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

Sponsor

Incyte Corporation (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04586244

Collaborator

(none)

Enrollment

Locations

Arms

30.8

Anticipated Duration (Months)

6.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Urothelial Carcinoma	Drug: retifanlimab Drug: epacadostat Drug: INCAGN02385 Drug: INCAGN02390	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

81 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Masking Description:

Open Label

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 5, 2022

Anticipated Primary Completion Date :

Apr 30, 2024

Anticipated Study Completion Date :

Jul 30, 2024

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

Immunologic intratumoral changes [up to 3 months]
Defined as change from baseline in CD8+ lymphocytes within resected tumor

Secondary Outcome Measures

Number of Treatment Emergent Adverse Events (TEAE) [up to 6 months]
Defined as any adverse event either reported for the first time or worsening of a pre-existing event after first dose of study drug up to 30 days after last dose of study drug.
pathological complete response [up to 3 months]
Defined as percentage of participants with absence of tumor as well as no observed tumor in the nodes post neoadjuvant therapy and pre-surgery.
Major pathological response [up to 3 months]
Defined as absence of tumor cells determined pre- surgery or in-Situ absence of tumor cells in the nodes and no metastases.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Iowa	Iowa City	Iowa	United States	52242
2	University of Cincinnati	Cincinnati	Ohio	United States	45267
3	Ohio State University Medical Center Division of H	Columbus	Ohio	United States	43210
4	Oregon Health & Science University	Portland	Oregon	United States	97239-4501
5	Hospital Saint Louis	Paris Cedex 10		France	75475
6	Hopital Europeen Georges Pompidou (Hegp)	Paris Cedex 15		France	75015
7	Institut Gustave Roussy	Villejuif Cedex		France	94805
8	Istituto Tumori Giovanni Paolo Ii Irccs Ospedale Oncologico Bari	Bari		Italy	70124
9	L AZIENDA OSPEDALIERO-UNIVERSITARIA DI BOLOGNA POLICLINICO S. ORSOLA ï¿½ MALPIGHI	Bologna		Italy	40138
10	Istituto Di Ricovero E Cura A Carattere Scientifico (Irccs) Ospedale San Raffaele	Milano		Italy	20132
11	Universita Campus Bio Medico Di Roma	Roma		Italy	00128
12	Azienda Ospedaliera Universitaria Integrata Verona (Ospedale Borgo Roma)	Verona		Italy	37124