Sacituzumab Govitecan Before Radical Cystectomy for the Treatment of Non-Urothelial Muscle Invasive Bladder Cancer

Inclusion Criteria:

• Participants must be at least 18 years of age on the day of signing informedconsent. Participant (or legally acceptable representative if applicable) provideswritten informed consent for trial

• Participants must have either histologically or by clinical consensus (based onimaging and/or exam under anesthesia) confirmed diagnosis of muscle invasive bladdercancer (cT2-T4aN0-N1M0 or cT1-4aN1M0 clinical stage per American Joint Commission onCancer [AJCC]). Patients with clinical node-positive (N1) stage are eligibleprovided the lymph node (LN) is confined to the true pelvis and is within theplanned surgical LN dissection template; cN1 is defined as a lymph node with >= 15mm short axis or biopsy-positive for carcinoma

• Must have clinical non-metastatic bladder cancer (M0) determined by cross-sectionalComputed tomography (CT) chest, abdomen and pelvis (CAP) or magnetic resonanceimaging (MRI)

• Review of pathology by local expert genitourinary (GU) pathologist is required. Anycomponent (%) of non-conventional urothelial (variant histology) noted ontransurethral resection of bladder tumour (TURBT) is allowed, for histologic typesnot listed below. However, for the variant histologic types listed below, thefollowing parameters need to be met:

• Squamous cell carcinoma / squamous cell features need to be pure or predominant (>= 1 variant histologic with total non-conventional urothelial component > 50%).

• Adenocarcinoma / glandular features need to be pure or predominant (>= 1variant histologic total non-conventional urothelial component > 50%).

• Any % of neuroendocrine / small cell histology is excluded.

• Patients must be considered unfit for cisplatin based on the Galsky et al. criteriaor refuse cisplatin despite adequate counseling in cisplatin-fit patients.Especially, for tumors containing squamous cell or glandular features, every effortshould be made to discuss the benefit of neoadjuvant cisplatin-based chemotherapyshown in the S8710 trial

• Participants must be deemed eligible for radical cystectomy (RC) and pelvic lymphnode dissection (PLND) by both urologist and medical oncologist

• TURBT that showed muscularis propria (or lamina propria for cT1N1 tumors) invasionshould be within 12 weeks prior to beginning study therapy. Patients must haveavailable tumor tissue from either initial or repeat TURBT, prior to starting studytherapy. Archival and/or fresh tumor tissue sample of a tumor lesion (TURBTspecimen) should be provided and must contain muscle invasive component, at least >=T2 tumor (for cT2 tumors), unless clinical stage is cT1N1M0 (in that case muscleinvasive component is not necessary). Formalin-fixed, paraffin embedded (FFPE)tissue blocks are preferred to slides. If submitting unstained cut slides, newly cutslides should be submitted to the testing laboratory, preferably within 14 days fromthe date slides are cut if possible. Patient must be willing to provide tumor tissuefor research. Research samples will not be used for unrelated studies

• A male participant must agree to use a contraception during the treatment period andfor at least 180 days after the last dose of study treatment and refrain fromdonating sperm during this period

• A female participant is eligible to participate if she is not pregnant, notbreastfeeding, and at least one of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) OR

• A WOCBP who agrees to follow the contraceptive guidance during the treatmentperiod and for at least 180 days after the last dose of study treatment.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2.Patients with ECOG PS 2 may be permitted only after discussion with the trialprimary investigator (PI) (Dr. Grivas). Evaluation of ECOG PS is to be performedwithin 7 days prior to the date of enrollment.

• Absolute neutrophil count (ANC) >= 1500/uL (within 10 days prior to the start ofstudy treatment)

• Platelets >= 100 000/uL (within 10 days prior to the start of study treatment)

• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 10 days prior to the start of studytreatment)

• Criteria must be met without erythropoietin dependency and without packed redblood cell (pRBC) transfusion within last 2 weeks prior to study drug treatment

• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculatedcreatinine clearance >= 30 ml/min (glomular filtration rate [GFR] can be used inplace of creatinine clearance; 24-hour urine collection can be used for moreaccurate estimate as needed) (within 10 days prior to the start of study treatment)

• Creatinine clearance (CrCl) should be calculated per institutional standard

• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with totalbilirubin levels > 1.5 x ULN (within 10 days prior to the start of study treatment)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])and Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 2.5 x ULN (within 10 days prior to the start of study treatment)

• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unlessparticipant is receiving anticoagulant therapy (within 10 days prior to the start ofstudy treatment)

• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant isreceiving anticoagulant therapy (within 10 days prior to the start of studytreatment)

• Patients must agree to undergo curative intent surgery.

Exclusion Criteria:

• Patients with any % of neuroendocrine / small cell histology

• Patients considered to be medically unfit for SG, TURBT or radical cystectomy (perinvestigator discretion)

• Prior systemic anti-cancer therapy, including investigational agent/device within 4weeks or prior radiation therapy within 2 weeks. Intravesical therapies are allowedwithout specified treatment interval

• Known locally advanced (unresectable, e.g. cT4b) or metastatic (cN2-3, M1) cancer onbaseline radiographic imaging (CT or MRI) obtained within 28 days prior toregistration

• Active infection requiring systemic antibiotic therapy at the time of trialinitiation. Human immunodeficiency virus (HIV)-positive patients on active therapyare eligible as long as their viral load is undetectable and CD4 count is withinnormal parameters during the time of trial therapy initiation

• Known history of active hepatitis B (defined as hepatitis B surface antigen [HBsAg]detected or positive hepatitis B virus [HBV] polymerase chain reaction [PCR] test)or known active hepatitis C virus (defined as HCV ribonucleic acid (RNA) [qualitative] detected) infection. Note: no testing for hepatitis B and hepatitis Cis required if there is no clinical suspicion of such infection

• History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results, interfere with the subject's participation for thefull duration of the trial, or is not in the best interest of the subject toparticipate, in the opinion of the treating investigator

• Known personality, psychiatric or substance abuse disorder that would interfere withcooperation with the requirements of the trial

• Patients may not have concurrent upper urinary tract (i.e., ureter, renal pelvis)invasive urothelial carcinoma. Patients with history of non-invasive (Ta, Tis) uppertract urothelial carcinoma that have been definitively treated with at least onepost-treatment disease assessment (i.e., cytology, biopsy, imaging) thatdemonstrates no evidence of residual disease are eligible. Previously treated orconcurrent non-invasive (Ta, Tis) urethra carcinoma is allowed, but history of orconcurrent invasive urethra carcinoma is excluded

• Patients may not have another malignancy that could interfere with the evaluation ofsafety or efficacy of of SG. Patients with prior malignancy will be allowed withoutPI approval in the following circumstances:

• Not currently active and completed therapy at least 2 years prior to the dateof registration.

• Non-invasive cancer, such as low risk cervical cancer or any carcinoma in situ.

• Localized (early stage) cancer treated with curative intent (without evidenceof recurrence and intent for further therapy), and in which no systemicchemotherapy was indicated (e.g., low/intermediate risk prostate cancer,non-melanoma skin cancer, etc.). Low/intermediate risk prostate cancer onactive surveillance or watchful waiting is allowed. Other cancers not meetingthese criteria must be discussed with trial PI (Dr. Grivas)

• Patients may not have undergone major surgery (e.g., intra-thoracic, intra-abdominalor intra-pelvic), open biopsy or significant traumatic injury =< 3 weeks prior tostarting SG, or who have not recovered from side effects of such procedure or injury

• Have active (based on symptoms, endoscopic or biopsy findings) chronic inflammatorybowel disease (ulcerative colitis, Crohn's disease) at time of trial therapyinitiation or history of GI perforation within 6 months of enrollment

• Patients may not have clinically significant cardiac diseases, including any of thefollowing:

• History or presence of serious uncontrolled ventricular arrhythmias.

• Any of the following within 6 months prior to starting study drug: myocardialinfarction (MI), severe/unstable angina, coronary artery bypass graft (CABG),New York Heart Association (NYHA) Class III or greater congestive heart failure (CHF) or left ventricular ejection fraction of < 40%, cerebrovascular accident (CVA), transient ischemic attack (TIA).

• Patients unwilling or unable to comply with the protocol or with known allergy toSG, its analogues, or excipients in the various formulations

• Patients may not participate in any other therapeutic clinical trials, includingthose with other investigational agents not included in this trial before radicalcystectomy

• WOCBP with positive urine pregnancy test within 72 hours prior to enrollment. If theurine test is positive or cannot be confirmed as negative, a serum pregnancy testwill be required for eligibility. Active lactation is exclusion

• History of allogeneic solid visceral organ transplant, Gilbert's disease, priorsystemic irinotecan or topotecan or other topoisomerase-1 inhibitor, or concomitantmedications that significantly interfere with ABCA1 transporter or UGT1A1 with noalternate option available