Efficacy and Safety Evaluation of EN3348 (Mycobacterial Cell Wall-DNA Complex [MCC]) as Compared With Mitomycin C in the Intravesical Treatment of Subjects With BCG Recurrent/Refractory Non-muscle Invasive Bladder Cancer
Condition: Bladder Neoplasm; Neoplasm Recurrence, Local; Transitional Cell, Carcinoma; Carcinoma in Situ; Mycobacterium
MeSH terms: Carcinoma; Neoplasms; Urinary Bladder Neoplasms; Carcinoma in Situ; Non-Muscle Invasive Bladder Neoplasms; Neoplasm Recurrence, Local; Recurrence
Intervention: EN3348; Mitomycin C
Intervention description: Induction: 6 weekly instillations. Maintenance: Monthly instillations to Month 12; Induction: 6 weekly instillations. Maintenance: Monthly instillations to Month 12
Intervention MeSH terms: Mitomycins; Mitomycin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 84.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Urinary Bladder Neoplasms; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urinary Bladder Diseases; Urologic Diseases; Mycobacterial cell wall DNA complex; Intravesical drug administration

Summary:

      This is a phase 3 randomized, active-controlled, open-label, multicenter study that will be
      conducted in approximately 120 investigational sites worldwide. Subjects with either
      recurrent or refractory NMIBC (Ta high grade, T1 low or high grade, CIS) will be eligible for
      participation in this study.

      Refractory disease is defined as evidence of persistent high grade bladder cancer (Ta HG, T1,
      and/or CIS) at least 6 months from the start of a full induction course of BCG with or
      without maintenance/re-treatment at 3 months.

      Recurrent disease is defined as reappearance of disease after achieving a tumor-free status
      by 6 months following a full induction course of BCG with or without maintenance/re-treatment
      at 3 months. Subjects with recurrent disease must have recurred within 18 months following
      the last dose of BCG.

      Approximately 450 subjects will be randomized. The primary objective of this study is to
      evaluate the efficacy of intravesical EN3348 as compared with mitomycin C in the treatment of
      subjects with recurrent or refractory NMIBC. The secondary objective is to evaluate the
      safety of EN3348 as compared with mitomycin C in the treatment of subjects with BCG recurrent
      or refractory NMIBC. This study will consist of 4 phases: Screening, Induction, Maintenance
      and Follow-Up and will be conducted over 3 years.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Is 18 years of age and older at time of consent signing

          -  Have either BCG recurrent or refractory NMIBC:

               -  Refractory disease is defined as evidence of persistent high grade bladder cancer
                  (Ta HG, T1 and/or CIS) at least 6 months from the start of a full induction
                  course of BCG with or without maintenance/re-treatment at 3 months

               -  Recurrent disease is defined as reappearance of disease after achieving a
                  tumor-free status by 6 months following a full induction course of BCG with or
                  without maintenance/re-treatment at 3 months. Subjects with recurrent disease
                  must have recurred within 18 months following the last dose of BCG

                    -  A full induction course of BCG is defined as at least 5 out of 6 total
                       expected instillations of BCG within a period of 2 months, regardless of
                       dose strength

          -  Have histologically confirmed NMIBC (according to 2004 WHO classification) within 8
             weeks prior to randomization

               -  High grade Ta papillary lesion(s)

               -  High or low grade T1 papillary lesion(s)(biopsy sample must include evidence of
                  muscularis propria)

               -  CIS, with or without Ta or T1 papillary tumor(s) of any grade

          -  Have had all visible papillary and resectable CIS lesion(s) removed by TURBT within 8
             weeks prior to randomization

          -  Available for the duration of the study including follow-up (approximately 36 months)

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status grade of 2 or
             less

          -  Have no evidence of urothelial carcinoma involving the upper urinary tract or the
             urethra (confirmed by extravesical work up, which may include radiological imaging
             and/or biopsy) within 6 months of randomization:

               -  If previous work up occurred more than 6 months from randomization, extravesical
                  work up must be repeated prior to randomization in order to determine eligibility

          -  Subjects (male and female) of child-bearing potential (including female subjects who
             are post-menopausal for less than 1 year) must be willing to practice effective
             contraception (as defined by the Investigator) during the study and be willing and
             able to continue contraception for 30 days after their last dose of study treatment

          -  Is able to understand and give written informed consent

        Exclusion Criteria:

          -  Current or previous history of muscle invasive bladder tumors

          -  Current or previous history of lymph node positive and/or metastatic bladder cancer

          -  Current evidence of pure squamous cell carcinoma, pure adenocarcinoma or pure
             undifferentiated carcinoma of the bladder

          -  Currently receiving systemic cancer therapy (cytotoxic/cytostatic or immunotherapy)

          -  Currently receiving treatment with a prohibited therapy

          -  Current or prior history of systemic lupus erythematosus

          -  Systemic immunotherapy within 6 months of randomization

          -  Treatment with an investigational agent within 30 days or 5 half lives from
             randomization, whichever is longer

          -  Prior treatment with an intravesical chemotherapeutic agent within 3 months of
             randomization except for single perioperative dose of chemotherapy immediately
             post-TURBT

          -  Prior treatment with EN3348 (MCC) or any other mycobacterial cell wall composition or
             formulation

          -  Refractory to mitomycin C (failure to achieve tumor-free status following minimum of a
             6 week induction course of mitomycin C)

          -  Contraindication to mitomycin C

          -  Untreated urinary tract or bladder infection

          -  ANC <1000/µL and hemoglobin <10 g/dL

          -  Known cardiovascular disease such as myocardial infarction within the past 3 months,
             unstable angina pectoris, congestive heart failure (NYHA Class III or IV) or
             uncontrolled cardiac arrhythmia

          -  Female subjects who are pregnant or lactating

          -  Congenital or acquired immune deficiency

          -  Have current or history of documented or suspected malignancy of any organ system
             (diagnosed, treated or untreated) within the past 5 years (with the exception of
             localized transitional cell carcinoma of the ureter treated with ureterectomy or
             nephroureterectomy, adequately treated basal cell or squamous cell carcinoma of the
             skin or asymptomatic non-metastatic prostate cancer either previously successfully
             treated or currently under active surveillance or receiving hormone therapy only)

          -  Bladder contracture or history of an inability to retain the instillate for a minimum
             of 1 hour, even with premedication

          -  Inability to tolerate intravesical administration or intravesical surgical
             manipulation (cystoscopy or biopsy)

          -  Clinically significant active infections

          -  Any medical or psychiatric condition which, in the opinion of the investigator, would
             preclude the participant from adhering to the protocol or completing the trial per
             protocol