Ph 1B B-701 in Combination With Pembrolizumab in Metastatic Transitional Cell Carcinoma of the Urothelial Tract

This research study is a Phase I clinical trial, which tests the safety of an
investigational intervention and also tries to define the appropriate dose of the
investigational intervention to use for further studies. "Investigational" means that the
intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved B-701 as a treatment for
any disease.

The FDA has not approved Pembrolizumab for Bladder Cancer but it has been approved for other
uses.

This is the first time that B-701 in combination with Pembrolizumab will be given to humans.

In this research study, Investigators are...

- Testing the effectiveness and safety of the combination of two experimental drugs
(B-701 and Pembrolizumab);

- Learning about the good and/or bad effects the drugs have on participants and their
cancer;

- Administering B-701 and Pembrolizumab, which are antibodies (proteins that bind to
other molecules), because...

- B-701 binds to a protein receptor called FGFR3 (fibroblast growth factor receptor
3). FGFR3 has been found to be present (expressed) or changed (mutated) on the
surface of in many types of cancer cells. Targeting FGFR3 may inhibit cancer
growth.

- Pembrolizumab binds to a protein cell surface receptor called PD-1, which is found
on certain types of lymphocytes and which are also involved in many types of
cancer;

- Treating participants with Pembrolizumab, which is approved by the FDA for the
treatment of Metastatic Melanoma, a Cancer of the skin;

- Collecting blood and tissue samples and other related medical information to learn more
about the development of cancer and predictors of response;

- And hoping to learn how the combination of study drugs work in the treatment of cancer
to help develop new treatments.

Inclusion Criteria:

- Participants must have Stage IV, locally advanced or metastatic (T4b, any N; or any
T, N2-3) urothelial bladder cancer or transitional cell carcinoma (TCC) arising in
another location of the urinary tract, including urethra, ureter, and renal pelvis.
The diagnosis must be histologically or cytologically confirmed. Mixed histologies
are permitted as long as TCC is the major component (i.e. > 50% of the pathologic
specimen). Pure or predominant squamous cell carcinomas or adenocarcinomas are not
permitted.

- Relapsed after or refractory to one or two prior lines of chemotherapy for advanced
or metastatic/recurrent disease (at least one cycle each) which have not included a
PD-L1 or FGFR inhibitor. At least one regimen should have included a platinum agent
unless contraindicated for the subject. Prior neoadjuvant or adjuvant chemotherapy
(without a PD-L1 or FGFR inhibitor) is permitted and will not be counted as
first-line chemotherapy, as long as the subject has not progressed within 12 months
of the last dose. However, a regimen of neoadjuvant or adjuvant chemotherapy will be
counted as first-line chemotherapy if the patient progressed within 12 months of the
last dose.

- Age ≥ 18 years

- Eastern cooperative oncology group (ECOG) performance status ≤ 1 (Karnofsky ≥ 60%)

- Participants must have normal organ and marrow function as defined below:

- leukocytes ≥ 3000/mcL

- absolute neutrophil count ≥ 1500/mcL

- platelets ≥ 75,000/mcL

- hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

- total bilirubin within normal institutional limits

- EXCEPTION: Subjects with known Gilbert's disease: total bilirubin ≤ 3 ×
institutional upper limit of normal (ULN)

- aspartate aminotransferase (AST) or serum glutamic oxaloacetic transaminase
(SGOT)/Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT)
≤ 2.5 × institutional ULN

- EXCEPTION: Subjects with documented liver metastases: AST and/or ALT ≤ 5 ×
institutional ULN

- creatinine within normal institutional limits OR

- creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels
above institutional normal (derived by the Cockcroft-Gault formula [Cockcroft
1976])

- albumin ≥ 2.5 mg/dL

- prothrombin time/international normalized ratio (PT/INR) and partial
thromboplastin time (PTT) ≤ 1.5 × institutional ULN

- Note: Screening labs should be performed within 10 days of treatment initiation.

- Absence of any psychological, familial, sociological, or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule (such
conditions should be discussed with the subject before study entry)

- The effects of B-701 on the developing human fetus are unknown. For this reason and
because PD-1 inhibitors such as pembrolizumab may potentially cause fetal harm, women
of child-bearing potential (defined as those who have not been surgically sterilized
or have not been free from menses for > 1 year) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner 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 study drug
administration.

- Female of childbearing potential should have a negative urine or serum pregnancy test
within 72 hours prior to receiving the first dose of study medications. If the urine
test is positive or cannot be confirmed as negative, a serum pregnancy test will be
required.

- Female 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 and through 4 months after the last dose of study medication.

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

Exclusion Criteria:

- Participants who have had chemotherapy, targeted small molecule therapy, or
radiotherapy within 2 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 2 weeks earlier.

- Participants who are receiving, or have received, any other investigational drugs or
devices within the 2 weeks prior to the first dose of study medications.

- Participants who received major surgery must be recovered adequately from the
toxicity and/or complications from the interventions prior to starting therapy.

- Participants with a diagnosis of immunodeficiency or who are receiving systemic
steroid therapy (>5 mg prednisone or its equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study treatment.

- Participants who have a primary central nervous system (CNS) malignancy, or
untreated/active CNS metastases (progressing or requiring anticonvulsants or
corticosteroids for symptomatic control). Individuals with a history of treated CNS
metastases are eligible, provided they meet all of the following criteria:

- Evaluable or measurable disease outside the CNS

- Radiographic demonstration of stability upon the completion of CNS directed
therapy and no evidence of interim progression (for at least 4 weeks prior to
the first dose of study drug) between the completion of CNS-directed therapy and
the screening radiographic procedure

- The screening CNS radiographic procedure is ≥ 8 weeks since completion of
radiotherapy and ≥ 4 weeks since the discontinuation of corticosteroids and
anticonvulsants Note: These exceptions do not include carcinomatous meningitis
which is excluded regardless of clinical stability.

- Participants with a history of allergic reactions attributed to monoclonal antibody
therapy (or recombinant antibody-related fusion proteins)

- Participants with active autoimmune disease that has required systemic treatment (>5
mg of prednisone or its equivalent) 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.

- Participants with known evidence of active, non-infectious pneumonitis.

- Participants with an active infection requiring systemic therapy.

- Participants who have 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.

- Participants who have had a prior anti-cancer monoclonal antibody (mAb) within 2
weeks prior to Cycle 1 Day 1 or who have not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to agents administered more than 2 weeks earlier.

- Participants unwilling or unable to discontinue use of prohibited therapies,
including any cytotoxic chemotherapy, radiotherapy, immunotherapy or biologic agent
(approved or investigational) for the treatment of TCC are ineligible.

- Participants with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements.

- Participants who have undergone a major surgical procedure or trauma within 4 weeks
prior to Cycle 1, Day 1. All wounds must be fully healed on Cycle 1, Day 1

- Participants with a history of other malignancy which could affect compliance with
the protocol or interpretation of results. Individuals with a history of curatively
treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the
cervix are allowed. Participants with a malignancy that has been treated with
curative intent will also be allowed if the malignancy has been in remission without
treatment for ≥ 2 years prior to Cycle 1, Day 1.

- Pregnant women are excluded from this study because the risks with B-701 are unknown
and pembrolizumab is a PD-1 inhibitor with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with B-701 and
pembrolizumab, breastfeeding should be discontinued. Women of child-bearing potential
must agree to use adequate birth control throughout the study duration.

- Hepatitis B, hepatitis C, and HIV serology-positive (or known history of HIV
seropositive status) participants are ineligible because these underlying diseases
will confound interpretation of important safety assessments, e.g. liver function
tests, increased potential for reactivation or exacerbation of viral infections. Such
individuals may be taking or require other drugs, and may be at higher risk of
opportunistic infections and adverse effects. Hepatitis B, hepatitis C, and HIV
serology-positive individuals were excluded from the pivotal pembrolizumab clinical
trial in melanoma, so safety of this drug in this setting is unknown.

- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at screening or any major episode of
infection requiring treatment with IV antibiotics or hospitalization (relating to the
completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1

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

- Participants who weigh > 110 kg will be ineligible due to study drug limitations