an umbrella study to determine the safety and efficacy of various monotherapy or combination therapies in neoadjuvant urothelial carcinoma

Conditions: Urothelial Carcinoma

Summary: this is a multicenter, open-label, randomized, phase 2 umbrella study of various neoadjuvant treatment combinations in participants who have muscle-invasive urothelial carcinoma of the bladder and are cisplatin-ineligible or refusing cisplatin therapy and awaiting radical cystectomy.

participants will be stratified based on programmed cell death-ligand 1 (pd-l1) combined positive score ( cps) \< 10 and pd-l1 cps ≥ 10.

Eligibility criteria:
inclusion criteria: * histologically confirmed transitional cell urothelial carcinoma. participants with mixed histologies are required to have a dominant (ie, 50% at least) transitional cell pattern. * clinical stage t2-t3b, n0, m0 muscle invasive urothelial carcinoma by ct (or mri) (stage ii-iiia per ajcc 2018) * refuse cisplatin therapy (does not apply in france) or are ineligible for cisplatin therapy per modified galsky criteria with exclusion of eastern cooperative oncology group( ecog) ps 2 participants * eligible for radical cystectomy * eastern cooperative oncology group (ecog) performance status( ps) 0 or 1. * pretreatment tumor biopsy must be a tumor block or 20 unstained slides from biopsy of primary tumor containing at least 20% tumor. * willingness to avoid pregnancy or fathering children from screening through 100 days in the us and 190 days in europe after the last dose of study drug exclusion criteria: * participation in any other study in which receipt of an investigational study drug or device occurred within 28 days or 5 half-lives (whichever is longer) before first dose. * previously received systemic therapy for bladder cancer or received prior treatment with checkpoint inhibitor agents (such as anti-pd-1, anti-pd-l1, anti-pd-l2, or anti-ctla-4). * evidence of measurable nodal or metastatic disease. * concurrent anticancer therapy. * has had major surgery within 4 weeks before enrollment (c1d1). * has had known additional malignancy other than muscle-invasive urothelial bladder cancer ( miubc) that is progressing or requires active treatment, along with some protocol exceptions, or history of other malignancy within 2 years of study entry, with some predefined-protocol exceptions. * has active autoimmune disease requiring systemic immunosuppression with corticosteroids (\> 10 mg daily doses of prednisone or equivalent) or immunosuppressive drugs within 2 years of day 1 of study treatment. * participants with laboratory values outside of protocol defined ranges. * active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (\> 10 mg/day of prednisone or equivalent). * has a known active hepatitis b (defined as hbsag and total anti-hbc positive results) or hepatitis c (hcv ab positive result and hcv rna \>llod) or hiv,hbv, hcv or hepatitis virus coinfection. * participants with hiv+ disease along with protocol defined exceptions that don't have undetectable viral load along with other protocol exceptions. * has known carcinomatous meningitis. * active infection requiring systemic antibiotics ≤ 14 days from first dose of study drug. * participants with known or suspected active covid-19 infection. * use of probiotics within 28 days from first dose of study drug. * current use of prohibited medication as per protocol. * has not recovered to ≤ grade 1 from toxic effects of previous therapy and/or complications from previous surgical intervention. * history or presence of an abnormal ecg that, in the investigator's opinion, is clinically meaningful. a screening qtcf interval \> 450 milliseconds is excluded. * history of a gastrointestinal condition (eg, inflammatory bowel disease, crohn's disease, ulcerative colitis) that may affect oral drug absorption. * has received a live vaccine within 30days of planned start of study therapy * participants with impaired cardiac function or clinically significant cardiac disease * prior allogenic tissue/solid organ transplant * evidence of interstitial lung disease or active, noninfectious pneumonitis. * has known hypersensitivity to any of the study drugs, excipients, including mannitol or another monoclonal antibody which cannot be controlled with standard measures (eg, antihistamines and corticosteroids). * any ≥ grade 2 immune-related toxicity while receiving prior immunotherapy. * history of serotonin syndrome after receiving 1 or more serotonergic drugs. * concomitant use of medications that are known to be substrates of cyp1a2, cyp2c8, or cyp2c19 with narrow therapeutic window are prohibited (see section 6.6.3). * patients who are receiving or required to receive medications that are known to be ugt1a9 inhibitors (see section 6.6.3).

Keywords: muscle-invasive cisplatin-ineligible urothelial carcinoma of the bladder radical cystectomy. epacadostat retifanlimab tim-3 lag-3