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|NCT02910700 : Study of the TRIplet Combination of Dabrafenib, Nivolumab, and Trametinib in Patients With Metastatic Melanoma (TRIDeNT)|
|Ages||Min: 18 Years Max: N/A|
1. Histologically confirmed metastatic melanoma (Stage IV) or unresectable Stage III that
have progressed on prior PD-1 directed therapy. Patients with BRAF or BRAF-wild-type
2. Prior therapies for metastatic melanoma are allowed, including chemo-, cytokine-,
immuno, biological and vaccine-therapy as long as they did not include BRAFi, MEKi.
Patients who have progressed on anti-PD-1 therapy in the adjuvant setting are also
allowed. Prior ipilimumab and/or PD-1 directed therapy will be allowed with a washout
period of 2 weeks and if all autoimmune adverse events have resolved to grade 1
(except endocrine abnormalities that require continuous replacement).
3. Evidence of evaluable disease.
4. ECOG Performance Status of 0 or 1.
5. Patients with melanoma brain metastases are allowed. Brain metastases status will
determine cohort allocation. Subjects with brain metastases are eligible if: [Cohort
A] (a) metastases have been treated and there is no magnetic resonance imaging (MRI)
evidence of progression for 2 weeks after treatment is complete and within 14 days of
the first dose of nivolumab administration; or [Cohort B] (b) if they are untreated
but asymptomatic and have had previous PD-1 treatment; or (c) if they are untreated
and symptomatic but symptoms are controlled on stable or decreasing doses of steroids
for 14 days prior to drug administration; or (d) they have untreated leptomeningeal
disease (LMD) as long as they fulfill all other eligibility requirements. Note:
Patients are excluded if they require high doses of systemic corticosteroids (> 8 mg
equivalent of dexamethasone) to control CNS symptoms.
6. Patients must have normal organ and marrow function as defined by the normal
laboratory ranges. Screening laboratory values must meet the following criteria and
should be obtained within one week prior to registration a.) WBC >/= 2000/µL b.)
Neutrophils >/=1500/µL c.) Platelets >/= 100 x103/µL d.) Hemoglobin > 9.0 g/dL e.)
Serum creatinine =1.5 x ULN or creatinine clearance (CrCl) >/= 40 mL/min (if using
the Cockcroft-Gault formula below): Female CrCl = (140 - age in years) x weight in kg
x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg
x 1.00 72 x serum creatinine in mg/dL f.) AST/ALT =3 x ULN g.) Total Bilirubin
=1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin <
7. Men and women age >/= 18 years
8. Women of childbearing potential (WOCBP) must 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 23 weeks (30 days plus the time required for nivolumab to undergo
five half-lives) after the last dose of investigational drug. WOCBP are those who have
not been surgically sterilized or have not been free from menses for > 1 year.
9. Women of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to the start of nivolumab.
10. Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 31
weeks after the last dose of investigational product. Women who are not of
childbearing potential (i.e., who are postmenopausal or surgically sterile) and
azoospermic men do not require contraception.
11. Ability to understand and the willingness to sign a written informed consent document.
1. Patients that had grade 3/4 immune-related AEs on ipilimumab that required more than
12 weeks of immune suppression with corticosteroids.
2. History of interstitial lung disease or pneumonitis.
3. History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
4. Active, known or suspected autoimmune disease. Subjects are permitted to enroll if
they have vitiligo, type I diabetes mellitus, residual hypothyroidism and/or
hypophysitis due to autoimmune condition only requiring hormone replacement, psoriasis
not requiring systemic treatment, or conditions not expected to recur in the absence
of an external trigger.
5. Require systemic treatment with either corticosteroids (> 8 mg daily prednisone
equivalents) or other immunosuppressive medications within 14 days of study drug
administration. Inhaled or topical steroids and adrenal replacement doses are
permitted in the absence of active autoimmune disease.
6. Known history of a positive test for hepatitis B virus or hepatitis C virus indicating
acute or chronic infection
7. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). HIV-positive patients on combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with dabrafenib and trametinib. In addition, these patients are at
increased risk of lethal infections when treated with marrow-suppressive therapy.
Appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated.
8. History of allergy or adverse drug reaction to the study drug components (nivolumab,
dabrafenib, or trametinib) or drugs of similar chemical or biologic composition.
Patients with a history of severe hypersensitivity reaction to any monoclonal antibody
should also be excluded.
9. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.
10. Uncontrolled intercurrent illness (requiring IV antibiotic treatment) including, but
not limited to, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements.
11. Pregnant and/or breastfeeding women are excluded from this study. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with nivolumab, dabrafenib, and trametinib, breastfeeding
should be discontinued if the mother is treated with nivolumab, dabrafenib, and
trametinib. These potential risks may also apply to other agents used in this study.
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