Dendritic Cell Therapy After Cryosurgery in Combination With Pembrolizumab in Treating Patients With Stage III-IV Melanoma That Cannot Be Remove by Surgery

PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR) of pembrolizumab combined with cryoablation
and intratumoral mature dendritic cells (mDCs) in patients with metastatic melanoma that has
failed to respond or has stopped responding to initial therapy with a PD-1 axis-blocking
monoclonal antibody.

SECONDARY OBJECTIVES:

I. To assess the safety profile of pembrolizumab combined with cryoablation and intratumoral
mDCs in patients with metastatic melanoma that have failed to respond or have stopped
responding to initial therapy with a PD-1 axis-blocking monoclonal antibody.

II. To determine median progression-free survival (PFS) obtained with this approach in this
patient population.

III. To determine median overall survival (OS) obtained with this approach in this patient
population.

TERTIARY OBJECTIVES:

I. To quantitate tumor infiltrating lymphocytes (TILs) in tumor biopsies prior to and
following cryoablation and intratumoral mDCs.

II. To measure PD-L1 levels in tumor biopsies and blood biopsies prior to and following
cryoablation and to assess whether a change in PD-L1 levels differ among those patients who
met the criteria for clinical benefit (progression-free and on study for at least 6 months)
and those who do not.

III. To measure peripheral blood mononuclear cells (PBMC) proliferation and function after
coculture with frozen tumor before and after intratumoral mDC injection.

OUTLINE:

Patients undergo apheresis over 4 hours on day 1 or course 1. Patients also receive
pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses with pembrolizumab repeat
every 21 days for up to 2 years in the absence of disease progression or unacceptable
toxicity. Within 36 hours after receiving pembrolizumab, patients undergo cryosurgery over 45
minutes on day 1 or 2 of courses 2 and 3. Patients also receive mature dendritic cells
intratumorally (IT) on day 1 or 2 of courses 2 and 3 after cryosurgery.

After completion of study treatment, patients are followed for up to 5 years

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of unresectable stage III or
metastatic melanoma (stage IV) not amenable to curative local therapy

- Documented progression of disease after initiation of therapy with OR lack of response
to therapy with a PD-1- or PD-L1-targeting monoclonal antibody (pembrolizumab,
nivolumab, etc) after at least 18 weeks; NOTE: This treatment could have been at any
time prior to registration

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

- Minimum of 3 radiographically apparent lesions such that there is:

- Minimum of one lesion in areas that have not been previously irradiated that is
considered measurable by Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 criteria AND

- Minimum of two lesions in areas that have not been previously irradiated that are
determined by interventional radiology to be of a size and in a location that a
single probe could ablate at least 75% of the lesion; Note: Hepatic lesions
measuring =< 3 cm may be treated, as determined by interventional radiology;
Note: Brain metastases are not acceptable as lesions defining measurable disease,
nor are they candidate lesions for cryoablation

- Adequate venous access for apheresis as assessed by apheresis team; NOTE: If a central
venous catheter is required for apheresis, the patient is not eligible

- Absolute neutrophil count (ANC) >= 1000/mm^3 obtained =< 14 days prior to registration

- Absolute lymphocyte count >= 500/mm^3 obtained =< 14 days prior to registration

- Platelet count >= 100,000/mm^3 obtained =< 14 days prior to registration

- Hemoglobin >= 10 g/dL obtained =< 14 days prior to registration

- Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert?s disease
obtained =< 14 days prior to registration

- Aspartate transaminase (AST/(serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine transaminase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
obtained =< 14 days prior to registration

- Creatinine =< 1.5 x ULN or calculated creatinine clearance >= 60 mL/min for subject
with creatinine ? 1.5 x institutional ULN obtained =< 14 days prior to registration

- Negative serum pregnancy test for persons of childbearing potential =< 7 days prior to
registration

- Provide written informed consent

- Willing to return to the enrolling institution for follow-up (during active treatment
and active monitoring phase of the study)

- Willing to provide tissue and blood samples for research purposes

- Willing to use adequate contraception while on the study and until 120 days after the
last dose of study drug

Exclusion Criteria:

- Any of the following:

- Pregnant persons

- Nursing persons

- History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C

- Active tuberculosis or active, non-infectious pneumonitis

- Evidence of interstitial lung disease

- Active infection requiring the use of systemic antibiotics

- Symptomatic congestive heart failure (New York Heart Association classification III or
IV cardiovascular disease, myocardial infarction =< 6 months prior to registration,
unstable angina pectoris or cardiac arrhythmia =< 3 months prior to registration, or
cardiac arrhythmia

- Currently receiving or have received any other investigational agent considered as a
treatment for the primary neoplasm =< 21 days prior to registration

- History of other primary malignancy requiring systemic treatment =< 3 years prior to
registration; patients must not be receiving chemotherapy or immunotherapy for another
cancer; patients must not have another active malignancy requiring active treatment;
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

- Failure to recover from prior side effects of immune checkpoint inhibitor therapy to
=< grade 1; NOTE: Patients will not be excluded for adrenal insufficiency or
hypothyroidism secondary to immunotherapy provided they are receiving hormonal
replacement

- Major surgery =< 4 weeks prior to registration

- Prior chemotherapy, targeted therapy, or radiation therapy =< 2 weeks prior to
registration or who has not recovered (i.e. to =< grade 1 or baseline) from an adverse
event due to the previously administered therapy

- History of hypersensitivity and anaphylactoid reactions to pneumococcal vaccine or any
component of the formulation, including diphtheria toxoid

- Active autoimmune disease such as Crohn?s disease, rheumatoid arthritis, Sjogrens?
disease, systemic lupus erythematosus, or similar conditions requiring systemic
treatment within the past 3 months or a documented history of clinically severe
autoimmune disease/syndrome difficult to control in the past; EXCEPTIONS (the
following are allowed):

- Vitiligo or resolved childhood asthma/atopy

- Intermittent use of bronchodilators or local steroid injections

- Hypothyroidism stable on hormone replacement

- Diabetes stable with current management

- History of positive Coombs test but no evidence of hemolysis

- Psoriasis not requiring systemic treatment

- Conditions not expected to recur in the absence of an external trigger

- Secondary adrenal insufficiency from previous hypophysitis, currently on
physiologic replacement steroid dosing only

- Coagulopathy, including the use of therapeutic anticoagulants that cannot be
discontinued for the cryoablation procedure; NOTE: Heparin for line patency without
detectable lab abnormalities for coagulation will be allowed

- Corticosteroid use =< 14 days prior to registration; NOTE: Patients must be off
systemic corticosteroids for at least 2 weeks prior to registration; this includes
oral or IV route of administration; patients on chronic corticosteroids for adrenal
insufficiency or other reasons may enroll if they receive less than 10 mg/day of
prednisone (or equivalent); patients receiving inhaled or intranasal or
intra-articular steroids are not excluded

- Active central nervous system (CNS) metastasis; NOTE: Patients with prior brain
metastases that are asymptomatic without corticosteroid use and stable or improved >=
90 days after treatment with surgery or radiation are not excluded

- Receipt of a live vaccine =< 30 days prior to registration