Clinical Trials

IRB Study Number 19-1472

Status Recruiting

Phase Phase 2

Location Cleveland Clinic Main Campus

Institute Taussig Cancer Institute

Description

Primary objective

• To determine the 3-year event free survival, defined as the proportion of patients without invasive or metastatic recurrence following definitive dose dense gemcitabine and cisplatin chemotherapy in those patients whose pre-treatment TURBT tumors harbor deleterious DDR gene alterations and who achieve <cT1 response to chemotherapy.

Secondary objective(s)

• To determine the clinical response rate (<cT1) for patients harboring deleterious DDR gene alterations following dose dense gemcitabine and cisplatin.
• To determine the bladder-intact and overall survival for DDR-altered patients with <cT1.
• For DDR gene altered patients who elect radical cystectomy despite <cT1, to determine the pT0 rate in this patient population.
• To determine the pathologic response rate at cystectomy and 3-year recurrence-free and overall survival for patients without DDR mutations who are registered onto this trial.
• To assess the local treatment burden (BCG therapy, resection of non-invasive disease) over time in the bladder-sparing group.

Inclusion Criteria

1. Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Urothelial carcinoma invading into the prostatic stroma with no histologic muscle invasion is allowed, provided the extent of disease is confirmed via imaging and/or EUA. The diagnostic TURBT sample must have been obtained within 60 days prior to registration.
2. 10-20 unstained slides (10 micron thickness) of formalin-fixed paraffin-embedded (FFPE) pre-treatment diagnostic transurethral resection (TUR) specimen available (for sequencing), with 2 (5 micron) slides at the start and end of the 10-

20 slides, for a total of 12-22 unstained slides. An FFPE block is also acceptable.

1. Clinical stage T2-T4aN0/xM0 disease
2. Medically appropriate candidate for radical cystectomy as assessed by surgeon
3. No concomitant multifocal carcinoma in situ; a single focus is allowed
4. One focus of muscle-invasive bladder cancer and/or a tumor <5 cm in size
5. No clinical or radiographic evidence for locally advanced or metastatic disease
6. No prior anti-PD-1, anti PD-L1 therapies, or systemic chemotherapy (prior intravesical induction immunotherapy for non-muscle invasive disease is allowed, defined as BCG x6 treatments; BCG refractory disease, defined as disease recurrence within 3 months of BCG therapy, is not allowed)
7. No prior radiation therapy to the bladder
8. No major surgery or radiation therapy <4 weeks of registration
9. This study involves an agent that has known genotoxic, mutagenic and teratogenic effects. For women of childbearing potential only, a negative pregnancy test done ≤ 14 days prior to registration is required.
10. Age ≥ 18 years
11. ECOG Performance Status 0-1
12. Required Initial Laboratory Values: (See Protocol)
13. No hydronephrosis refractory to urinary diversion
14. No evidence of NYHA functional class III or IV heart disease
15. No ongoing cardiac dysrhythmias of NCI CTCAE Version 5.0 grade >2
16. No pre-existing sensory grade >2 neuropathy
17. No pre-existing grade >2 hearing loss
18. No serious intercurrent medical or psychiatric illness, including serious active infection
19. None of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack
20. No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the drugs used in this trial. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy, when indicated.
21. No history of allergic reaction attributed to compounds of similar chemical or biologic composition to the agents used in this study.
22. No concurrent treatment on another clinical trial; supportive care trials or nontherapeutic trials (e.g., quality of life) are allowed.
23. No prior malignancy except for: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years. Patients with localized prostate cancer who are being followed by an active surveillance program are also eligible.

Exclusion Criteria

none