Combination Therapy With Pembrolizumab and sEphB4-HSA in Previously Treated Urothelial Carcinoma

PRIMARY OBJECTIVES:

I. To determine the feasibility of using pembrolizumab-recombinant EphB4-HSA fusion protein
(sEphB4-HSA) combination in patients with advanced urothelial carcinoma.

II. To measure the overall survival (OS).

SECONDARY OBJECTIVES:

I. To measure the progression-free survival (PFS). II. To measure the objective response rate
(ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

TERTIARY OBJECTIVES:

I. To examine programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1),
programmed cell death 1 ligand 2 (PD-L2) and EPH receptor B4 (EphB4) expression by tumor
cells (TC) as well as immune cells (IC)- macrophages and T cells- in tumor tissue and
correlate them with ORR, PFS and OS.

II. To examine the tumor tissue T cell frequency (counts), tumor tissue T cell clonality
using T cell receptor (TCR) sequencing, and peripheral blood T cell clonality, pre-treatment
and post-treatment and correlate these with ORR, PFS and OS.

III. To measure the phenotype of lymphocytes and myeloid derived suppressor cells (MDSC), in
pre and post-treatment blood samples and correlate these with ORR, PFS and OS; an extra blood
sample for future studies will also be collected and banked.

IV. To examine peripheral blood circulating tumor cells (CTCs) for enumeration and molecular
analysis in pre and post-treatment blood samples, and correlate these with ORR, PFS and OS.

V. To collect and bank tumor tissue. VI. To examine the role of adding positron emission
tomography (PET) to a contrast computed tomography (CT) for evaluation of response to
treatment.

OUTLINE:

Patients receive recombinant EphB4-HSA fusion protein intravenously (IV) over 60 minutes on
days 1, 8, and 15 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3 weeks
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6-12
weeks.

Inclusion Criteria:

- Be willing and able to provide written informed consent/assent for the trial

- Advanced (metastatic or recurrent) pathologically proven urothelial carcinoma which is
refractory to platinum based due to disease progression on a platinum containing
regimen; patients progressing within 12 months of their last dose of platinum-based
neoadjuvant or adjuvant chemotherapy will be considered platinum refractory

- Have measurable disease based on RECIST 1.1

- 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 for 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; an optional core biopsy will
be requested from an accessible metastatic site after 2 cycles of treatment

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

- 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)

- Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also
be used in place of creatinine or creatinine clearance [CrCl]) >= 30mL/min for subject
with creatinine levels > 1.5 X institutional upper limit of normal (ULN)

- Serum total bilirubin =< 1.5 X ULN or direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN

- 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 subjects with liver metastases

- Albumin >= 2.5 mg/dL

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

- Recovered to grade 1 from the effects (excluding alopecia) of any prior therapy for
their malignancies

- Female subject 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

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 (ie, =< 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 (ie, =< grade 1 or at
baseline) from adverse events due to a previously administered agent; Note: subjects
with =< grade 2 neuropathy are an exception to this criterion and may qualify for the
study; Note: 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 or early stage carcinoma of the cervix that has undergone potentially curative
therapy or in situ cervical cancer; patients with incidental prostate cancer diagnosed
at cystectomy or deemed appropriate for surveillance based on national guidelines will
be allowed to enroll

- 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

- 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 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 an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or
sEsphB4-HSA

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

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

- Major systemic infection requiring antibiotics 72 hours or less prior to first dose of
study drug

- Has New York Heart Association (NYHA) class 3 or 4, myocardial infarction, acute
coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive
pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any
other intercurrent medical condition that contraindicates treatment with sEphB4HSA or
pembrolizumab (MK-3475) or places the patient at undue risk for treatment related
complications

- Any other condition, including mental illness or substance abuse, deemed by the
investigator to be likely to interfere with a patient's ability to sign informed
consent, cooperate and participate in the study, or interferes with the interpretation
of the results

- Any active bleeding in the last =< 4 weeks or have an otherwise known bleeding
diathesis

- 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 (eg, flu-mist) are live attenuated
vaccines, and are not allowed