Pembrolizumab in Treating Patients With Relapsed or Refractory Stage IB-IVB Mycosis Fungoides or Sezary Syndrome

PRIMARY OBJECTIVES:

I. To assess the response rate of MK-3475 (pembrolizumab) in subjects with
relapsed/refractory mycosis fungoides/Sezary syndrome (MF/SS).

SECONDARY OBJECTIVES:

I. To explore the clinical activity of MK-3475 in subjects with relapsed/refractory MF and SS
with respect to the following endpoints: duration of response (DOR); progression-free
survival (PFS); overall survival (OS).

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses repeat
every 3 weeks for up to 2 years (6 months for patients achieving complete response [CR]) in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 12
weeks.

Inclusion Criteria:

- This trial will include subjects with stage IB-IVB MF/SS (maximal stage since
diagnosis will determine eligibility), and who have relapsed, are refractory, or
progressed after at least one standard systemic therapy; 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 and adverse event (AE) recovery
period from previous treatments without treatment between documentation of
relapse/progression and enrollment of specifically:

- >= 2 weeks for local radiation therapy

- >= 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 8 weeks

- >= 15 weeks for anti-cluster of differentiation (CD)137 or anti-cytotoxic
T-lymphocyte-associated protein 4 (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 AEs due to
procedures performed or therapeutic agents administered

- >= 2 weeks for retinoids, interferons, vorinostat, romidepsin, denileukin
diftitox, and therapeutic doses of oral corticosteroids (physiologic replacement
doses of oral corticosteroids are allowed, topical corticosteroids are allowed)

- >= 2 weeks for phototherapy

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

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

- Life expectancy of at least 6 months

- Performed within 10 days of treatment initiation: Leukocytes >= 2,000/mcL

- Performed within 10 days of treatment initiation: Absolute neutrophil count >=
1,500/mcL

- Performed within 10 days of treatment initiation: Platelets >= 100,000/mcL

- Performed within 10 days of treatment initiation: Hemoglobin >= 9 g/dL OR >= 5.6
mmol/L

- Performed within 10 days of treatment initiation: Serum total bilirubin =< 1.5 x upper
limit of normal (ULN) OR direct bilirubin =< ULN for subjects with total bilirubin
levels > 1.5 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: Serum creatinine =< 1.5 x ULN OR
measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine
clearance (CrCl) levels > 1.5 x institutional ULN (glomerular filtration rate [GFR]
can also be used in place of creatinine or CrCl)

- Performed within 10 days of treatment initiation: International normalized ratio (INR)
or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant
therapy in which case the INR or PT must be within the therapeutic range of intended
use for the anticoagulant

- Performed within 10 days of treatment initiation: Activated partial thromboplastin
time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy in which
case the aPTT must be within the therapeutic range of intended use for the
anticoagulant

- Performed within 10 days of treatment initiation: Thyroid stimulating hormone (TSH)
within institutional limits (ie: normal); if TSH is greater or less than institutional
limits patients may participate if their thyroxine (T4) is within normal limits (WNL);
patients may be on a stable dose of replacement thyroid medication; dose adjustments
are allowed if needed

- Patients must provide tissue from a punch biopsy of the skin at baseline, at the time
of a clinical event (at the time of response, progression or appearance of a new
lesion) and at the end of treatment; additional punch biopsies every 3 cycles are
optional; an archival tissue sample is optional

- 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

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) from the time of the
pre-study visit, through the course of the study and for 120 days after the last dose
of study medication

- Female patients of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to 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 should be willing to use 2 methods of
birth control or be surgically sterile, or abstain from heterosexual activity
from the time of the pre-study visit, through the course of the study and for 120
days after the last dose of study medication; patients of childbearing potential
are those who have not been surgically sterilized or have not been free from
menses for > 1 year

- Should a woman become pregnant or suspect she is pregnant while she 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 prior to the study, for the duration of study
participation, and 4 months after completion of MK-3475 administration

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

Exclusion Criteria:

- Patients who have had chemotherapy or targeted small molecule therapy within 4 weeks
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who
have not recovered from adverse events due to agents administered more than 4 weeks
earlier

- Note: patients with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- Note: if patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy

- Patients who are currently participating in or have participated in a study of an
investigational agent or using an investigational device within 4 weeks of the first
dose of treatment

- Has a diagnosis of immunodeficiency or is receiving therapeutic systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of trial treatment

- Has had a prior monoclonal antibody within 4 weeks prior to 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

- 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, or in situ cervical cancer that has undergone potentially curative therapy

- 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 for at least 4 weeks prior
to 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 prior to trial treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-3475

- Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents; patients with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule; patients that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study; the use of physiologic doses of corticosteroids may be
approved after consultation with the protocol principal investigator (PI) and Cancer
Immunotherapy Trials Network (CITN); patients with hypothyroidism stable on hormone
replacement or Sjogren's syndrome will not be excluded from the study

- 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

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

- Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-ligand
(L)1, anti-PD-L2

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, interstitial lung disease or active, non-infectious pneumonitis,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements

- History of other pulmonary disease such as emphysema or chronic obstructive pulmonary
disease, (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

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-study visit through 120 days
after the last dose of trial treatment; breastfeeding should be discontinued if the
mother is treated with MK-3475

- Men and non-pregnant, non-breast-feeding women may be enrolled if they are
willing to use 2 methods of birth control or are considered highly unlikely to
conceive; highly unlikely to conceive is defined as 1) surgically sterilized, or
2) postmenopausal (a woman who is >= 45 years of age and has not had menses for
greater than 1 year will be considered postmenopausal), or 3) not heterosexually
active for the duration of the study; the two birth control methods can be
barrier method or a barrier method plus a hormonal method to prevent pregnancy;
patients should start using birth control from the time of the pre-study visit,
through the course of the study and for 120 days after the last dose of study
medication; the following are considered adequate barrier methods of
contraception: diaphragm, condom (by the partner), copper intrauterine device,
sponge, or spermicide; appropriate hormonal contraceptives will include any
registered and marketed contraceptive agent that contains an estrogen and/or a
progestational agent (including oral, subcutaneous, intrauterine, or
intramuscular agents)

- Patients should be informed that taking the study medication may involve unknown
risks to the fetus (unborn baby) if pregnancy were to occur during the study; in
order to participate in the study they must adhere to the contraception
requirement (described above) for the duration of the study and during the
follow-up period; if there is any question that a patient will not reliably
comply with the requirements for contraception, that patient should not be
entered into the study

- If a patient inadvertently becomes pregnant while on treatment with MK-3475, the
patient will immediately be removed from the study; the site will contact the
patient at least monthly and document the patient's status until the pregnancy
has been completed or terminated; the outcome of the pregnancy will be reported
without delay and within 24 hours if the outcome is a serious adverse experience
(e.g., death, abortion, congenital anomaly, or other disabling or
life-threatening complication to the mother or newborn); the study investigator
will make every effort to obtain permission to follow the outcome of the
pregnancy and report the condition of the fetus or newborn; if a male patient
impregnates his female partner the study personnel at the site must be informed
immediately and the pregnancy reported and followed

- 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

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

- Has received a live vaccine within 30 days prior to the first dose of trial treatment

- Has a known human T-lymphotropic virus type 1 (HTLV) infection

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