Sunrise 4

1. ≥ 18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.

2. Histologically proven, cT2-T4a N0, M0 infiltrating urothelial carcinoma (AJCC 2017) of the bladder. Initial diagnosis must have been within 90 days of randomization date.

Participants with variant histologic subtypes (eg squamous differentiation) are allowed if urothelial (transitional cell) differentiation is predominant (eg, < 20% variant histologic subtype). However, the presence of any neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features will make a participant ineligible.

3. Participants with an individual intravesical tumour size of ≤ 3 cm following TURBT are eligible. Participants with persistent multifocal tumours at screening must undergo a second debulking, re-staging TURBT to reduce the tumour burden. Participants will be ineligible if any individual tumour is > 3 cm.

4. Deemed eligible for and willing to undergo RC by the attending urologist.

5. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0 or 1 .

6. Thyroid function tests within normal range or stable on hormone supplementation per Investigator assessment.

7. Adequate bone marrow, liver, and renal function:

a. Bone marrow function (without the support of cytokines or erythropoiesis stimulating agent in preceding two weeks):

i. Absolute neutrophil count (ANC) ≥ 1,000/mm3

ii. Platelet count ≥ 75,000/mm3

iii. Haemoglobin ≥ 8.0 g/dL

b. Liver function:

i. Total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 x ULN (except participants with Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL),

ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x institutional ULN

c. Renal function:

i. Creatinine clearance > 40 mL/min calculated using the Cockcroft-Gault formula.

8. Participants must refuse cisplatin-based combination chemotherapy (and understand the risk and benefits of doing so) or be deemed ineligible for cisplatin-based chemotherapy by meeting at least one of the following criteria:

• GFR < 60 mL/min/1.73 m2 (assessed using the CKD-EPI equation)

• Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≥ 2 audiometric hearing loss

• CTCAE version 5.0 Grade ≥ 2 peripheral neuropathy

9. Prior systemic chemotherapy for indications other than urothelial cell carcinoma of the bladder is permitted, but interval between this treatment and study enrolment must exceed 24 months. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI-CTCAE version 5.0) or baseline before administration of study drug. Participants with toxicities attributed to prior anticancer therapy which are not expected to resolve and result in long lasting sequelae, such as peripheral neuropathy after platinum-based therapy or audiometric hearing loss, are ineligible.

10. All adverse events associated with any prior surgery must have resolved to CTCAE version 5.0 Grade < 2 prior to randomization. 

1. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:

a. skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.

b. non-invasive cervical cancer treated within the last 24 months that is considered completely cured.

c. Localized prostate cancer (N0M0):

• with a Gleason score of 6, treated may include surgery, radiation, or ablation) within the last 24 months or untreated and under active surveillance,

• with a Gleason score of 3+4 that has been treated (may include surgery, radiation, or ablation) more than 6 months prior to full study screening and considered to have a very low risk of recurrence,

• or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.

d. Breast cancer:

• adequately treated lobular carcinoma in situ or ductal carcinoma in situ,

• or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence.

e. Malignancy that is considered cured with minimal risk of recurrence.

2. Must not have received prior systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 2 years prior to starting study treatment (treatment exceptions not precluding participants from enrolment are noted in the active malignancies exclusion criterion).

3. Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder. Ta/T1/CIS of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephroureterectomy more than 24 months prior to randomization.

4. Participants must not have evidence of cT4b, or N1-3, or M1 disease based on local radiology staging (chest, abdomen, and pelvis must be performed using CT or MRI) within 42 days prior to randomization.

5. Presence of any bladder or urethral anatomic feature that, in the opinion of the Investigator, may prevent the safe placement, indwelling use, or removal of TAR-200.

6. Uncontrolled adrenal insufficiency. 

Research Nurse: Amanda Cook (x4656) Amanda.Cook@lthtr.nhs.uk

Administrator: Yecora Lecanda-Swarbrick (x3766)