A Study of Pembrolizumab on the Tumoral Immunoprofile of Gynecologic Cancers

Epithelial gynecologic malignancies are tumors of müllerian origin, which include ovarian,
endometrial, fallopian tube, and primary peritoneal cancers, and account for >70,000 new
diagnoses and >22,000 deaths per year in the United States alone. Treatment typically
consists of a thorough cytoreductive and staging surgery in combination with platinum/taxane
chemotherapy. Newer approaches adding anti-angiogenic therapies to chemotherapy have resulted
in moderate improvements in recurrence free survival. However, despite these aggressive
treatments, the majority of women with advanced stage at diagnosis will experience relapse.
Unfortunately, relapsed disease is incurable and women ultimately die of their disease
despite maximal efforts at cancer control using subsequent chemotherapy or targeted agents.
There has been significant interest in incorporating immune checkpoint therapies in the
treatment of gynecologic malignancies, especially given the durable remissions associated
with these therapies in the treatment of melanoma and early indications of durable responses
in recurrent ovarian cancer. At this time, little is known about whether or how to combine
chemotherapy, anti-angiogenic therapies, and immunologic therapies for maximal benefit.
Understanding the tumor microenvironment, particularly immune and angiogenic factors that
contribute to tumor survival, as well as the changes that occur in response to immunotherapy
is critical to identify favorable biomarker profiles which could lead to improved prognostic
outcomes and inform the development and sequencing of therapies to maximize benefit.

Inclusion Criteria:

1. Have histologically or cytologically confirmed gynecologic tumor of müllerian origin,
specifically epithelial ovarian, fallopian tube, primary peritoneal, or uterine
endometrial cancer.

2. Have disease amenable to surgical resection.

3. Be willing and able to provide written informed consent for the trial.

4. Be at least 18 years of age on day of signing informed consent.

5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion. Subjects for whom newly-obtained samples cannot be provided (e.g.
inaccessible or subject safety concern) may submit an archived specimen only upon
agreement of the investigator.

6. Have a performance status of 0 or 1 on the ECOG Performance Scale.

7. Demonstrate adequate organ function as defined below. All screening labs should be
performed within 10 days of study drug administration:

7a. ANC ≥ 1,500/mcL

7b. Platelets ≥ 100,000/mcL

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

7d. Serum creatinine ≤ 1.5 times the upper limit of normal or calculated creatinine
clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 times institutional upper
limit of normal

7e. Serum total bilirubin ≤ 1.5 times the upper limit of normal or direct bilirubin ≤ the
upper limit of normal with total bilirubin levels > 1.5 times upper limit of normal

7f. AST and ALT ≤ 2.5 times the upper limit of normal or ≤ 5 times the upper limit of
normal for subjects with liver metastases

7g. Albumin > 2.5 mg/dL

7h. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 times the upper
limit of normal unless subject is receiving anticoagulant therapy as long as PT or PTT is
within therapeutic range of intended use of anticoagulants

7i. Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 times the upper limit of normal
unless subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants

8. 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.

9. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity until planned
hysterectomy/oophorectomy. Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year.

Exclusion Criteria:

1. Is currently participating and receiving a 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 study drug administration.

2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to study drug
administration.

3. Has a known history of active TB (Bacillus Tuberculosis)

4. Hypersensitivity to pembrolizumab or any of its excipients.

5. 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
due to agents administered more than 4 weeks earlier.

6. Has received prior chemotherapy, targeted small molecule therapy, or radiation therapy
for the current gynecologic malignancy.

NOTE: Subjects who have received treatment for a prior unrelated malignancy must have
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously
administered agent.

NOTE: If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy.

7. 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.

8. 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 study drug administration 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 study drug administration. This exception does
not include carcinomatous meningitis which is excluded regardless of clinical
stability.

9. 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.

10. Has known history of, or any evidence of active, non-infectious pneumonitis.

11. Has an active infection requiring systemic therapy.

12. 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.

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

14. Is pregnant or breastfeeding.

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

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

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

18. 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.