TROPICS 04

Subjects meeting all of the following inclusion criteria at Screening/C1D1 of treatment will be eligible for participation in the study:

1. Female or male subjects, ≥ 18 years of age, able to understand and give written informed consent.

2. Subjects with histologically documented metastatic or locally advanced unresectable UC defined as [Tumor (T) 4b, any node (N) or Any T, N 2-3]. Tumors of upper and lower urinary tract are permitted. Mixed histologic types are allowed if urothelial is the predominant histology.

3. ECOG performance status score of 0 or 1.

4. Subjects with progression or recurrence following receipt of platinum-containing regimen (cisplatin or carboplatin) and anti PD-1/PD-L1 therapy for metastatic or locally advanced unresectable disease will be enrolled.

a. Subjects with recurrence or progression ≤ 12 months following completion of platinum-containing chemotherapy and/or anti PD-1/PD-L1 therapy given in neoadjuvant/adjuvant setting may utilize that line of therapy to be eligible for the study. The 12-month period is counted from completion of platinum therapy or surgical intervention.

b. Subjects who received only concurrent chemoradiation for bladder preservation without further systemic therapy are not eligible to enroll in the study. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen and no progression was noted prior to the change in platinum.

5. Subjects with previously treated brain metastases may participate in the study provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and stabilization of all neurologic symptoms, have no evidence of new or enlarging brain metastases, and are not using steroids > 20 mg of prednisone (or equivalent) daily for brain metastases for at least 7 days prior to first dose of the study drug.

6. Adequate hematologic counts without transfusion or growth factor support within 1 week of study drug initiation [hemoglobin ≥ 9 g/dL, absolute neutrophil count (ANC) ≥ 1,500/mm3, and Platelets ≥ 100,000/μL].

7. Adequate hepatic function (Bilirubin ≤ 1.5 x institution upper limit of normal (IULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x IULN or ≤ 5 x IULN if known liver metastases and serum albumin > 3 g/dL). Docetaxel will only be option in TPC arm for subjects with a total bilirubin ≤ 1 x IULN, and an AST and/or ALT ≤ 1.5 x IULN if alkaline phosphatase is also > 2.5 x IULN.

8. Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation or other validated instruments (e.g. Modification of Diet in Renal Disease [MDRD] equation).

9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

10. Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 6 months after the last dose of study drug. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 years.

11. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 3 months after the last dose of study therapy. 

Subjects meeting any of the following exclusion criteria at Screening/C1D1 of treatment will not be enrolled in the study:

1. Women who are pregnant or lactating.

2. Have had a prior anti-cancer mAb/ ADC within 4 weeks prior to C1D1 or have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to C1D1. Subjects participating in observational studies are eligible.

3. Have received prior chemotherapy for UC with all available SOC therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy).

4. Have not recovered (i.e., ≤ Grade 1) from AEs due to previously administered chemotherapeutic agent.

• Note: Subjects with ≤ Grade 2 neuropathy or any grade of alopecia are an exception to this criterion and will qualify for the study.

• Note: If subjects received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study therapy.

5. Have previously received topoisomerase 1 inhibitors.

6. Have an active second malignancy.

• Note: Subjects with a history of malignancy that have been completely treated and with no evidence of active cancer for 3 years prior to enrollment, or subjects with surgically cured tumors with low risk of recurrence are allowed to enroll in the study after discussion with the medical monitor.

7. Have active cardiac disease, defined as:

a. Myocardial infarction or unstable angina pectoris within 6 months of C1D1.

b. History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation.

c. New York Heart Association (NYHA) Class III or greater congestive heart failure or left ventricular ejection fraction of < 40%.

8. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or gastrointestinal (GI) perforation within 6 months of enrollment.

9. Have an active serious infection requiring anti-infective therapy (Contact medical monitor for clarification).

10. Have known history of Human Immunodeficiency Virus (HIV)-1/2 with uncontrolled viral load and on medications that may interfere with SN-38 metabolism.

11. Have active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV). In subjects with a history of HBV or HCV, subjects with a detectable viral load will be excluded.

12. Have other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.

13. Have inability to tolerate or are allergic to any potential TPC agent or sacituzumab govitecan or unable or unwilling to receive the doses specified in the protocol.

14. Have inability to complete all specified study procedures for any reason. 

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

Administrator: Chris Taylor (x3766)