Inclusion Criteria:
- - Males or females age >= 18 years.
- - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
- - Histologically confirmed locally advanced/unresectable or metastatic cutaneous
melanoma.
- - Measurable disease per RECIST version (v.
) 1.1 criteria using imaging scans, OR
peripheral lesions that can be adequately documented with a picture and a ruler even
if they do not meet RECIST criteria.
- - Patient must have failed prior alphaPD-1 or alphaPD-1 + alphaCTLA-4 therapy in the
metastatic setting.
- - V600BRAF wildtype tumor status confirmed by Clinical Laboratory Improvement Act (CLIA)
approved lab.
- - Hemoglobin >= 8.0 g/dL.
- - Whole blood cell count (WBC) >= 2,000/mm^3.
- - Absolute neutrophil count >= 1,500/mm^3.
- - Platelet count >= 75,000/mm^3.
- - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x
institutional upper limit of normal (ULN), (=< 5.0 x ULN in those with hepatic
metastases)
- Bilirubin =< 1.5 x ULN; for subjects with documented/suspected Gilbert's disease,
bilirubin =< 3 x ULN.
- - Serum creatinine =< 2.0 x upper limit of normal (ULN)
- Left ventricular ejection fraction (LVEF) >= 50% assessed by echocardiogram (ECHO) or
multiple-gated acquisition (MUGA) scan completed =< 180 days (6 months) before
initiation of protocol treatment.
- - Patients must be willing to submit blood and tissue specimens for translational
medicine studies.
- - Patients must have a site of disease amenable to biopsy and be a candidate for biopsy.
- - Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) at screening and within 24 hours prior to the start of study drug.
- - Women of childbearing potential (WOCBP) must be willing to use either two adequate
barrier methods or a barrier method plus a hormonal method of contraception to prevent
pregnancy, or to abstain from heterosexual activity (complete abstinence) throughout
the study, starting with visit 1 through 5 months after the last dose of study
therapy.
Approved contraceptive methods include, for example, intrauterine device,
diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms
with spermicide, or oral contraceptives. Spermicides alone are not an acceptable
method of contraception. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately.
- - Male patients must agree to use an adequate method of contraception, or to abstain
from heterosexual activity (complete abstinence) starting with the first dose of study
drug through 5 months after the last dose of study therapy.
Exclusion Criteria:
- - Contraindications to tumor biopsy (coagulopathy, known history of keloid formation,
etc.)
- Women who are pregnant or breastfeeding.
- - Prior therapy with a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib)
- Known hypersensitivity or contraindication to any component of binimetinib or its
excipients.
- - Inability to swallow and retain study drug.
- - Patients who have received prior lines of systemic therapy in the advanced/metastatic
setting (not including, neoadjuvant, adjuvant, or maintenance therapy)
- Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic
biologic therapy (e.g., erlotinib, cetuximab, bevacizumab etc.), within 14 days prior
to start of study treatment or exposure to any investigational drug within 7 days
prior to screening visit or for which 5 half-lives have not elapsed.
- - Participants who have undergone major surgery (e.g., in-patient procedures) =< 6 weeks
prior to start of study treatment or who have not recovered from side effects of such
procedure.
- - Participants who have had radiotherapy =< 14 days prior to start of study treatment or
who have not recovered from side effects of such procedure.
Note: Palliative radiation
therapy must be complete 7 days prior to the first dose of study treatment.
- - Participants who have not recovered to =< grade 1 from toxic effects of prior therapy
before starting study treatment.
- - Note: Stable chronic conditions (=< grade 2) that are not expected to resolve
(such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies)
are exceptions and may enroll.
- - Uncontrolled or symptomatic brain metastases or leptomeningeal carcinomatosis that are
not stable, require steroids, are potentially life-threatening or have required
radiation within 28 days prior to starting study drug.
Note: Patients with previously
treated brain metastases may participate provided they are stable (e.g., without
evidence of progression by radiographic imaging for at least 28 days before the first
dose of study treatment and neurologic symptoms have returned to baseline), and have
no evidence of new or enlarging brain metastases or central nervous system (CNS)
edema, and does not require steroids at least 7 days before the first dose of study
treatment.
- - Subjects with active, known, or suspected autoimmune disease.
Subjects with type I
diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll.
- - Uncontrolled or significant cardiovascular disease including, but not limited to, any
of the following:
- Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6
months prior to consent.
- - Uncontrolled angina within the 3 months prior to consent.
- - Any history of clinically significant arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled
atrial fibrillation)
- Corrected QT (QTc) prolongation > 480 msec.
- - History of other clinically significant cardiovascular disease (i.e.,
cardiomyopathy, congestive heart failure with New York Heart Association [NYHA]
functional classification III-IV, pericarditis, significant pericardial effusion,
significant coronary stent occlusion, poorly controlled deep venous thrombosis,
etc)
- Cardiovascular disease-related requirement for daily supplemental oxygen.
- - History of two or more myocardial infarctions OR two or more coronary
revascularization procedures.
- - Subjects with history of myocarditis, regardless of etiology.
- - History of thromboembolic or cerebrovascular events =< 12 weeks prior to the
first dose of study treatment.
Examples include transient ischemic attacks,
cerebrovascular accidents, hemodynamically significant (i.e. massive or
sub-massive) deep vein thrombosis or pulmonary emboli.
- - Note: Patients with either deep vein thrombosis or pulmonary emboli that
does not result in hemodynamic instability are allowed to enroll as long as
they are on a stable dose of anticoagulants for at least 4 weeks.
- - Note: Patients with thromboembolic events related to indwelling catheters or
other procedures may be enrolled.
- - A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year
prior to informed consent.
- - Participants with a condition requiring systemic treatment with corticosteroids (> 10
mg daily prednisone or equivalent)
- Subjects receiving any other investigational or standard antineoplastic agents.
- - Patients with severe grade 3-4 toxicities due to anti-PD-1 monotherapy during first
line.
Toxicities due to combination PD-1/CTLA-4 blockade will not be exclusionary.
- - Inability to give informed consent.
- - History of malignancies except cured basal cell carcinoma, cutaneous squamous cell
carcinoma, melanoma in situ, superficial bladder cancer or carcinoma in situ of the
cervix; for other malignancies, must be documented to be free of cancer for >= 2
years.
All other cases can be considered on a case by case basis at the discretion of
the principal investigator.
- - Any condition that might interfere with the subject's participation in the study,
safety, or in the evaluation of the study results.
- - Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or the follow-up period of an interventional study.
- - Active or prior documented inflammatory bowel disease.
- - History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required
steroids or has current ILD/pneumonitis or where suspected ILD/pneumonitis cannot be
ruled out by imaging at screening.
- - Impairment of gastrointestinal function or disease which may significantly alter the
absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or
diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal
absorption), or recent (=< 3 months) history of a partial or complete bowel
obstruction, or other conditions that will interfere significantly with the absorption
of oral drugs.
- - Concurrent neuromuscular disorder that is associated with elevated creatine kinase
(CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral
sclerosis, spinal muscular atrophy)
- History or current evidence of retinal venous occlusion (RVO) or current risk factors
for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity
or hypercoagulability syndromes); history of retinal degenerative disease.
- - Prisoners or subjects who are involuntarily incarcerated.
- - Note: under certain specific circumstances a person who has been imprisoned may
be included or permitted to continue as a subject.
- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness
