Pembrolizumab in Subjects With Incurable Platinum-Refractory Germ Cell Tumors

OUTLINE: This is a multi-center study.

Eligible subjects must have received initial cisplatin-based combination therapy, such as
bleomycin-etoposide-cisplatin (BEP), cisplatin-etoposide (EP), etoposide-ifosfamide-cisplatin
(VIP), or similar regimens AND demonstrated progression following the administration of at
least one 'salvage' regimen for advanced germ cell neoplasm, such as high dose chemotherapy,
paclitaxel-ifosfamide-cisplatin (TIP), or vinblastine-ifosfamide-cisplatin (VeIP).

INVESTIGATIONAL TREATMENT:

Pembrolizumab 200mg IV every 3 weeks until progression or toxicity. Treatment will continue
for up to 52 weeks in the absence of prohibitive toxicities or disease progression.

The following screening labs to demonstrate adequate organ function must be performed within
10 days of treatment initiation:

Hematological:

- Absolute neutrophil count (ANC) ≥1,500 /mcL

- Platelets ≥100,000 / mcL

- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or hematopoietin (EPO) dependency
(within 7 days of assessment)

Renal:

- Serum creatinine ≤1.5 X upper limit of normal (ULN) OR

- Measured or calculated creatinine clearance ≥60 mL/min for subject with creatinine
levels >1.5 X institutional ULN

- Glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine
clearance (CrCl)

Hepatic:

- Serum total bilirubin ≤ 1.5 X ULN OR

- Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

- Albumin >2.5 mg/dL

Coagulation:

- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject
is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants

- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants

Inclusion Criteria:

- Written informed consent and HIPAA authorization for release of personal health
information. NOTE: HIPAA authorization may be included in the informed consent or
obtained separately.

- Age ≥ 18 years at the time of consent.

- ECOG Performance Status of 0 or 1 within 14 days prior to registration for protocol
therapy.

- Subjects must have histological or serological proof of metastatic germ cell neoplasm
(gonadal or extragonadal primary) with disease not amenable to cure with either
surgery or chemotherapy. Subjects with seminoma and non-seminoma are eligible, as are
women with ovarian GCTs.

- Subjects must have evidence of recurrent or metastatic carcinoma by one or more of the
following: the appearance of metastatic disease on chest x-ray or CT scan, or the
appearance of rising tumor marker: AFP or beta-HCG. NOTE: If a rising tumor marker is
the only evidence of progressive disease, at least 2 consecutive rising values at
least one week apart are needed. Subjects with only evidence of disease as rising
tumor marker AFP and beta-HCG will be provided alternate causes of increased serum
levels of these markers are not present, such as cross reaction with luteinizing
hormone (LH) (that can be tested if needed by testosterone suppression of LH),
hepatitis, use of marijuana, or second primary tumor, etc.

- Subjects must have received initial cisplatin based combination therapy, such as
bleomycin-etoposide-cisplatin (BEP), cisplatin-etoposide (EP),
etoposide-ifosfamide-cisplatin (VIP), or similar regimens AND demonstrated progression
following the administration of at least one 'salvage' regimen for advanced germ cell
neoplasm, such as high dose chemotherapy, paclitaxel-ifosfamide-cisplatin (TIP), or
vinblastine-ifosfamide-cisplatin (VeIP).

- "Failure" of prior therapy is defined as: a >25% increase in the products of
perpendicular diameters of measurable tumor masses during prior therapy which are not
amenable to surgical resection; the presence of new tumors which are not amenable to
surgical resection; an increase in AFP or beta-hCG (two separate determinations at
least one week apart are required if rising tumor markers are the only evidence of
failure). NOTE: Subjects with clinically growing "teratoma" (normal declining tumor
markers and radiographic or clinical progression) should be considered for surgery.

- Subjects are eligible after first line platinum based chemotherapy if their disease
has relapsed and they have Primary Mediastinal Non Seminomatous Germ Cell tumor
(PMNSGCT) or late relapse (> 2 years) not amenable to surgical resection.

- Subjects must be willing to provide tissue from a newly obtained core or excisional
biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6
weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom
newly-obtained samples cannot be provided (e.g., inaccessible or subject safety
concern) may submit an archived specimen only upon agreement from the sponsor
investigator

- Female subjects 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 subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication . Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.

- Male subjects should 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.

- Measurable disease according to RECIST v1.1 obtained by imaging within 28 days prior
to registration.

Exclusion Criteria:

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

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

- Has a known history of active TB (Bacillus Tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients.

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
(AE) due to agents administered more than 4 weeks earlier.

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent. NOTE 1: Subjects
with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the
study. NOTE 2: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.

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

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four 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. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.

- Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Presence of interstitial lung disease or history of pneumonitis requiring treatment
with corticosteroids.

- Has an active infection requiring systemic therapy.

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

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.

- Has received prior therapy with PD-1, PD-L1, or CTLA-4 inhibitors.

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Has received a live vaccine within 30 days of planned start of study therapy. NOTE:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.