Inclusion Criteria:
- - Participants must have histologically confirmed metastatic or unresectable melanoma.
- - Participants must have measurable disease, defined as at least one lesion that can
be accurately measured in at least one dimension (longest diameter to be recorded)
as ≥ 20 mm with conventional techniques or as ≥10 mm with spiral CT scan.
See
section 11 for the evaluation of measureable disease.
- - Participants may have previously received ipilimumab, adjuvant anti-PD1 therapy, or
high-dose IL-2.
They may not have previously been treated with BRAF inhibitors
(vemurafenib, dabrafenib, encorafenib), MEK inhibitors (selumetinib, trametinib,
binimetinib, cobimetinib), and/or anti-PD1/PDL1 monoclonal antibodies for metastatic
or unresectable disease. Participants must allow 2 weeks between prior chemotherapy
targeted small molecule therapy, or radiation therapy prior to study Day 1 or
recovery (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously
administered agent.
- - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
- - Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
- - Age greater than or equal to 18 years.
Because no dosing or adverse event data are
currently available on the use of the combination of trametinib with or without
dabrafenib, and pembrolizumab in participants less than 18 years of age, children
are excluded from this study.
- - ECOG performance status ≤1.
- - Life expectancy of greater than three months.
- - Participants must have normal organ and marrow function as defined below:
- Leukocytes ≥ 3,000/mcL.
- - Absolute neutrophil count ≥ 1,500/mcL.
- - Platelets ≥ 100,000/mcL.
- - total bilirubin ≤ 1.5 X institutional upper limits of normal; total bilirubin >
1.5X above institutional upper limits of normal will be allowed if direct
bilirubin is within normal limits or if patients has a documented history of
Gilbert's disease.
- - AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal.
- - Creatinine within normal institutional limits or creatinine clearance ≥ 60
mL/min/1.73 m2 for subjects with creatinine levels about institutional normal.
- - Participants must have BRAFV600-mutation status known.
- - Participants must have disease amenable to and be willing to undergo serial core or
excisional biopsies of a tumor lesion(s).
- - Because both dabrafenib and trametinib are class D agents with the potential for
teratogenic or abortifacient effects.
Because there is an unknown but potential risk
of adverse events in nursing infants secondary to treatment of the mother with
either dabrafenib and trametinib, breastfeeding should be discontinued if the mother
is treated with either dabrafenib, trametinib, or the combination of dabrafenib and
trametinib. Female subjects of childbearing potential should be willing to use 2
methods of birth control or be surgically sterile, or abstain from heterosexual
activity for the course of the study through 120 days after the last dose of study
medication. Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year. 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 subjects
should agree to use an adequate method of contraception starting with the first dose
of study therapy through 120 days after the last dose of study therapy.
- - Ability to understand and the willingness to sign a written informed consent
document.
Exclusion Criteria:
- - Participants treated with prior chemotherapy, or radiation therapy within 2 weeks
prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from
adverse events due to a previously administered agent.
- - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
- - Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
- - Participants previously treated with BRAF inhibitors (vemurafenib, dabrafenib,
encorafenib), MEK inhibitors (selumetinib, trametinib, binimetinib, cobimetinib),
and/or anti-PD1/PDL1 monoclonal antibodies for metastatic or unresectable disease.
Any other prior therapy will be allowed (including ipilimumab, adjuvant anti-PD1
therapy, high-dose IL-2).
- - Participants with symptomatic brain metastases will be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events.
Subjects with asymptomatic, stable brain metastases and/or who have
been previously treated for these conditions that are asymptomatic in the absence of
corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with
verification by imaging (brain MRI completed at screening demonstrating no current
evidence of progressive brain metastases.
- - Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier.
- - Patients may not be receiving any other anti-neoplastic agents.
- - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of
trial treatment.
- - Pregnant women are excluded from this study because both dabrafenib and trametinib
are class D agents with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk of adverse events in nursing infants
secondary to treatment of the mother with either dabrafenib and trametinib,
breastfeeding should be discontinued if the mother is treated with either
dabrafenib, trametinib, or the combination of dabrafenib and trametinib.
- - Participants known to be HIV-positive and on combination antiretroviral therapy are
ineligible because of the potential for pharmacokinetic interactions with either
dabrafenib or trametinib.
Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.
- - Participants who have had major surgery < 2 weeks prior to entering the study.
- - Has a known history of active TB (Bacillus Tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients.
- - No symptomatic or untreated leptomeningeal disease.
- - Participants are not permitted to receive enzyme inducing anti-epileptic drugs.
- - Has active autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs).
Replacement therapy (eg., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
- - Has a history of (non-infectious) pneumonitis that required steroids or
current/active pneumonitis.
- - History of current evidence of retinal vein occlusion (RVO) or retinal pigment
epithelial detachment (RPED):
- History of RVO or RPED.
- - Visible retinal pathology as assessed by ophthalmic exam that is considered a risk
factor for RVO or RPED such as evidence of new optic disc cupping, evidence of
visual field defects, and intraocular pressure >21 mm Hg.
- - Uncontrolled intercurrent illness including, but not limited to:
- Ongoing or active infection.
- - LVEF <50% as determined by either MUGA scan or Echo.
- - Documented myocardial infarction or unstable/uncontrolled cardiac disease (eg,
unstable angina, severe arrhythmias, congestive heart failure [New York Heart
Association (NYHA) > Class II]) within 6 months of study entry.
- - Arterial thrombosis or vascular ischemic events, such as transient ischemic
attack, cerebral infarction, within 6 months prior to study entry.
- - Serious or non-healing wound.
- - History of any medical condition including cardiovascular disease or chronic
obstructive pulmonary disease (COPD), that in the opinion of the investigator,
may increase the risks associated with study participation or study treatments
or may interfere with the conduct of the study or interpretation of study
results.
- - Psychiatric illness/social situations that would limit compliance with study
requirements.
- - Individuals with a history of a different malignancy are ineligible except for the
following circumstances.
- - Individuals with a history of other malignancies are eligible if they have been
disease-free for at least 3 years and are deemed by the investigator to be at
low risk for recurrence of that malignancy.
- - Individuals with the following cancers are eligible if diagnosed and treated
within the past 3 years: cervical cancer in situ and basal cell or squamous
cell carcinoma of the skin.
- - Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
- Has received a live vaccine within 30 days of planned start of study therapy
