Pembrolizumab in Treating Patients With Desmoplastic Melanoma That Can or Cannot Be Removed by Surgery
Pembrolizumab in Treating Patients With Desmoplastic Melanoma That Can or Cannot Be Removed by Surgery
This pilot phase II trial studies how well pembrolizumab works in treating patients with
 desmoplastic melanoma (DM) that can be removed by surgery (resectable) or cannot be removed
 by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as pembrolizumab,
 may help the body's immune system attack the cancer, and may interfere with the ability of
 tumor cells to grow and spread.
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)

 OTHER 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 cycles. Patients with potentially resectable
 disease undergo surgery. Patients with tumor progression and unresectable disease may receive
 one additional cycle 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 cycles 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

 -  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) (obtained within 28 days prior to
 registration)

 -  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 due to unknown teratogenic side effects

 -  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