Pembrolizumab in Treating Patients With Desmoplastic Melanoma That Can or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To evaluate the pathologic complete response rate (pCR) in patients with resectable
desmoplastic melanoma treated with neoadjuvant MK-3475 (pembrolizumab). (Cohort A) II. To
evaluate the complete response rate (confirmed and unconfirmed) in patients with unresectable
desmoplastic melanoma treated with MK-3475 (pembrolizumab). (Cohort B)

SECONDARY OBJECTIVES:

I. To estimate the 9 week response rate (RR) (unconfirmed complete and partial responses)
among patients with measurable disease. (Cohort A) II. To estimate the median overall
survival (OS). (Cohort A) III. To evaluate safety and tolerability of MK-3475 (pembrolizumab)
in the neoadjuvant setting. (Cohort A) IV. To estimate the median progression-free survival
(PFS). (Cohort B) V. To estimate the median overall survival (OS). (Cohort B) VI. To evaluate
safety and tolerability of MK-3475 (pembrolizumab) in this setting. (Cohort B)

TERTIARY OBJECTIVES:

I. To evaluate the hypothesis that higher mutational load in the patient derived baseline
tumor biopsy samples is associated with higher pathologic complete response (pCR).

II. To evaluate T cell infiltration into the tumors in DM patients and correlate with
response to programmed cell death protein 1 (PD-1) blockade.

III. To evaluate the clonality of tumor infiltrating T cells in DM patients and correlate
with response to PD-1 blockade.

IV. To evaluate adaptive immune resistant mechanism in DM tumors.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
Treatment repeats every 21 days for up to 3 courses. Patients with potentially resectable
disease undergo surgery. Patients with tumor progression and unresectable disease may receive
one additional course of pembrolizumab.

COHORT B: Patients with unresectable disease receive pembrolizumab IV over 30 minutes on day
1. Treatment repeats every 21 days for up to 34 courses in the absence of disease progression
or toxicity.

After completion of study treatment, patients are followed up at 6 and 12 weeks, then every 3
months for 1 year, and every 6 months for 4 years.

Inclusion Criteria:

- COHORT A: Patients must have histologically or cytologically confirmed primary
desmoplastic melanoma that is deemed resectable; the decision to perform surgery on
patients must be based on good clinical judgment; eligible patients for surgical
resection must have disease that, in the judgment of the surgeon, is deemed completely
resectable resulting in free surgical margins; patients must have residual disease
after initial biopsy which can be measurable or non-measurable disease per Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1; residual disease can either be
confirmed with fine-needle aspiration (FNA) or if measurable disease is present, no
FNA needs to be obtained OR

- COHORT B: Patients must have histologically or cytologically confirmed primary
desmoplastic melanoma that is unresectable; patients in Cohort B must have measurable
disease per RECIST 1.1

- Contrast-enhanced computed tomography (CT) scans of the chest, abdomen and pelvis are
required; a whole body positron emission tomography (PET)/CT scan with diagnostic
quality images and intravenous iodinated contrast may be used in lieu of a contrast
enhanced CT of the chest, abdomen and pelvis; imaging of the head and neck is required
only if the patient has a head/neck primary; contrast may be omitted if the treating
investigator believes that exposure to contrast poses an excessive risk to the
patient; if skin lesions are being followed as measurable disease, photograph with a
ruler included and physician measurements, must be kept in the patient's chart as
source documentation; all measurable lesions must be assessed within 28 days prior to
registration; tests to assess non-measurable disease must be performed within 42 days
prior to registration; all disease must be assessed and documented on the baseline
tumor assessment form (RECIST 1.1)

- Patients must not have known brain metastases unless brain metastases have been
treated and patient is asymptomatic with no residual neurological dysfunction and has
not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 14
days prior to registration

- Patients must not have received prior systemic treatment for this melanoma

- Patients must not be planning to receive concomitant other biologic therapy, radiation
therapy, hormonal therapy, other chemotherapy, anti-cancer surgery or other
anti-cancer therapy while on this protocol

- Patients must not have received radiation therapy, non-cytotoxic agents or
investigational agents or systemic corticosteroids within 14 days prior to
registration

- Patients may have received prior surgery; all adverse events associated with prior
surgery must have resolved to =< grade 1 (per Common Terminology Criteria for Adverse
Events [CTCAE] 4.0) prior to registration

- Obtained within 28 days prior to registration: Absolute neutrophil count (ANC) >=
1,500/mcl

- Obtained within 28 days prior to registration: Platelets >= 50,000/mcl

- Obtained within 28 days prior to registration: Hemoglobin >= 8 g/dL

- Obtained within 28 days prior to registration: Total bilirubin =< 1.5 x institutional
upper limit of normal (IULN) (or =< 3.0 x IULN with Gilbert's syndrome)

- Obtained within 28 days prior to registration: Aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known
liver metastases)

- Patients must have lactate dehydrogenase (LDH) performed within 28 days prior to
registration

- Patients must have Zubrod performance status =< 2

- Patients must not have history of (non-infectious) pneumonitis that required steroids
or current pneumonitis

- Patients must not have an active infection requiring systemic therapy

- Patients must not have active autoimmune disease that has required systemic treatment
in past 2 years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment

- Patients must not have received live vaccines within 42 days prior to registration;
examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin
(BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are not allowed

- Patients known to be human immunodeficiency virus (HIV) positive are eligible if they
meet the following criteria within 30 days prior to registration: stable and adequate
CD4 counts (>= 350 mm^3), and serum HIV viral load of < 25,000 IU/ml; patients must be
on a stable anti-viral therapy

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, adequately treated in situ cancer, adequately
treated stage I or II cancer (including multiple primary melanomas) from which the
patient is currently in complete remission, or any other cancer from which the patient
has been disease free for three years

- Women of childbearing potential must have a negative urine or serum pregnancy test
within 28 days prior to registration; women/men of reproductive potential must have
agreed to use an effective contraceptive method for the course of the study through
120 days after the last dose of study medication; 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; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy, or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures; patients must not be pregnant or
nursing

- Patients must have specimens available and institutions must be planning to submit for
centralized pathology review and for integrated translational medicine objectives

- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process, the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system