Pembrolizumab, Bevacizumab, and Cyclophosphamide in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

PRIMARY OBJECTIVES:

I. To evaluate improvement in progression-free survival for patients treated with
anti-programmed cell death 1 (anti-PD1) pembrolizumab in combination with intravenous (IV)
bevacizumab and oral metronomic cyclophosphamide as compared to patients treated with other
second line chemotherapeutic agents.

SECONDARY OBJECTIVES:

I. To obtain pilot data on clinical response rates using both Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 criteria and immune related response criteria (irRECIST).

II. To obtain data on changes in tumor microenvironment prior to and subsequent to therapy
and, to screen for potential biomarkers to predict clinical benefit.

III. To determine the safety and tolerability of the treatment combination in the study
population.

IV. To evaluate overall survival in patients treated with anti-PD1 pembrolizumab in
combination with IV bevacizumab and oral metronomic cyclophosphamide.

V. To assess the impact of the combination of anti-PD1 pembrolizumab, IV bevacizumab and oral
metronomic cyclophosphamide on anti-tumor immune responses in ovarian cancer.

OUTLINE:

Patients receive pembrolizumab IV over 30 minutes and bevacizumab IV over 30-90 minutes on
day 1 and cyclophosphamide orally (PO) once daily (QD) on days 1-21. Treatment repeats every
3 weeks for up to 12 months (or 17 courses) in the absence of disease progression or
unacceptable toxicity. Patients without evidence of disease progression may continue
treatment in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 3 months
for 1 year, and every 12 weeks and 6 months thereafter.

Inclusion Criteria:

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Have measurable disease per RECIST 1.1 criteria present

- Participant may have serous, endometrioid, clear cell, mucinous or undifferentiated
type of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer

- Histologic confirmation of the original primary tumor is required via the
pathology report

- Participant can be either platinum-sensitive (platinum free interval [PFI] >= 6 months
prior to recent recurrence) or platinum-resistant (PFI < 6 months prior to recent
recurrence). If the participant has a platinum sensitive disease, she may only enroll
in this clinical trial if there is a contraindication for her to receive further
treatment with platinum-based chemotherapy (such as serious, persistent toxicity or
sever hypersensitivity to platinum agents or she declines standard of care).

- Participant must be willing to undergo core or excisional biopsy of a tumor lesion
within 4 weeks (28 days) prior to initiation of treatment on day 1 and after 3 cyles
of study treatment; participants 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 principal investigator

- Absolute neutrophil count (ANC): >= 1,500 /mcL

- Platelets: >= 100,000 / mcL

- Hemoglobin: >= 9 g/dL or 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 7 days of assessment)

- Serum creatinine: =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance >= 60 mL/min for participant with creatinine levels > 1.5 X
institutional ULN; glomerular filtration rate (GFR) can also be used in place of
creatinine or creatinine clearance (CrCl)

- Urine protein creatine ratio (UPCR) < 1 prior to enrollment

- Serum total bilirubin: =< 1.5 X ULN OR direct bilirubin =< ULN for participants with
total bilirubin levels > 1.5 ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase[SGOT]) and
alanine transaminase (ALT) (serum glutamic pyruvic transaminase [SGPT]): =< 2.5 X ULN
OR =< 5 X ULN for participants with liver metastases

- Albumin: > 2.5 mg/dL

- International normalized ratio (INR) or prothrombin time (PT): =< 1.5 unless
participant is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants

- Activated partial thromboplastin time (aPTT): =< 1.5 X ULN unless participant is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants

- Participants of childbearing potential must 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

- Participants of childbearing potential must 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 (participants 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

- Participant has recovered from toxicities of prior chemotherapy or other therapy (to
grade 2 or less)

- Participant may have received prior investigational therapy (including immune therapy)

- Participant may have received prior hormonal therapy

- Participant may have received bevacizumab (or other antiangiogenic agent) and/or
cyclophosphamide in the past

- Participant has had at least 4 weeks of postoperative recovery from surgery prior to
enrollment to ensure complete wound healing; participants with bowel resections at
surgery should begin protocol at least 42 days after surgery

- Ability to swallow and retain oral medication

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

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 or, is taking any other medication that might affect immune function

- Has a known history of active bacillus tuberculosis (TB)

- Hypersensitivity to bevacizumab, cyclophosphamide, 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
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: participants with =< grade 2 neuropathy are an exception to this criterion
and may qualify for the study

- Note: if participant received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy and, has to be at least 28 days after the surgery

- 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 cervical cancer in situ that
has undergone potentially curative therapy

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; participants 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 6
months (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) is not
considered a form of systemic treatment

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

- 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 participant'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

- Is pregnant or breastfeeding, or expecting to conceive 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 an anti-PD-1, anti-programmed cell death 1 ligand 1
(PD-L1), or anti-programmed cell death 1 ligand 2 (PD-L2) agent

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- 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 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., FluMist)
are live attenuated vaccines, and are not allowed

- Active or history of inflammatory bowel disease (colitis, Crohn's), diverticulitis,
irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal
conditions associated with diarrhea; active or history of systemic lupus erythematosus
or Wegener's granulomatosis

- Participant has clinical symptoms or signs of partial or complete gastrointestinal
obstruction or, requires parenteral hydration and/or nutrition

- Participant requires, or is likely to require, more than a two-week course of
corticosteroids for intercurrent illness; participant must complete the course of
corticosteroids 2 weeks before screening to meet eligibility

- Participant has a serious, non-healing wound, ulcer, or bone fracture

- Participant has a clinically significant cardiovascular disease including:

- Uncontrolled hypertension, defined as systolic > 150 mmHg or diastolic > 90 mmHg

- Myocardial infarction or unstable angina within 6 months prior to enrollment

- New York Heart Association (NYHA) grade II or greater congestive heart failure

- Participant has a grade II or greater peripheral vascular disease

- Participant has a clinically significant peripheral artery disease (e.g. those
with claudication, within 6 months)

- Participant has organ allografts

- Participant is receiving medication(s) that might affect immune function

- Unwilling or unable to follow protocol requirements