Vicinium Treatment for Subjects With Non-muscle Invasive Bladder Cancer Previously Treated With BCG

Bladder cancer is the 6th most common cancer in the United States, affecting more men than
women. The usual first treatment for NMIBC (Ta, T1, and CIS) is transurethral resection of
the bladder tumors followed by intravesical immunotherapy, most commonly with bacillus
Calmette-Guérin (BCG).

Because of the high risk for development of muscle invasive disease, cystectomy is
recommended for CIS and high-grade Ta and T1 patients who experience disease recurrence
following intravesical therapy. For patients unable or unwilling to undergo cystectomy,
treatment options are limited.

Vicinium contains the active pharmaceutical ingredient VB4-845, which is a recombinant fusion
protein produced in Escherichia coli (E. coli) that expresses a humanized single-chain
antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked
to ETA(252-608). Once bound to the EpCAM antigen on the surface of carcinoma cells, Vicinium
is internalized through an endocytic pathway. The ETA(252-608) is cleaved off and induces
cell death by irreversibly blocking protein synthesis.

In vitro and in vivo pharmacology demonstrated that Vicinium exhibits potent activity
[inhibitory concentration 50% (IC50) = 0.001 - 10 pM] against numerous cell lines and
effectively inhibits tumor growth in several human xenograft animal models. A Phase 2 study
evaluated once-weekly instillations of Vicinium 30 mg over 6 or 12 weeks, followed by up to 3
maintenance cycles (3 once-weekly instillations followed by a 9-week drug-free period) in 45
subjects with histologically-confirmed TCC of the bladder and residual CIS with or without
concurrent Ta or T1 who were refractory or intolerant to BCG. A complete response (defined as
no histological evidence of disease and negative urine cytology at the 3-monthly evaluations)
was achieved by 44% of subjects, and 16% of subjects remained disease-free at 1-year. A
post-study assessment found that these subjects were still disease-free at 18-25 months. The
median time to recurrence was 134 days longer in subjects who received 12 weeks of induction
therapy compared to 6 weeks.

This is an open-label, non-randomized, multicenter study in adults with NMIBC, specifically
CIS (with or without papillary disease), high-grade Ta or any grade T1 papillary disease, who
have previously failed BCG treatment (i.e., not those who are intolerant) with or without
interferon. The study consists of a Screening period, a 12-week Induction Phase, and a
Maintenance Phase of up to 21 monthly cycles for a total treatment period of up to 104 weeks.
This is an outpatient study, but all treatments are administered in the study clinic.

Inclusion Criteria:

1. Histologically-confirmed non muscle-invasive urothelial carcinoma (transitional cell
carcinoma) of the bladder as follows:

1. CIS (with or without papillary disease) OR

2. Any grade T1 papillary disease OR

3. High-grade Ta papillary disease based on a biopsy within 8 weeks of the initial
dose of study treatment. If multiple bladder biopsies are required to confirm
eligibility, the last bladder biopsy to the initial dose of study treatment must
be within 8 weeks. This diagnosis must be confirmed by the independent central
pathology reviewer prior to subject enrollment. A subject with persistent T1
disease on the second (i.e., restaging) TURBT may be enrolled in this study only
if the investigator documents the subject declines cystectomy.

2. Subjects must have received adequate BCG treatment defined as at least 2 courses of
BCG, i.e., at least one induction and one maintenance course or at least 2 induction
courses. The initial induction course must be at least 5 treatments within a 7-week
period. The second course (induction or maintenance) must be at least 2 treatments
within a 6-week period. The "5+2" doses of BCG must be given within approximately 1
year (i.e., the start of one course to start of the second course within 12 months ±1
month) and for the same disease episode for which the subject is enrolling. Treatment
must be considered "full-dose" BCG (see Section 10). If additional doses or courses of
BCG above the minimum "5+2" are given, these do not have to be within the same
approximate 12 month timeframe.

Subjects who were unable to receive at least 5 doses of BCG in a first course and at
least 2 doses of BCG in a second course due to intolerance are not eligible.

Subjects who began their initial course of BCG with "full-dose" BCG and required
dose-reductions due to adverse events but are still able to tolerate at least "5+2"
doses of BCG are considered to meet the requirement for "adequate BCG." Subjects who
received less than "full dose" BCG (e.g., 1/3rd dosing) as a standard regimen and not
due to dose reductions because of AEs are not eligible.

The BCG may have been given in combination with interferon. When BCG is given
simultaneously in combination with interferon, 1/3rd dosing of BCG is acceptable.

3. The subject's disease is refractory or has relapsed following adequate BCG treatment.
Refractory disease is defined as disease which persists at the first evaluation
following adequate BCG. Relapsed disease is defined as having a complete response to
adequate BCG but recurs at a subsequent evaluation.

Subjects will enroll into one of three cohorts based on their type of disease and the
time to refractory/relapsed disease following their last dose of BCG as follows:

- Cohort 1: Subjects with CIS with or without associated papillary disease whose
disease is determined to be refractory or relapsed within 6 months of the last
dose of adequate BCG treatment.

- Cohort 2: Subjects with CIS with or without associated papillary disease whose
disease is determined to be refractory or relapsed more than 6 months but within
11 months of the last dose of adequate BCG treatment.

- Cohort 3: Subjects with high-grade Ta or any grade T1 papillary disease (without
CIS) whose disease is determined to be refractory or relapsed within 6 months of
the last dose of adequate BCG treatment.

For eligibility and cohort assignment, 6 months is defined as 30 weeks i.e., 26 weeks
(6 months) plus an additional 4 weeks to accommodate scheduling variations and for
diagnostic work-up and 11 months is defined as 50 weeks i.e., 48 weeks (11 months)
plus an additional 2 weeks to accommodate scheduling variations and for diagnostic
work-up.

For subjects enrolling in Cohort 2: The investigator documents he/she would not treat
the subject with additional BCG at the time of study entry.

4. Male or non-pregnant, non-breastfeeding female, age 18 years or older at date of
consent.

5. All women of childbearing potential (WOCBP) must have a negative pregnancy test within
7 days of the first dose of study therapy. A woman is not of childbearing potential if
she has undergone surgical sterilization (bilateral tubal ligation, total
hysterectomy, or bilateral oophorectomy) or if she is ≥55 years of age and has had no
menstrual bleeding of any kind including menstrual period, irregular bleeding,
spotting, etc., for at least 12 months and there is no other cause of amenorrhea
(e.g., hormonal therapy, prior chemotherapy).

6. 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. WOCBP and males whose sexual partners are WOCBP agree to use barrier
contraception and a second form of contraception while receiving study treatment and
for 120 days following their last dose of study treatment.

7. Karnofsky performance status ≥ 60 (Appendix 1).

8. Adequate organ function, as defined by the following criteria:

- Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x
upper limit of normal (ULN);

- Total serum bilirubin ≤ 1.5 x ULN (CTCAE Grade ≤ 1);

- Serum creatinine ≤ 1.5 x ULN; or a creatinine clearance ≥40 mL/min;

- Hemoglobin ≥8.0 g/dL;

- Absolute neutrophil count ≥1500/mm3;

- Platelets ≥75,000/mm3

9. Ability to understand and sign an Independent Ethics Committee- or Institutional
Review Board-approved informed consent document indicating that the subject (or
legally acceptable representative) has been informed of all aspects of the trial and
is willing and able to comply with scheduled visits, treatment plan, laboratory tests,
and other study procedures. The informed consent document must be signed prior to the
subject undergoing tests or procedures solely for determining study eligibility and
prior to receiving any protocol treatment.

Exclusion Criteria:

1. The subject is pregnant or breastfeeding.

2. Evidence of urethral or upper tract transitional cell carcinoma (TCC) within the past
2 years. Subjects with T1 disease must have no evidence of upper or lower tract
disease or a more advanced stage of disease by CT urogram or MRI urogram of the
abdomen and pelvis performed within 8 weeks of the first dose of study treatment. If
intravenous contrast is contraindicated, retrograde ureteropyelography, or CT or MRI
without intravenous contrast may be performed.

3. 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. Subjects with
hydronephrosis that is unequivocally unrelated to upper tract malignancy may be
considered eligible with Sponsor approval.

4. Any intravesicular or other chemotherapy treatment within 2 weeks or any
investigational agent within 4 weeks prior to the initial dose of study drug.

5. History of recurrent severe urinary tract infections (UTIs) per investigator judgment.
Subjects with a current UTI requiring antibiotic treatment may defer the initiation of
Vicinium treatment on Day 1 until resolution of the UTI (even if this extends the
screening period requirements to start of Vicinium treatment).

6. Active, uncontrolled impairment of the urogenital, renal, hepatobiliary,
cardiovascular, gastrointestinal, neurologic or hematopoietic systems which, in the
opinion of the Investigator, would predispose the subject to the development of
complications from the administration of intravesical therapy and/or general
anesthesia.

7. The subject has a diagnosis of another malignancy within 2 years before the first dose
of study treatment, except for superficial skin cancer 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. However, subjects with low-risk prostate cancer, e.g.:

- Clinically localized disease (≤T2a) and

- Gleason score 6 (3+3) and

- Serum PSA <10 ng/mL undergoing active surveillance may be enrolled with agreement
of the sponsor.

8. A QTc interval of >470 msec by the Fridericia formula (QTcF), at the Screening ECG. If
the subject's QTcF is >470 msec on the initial ECG, a total of 3 ECGs should be
obtained at least 3 minutes apart and all within 30 minutes. The average of the 3
QTcF's will be used to determine eligibility. Known or suspected causes of prolonged
QTc can be treated (e.g., hypocalcemia, hypokalemia, hypomagnesimia) and the ECGs may
be repeated. If the subject initiates treatment with a drug known to prolong the QTc
during the Screening period after the initial Screening ECGs were obtained, the
Screening ECGs must be repeated once the new drug has reached steady state to ensure
the average QTcF remains ≤470 msec. For subject's whose heart rate is <60 bpm, the
Bazett correction formula (QTcB) may be used.

9. Subjects who, in the opinion of the Investigator, cannot tolerate intravesical
administration or intravesical surgical manipulation (cystoscopy, biopsy) due to the
presence of serious comorbid condition(s) (e.g., uncontrolled cardiac or respiratory
disorders).

10. Local or severe allergy to any components of the drug regimen.