Pembrolizumab and Interferon Gamma-1b in Treating Patients With Stage IB-IVB Relapsed or Refractory Mycosis Fungoides and Sezary Syndrome

PRIMARY OBJECTIVES:

I. To assess the overall response rate (ORR) of MK-3475 (pembrolizumab) and interferon
gamma-1b (IFN-G) (Actimmune) combination immunotherapy in subjects with previously treated
mycosis fungoides or sezary syndrome. (Treatment Group 1) II. To determine whether the
combination of interferon gamma-1b (ACTIMMUNE) and MK-3475 (pembrolizumab) improves the ORR
of pembrolizumab in patients with unresectable or metastatic synovial sarcoma. (Treatment
Group 2)

SECONDARY OBJECTIVES:

I. To explore the safety/tolerability and clinical activity of MK-3475 (pembrolizumab) and
IFN-G (Actimmune) in subjects with previously treated mycosis fungoides or sezary syndrome
with respect to safety and tolerability, time to response (TTR), duration of response (DOR),
progression-free survival (PFS), event-free survival (EFS), and percentage of all patients
who have a response duration of at least 12 months (ORR12). (Treatment Group 1) II. To
determine the progression-free survival (PFS) and overall survival (OS) for patients with
advanced synovial sarcoma receiving interferon gamma-1b and MK-3475 (pembrolizumab).
(Treatment Group 2) III. To determine the tolerability of the combination of interferon
gamma-1b and MK-3475 (pembrolizumab) based on Common Terminology Criteria for Adverse Events
(CTCAE) version 5.0. (Treatment Group 2)

EXPLORATORY OBJECTIVES:

I. To investigate the relationship between the following putative biomarkers for combination
immunotherapy of MK-3475 pembrolizumab) and IFN-gamma (Actimmune) and clinical outcomes (as
measured by safety/tolerability and ORR, DOR, PFS, EFS) in subjects with previously treated
mycosis fungoides or sezary syndrome, including tumor/microenvironment (PD-1/PD-L1/PD-L2
expression, cytotoxic T lymphocyte [CTL]s, regulatory T cell [Treg]s, macrophages, dendritic
cell [DC]s; nanostring gene expression profile), systemic immune response (flow cytometry,
mass cytometry [CyTOF], Luminex multiplexed cytokine profile), and molecular/genomic immune
correlates (exome sequencing, high throughput sequencing [HTS] for T cell receptor [TCR]).
(Treatment Group 1) II. To investigate paired, serial biopsy specimens from pre-treatment and
8-12 weeks after starting treatment for MHC class I expression (scored by pathologist),
number of infiltrating T cells per mm^2, tumor associated macrophage number and phenotype
using multiplex immunohistochemistry, T cell clonality, gene expression profiling. (Treatment
Group 2) III. To investigate peripheral blood samples from patients to determine the number
and phenotype of T cells specific for computed tomography (CT) antigens and potential
neo-antigens, the phenotype and activation state of circulating monocytes and peripheral
blood mononuclear cell (PBMC), and cytokines associated with response (Treatment Group 2)

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses
repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected
toxicity. Patients also receive interferon gamma-1b subcutaneously (SC) 3 times per week for
12 weeks, and then follow 3 weeks on and 3 weeks off schedule for up to 2 years in the
absence of disease progression or unexpected toxicity.

GROUP II: Patients pembrolizumab IV over 30 minutes on day 1 and interferon gamma-1b SC once
a week. Courses repeat every 3 weeks for up to 2 years in the absence of disease progression
or unexpected toxicity.

After completion of study treatment, patients are follow up for 30 days and then every 12
weeks for up to 1 year.

Inclusion Criteria:

- MYCOSIS FUNGOIDES /SEZARY SYNDROME (TREATMENT GROUP I)

- Stage IB-IVB mycosis fungoides or sezary syndrome, and who have relapsed, are
refractory, or progressed after at least one standard systemic therapy; maximal stage
since diagnosis will determine eligibility; current disease stage at time of entry
will also be documented but will not be used for eligibility

- Subjects must have the following minimum wash-out from previous treatments and without
treatment between documentation of relapse/progression and enrollment:

- >= 2 weeks for local radiation therapy

- >= 8 weeks for low dose (12 Gy or less) total skin electron beam therapy (TSEBT)

- >= 4 weeks for systemic cytotoxic anticancer agents, anticancer investigational
agents that are not defined as immunotherapy, or for tumor-targeting monoclonal
antibodies (mAbs) with the exception of alemtuzumab for which the washout is at
least 16 weeks

- >= 15 weeks for anti-CD137 or anti-CTLA-4 (including ipilimumab or any other
antibody or drug specifically targeting T-cell co-stimulation or checkpoint
pathways)

- >= 2 weeks from resolution (i.e., < grade 1 or at baseline) from adverse event
(AE)s due to procedures performed or therapeutic agents administered

- >= 2 weeks for retinoids, interferons, vorinostat, romidepsin and denileukin
diftitox

- >= 4 weeks for doses of systemic corticosteroidsgreater than 10 mg/day of
prednisone or equivalent; patients who are on physiologic doses of
corticosteroids (prednisone equivalent 10 mg/day or less) may participate,
however, they must be on a stable dose for at least 4 weeks before enrollment;
patients who are on low or moderate potency topical corticosteroids may
participate if they are on a stable dose for at least 4 weeks before enrollment;
inhaled corticosteroids are acceptable; local injections of corticosteroids are
acceptable; all corticosteroids will be reported as concomitant medications

- >= 2 weeks for phototherapy

- >= 1 week for topical therapy (including retinoid, nitrogen mustard, or
imiquimod)

- Patients with prior treatment with IFN-gamma will be eligible, if they previously
tolerated IFN-gamma, however patients must be off of IFN-gamma for at least three
weeks before initiation of therapy on this trial

- Age >= 18 years

- Have measurable disease based on modified severity-weighted assessment tool (mSWAT);
tumor lesions situated in a previously irradiated area are considered measurable if
progression has been demonstrated in such lesions

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale

- Absolute neutrophil count (ANC) >= 1500/mcL (performed within 10 days of treatment
initiation)

- Platelets >= 100000/mcL (performed within 10 days of treatment initiation)

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 10 days of treatment
initiation)

- Creatinine =< 1.5 x upper limit normal (ULN) (performed within 10 days of treatment
initiation) OR

- Measured or calculated creatinine clearance >= 60 mL/min for patient with creatinine
levels > 1.5 x institutional ULN (performed within 10 days of treatment initiation)

- Creatinine clearance (CrCl) should be calculated per institutional standard;
glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl

- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total
bilirubin levels > 1.5 x ULN (performed within 10 days of treatment initiation)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN OR =< 5 x ULN for patients with liver metastases (performed within 10 days of
treatment initiation)

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) before to study entry and
for the duration of study participation; female patients of childbearing potential
must have a negative urine or serum pregnancy test within 72 hours before receiving
the first dose of study medication; if the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required; female patients of
childbearing potential must be willing to use an adequate method of contraception for
the course of the study through 120 days after the last dose of study medication;
Note: abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the patient; male patients of reproductive potential must agree to
use an adequate method of contraception starting with the first dose of study therapy
through 120 days after the last dose of study therapy; Note: abstinence is acceptable
if this is the usual lifestyle and preferred contraception for the patient; 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 MK-3475 (pembrolizumab) and interferon-gamma administration

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

- SYNOVIAL SARCOMA (TREATMENT GROUP II)

- Diagnosis of translocation associated sarcoma that generally expresses NY-ESO-1 (e.g.,
synovial sarcoma or myxoid/round cell liposaromca); tumor must have been reviewed by a
bone and soft tissue pathologist; patient must have metastatic or unresectable disease

- At least one prior line of chemotherapy

- Age >= 12 years; patients >= 18 years of age must be able and willing to provide
informed consent; patients under 18 years of age must have a parent or guardian
willing and able to provide consent

- ECOG performance status of 0, 1 or 2

- Life expectancy greater than or equal to (>=) 12 weeks

- Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1

- Tumor safely accessible for biopsy

- Adequate hematologic and end organ function

- For female participants of childbearing potential and male participants with partners
of childbearing potential, agreement (by participant and/or partner) to use highly
effective form(s) of contraception

Exclusion Criteria:

- MYCOSIS FUNGOIDES /SEZARY SYNDROME (TREATMENT GROUP I):

- Has disease that is suitable for local therapy administered with curative intent

- Patients who have had chemotherapy or targeted small molecule therapy within 4 weeks
(6 weeks for nitrosoureas or mitomycin C) before entering the study

- Patients who have had an allogeneic stem cell transplant are excluded

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2

- Patients who have received an investigational agent or have used an investigational
device within 4 weeks of the first dose of study drug

- Has a history of a well-characterized and defined immune deficiency before the
diagnosis of mycosis fungoides or sezary syndrome or is receiving systemic steroid
therapy greater than 10mg/day of prednisone or equivalent within 4 weeks or any other
form of immunosuppressive therapy within 7 days before the first dose of trial
treatment; the use of physiologic replacement doses of corticosteroids, along with
topical, inhaled and local injection is discussed

- Has had a prior monoclonal antibody within 4 weeks before study day 1 or who has not
recovered (i.e., =< grade 1 or at baseline) from AEs due to agents administered more
than 4 weeks earlier

- Note: the following will not be exclusionary: patients may have any grade
alopecia or lymphopenia and still participate if other inclusion/exclusion
criteria are met; patients may have grade 1 or 2 neuropathy at baseline and still
participate if other inclusion/exclusion criteria are met

- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy, or in situ cervical cancer

- Patients with known brain metastases should be excluded from this clinical trial;
patients with carcinomatous meningitis should also be excluded; patients with
previously treated brain metastases may participate provided they are stable (without
evidence of progression by imaging using the identical imaging modality for each
assessment, either magnetic resonance imaging [MRI] or computed tomography [CT] scan,
for at least 4 weeks before the first dose of trial treatment and any neurologic
symptoms have returned to baseline), have no evidence of new or enlarging brain
metastases, and are not using steroids for at least 7 days before trial treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-3475 (pembrolizumab) and interferon-gamma; patients who are
hypersensitive to Escherichia (E). coli are also excluded

- Has an active autoimmune disease that has required systemic treatment in the 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

- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial, or is not in the best interest of
the patient to participate, in the opinion of the treating investigator

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, interstitial lung disease or active, non-infectious pneumonitis, congestive
heart failure New York Heart Association (NYHA) grade >= 3, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with MK-3475 (pembrolizumab); patients are excluded from this
study if pregnant or breastfeeding, or expecting to conceive or father children within
the projected duration of the trial, starting with the screening visit through 120
days after the last dose of trial treatment

- Patients who are human immunodeficiency virus (HIV) positive may participate IF they
meet the following eligibility requirements:

- They must be stable on their anti-retroviral regimen, and they must be healthy
from an HIV perspective

- They must have a CD4 count of greater than 250 cells/mcL

- They must not be receiving prophylactic therapy for an opportunistic infection

- Must be on antiretroviral therapy and there must be minimal interactions or
overlapping toxicity of the antiretroviral therapy with the experimental cancer
treatment

- HIV viral load must be < 200 copies/ mm^3 by standard clinical assays

- Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg]
reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA]
[qualitative] is detected)

- Note: the following will not be exclusionary:

- A positive hepatitis B serology indicative of previous immunization (i.e.,
HBsAb positive and hepatitis B virus core antibody [HBcAb] negative), or a
fully resolved acute hepatitis B virus (HBV) infection

- Patients with chronic HBV suppressed by appropriate antiretroviral therapy
with activity against HBV, as outlined in Department of Health and Human
Services (DHHS) guidelines

- Positive HCV serology but no detectable HCV RNA, indicative of spontaneously
cleared HCV infection

- Patients who have been successfully treated for HCV as long as therapy for
HCV has been completed

- Has received a live vaccine within 30 days before to the first dose of trial
treatment; examples of live vaccines include, but are not limited to, the following:
measles, mumps, rubella, chicken pox, yellow fever, seasonal flu (some), H1N1 flu,
rabies, Bacille Calmette-Guerin (BCG), and typhoid vaccine; seasonal flu vaccines that
do not contain live virus are permitted

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- SYNOVIAL SARCOMA (TREATMENT GROUP II):

- Any approved or investigational anti-cancer therapy within 14 days prior to initiation
of study treatment

- Prior treatment with anti-programmed death-1 (anti-PD-1) or anti-programmed
death-ligand 1 (anti-PD-L1) therapeutic antibodies is allowed as is prior therapy with
other immunotherapies

- Active or untreated central nervous system (CNS) metastases as determined by computed
tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and
prior radiographic assessments; patients with prior brain metastases or CNS disease
are permitted, but must have completed treatment and either (1) have no evidence of
active CNS disease for at least 4 weeks prior to the first dose OR (2) have stable CNS
lesions, or be at least 2 weeks past radiation or gamma-knife therapy; patients with
past CNS disease must also have a screening head CT or MRI demonstrating stable
disease compared to their most recent CNS evaluation

- Active therapy for malignancies other than synovial sarcoma

- Pregnant and lactating women

- New York Heart Association (NYHA) class 3 or 4 or clinically symptomatic
cardiovascular disease

- Severe infections requiring intravenous antibiotic treatment within 2 weeks prior to
initiation of treatment

- Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
of treatment

- Active autoimmune disease requiring systemic treatment with steroids greater than 10
mg/day of prednisone or who have required steroids with a dose of 40 mg/day for the
treatment of their autoimmune disease more than twice over the past year; patients
with an autoimmune disease who are on active therapy with a drug targeting TNF alpha

- Prior allogeneic stem cell or solid organ transplant

- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening
chest CT scan

- HIV on effective antiretroviral therapy will not be excluded

- Uncontrolled HBV infection, defined as plasma HBV DNA detectable by polymerase chain
reaction (PCR)

- Note: the following will NOT be exclusionary:

- A positive hepatitis B serology indicative of previous immunization (i.e.,
HBsAb positive and HBcAb negative), or a ful