Inclusion Criteria:
- - Able to provide written informed consent.
- - Age >= 18 years at the time of informed consent.
- - Histologically confirmed diagnosis of melanoma.
- - Presence of BRAFV600 mutation in tumor tissue previously determined by a local assay
(including immunohistochemistry [IHC]) at any time prior to Screening or during
Screening.
- - Cohort A: BRAF V600 mutant melanoma patients with progressive central nervous system
(CNS) metastases.
This includes patients with parenchymal brain metastases and/or LMD.
- - Cohort A: Prior therapy with Food and Drug Administration (FDA)-approved BRAF
inhibitors (+/- MEK inhibitors) is required.
- - No washout period is required.
- - Cohort A: Prior therapy with immunotherapy or other investigational agents is allowed.
- - Washout period of 14 days since last dose.
- - Cohort B: BRAF V600 mutant melanoma patients who are treatment naive to BRAF/MEK
inhibitors with CNS metastases, including LMD.
Prior treatment with immunotherapy is
permitted.
- - For patients with parenchymal brain metastases (mets) without LMD.
- - Metastatic disease to the brain with at least 1 progressing parenchymal brain
lesion >= 0.5 cm and =< 3 cm, defined as a magnetic resonance imaging (MRI)
contrast-enhancing lesion that may be accurately measured in at least 1 dimension.
- - Patients must have investigator assessed radiographic and/or CSF cytological
evidence of LMD.
- - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
(PS) of =< 2.
- - Patients may receive steroids to control symptoms related to CNS involvement.
- - For patients with parenchymal brain metastases the dose must be =< 2 mg per 24
hours of dexamethasone (or the equivalent).
Patient's symptoms should experience
stability of neurological symptoms for at least 7 days, or on tapering dose of
steroids. Physiologic replacement doses for adrenal insufficiency is allowed on
this protocol.
- - For patients with LMD: the dose must be =< 4 mg per 24 hours of dexamethasone (or
the equivalent).
Physiologic replacement doses for adrenal insufficiency is
allowed on this protocol.
- - Radiation therapy:
- For patients with parenchymal brain mets: prior radiation therapy, including
stereotactic (SRS) or whole brain radiation (WBXRT) is allowed, but patient must
be progressing in or having at least 1 new CNS lesion.
Prior SBRT to extracranial
lesions is allowed. Washout to prior radiation 14 days.
- - For patients with LMD: Patients who have received radiation to brain and/or
spine, including WBXRT, SRS, or SBRT, are eligible, but must have completed
radiation treatment at least 7 days prior to the start of treatment.
- - Prior therapy with systemic immunotherapy or other investigational agents is allowed.
- - Washout period of 14 days since last dose.
- - Other cancer directed treatment:
- Concurrent treatment with other anti-cancer systemic therapies is not allowed.
No
other concomitant intrathecal therapy with another agent will be allowed. For
patients that have received other systemic therapies, the minimum wash out period
is as follows:
- - Patients that received previous intrathecal therapy must have received their
last treatment >= 7 days prior to the start of treatment.
- - Patients who have received systemic chemotherapy must have received their
last treatment >= 21 days prior to the start of treatment.
Patients must have appropriate laboratory parameters as defined below:
- - Absolute neutrophil count (ANC) 1.5 X 10^9/L.
- - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) =< 1.5 X upper limit of normal (ULN)
- Total bilirubin =< 1.5 X ULN (isolated bilirubin > 1.5 X ULN is acceptable if
bilirubin is fractionated and direct bilirubin < 35%)
- NOTE: Patients with documented Gilbert syndrome or hyperbilirubinemia due to
non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following
discussion and agreement with the primary investigator.
- - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 X ULN, in
patients with liver metastases ≤5 X ULN.
- - Creatinine ≤ 1.5 X ULN OR calculated creatinine clearance ≥50 mL/min OR 24-hour urine
creatinine clearance ≥50 mL/min.
- - Female patients of childbearing potential must have a negative serum and/or urine
pregnancy test result.
- - Female patients of childbearing potential must agree to protocol-approved methods of
contraception and to not donate ova from Screening until 30 days after the last dose
of study drug.
Male patients must agree to use methods of contraception that are
highly effective or acceptable and to not donate sperm from Screening until 90 days
after the last dose of study drug.
- - The patient is deemed by the Investigator to have the initiative and means to comply
with scheduled visits, treatment plan and study procedures.
Exclusion Criteria:
- - Evidence of active infection =< 7 days prior to initiation of study drug therapy (does
not apply to viral infections that are presumed to be associated with the underlying
tumor type required for study entry)
- Use of non-oncology vaccines containing live virus for prevention of infectious
diseases within 30 days of prior to study drug.
Dead virus vaccines (e.g Flu) are
allowed, even during treatment with study drug.
- - Inability to swallow and retain study treatment.
- - Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on
antiretroviral therapy (ART)
- Impaired cardiovascular function or clinically significant cardiovascular disease
including, but not limited to, 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.
- - Congestive heart failure requiring treatment (New York Heart Association grade >=
2)
- A left ventricular ejection fraction (LVEF) < 50% as determined by multigated
acquisition (MUGA) or echocardiogram (ECHO)
- History or presence of clinically significant cardiac arrhythmias (including
resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal
supraventricular tachycardia)
- Baseline Fridericia's correction formula (QTcF) interval >= 480 msec.
Can be
repeated up to three times to confirm.
- - Concurrent neuromuscular disorder (e.g., inflammatory myopathies, muscular dystrophy,
amyotrophic lateral sclerosis, spinal muscular atrophy)
- Impairment of gastrointestinal function or disease which may significantly alter the
absorption of study treatment (e.g., uncontrolled nausea, vomiting or diarrhea;
malabsorption syndrome; small bowel resection).
Known history of 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); history of retinal degenerative disease.
- - Use of herbal supplements, medications or foods that are moderate or strong inhibitors
or inducers of cytochrome P450 (CYP) 3A4/5 =< 1 week prior to the start of study
treatment.
- - History of a thromboembolic event < 12 weeks prior to starting study treatment.
Examples of thromboembolic events include transient ischemia attack, cerebrovascular
accident, deep vein thrombosis or pulmonary embolism. Catheter-related venous
thrombosis is not considered a thromboembolic event for this trial even if < 12 weeks
prior to starting study treatment. Note: Patients with either deep vein thrombosis or
pulmonary emboli that do not result in hemodynamic instability are allowed to enroll
as long as they are stable, asymptomatic and on stable anticoagulants for at least 2
weeks. Additionally, patients with thromboembolic events related to indwelling
catheters or other procedures may be enrolled.
- - Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- - NOTE: Patients with laboratory evidence of cleared HBV or HCV infection may be
enrolled.
- - NOTE: Patients with no prior history of HBV infection who have been vaccinated
against HBV and who have a positive antibody against hepatitis B surface antigen
as the only evidence of prior exposure may enroll.
- - Pregnancy or breastfeeding or patients who plan to become pregnant during the duration
of the study.
- Other severe, acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
treatment administration or that may interfere with the interpretation of study
results and, in the judgment of the Investigator, would make the patient an
inappropriate candidate for the study
