| Eligibility |
Inclusion Criteria:
- Willing and able to provide written informed consent/assent for the trial.
- Being = 18 years of age on day of signing informed consent.
- Histologically confirmed diagnosis of locally advanced, unresectable or metastatic
melanoma AJCC (2017) Stage IIIB, IIIC, IIID or IV with no active brain metastasis. All
known CNS lesions must have been only treated with stereotactic therapy or surgery at
least 4 weeks prior to the first dose of trial treatment AND they are stable (without
evidence of progression by imaging for at least 4 weeks prior to the first dose of
trial treatment and any neurologic symptoms have returned to baseline); there is no
evidence of new or enlarging brain metastases, and the patient must not have used
steroids in dosing exceeding 10 mg daily of prednisone equivalent for at least 3 weeks
prior to trial treatment.
- Treatment naive patient for locally advanced unresectable or metastatic melanoma.
Prior adjuvant or neoadjuvant systemic therapy is permitted (in stage II, III and IV
with no evidence of disease) if all related adverse events have either returned to
baseline or stabilized.
(i) Anti-PD-1, anti-CTLA-4, BRAF/MEK inhibitor therapy with at least 6 months between
the last dose and date of recurrence.
(ii) Interferon therapy and chemotherapy with the last dose at least 6 weeks prior to
registration.
(iii) Radiotherapy with the last radiation at least 28 days prior to registration.
Participants must have recovered from all radiation-related toxicities. Note: radiated
lesions cannot be used as measurable lesions unless there is clear evidence of progression.
Patients who are in follow-up period of a clinical trial in adjuvant setting may be
enrolled.
- Measurable disease, i.e., present with at least one measurable lesion per RECIST,
version 1.1, for the definition of a measureable lesion.
- Presence of BRAF mutation V600 in tumor tissue from an archival tissue sample or newly
obtained core or excisional biopsy of a tumor lesion prior to enrollment.
- Performance status of 0 or 1 on the ECOG Performance Scale.
- Adequate organ function: ANC =1,500 /mcL, Platelets =100,000 / mcL, Hemoglobin =9 g/dL
OR =5.6 mmol/L, Serum creatinine OR Measured or calculated CrCl =1.5 X ULN OR =50
mL/min for subject with creatinine levels > 1.5 X institutional ULN, Serum total
bilirubin = 1.5 X ULN OR Direct bilirubin = ULN for subjects with total bilirubin
levels > 1.5 ULN, AST and ALT = 2.5 X ULN OR = 5 X ULN for subjects with liver
metastases.
- Adequate cardiac function:
- LVEF = 50% as determined by multiple gated acquisition (MUGA) scan or
echocardiogram
- Corrected QT (QTc) interval = 480ms
- All treatment-related toxicities of prior adjuvant or neoadjuvant systemic therapy
(except alopecia) must be = Grade 1 according to the CTCAE version 4.03:
- Able to take oral medications.
- Female subject of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
- Female patients of childbearing potential and male patients with partners of
childbearing potential must agree to always use a highly effective form of
contraception according to CTFG starting with the first dose of study therapy during
the course of this study and for at least 120 days after the last dose of study
medication
Exclusion Criteria:
- Currently participating in or having participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of
treatment.
- Diagnosis of immunodeficiency or receiving systemic steroid therapy in dosing
exceeding 10 mg daily of prednisone equivalent or any other form of immunosuppressive
therapy within 7 days prior to study Day 1.
- Prior therapy (except if given as adjuvant or neoadjuvant therapy for melanoma) with
an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody or any other
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint
pathways (except for interferon given as adjuvant or neoadjuvant therapy for
melanoma).
- Prior therapy (except if given as adjuvant or neoadjuvant therapy for melanoma) with a
BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib) and
/ or MEK inhibitor (including but not limited to trametinib, AZD6244, binimetinib,
cobimetinib).
- Any previous anti-cancer treatment, extensive radiotherapy or investigational agent
for locally advanced unresectable or metastatic melanoma.
- Known additional malignancy that is progressing or required active treatment within 3
years prior to the study.
- Known active CNS metastases and/or carcinomatous meningitis.
- Presence of uveal melanoma.
- History of leptomeningeal metastases.
- History or current evidence of CSR or RVO or predisposing factors to RVO or CSR (e.g.
uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history
of hyperviscosity or hypercoagulability syndromes).
- History of retinal degenerative disease.
- History of allogeneic bone marrow transplantation or organ transplantation.
- History of Gilbert's syndrome.
- Uncontrolled arterial hypertension despite medical treatment.
- Patients who have neuromuscular disorders associated with elevated creatine kinase
(e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,
spinal muscular atrophy).
- Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative
disease, uncontrolled nausea, vomiting, malabsorption syndrome, small bowel
resection).
- Evidence of interstitial lung disease or active, non-infectious pneumonitis or history
of (non-infectious) pneumonitis that required steroids.
- Active infection requiring systemic therapy.
- Pregnancy or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
until up to 120 days after the last dose of trial treatment.
- Positive test for HIV.
- Positive test for Hep B or Hep C.
- Receiving a live vaccine within 30 days prior to the first dose of trial treatment.
- Known hypersensitivity reaction to any of the components of study treatment.
- Medical, psychiatric, cognitive or other conditions, including known alcohol or drug
abuse that would not permit the subject to complete the study or sign informed
consent.
- Patients taking non-topical medication known to be a strong inhibitor of CYP3A4.
- History of life-threatening toxicity related to prior immune therapy (e.g. anti-CTLA-4
or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting
T-cell co-stimulation or immune checkpoint pathways) or kinase inhibition (e.g. BRAF
and/or MEK inhibitor) except those that are unlikely to re-occur with standard
countermeasures (e.g. hormone replacement after adrenal crisis).
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