Durvalumab and Vicinium in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)

Background:

In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390
deaths associated with bladder cancer. Bladder cancer is associated with the highest costs
among all types of cancer, due to the need for lifelong routine monitoring and treatment.
Approximately 70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and
are treated by transurethral resection of bladder tumor (TURBT) followed by intravesical
treatment with BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of high
grade disease, these therapies can become ineffective over time in up to two-thirds of
patients and disease progression to muscle invasive bladder cancer (MIBC) can occur. In
patients who present with CIS (carcinoma in situ) rates of progression are greater than 50%.
Progression to MIBC portends a poor outcome as only 50% of patients will survive five years
despite undergoing radical cystectomy. Clearly, there is a large unmet need in therapeutic
options for NMIBC that recurs or progresses.

Vicinium is a recombinant fusion protein, VB4-845, that contains a humanized single-chain
antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked
to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed on
the surface of urothelial carcinoma cells and therefore represents a good target for Vicinium
to bind to. In a previous phase II study in BCG refractory or BCG intolerant patients with
high grade bladder cancer, 16% of patients treated with induction and maintenance therapy
with Vicinium remained disease-free at 1 year. As a result, Vicinium is currently being
evaluated as a single agent in a phase III trial.

Pre-clinical work with a drug called Proxinium, an earlier version of Vicinium, demonstrated
an abscopal effect and synergy with the use of a checkpoint blockade inhibitor. Although it
was done in a NSCLC model, the results were impressive in causing tumor shrinkage. Durvalumab
is a human monoclonal antibody (MAb) that inhibits binding of programmed cell death ligand 1
(PD-L1) (B7 homolog 1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1
(PD-1; CD279) and CD80 (B7-1). Durvalumab has been demonstrated to have activity against
advanced metastatic urothelial bladder cancer whose tumor has progressed during or after one
standard platinum-based regimen in a phase I trial.

Therefore, this trial will take two agents with single agent activity against urothelial
cancer and combine them in a Phase I trial for patients with high-grade NMIBC Previously
Treated with BCG.

Objectives:

Primary Objectives:

-To evaluate the safety and tolerability of durvalumab and Vicinium when administered in
combination to subjects with BCG-refractory high-grade NMIBC

Eligibility:

- Subjects must have a histologically-confirmed high-grade non-muscle invasive urothelial
carcinoma (transitional cell carcinoma) of the bladder as follows:

- Carcinoma-in-situ (CIS) with or without papillary tumors

- High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of
the initial dose of study treatment. If multiple bladder biopsies/TURBTs are
required to confirm eligibility, the timing of the last bladder biopsy to the
initial dose of study treatment must be within 12 weeks.

- Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology
and the FDA: Subjects must have received at least two courses of intravesical BCG (at
least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a
maintenance regimen or at least 2 doses of a repeat induction course). See exception
below for persistent T1 disease below. There is no upper limit on the amount of prior
BCG a subject may have received.

- Patients with persistent T1 high grade disease on TURBT following a single induction
course of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that
the patient is surgically unfit for cystectomy as deemed by the investigator or the
patient declines cystectomy

Design:

This is a Phase I, open-label study of the combination of durvalumab and Vicinium in subjects
with high-grade NMIBC previously treated with BCG.

- All subjects will receive Vicinium intravesically and durvalumab systemically at the
standard doses for both drugs as determined by Phase II trials for each drug, as no
synergy or additive effect is expected for adverse events.

- Vicinium is administered in a 12-week Induction Phase followed by a Maintenance Phase
for at least one year with an option for a total of up to 2 years of treatment. During
the Induction Phase, Vicinium is administered once weekly for 12 weeks. During the
Maintenance Phase, Vicinium is administered every other week. The dose of Vicinium is 30
mg in 50 mL of saline.

Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with
an option to continue therapy for an additional 12 months (total of 24 months) provided that
patient is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment
Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued
in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months
to provide an immune boost.

- Vicinium will be given as monotherapy for 1 week followed by treatment with the
combination of Vicinium and durvalumab starting week 2.

- In the initial six patients, three subjects at a time will enroll at these doses and
schedules. Dose-liming toxicity (DLT) for each subject will be determined during the
initial 6-week period that the subject is on treatment (i.e., the DLT period). When all
subjects in the initial cohort have been on treatment through the DLT period, all
available safety data will be considered in decisions to enroll additional subjects at
this dose level, or to de-escalate the dose(s) of study drug(s), based on a standard 3 +
3 design. There will be no dose escalations in this study. The dose of durvalumab will
remain at 1500 mg every 4 weeks, and the dose of each intravesical Vicinium treatment
can be reduced to 20 mg if the initial doses in combination induce DLTs.

- After the first six patients, an additional 18 subjects will be enrolled at the initial
doses or at the reduced doses (if DLTs resulted in the first 6 patients) in order to
obtain additional safety data, biomarker data and preliminary anti-tumor activity.

Each subject s course will consist of the following periods:

- Screening/Baseline Period: The subject is consented and undergoes screening assessments
to determine eligibility for the study.

- Treatment Period: The subject is treated and monitored for safety. Biomarker data will
be obtained prior to treatment and at periodic intervals during treatment. Subjects who
remain free of high-grade NMIBC after 12 months of study treatment may continue to
receive treatment for an additional 12 months until they develop recurrent high-grade
disease, disease progression, or intolerable toxicity, or meet another withdrawal
criterion (e.g., consent withdrawal, pregnancy).

- Post-Treatment. The subject will return to the study site montly for up to 90 days after
the last dose of immunotherapy for end-of-treatment assessments. Subjects with ongoing
clinically significant related AEs or SAEs will have additional follow-up after the
initial post-treatment visit.

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed by NCI Laboratory of
Pathology as high grade non-muscle invasive urothelial (transitional cell carcinoma)
of the bladder as follows:

- Carcinoma-in-situ (CIS) with or without papillary tumors

- High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of
the initial dose of study treatment. If multiple bladder biopsies/TURBTs are
required to confirm eligibility, the timing of the last bladder biopsy to the
initial dose of study treatment must be within 12 weeks.

- Patients with persistent T1 high grade disease on TURBT following a single
induction course of BCG (at least 5 of 6 doses) may also be eligible for this
trial provided that the patient is surgically unfit for cystectomy as deemed by
the investigator or the patient declines cystectomy.

- Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology
and the FDA: Subjects must have received at least two courses of intravesical BCG (at
least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under
a maintenance regimen or at least 2 doses of a repeat induction course). Please note
exception above for persistent T1 disease. There is no upper limit on the amount of
prior BCG a subject may have received.

- Patients who have met eligibility criterion above must have received last BCG dose
within a year of enrollment.

- The investigator must document that he/she believes the subject would not benefit from
additional BCG treatment at the time of study entry.

- Age >= 18 years at time of signing the informed consent form (ICF). Because no dosing
or adverse event data are currently available on the use of Vicinium in combination
with durvalumab in patients <18 years of age, children are excluded from this study,
but will be eligible for future pediatric trials. Furthermore, NMIBC does not occur in
children.

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

- Adequate normal organ and marrow function as defined below:

- Hemoglobin >= 9.0 g/dL

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3)

- Platelet count >= 75 x 10^9/L (>75,000 per mm^3)

- Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal
(ULN).

- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 x institutional ULN

- Creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)
or by 24-hour urine collection for determination of creatinine clearance:

- Males: Creatinine CL (mL/min) = (Weight (kg) x (140 - Age))/72 x serum
creatinine (mg/dL)

- Females: Creatinine CL (mL/min)= (Weight (kg) x (140 - Age) x 0.85 )/72 x
serum creatinine (mg/dL)

- Female subjects must either be of non-reproductive potential (i.e., post-menopausal as
described below) OR history of surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or must have a negative serum pregnancy test upon
study entry.

- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution

- Women >= 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, or had
chemotherapy-induced menopause with last menses >1 year ago

- The effects of Vicinium and durvalumab on the developing human fetus are unknown. For
this reason, all sexually active subjects agree to use barrier contraception (i.e.,
condoms) while receiving study treatment and for 120 days following their last dose of
study treatment. Female subjects of child-bearing potential and male subjects whose
sexual partners are WOCBP agree to use barrier contraception and a second form of
contraception while receiving study treatment and for 4 months following their last
dose of study treatment. 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.

- Written informed consent obtained from the subject prior to performing any protocol-
related procedures

- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.

- Body weight > 30 kg

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

- QT interval corrected for heart rate using Fridericia s formula (QTcF) >=470 ms. (Any
clinically significant abnormalities detected require triplicate ECG results and a
mean QT interval corrected for heart rate using Fridericia s formula (QTcF) >=470 ms
calculated from 3 ECGs.)

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Vicinium or durvalumab or other agents used in the study.

- 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.
Urinary tract infections (UTIs) are excluded from being an exclusion criterion for
treatment unless they are grade 3 or higher.

- Pregnant women are excluded from this study because it is unknown whether Vicinium
and/or durvalumab have any teratogenic effects. In nursing mothers, breastfeeding
should be discontinued as these medications may have the potential risk for adverse
events in nursing infants secondary to treatment of the mother.

- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab

- Evidence of non-bladder urothelial (transitional cell) carcinoma by biopsy, cytology,
or radiological imaging within the past 2 years of treatment (e.g. upper tract
transitional cell carcinoma, urethral urothelial carcinoma).

- Subjects with hydronephrosis, except for those subjects where hydronephrosis has been
longstanding (i.e., predates the diagnosis of the CIS, Ta, or T1 by more than 2 years)
and diagnostic evaluation at screening shows no evidence of tumor causing the
hydronephrosis.

- Any other anticancer therapy (e.g., chemotherapy, biologic therapy, immunotherapy,
targeted therapy, endocrine therapy, radiation therapy, intravesical therapy,
investigational agent) within 28 days of the first dose of study therapy (and within 6
weeks for nitrosourea or mitomycin C) other than a single dose of intravesical
chemotherapy which is permitted between 28 days and 14 days prior to the first dose of
study treatment.

- The subject has a diagnosis of another malignancy within 2 years before the first dose
of study treatment, except for superficial skin cancer, localized prostate cancer on
active surveillance, or localized solid tumors deemed cured by surgery and not treated
with systemic anticancer therapy and not expected to require anticancer therapy in the
next 2 years i.e., while the subject may be taking study treatment.

- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid.

- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g. colitis or Crohn s disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion:

- Subjects with vitiligo or alopecia

- Subjects with hypothyroidism (e.g. following Hashimoto syndrome) stable on
hormonal replacement

- Any chronic skin condition that does not require systemic therapy

- Subjects without active disease in the last 5 years may be included but only
after consultation with the Principal Investigator

- Subjects with celiac disease controlled by diet alone

- History of primary immunodeficiency.

- History of allogeneic organ transplant.

- History of hypersensitivity to durvalumab or any excipient

- History of hypersensitivity to Vicinium or its components

- Active infection with tuberculosis (clinical evaluation that includes clinical
history, physical examination, and radiographic findings, and PPD testing if
indicated), hepatitis B (known positive HBV surface antigen (HBsAg) result, hepatitis
C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects with a past
or resolved HBV infection (defined as the presence of hepatitis B core antibody
[anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV)
antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

- History of leptomeningeal carcinomatosis

- Receipt of live attenuated vaccination within 30 days prior to the first dose of
Vicinium or durvalumab

- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results

- Subjects with uncontrolled seizures

- Any unresolved toxicity NCI CTCAE Grade >=2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria

- Subjects with Grade >=2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Principal Investigator.

- Subjects with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the
Principal Investigator.