Vicinium Treatment for Subjects With Non-muscle Invasive Bladder Cancer Previously Treated With BCG
Condition: Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms
Intervention: Vicinium
Intervention description: Intravesical administration
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 133.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Urinary Bladder Cancer; Non-muscle invasive bladder cancer; Bladder Neoplasm; Bladder Tumor; CIS; Papillary bladder cancer; High grade bladder cancer

Summary:

      Because of the high risk for development of muscle invasive disease, cystectomy is
      recommended for CIS, high-grade Ta and T1 patients who experience disease recurrence
      following intravesical therapy. Vicinium is an experimental agent that may provide an
      alternative to cystectomy
    

Eligibility criteria:

        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.