Multi-center Study to Evaluate the Efficacy and Safety of Maintenance Therapy With Valrubicin Versus no Maintenance, in Subjects Treated With Valrubicin Induction for Carcinoma in Situ (CIS) of the Bladder

A PHASE 3B, RANDOMIZED, OPEN-LABEL, MULTI-CENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF MAINTENANCE THERAPY WITH VALRUBICIN VERSUS NO MAINTENANCE, IN SUBJECTS TREATED WITH VALRUBICIN INDUCTION FOR CARCINOMA IN SITU (CIS) OF THE BLADDER

This is a Phase 3b open-label, randomized, parallel-arm, multicenter study to evaluate the efficacy and safety of 10 monthly intravesical administrations of maintenance therapy with valrubicin following induction with valrubicin as compared to induction with valrubicin only in subjects with CIS of the bladder. The randomization will be 1:1 and subjects will be stratified by tumor type (CIS plus papillary disease vs. CIS only) and time from last bacillus Calmette-Guerin (BCG) failure (>1 year vs. <1 year).

Inclusion Criteria:

1. Is 18 years of age and older at time of consent signing

2. Have histologically confirmed diagnosis of CIS of the bladder and received valrubicin induction therapy per the labeled indication.

3. Is disease-free following induction with intravesical valrubicin

   • Disease-free is defined as negative biopsy 10 to 12 weeks after the initiation of valrubicin induction
   • Valrubicin induction is defined as having received at least 3 of 6 weekly instillations

4. Is available for the duration of the study including follow-up (minimum 12 months from randomization)

5. Have an Eastern Cooperative Oncology Group (ECOG) performance status grade of 2 or less

6. Have no evidence of urothelial carcinoma involving the upper urinary tract or prostatic urethra (confirmed by extravesical work up, which may include radiological imaging and/or biopsy) within 6 months prior to randomization

7. 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 abstinence or 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

8. Is able to understand and give written informed consent

Exclusion Criteria:

1. Have current or previous history of muscle-invasive bladder cancer (MIBC)

2. Current or previous history of lymph node positive and/or metastatic bladder cancer

3. Have current evidence of pure squamous cell carcinoma, pure adenocarcinoma or pure undifferentiated carcinoma of the bladder

4. Is currently receiving systemic anti-cancer therapy (cytotoxic/cytostatic, immunotherapy or radiation)

5. Received treatment with an investigational agent within 30 days or 5 half-lives prior to randomization, whichever is longer

6. Received treatment with an intravesical chemotherapeutic agent (other than valrubicin or a single administration of mitomycin C post-transurethral resection of bladder tumor [TURBT]) within 3 months prior to randomization

7. Received treatment with valrubicin other than induction within 3 months prior to randomization

8. Have contraindication to valrubicin

   • Known hypersensitivity to anthracyclines or polyoxyl castor oil
   • Small bladder capacity, i.e. unable to tolerate a 75 mL instillation
   • Concurrent urinary tract infection

9. Absolute neutrophil count (ANC) <1000/µL and hemoglobin <10 g/dL

10. Have active 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

11. Female subjects who are pregnant or lactating

12. Subjects of childbearing potential who are unwilling to practice abstinence or effective contraception (as defined by investigator) during the study and for 30 days after last dose of study treatment

13. 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 adequately treated basal cell or squamous cell carcinoma of the skin and asymptomatic non-metastatic prostate cancer either previously successfully treated or currently under active surveillance or receiving hormone therapy only)

14. Is unable to tolerate intravesical administration or intravesical surgical manipulation (cystoscopy or biopsy) even with premedication

15. Have ongoing clinically significant active infections

16. Have 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