A Study of NDV-01 (Sustained-release Gemcitabine-docetaxel) in Participants With Non-muscle Invasive Bladder Cancer

The study is comprised of two cohorts, described in the sections that follow.

Cohort 1 (Intermediate Risk)

Cohort 1 is a randomized, open-label, parallel group, multi-center, Phase 3 study evaluating the efficacy and safety of the NDV-01 versus observation in participants with histologically confirmed IR-NMIBC. Eligible participants must have IR-NMIBC according to the AUA/Society of Urologic Oncology (SUO) guidelines definition and at least one of the following risk factors: multiple LG tumors (Ta), solitary LG tumor >3 cm, solitary HG tumor < 3 cm, early recurrence of LG tumor (<1 year), frequent recurrence (>1 per year), or recurrence after prior intravesical chemotherapy. LGT1 tumors are the exception. The IR-NMIBC diagnosis qualifying the participant for the study must be within 90 days of randomization. All participants in Cohort 1 will have undergone TURBT with complete resection of all papillary diseases and will be confirmed to be disease-free within 90 days prior to randomization. All enrolled participants will have histologically confirmed IR-NMIBC.

A target of 276 participants will be randomized 1:1 (N=138 per arm) to treatment with either NDV-01 (Treatment Group) or observation (Control Group). Participants will be stratified based on 1) low-grade vs. high-grade disease and 2) the use of perioperative chemotherapy (Yes/No). Eligible participants should have had a TURBT or tumor excision within 90 days of randomization. The TURBT procedure may include a single dose of perioperative chemotherapy per the Investigators' decision and local standard of care.

Participants in the Treatment Group will have NDV-01 instilled into the bladder via a urethral catheter on Day 1 of the Treatment Phase (i.e., start of Week 0) and NDV-01 will be delivered biweekly for 12 weeks, followed by maintenance therapy once every month for up to 12 months after Day 1.

Participants in the Control Group will be observed with cystoscopy, urinary cytology, and biopsy (if indicated). Participants in the Control Group who demonstrate recurrence will be provided the option for crossover and receive treatment with NDV-01 within 12 weeks of disease recurrence. Crossover participants will begin NDV-01 instillations (within 12 weeks of recurrence) at Treatment Day 1 (see Table 2) and will complete Years 2-3 of the Follow-up Period, or will be discontinued at study closure, whichever occurs first.

Additionally, in the event of a positive study result (compelling results for disease-free survival [DFS]) at any of the planned analyses, and upon further notification by the Sponsor at the discretion of the IDMC, participants in the Control Group may have the opportunity to crossover and receive NDV-01 for up to one year.

For all participants, an End of Treatment (EOT) visit will take place at the time of the last dose of the participant's randomized treatment, observation, or discontinuation of study treatment (±1 week). After the EOT visit, participants will continue into the Follow-up Phase of the study, comprised of a 30-day Safety Follow-Up Period (30 days [+1 week] from EOT), and a follow-up period of 2 to 5 years, culminating at the time of death, withdrawal of consent, or end of study, whichever occurs first.

The end of study is considered as 5 years after the last participant is randomized in the study. This will ensure approximately 4 years of follow-up after the final dose of study drug.

Cohort 2 (HR BCG-Unresponsive Disease Refractory to First-Line Therapies)

Cohort 2 is an open-label, multicenter, single-arm, Phase 3 study evaluating the efficacy and safety of NDV-01 in two high-risk NIMBC populations:

• Cohort 2a will include participants with BCG-unresponsive HR-NMIBC with CIS of the bladder, with or without coexisting papillary Ta/T1 tumor(s) who are ineligible for or have elected not to undergo cystectomy at the time of enrollment and have received 1 or 2 lines of therapy after meeting criteria for BCG unresponsiveness and experienced biopsy confirmed CIS disease within 12 months of last treatment.
• Cohort 2b will include participants with BCG-unresponsive HR NMIBC Ta/T1 tumor(s) who are ineligible for or have elected not to undergo cystectomy at the time of enrollment and have received 1 or 2 lines of therapy after meeting criteria for BCG unresponsiveness and experienced biopsy confirmed HG papillary disease within 6 months of last treatment.

All participants in Cohort 2 will undergo a screening Period of up to 28 days and will receive study drug on Days 1, 14, 28, 42, 56, and 70. Participants will then have a Day 90 disease assessment visit, which should occur within 20 days (±5 days) of the Day 70 instillation of NDV-01.

At Day 90:

• Participants who experience CR/RFS will receive maintenance therapy once monthly until recurrence/progression or for a total treatment duration of 3 years.
• Participants who have suspected persistent or recurrent disease (e.g., papillary tumor) will undergo standard-of-care TURBT of visible lesions.
• Participants with suspected CIS will undergo biopsy of the lesion(s) and resection/fulguration of CIS lesions.
• Participants with disease recurrence but no progression can be considered for re-induction instillation course (6 bi-weekly instillations) if deemed appropriate and feasible by the investigator, after undergoing a biopsy/TURBT to eradicate all gross tumor and confirm non-progression (e.g., Ta to T1).
• Participants with disease progression (stage progression [e.g. Ta → T1 or CIS → T1]) will discontinue treatment.

Participants without CR (non-responders) at Day 180 will discontinue treatment. Additionally, participants who do not maintain CR any time after Day 180 will discontinue treatment.

Participants demonstrating CR at the Day 180 (±4 days) Disease Assessment visit will receive NDV-01 monthly maintenance instillations from Day 180 to Day 1080 or until disease recurrence. Disease Assessment visits will be performed every 3 months.

Participants who are non-responders and come off treatment will be followed for safety for 8 weeks, and after the 8-week assessment visit, they will be followed by telephone call every 3 months until 1 year after the EOT Visit to determine treatment and cystectomy-related information. Tissue from participants who elect to undergo cystectomy may be analyzed for exploratory purposes, if available.

Participants who have continued CR at Day 360 may continue with monthly Maintenance instillations through Day 1080 (with maintained CR) or enter the Follow-Up Period for quarterly visits (every 3 months) through Day 1080 or until non-response (persistent disease, recurrent disease, or progression). Participants will undergo an End of Treatment visit following the last Maintenance Treatment instillation.

Cohort 1 Inclusion Criteria:

• Be ≥18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place) at the time of informed consent.
• Have a histologically confirmed diagnosis (within 90 days of randomization) of IR NMIBC based on the AUA/SUO criteria of IR NMIBC (excluding LGT1 tumors).
• Participant must be willing to undergo all study procedures (e.g., multiple cystoscopies from Screening through the end of study and TURBT for assessment of recurrence/progression) and receive the assigned treatment, including intravesical chemotherapy if randomized into that arm.
• Participant must have ≥ 1 IBCG risk factors: 1) multiple tumors, 2) early recurrence (within 1 year), 3) frequent recurrences (> 1 per year), 4) tumor size (> 3 cm), 5) failure of prior induction intravesical therapy.
• Visible papillary disease must be fully resected prior to randomization, and absence of disease must be documented at Screening cystoscopy. The same method for visualizing disease at Screening cystoscopy should be used throughout for the participant (white light versus enhanced cystoscopic method [e.g., blue light cystoscopy, narrow-band imaging]).

All pathology specimens must be predominantly urothelial (transitional cell) and have less than 20% variant (e.g., sarcomatoid, squamous component) histology.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

Cohort 1 Exclusion Criteria:

• Histologically confirmed stage T1 tumors.
• Histologically confirmed diagnosis of HR NMIBC (including CIS) or muscle-invasive bladder cancer (MIBC), locally advanced, nonresectable, or metastatic urothelial carcinoma at any time prior to enrollment.
• Has had urothelial carcinoma outside of the urinary bladder (including prostatic urethra, ureter, or renal pelvis) or has a predominant histological variant of urothelial carcinoma (UC). Ta/any T1, CIS of the upper urinary tract is allowable if treated with complete nephroureterectomy more than 24 months prior to initiating study.
• Participant has tumor(s) involving the prostatic urethra (ductal or stromal).
• N+ and/or M+ per computed tomography (CT)/magnetic resonance (MR) urography.
• Received an investigational treatment for bladder cancer within 6 months prior to randomization, before the planned first dose of study treatment, or is currently enrolled in an investigational study.
• Received adjuvant induction intravesical chemotherapy within 3 months of current diagnosis. Peri-operative instillation of a single dose of intravesical chemotherapy is allowed per institutional guidelines.
• Received prior intravesical treatment with immunotherapy, including BCG, within 3 months prior to randomization.

Cohort 2 Inclusion Criteria:

• Cohort 2a: BCG-unresponsive NMIBC with CIS of the bladder, with or without coexisting papillary Ta/T1 tumor(s) who are ineligible for or have elected not to undergo cystectomy at the time of enrollment and have received 1 or 2 lines of therapy after meeting criteria for BCG unresponsiveness and experienced biopsy confirmed CIS disease within 12 months of last treatment, where:

• Adequate BCG regimen consists of at least 2 courses of BCG, where the first course (induction) must have included at least 5 of 6 doses and the second course may have included a re-induction (at least 2 of 6 treatments) or maintenance (at least 2 of 3 doses). Adequacy of the BCG regimen will be determined by the Investigator in conjunction with the Sponsor.
• Treatment after BCG unresponsiveness includes either approved or in development therapy
• Post-treatment presence of CIS must be documented or indicated by pathology at screening or within 4 months of screening (provided no therapy for CIS disease was given after the most recent biopsy).
• For inclusion, a participant with BCG-unresponsive disease (as defined above) must have received up to two lines of therapy for BCG-unresponsive disease and who are being considered for radical cystectomy. Such therapies may include agents approved or in development (e.g., pembrolizumab, nadofaragene firodenovec, nogapendekin alfa inbakicept-pmln, cretostimogene grenadenorepvec, detalimogene voraplasmid, TARA-002, gemcitabine intravesical system (INLEXZO®), gemcitabine-docetaxel, gemcitabine, MMC, or valrubicin monotherapy. Participant will have demonstrated biopsy-proven recurrence with HG papillary disease (without CIS) after one or two first-line therapy(ies).
• Cohort 2b: BCG-unresponsive NMIBC of the bladder, with papillary Ta/T1 tumor(s) and without co-existing CIS, who are ineligible for or have elected not to undergo cystectomy at the time of enrollment and have experienced recurrent Ta/T1 disease within 12 months of treatment with 1 or 2 lines of therapy after BCG-unresponsive status.

• For inclusion, a participant with BCG-unresponsive disease (as defined above) must have received up to two lines of therapy for BCG-unresponsive disease and who are being considered for radical cystectomy. Such therapies may include agents approved or in development (e.g., pembrolizumab, nadofaragene firodenovec, nogapendekin alfa inbakicept-pmln, cretostimogene grenadenorepvec, detalimogene voraplasmid, TARA-002, gemcitabine intravesical system (INLEXZO®), gemcitabine-docetaxel, gemcitabine, MMC, or valrubicin monotherapy. Participant will have demonstrated biopsy-proven recurrence with HG papillary disease (without CIS) after one or two first-line therapy(ies).

All Cohort 2

• A participant with HG T1 may be eligible after repeat-TURBT showing non-invasive (Ta or less) or no disease. Either original or repeat-TURBT must confirm that muscularis propria is present and uninvolved in the specimen.
• All specimens must be predominantly urothelial (transitional cell) carcinoma with or without squamous or glandular differentiation. Pure squamous or glandular tumors will not be included. A participant with less than 10% micropapillary histology will be included. All other variant histology (e.g., plasmacytoid, small cell, nested, trophoblastic variants) will not be included.

Cohort 2 Exclusion Criteria:

• Has had urothelial carcinoma outside of the urinary bladder (i.e., urethra, ureter, or renal pelvis) or has a predominant histological variant of UC. Ta/any T1, CIS of the upper urinary tract is allowable if treated with complete nephroureterectomy more than 24 months prior to initiating study and is considered to be without evidence of recurrent disease.

• Participants have tumor(s) involving the prostatic urethra (ductal or stromal).
• N+ and/or M+ per computerized tomography (CT)/Magnetic Resonance Imagery (MR) urography.
• History of prior T2/T3 urothelial carcinoma of the bladder.
• Concurrent treatment with any chemotherapeutic agent.
• Intravesical chemotherapy within 3 months of enrollment (including INLEXZO®, gemcitabine-docetaxel)