CDX-1401 and Poly-ICLC Vaccine Therapy With or Without CDX-301 in Treating Patients With Stage IIB-IV Melanoma

PRIMARY OBJECTIVES:

I. To determine whether the immune response to cancer/testis antigen 1B (NY-ESO-1) elicited
by vaccination with CDX-1401 (anti-DEC205-NY-ESO-1 fusion protein vaccine) plus
polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose
(poly-ICLC) is substantially increased by prior expansion in the number of circulating
dendritic cells (DC) by therapy with CDX-301 (fms-related tyrosine kinase 3 ligand [Flt3L])
(recombinant flt3 ligand).

II. To determine whether the proportion of responders to NY-ESO-1 is > 50% when T cell
responses are elicited by vaccination with CDX-1401 plus poly-ICLC in combination with
CDX-301 (Flt3L) 75 mcg/kg/day administered prior to vaccination for 5 days in both of the
first two vaccine cycles; and for 5 days in the first vaccine cycle only.

SECONDARY OBJECTIVES:

I. To assess the effect of the vaccine regimen on immune responses to other ongoing and
nascent antitumor response antigens associated with melanoma (e.g., PRAME, MAGE-A3, p53, and
gp100) as well as memory viral responses (influenza A) and chronic viral responses
(cytomegalovirus [CMV], Epstein-Barr virus [EBV]).

II. To assess the effect of the vaccine regimen on the frequency and phenotypic character of
peripheral blood mononuclear cell (PBMC) subsets including DCs, monocyte populations, T
cells, and natural killer (NK) cells.

III. To assess the safety, tolerability, and clinical efficacy of the vaccine regimens.

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive recombinant flt3 ligand subcutaneously (SC) on days -7 to -1, 1-3,
and 22-28 of course 1 and on days 1-3 of course 2 only; DEC-205/NY-ESO-1 fusion protein
CDX-1401 SC or intradermally (ID) on day 1; and poly-ICLC SC on days 1 and 2. Treatment
repeats every 28 days for 4 courses in the absence of disease progression or unacceptable
toxicity.

ARM II: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 and poly-ICLC as in Arm I.
Treatment repeats every 28 days for 4 courses in the absence of disease progression or
unacceptable toxicity.

ARM III: Patients receive recombinant flt3 ligand SC on days -7 to -3 and 22-26 of course 1
only and DEC-205/NY-ESO-1 fusion protein CDX-1401 and poly-ICLC as in Arm I. Treatment
repeats every 28 days for 4 courses in the absence of disease progression or unacceptable
toxicity.

ARM IV: Patients receive recombinant flt3 ligand SC on days -7 to -3 of course 1 only, and
DEC-205/NY-ESO-1 fusion protein CDX-1401 and poly-ICLC as in Arm I. Treatment repeats every
28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 and 12 weeks and then
annually thereafter.

Inclusion Criteria:

- Patients with fully resected stage IIb through IV melanoma, with melanoma validated by
histology or cytology, who have NOT received prior therapy

- Patients may have had primary cutaneous, mucosal, or ocular melanoma or
metastasis from an unknown primary site

- Tissue should be submitted for evaluation of NY-ESO-1 expression and T-cell
infiltrates; however, availability of tissue and/or positivity for NY-ESO-1 is
not mandatory

- Prior therapy requirements:

- Prior radiation, chemotherapy or biologics NOT allowed

- Not currently receiving any anticancer therapy

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

- Life expectancy of at least 6 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 75,000/mcL

- Hemoglobin > 9 g/dL

- Total bilirubin < 1.5 x institutional upper limit of normal (bilirubin < 3 x
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])
=< 2.5 x institutional upper limit of normal

- 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

- The first six patients enrolled in the Flt3L arm of the study cannot be human
immunodeficiency virus (HIV)-positive; after the evaluation of safety in the first 6
patients, HIV-positive patients with adequate immune function as evidenced by stable
cluster of differentiation (CD)4 counts >= 350/mm^3 are allowed to participate if the
following criteria are met:

- Maintained on stable antiretroviral therapy with no significant drug
interactions, and

- No recent history of acquired immune deficiency syndrome (AIDS) indicator
conditions (> 2 years from enrolling in trial), and

- Physician providing patient's care for HIV must also approve of patient entering
the study

- Both men and women of all races and ethnic groups are eligible for this trial

- Females of childbearing potential must have a negative pregnancy test within 7 days
before the initiation of protocol therapy

- 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 completion of CDX-1401 or
CDX-301 administration

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

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

Exclusion Criteria:

- Patients who have had cytotoxic chemotherapy, radiotherapy, interferon (IFN), or
ipilimumab before entering the study

- Immunosuppressive therapy within 30 days prior to initiation of protocol therapy

- Steroid 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 or topical corticosteroids are permitted

- Patients who are receiving any other investigational agents

- Current or history of systemic autoimmune disease requiring systemic therapy

- NOTE: The following will not be exclusionary:

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

- Clinical evidence of vitiligo

- Other forms of depigmenting illness

- 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 (within the last 6 months)

- Cirrhosis or chronic hepatitis C virus positivity or chronic hepatitis B infection

- NOTE: 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 virus infection is not
an exclusion criterion

- Known history of immunodeficiency disorder other than HIV-positive status

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

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

- Other invasive cancers that are clinically active

- Pregnancy or 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 CDX-1401 or CDX-301 and poly-ICLC

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to CDX-1401 or CDX-301 or poly-ICLC

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

- 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

- 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

- Vaccinations other than those given as part of this research study (with the exception
of influenza vaccine) are prohibited throughout the duration of study participation

- NOTE: Influenza vaccination (inactivated) is permitted during the flu season; the
preferred time is 7 to 14 days after CDX-1401 administration