Epacadostat and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma

PRIMARY OBJECTIVES:

I. To determine the extent to which a regimen of INCB024360 (epacadostat) that normalizes
serum kynurenine (Kyn)/ tryptophan (Trp) ratios alters the tumor microenvironment of
melanoma, including determining the number and character of tumor-infiltrating lymphocytes as
determined by examination of serial biopsies with immunohistochemistry (IHC) and gene
signatures.

II. To determine the extent to which continued INCB024360 treatment plus the addition of the
multipeptide melanoma vaccine, MELITAC 12.1 (MELITAC 12.1 peptide vaccine), further alters
the tumor microenvironment of melanoma, including determining the number and character of
tumor-infiltrating lymphocytes as determined by serial biopsies evaluating IHC and gene
signatures.

SECONDARY OBJECTIVES:

I. To determine whether a regimen of INCB024360 that normalizes serum Kyn/Trp ratios plus
MELITAC 12.1 vaccine changes the level or character of the vaccine-induced clusters of
differentiation (CD) 8+ and CD4+ T-cell immune responses as measured in peripheral blood, as
compared to prior published experience.

II. To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the number
and character of peripheral blood mononuclear cell (PBMC) populations, including T and
natural killer (NK) cells, as evaluated by multiparameter flow cytometry.

III. To evaluate the extent to which INCB024360 plus MELITAC 12.1 vaccine alters the PBMC
transcriptome.

IV. To assess the safety and tolerability of INCB024360 plus MELITAC 12.1 vaccine.

V. To obtain preliminary data on the tumor response rate of INCB024360 plus MELITAC 12.1
vaccine by objective response rate (ORR), time to tumor progression, and overall survival.

VI. To associate any observed changes with the expression of IDO1 protein by IHC in tumor or
tumor-infiltrating cells.

OUTLINE:

Patients receive epacadostat orally (PO) twice daily (BID) on days 1-98 and receive MELITAC
12.1 peptide vaccine intradermally (ID)/subcutaneously (SC) on days 21, 28, 35, 56, 77, and
98. Treatment with epacadostat may repeat every 98 days for up to 3 additional courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Inclusion Criteria:

- Patients must have malignant melanoma validated by histology or cytology; patients may
have had primary cutaneous, mucosal, or ocular melanoma or metastasis from an unknown
primary site

- NOTE: patients must have measurable disease, defined as at least 1 lesion that
can be accurately measured in at least 1 dimension (longest diameter to be
recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with
conventional chest x-ray or as >= 10 mm with spiral computed tomography (CT)
scan, magnetic resonance imaging (MRI), or calipers by clinical exam

- Unresectable stage III or IV validated by clinical criteria (including recurrent
melanoma), or patients with multiple skin/soft tissue metastases of melanoma that may
be resectable but are judged to have a future recurrence risk exceeding 70% (e.g.,
large adenopathy, distant skin metastases or multiple in-transit melanoma metastases);
tumor deemed amenable to biopsy (excisional, incisional, or core, with at least 100
mm^3 tumor volume per biopsy date) and fine-needle aspiration (FNA) biopsy

- NOTE: optimally, patients will have tumor approachable for three serial biopsies
during the trial; for patients with only one or two tumors approachable for
biopsy, available tumor blocks from prior biopsies can serve as the pretreatment
sample, but only if formalin-fixed tumor tissue is available and adequate to
provide at least 20 unstained slides with sufficient tumor for analysis

- NOTE: patients with unresectable advanced stage III or IV melanoma (including
recurrent melanoma) are only eligible if they have failed at least one other
first-line systemic therapy (other than adjuvant therapy); exceptions to this
requirement are those patients who have refused and/or are ineligible for other
systemic therapies

- NOTE: v-raf murine sarcoma viral oncogene homolog B inhibitor (BRAFi) should be
considered for all 'unresectable" or metastatic melanoma with BRAFV600E mutation;
for low burden in-transit disease patients may enter trial without prior systemic
therapy

- Stage IV no evidence of disease (NED) is excluded by this criterion

- Patients may have had prior systemic therapy without constraint on the number of prior
treatment regimens except:

- Patients may not have had > 450 mg/m^2 doxorubicin

- Patients may not have had > 3000 centigray (cGy) to fields encompassing the
entire pelvis

- Patients must not be on any other systemic therapy within the following intervals
before study enrollment:

- 1 week after stereotactic radiosurgery of the brain or comparable technology

- 4 weeks after cytotoxic chemotherapy or external beam radiation therapy

- 6 weeks after chemotherapy regimens including BCNU (carmustine) or mitomycin C

- Patients who experience melanoma progression (by Response Evaluation Criteria in
Solid Tumors [RECIST] 1.1 criteria) while on or after treatment with programmed
cell death 1 (PD-1) or PD ligand-1 (PDL-1) antibody may enroll on this study

- NOTE: Patients must be off PD-1/PDL- antibody for at least 2 weeks to assess
for delayed toxicity before being enrolled and receiving INCB024360;
patients who are enrolled 2 weeks and up to 6 weeks after the last dose of
PD-/PDL-1 antibody will enroll in cohort B and receive 100 mg BID of
INCB024360; patients enrolled beyond the 6 week period after failing
anti-PD-1/PDL-1 will be enrolled in cohort A; cohort A patients will receive
300 mg BID of INCB024360; patients must not have active grade 2 autoimmune
toxicities attributed to these antibodies at study entry

- 8 weeks after ipilimumab, other cytotoxic T-lymphocyte-associated protein 4
(CTLA-4) antibody or other immunologically active antibody

- NOTE: Patients receiving prior CTLA-4, anti-PD1 antibody or other
immunologic therapy must show evidence of normal pituitary function at
baseline and must not have active grade 2 autoimmune toxicities attributed
to these antibodies at study entry

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 70%)

- Life expectancy of at least 6 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 75,000/mcL

- Hemoglobin > 9 g/dL

- Total bilirubin < 1.5 x institutional upper limit of normal (bilirubin < 3 ×
institutional upper limit of normal for Gilbert's syndrome)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
up to 2.5 times upper limit normal (ULN)

- Creatinine < 1.5 x institutional upper limit of normal OR

- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

- Prothrombin time (PT), international normalized ratio (INR) =< 1.5 x institutional ULN
unless patient is therapeutically anticoagulated; if on anticoagulants, PT/INR need to
be within appropriate anticoagulation limits for the clinical indication; patients who
are receiving anticoagulants may participate in the trial if their anticoagulation can
be stopped safely for several days at the time of each biopsy

- Thyroid-stimulating hormone (TSH) up to 4 times ULN if thyroxine (T4) is normal

- T4 within normal limits; if abnormal and patient is receiving thyroid replacement
therapy, the thyroid medication may be adjusted and the T4 may be re-tested

- Patients must express human leukocyte antigen (HLA) -A1+, -A2+, or -A3+ (80% of
patients)

- Lactate dehydrogenase (LDH) < 5 × upper limits of normal

- (NOTE: these criteria will select against patients with bulky disease and will
select for patients with less disease and earlier disease)

- Participants must not have had prior autoimmune disorders requiring cytotoxic or
immunosuppressive therapy, or autoimmune disorders with visceral involvement;
participants must not have an active or inactive autoimmune disorders (e.g.,
rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory
bowel disease, etc.); participants who are receiving therapy for an autoimmune or
inflammatory disease requiring these therapies are also excluded

- The following will not be exclusionary:

- Resolved ipilimumab associated inflammatory disease

- The presence of laboratory evidence of autoimmune disease (e.g., positive
antinuclear antibody [ANA] titer) without associated symptoms

- Subjects with vitiligo, thyroiditis, or atopic dermatitis, but otherwise not
meeting this criterion may be enrolled; individual cases can be discussed with
the sponsor

- Not likely curable with surgery alone

- Not currently receiving therapy

- Females of childbearing potential must have a negative pregnancy test within 48 hours
before initiating protocol therapy

- NOTE: women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control or abstinence) before
study entry and for the duration of study participation; 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; men treated or
enrolled on this protocol must also agree to use adequate contraception before
the study, for the duration of study participation, and 4 months after completing
INCB024360 and MELITAC 12.1 administration

- NOTE: subjects are considered not of child bearing potential if they are
surgically sterile, have undergone a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy, or are postmenopausal; menopause is the age associated
with complete cessation of menstrual cycles and menses, and implies the loss of
reproductive potential; by a practical definition, the term assumes menopause
after 1 year without menses with an appropriate clinical profile at the
appropriate age

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

Exclusion Criteria:

- Patients who have had cytotoxic chemotherapy, radiotherapy, interferon (IFN),
immunosuppressive therapy, or steroids within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) before entering the study or those who have not recovered from adverse
events (AEs) due to agents administered more than 4 weeks earlier

- Ipilimumab or other immunologically active therapy within 8 weeks of enrollment; NOTE:
patients who experience melanoma progression (by RECIST 1.1 criteria) while on or
after treatment with PD-1 or PDL-1 antibody may enroll on this study

- Active immunosuppressive therapy, including concurrent systemic immunosuppressive
therapy or steroid therapy with more than 7 consecutive days of steroids within the
prior 4 weeks

- The use of prednisone or equivalent < 0.125 mg/kg/day (absolute maximum of 10
mg/day) as replacement therapy is permitted

- Inhaled corticosteroids are permitted

- Cardiovascular disease that meets one of the following: congestive heart failure (New
York Heart Association class III or IV), active angina pectoris, or recent myocardial
infarction or acute coronary syndrome (within the last 6 months)

- History of peripheral vascular disease (PVD) that has required surgical or
percutaneous intervention or documented PVD that requires medical management with
medications such as acetylsalicylic acid (ASA) + clopidogrel; patients with diabetes
that is not well controlled are excluded from participation; not well controlled is
defined as a hemoglobin (Hgb) A1C of greater than 7.5%

- Current or history of systemic autoimmune disease requiring systemic therapy,
including significant autoimmunity associated with prior ipilimumab therapy or therapy
with antibodies to PD-1 or PD-L1

- Cirrhosis, chronic hepatitis C virus positivity, or chronic hepatitis B infection;
subjects who may not tolerate immune-mediated hepatitis due to compromised hepatic
reserve also excluded from participation including: subjects with extensive liver
metastasis (as judged by the investigator); subjects who drink more than two standard
alcoholic beverages per day on a regular basis; subjects who consume more than 2 grams
of acetaminophen per day on a regular basis

- A positive hepatitis B serology indicative of previous immunization (i.e.,
hepatitis B surface antibody [HBsAb]-positive and hepatitis B core antibody
[HBcAb]-negative), or a fully resolved acute hepatitis B infection is not an
exclusion criterion

- Patients who are receiving any other investigational agents for melanoma

- Patients who have had a grade one or grade two gastrointestinal adverse event during
or after receiving anti-CTLA-4, anti-PD1 or anti-PD, without a colonoscopy verifying
complete resolution of the adverse event

- Patients who have experienced bowel perforation, neurologic involvement, Guillain
Barré syndrome, Myasthenia Gravis, Steven Johnson syndrome and other intractable
events or grade 4 non-laboratory toxicity

- Uncontrolled intercurrent illness 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

- Pregnancy, nursing, or unwilling to take adequate birth control during therapy

- NOTE: pregnant women are excluded from this study; breastfeeding should be
discontinued if the mother is treated with INCB024360 and MELITAC 12.1

- Known human immunodeficiency virus (HIV) or other history of immunodeficiency disorder

- NOTE: HIV-positive patients taking combination antiretroviral therapy are
ineligible

- Extensive active brain disease, including symptomatic brain metastases or the presence
of leptomeningeal disease

- Patients with brain metastasis, after definitive therapy with surgery or
stereotactic radiation and stable off steroids for > 4 weeks, are eligible

- Any malignancy that has not been in complete remission for at least 3 years

- NOTE: patients with cured basal or squamous cell skin cancer are not excluded;
patients with a history of excised in situ cancers, including breast, cervical,
colon, superficial bladder, prostate or other body system are not excluded; study
entry will be allowed at the discretion of the Principal Investigator

- NOTE: recurrence of the in situ cancer or tumor at the time of study entry would
be exclusionary

- Monoamine oxidase (MAO) inhibitor use within the past 3 weeks or prior evidence of
serotonin syndrome

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to INCB024360, MELITAC 12.1, or other vaccine components

- Prior organ allograft or allogeneic transplantation, if the transplanted tissue is
still in place

- Medical or psychiatric illness that would, in the opinion of the investigator,
preclude participation in the study or the ability of patients to provide informed
consent for themselves

- History of pulmonary disease such as emphysema or chronic obstructive pulmonary
disease (COPD), (forced expiratory volume in one second [FEV1] > 60% of predicted for
height and age); pulmonary function tests (PFTs) are required in patients with
prolonged smoking history or symptoms of respiratory dysfunction

- Use of any UDP glucuronosyltransferase 1 family, polypeptide A9 (UGT1A9) inhibitor
including: acitretin, amitriptyline, androsterone, cyclosporine, dasatinib,
diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide,
geftinib, gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, imipramine,
ketoconazole, lineoleic acid, mefenamic acid, mycophenolic acid, niflumic acid,
nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid propofol, quinidine,
ritonavir, Sorafenib, sulfinpyrazone, valproic acid and verapamil from screening
through follow-up period

- Low-dose Coumadin (1 mg) is acceptable; however, doses that increase INR are not
permitted; if an alternative to Coumadin-based anticoagulants cannot be used, the INR
should be monitored weekly after initiation of therapy and upon discontinuation of
INCB024360, until INR normalization