Brief Title: Monotherapy or Combination Therapies in Neoadjuvant Urothelial Carcinoma

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Immunologic intratumoral changes

Primary Outcome 1 - Timeframe: up to 3 months

CONDITION

• Urothelial Carcinoma

ELIGIBILITY

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).

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Diane Hershock, MD

Role: Study Director

Affiliation: Incyte Corporation

Overall Contact

Name: Diane Hershock, MD

Phone: 1.855.463.3463, +800 00027423

Email: medinfo@incyte.com, eumedinfo@incyte.com

LOCATION