vaginal ring or transdermal hormone
contraception
- b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- c. Barrier methods of contraception: Condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository
- In case of use of oral contraception, women should have been stable on the same
pill before taking study treatment
- Note: Oral contraceptives are allowed but should be used in conjunction with a
barrier method of contraception
- Women are considered post-menopausal and not of child bearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
ligation at least six weeks ago; in the case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone level
assessment is she considered not of child bearing potential
- Sexually active males unless they use a condom during intercourse while taking the
drug and for 8 weeks after stopping treatment and should not father a child in this
period; a condom is required to be used also by vasectomized men
- Medical, psychiatric, cognitive or other conditions that may compromise the patient's
ability to understand the patient information, give informed consent, comply with the
study protocol or complete the study
