Nivolumab and Trametinib With or Without Dabrafenib in Treating Patients With BRAF Mutated or Wild Type Metastatic Stage III-IV Melanoma That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability, and efficacy (objective response rates by Response
Evaluation Criteria in Solid Tumors [RECIST] 1.1) of nivolumab in combination with dabrafenib
and/or trametinib in patients with BRAF-mutated metastatic melanoma.

SECONDARY OBJECTIVES:

I. Safety and tolerability of the triplet combination (nivolumab-dabrafenib-trametinib
[NDT]).

II. Efficacy of the combinations as measured by the depth and duration of response by RECIST
1.1 on Cohort A, and modified RECIST 1.1 (to include intracranial response) in Cohort B III.
Pharmacodynamic evaluation of combination on circulating markers (immune monitoring).

IV. Pharmacodynamic evaluation of combination on tumor tissues. V. Progression- free survival
and overall survival.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM A (NDT): Patients receive nivolumab intravenously (IV) over 30 minutes on day 1,
dabrafenib orally (PO) twice daily (BID) on days 1-28, and trametinib PO once daily (QD) on
days 1-28.

ARM B (NT, CLOSED TO ACCRUAL ): Patients receive nivolumab IV over 30 minutes on day 1 and 15
and trametinib PO QD on days 1-28.

In both arms, courses repeat every 28 days for 3 years in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days then every 3 months
for up to 3 years.

Inclusion Criteria:

- 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
are eligible

- 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 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)

- Evidence of evaluable disease

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- 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 central nervous system (CNS) symptoms

- White blood cells (WBC) >= 2000 /uL (within one week prior to registration)

- Neutrophils >= 1500 /uL (within one week prior to registration)

- Platelets >= 100 x 10^3 /uL (within one week prior to registration)

- Hemoglobin > 9.0 g/dL (within one week prior to registration)

- Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl)
>= 40 mL/min (if using the Cockcroft-Gault formula) (within one week prior to
registration)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (within one
week prior to registration)

- Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have
total bilirubin < 3.0 mg/dL) (within one week prior to registration)

- 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

- Women of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to the start of nivolumab

- 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

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients that had grade 3/4 immune-related adverse events (AEs) on ipilimumab that
required more than 12 weeks of immune suppression with corticosteroids

- History of interstitial lung disease or pneumonitis

- History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency

- 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

- 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

- Known history of a positive test for hepatitis B virus or hepatitis C virus indicating
acute or chronic infection

- 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; appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated

- 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

- 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

- 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

- Pregnant and/or breastfeeding women are excluded from this study; breastfeeding should
be discontinued if the mother is treated with nivolumab, dabrafenib, and trametinib