An Umbrella Study to Determine the Safety and Efficacy of Various Monotherapy or Combination Therapies in Neoadjuvant Urothelial Carcinoma (Optimus)

An Open-Label, Randomized, Phase 2, Umbrella Study to Investigate the Biological Rational of Various Neoadjuvant Therapies for Participants With Muscle-Invasive Urothelial Carcinoma of the Bladder Who Are Cisplatin-Ineligible or Refuse Cisplatin Therapy and Undergoing Radical Cystectomy

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.

Study Overview

• Status: Terminated
• Conditions: Urothelial Carcinoma
• Intervention / Treatment: Drug: retifanlimab; Drug: epacadostat; Drug: INCAGN02385; Drug: INCAGN02390

Detailed Description

Participants will be stratified based on Programmed cell Death-Ligand 1 (PD-L1) Combined Positive Score ( CPS) < 10 and PD-L1 CPS ≥ 10.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75475
    • Hospital Saint Louis
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou (HEGP)
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Italy
  • Bari, Italy, 70124
    • Istituto Tumori Giovanni Paolo II Irccs Ospedale Oncologico Bari
  • Bologna, Italy, 40138
    • L Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi
  • Milan, Italy, 20132
    • Istituto Di Ricovero E Cura A Carattere Scientifico (Irccs) Ospedale San Raffaele
  • Roma, Italy, 00128
    • Universita Campus Bio Medico Di Roma
  • Verona, Italy, 37124
    • Azienda Ospedaliera Universitaria Integrata Verona (Ospedale Borgo Roma)
• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center Division of H
  • Oregon
    • Portland, Oregon, United States, 97239-4501
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Group A; epacadostat will be administered in combination with retifanlimab.	Drug: retifanlimab; retifanlimab will be administered via IV over 30 minutes (+ 15 min) on Day 1 of each 28-day cycle, up to 3 cycles,; Drug: epacadostat; epacadostat will be administered daily twice daily orally up to and including day of surgery.
Experimental: Treatment Group B; retifanlimab will be administered as monotherapy.	Drug: retifanlimab; retifanlimab will be administered via IV over 30 minutes (+ 15 min) on Day 1 of each 28-day cycle, up to 3 cycles,
Experimental: Treatment Group C; epacadostat will be administered as monotherapy.	Drug: epacadostat; epacadostat will be administered daily twice daily orally up to and including day of surgery.
Experimental: Treatment Group D; retifanlimab will be administered in combination with INCAGN02385.	Drug: retifanlimab; retifanlimab will be administered via IV over 30 minutes (+ 15 min) on Day 1 of each 28-day cycle, up to 3 cycles,; Drug: INCAGN02385; INCAGN02385 will be administered via IV over 30 minutes (-5/+10 min) every 2 weeks.
Experimental: Treatment Group E; retifanlimab will be administered in combination with INCAGN02385 and INCAGN02390.	Drug: retifanlimab; retifanlimab will be administered via IV over 30 minutes (+ 15 min) on Day 1 of each 28-day cycle, up to 3 cycles,; Drug: INCAGN02385; INCAGN02385 will be administered via IV over 30 minutes (-5/+10 min) every 2 weeks.; Drug: INCAGN02390; INCAGN02390 will be administered via IV over 30 minutes (-5/+10 min) every 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in CD8+ Lymphocytes Within the Resected Tumor	Fold Change from Baseline in CD8+ lymphocytes = CD8+ Lymphocytes at cystectomy divided by CD8+ lymphocytes at Screening. Translational data in all but the retifanlimab 500 mg Q4W treatment group were limited and insufficient to assess this outcome measure.	up to 69 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)	An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study drug.	up to 159 days
Number of Participants With Any ≥Grade 3 TEAE	An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study drug. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.	up to 159 days
Pathological Complete Response Rate	Pathological complete response rate was defined as the percentage of participants with ypT0N0.	up to 69 days
Major Pathological Response	Major pathological response was defined as the percentage of participants with residual ypT0/1/a/isN0M0.	up to 69 days

Collaborators and Investigators

• Sponsor: Incyte Corporation
• Investigators: Study Director: Diane Hershock, MD, Incyte Corporation

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2022
• Primary Completion (Actual): January 29, 2024
• Study Completion (Actual): January 29, 2024

Study Registration Dates

• First Submitted: October 8, 2020
• First Submitted That Met QC Criteria: October 8, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Estimated): October 30, 2025
• Last Update Submitted That Met QC Criteria: October 15, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: retifanlimab; LAG-3; TIM-3; Muscle-invasive cisplatin-ineligible; urothelial carcinoma of the bladder; radical cystectomy.; epacadostat
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Transitional Cell; epacadostat
• Other Study ID Numbers: INCB 24360-901; 2020-002244-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency

• IPD Sharing Time Frame: Data will be shared after the primary publication or 2 years after the study has ended for market authorized products and indications.
• IPD Sharing Access Criteria: Data from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.incyteclinicaltrials.com website. For approved requests, the researchers will be granted access to anonymized data under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No