An Umbrella Study to Determine the Safety and Efficacy of Various Monotherapy or Combination Therapies in Neoadjuvant Urothelial Carcinoma
- Conditions
- Urothelial Carcinoma
- Interventions
- Registration Number
- NCT04586244
- Lead Sponsor
- Incyte Corporation
- 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.
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 30
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment Group A retifanlimab epacadostat will be administered in combination with retifanlimab. Treatment Group A epacadostat epacadostat will be administered in combination with retifanlimab. Treatment Group D retifanlimab retifanlimab will be administered in combination with INCAGN02385. Treatment Group E retifanlimab retifanlimab will be administered in combination with INCAGN02385 and INCAGN02390. Treatment Group D INCAGN02385 retifanlimab will be administered in combination with INCAGN02385. Treatment Group B retifanlimab retifanlimab will be administered as monotherapy. Treatment Group C epacadostat epacadostat will be administered as monotherapy. Treatment Group E INCAGN02385 retifanlimab will be administered in combination with INCAGN02385 and INCAGN02390. Treatment Group E INCAGN02390 retifanlimab will be administered in combination with INCAGN02385 and INCAGN02390.
- Primary Outcome Measures
Name Time Method Change From Baseline in CD8+ Lymphocytes Within the Resected Tumor up to 69 days 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Any Treatment-emergent Adverse Event (TEAE) up to 159 days 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.
Number of Participants With Any ≥Grade 3 TEAE up to 159 days 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.
Pathological Complete Response Rate up to 69 days Pathological complete response rate was defined as the percentage of participants with ypT0N0.
Major Pathological Response up to 69 days Major pathological response was defined as the percentage of participants with residual ypT0/1/a/isN0M0.
Trial Locations
- Locations (12)
Istituto Tumori Giovanni Paolo Ii Irccs Ospedale Oncologico Bari
🇮🇹Bari, Italy
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Institut Gustave Roussy
🇫🇷Villejuif Cedex, France
University of Iowa
🇺🇸Iowa City, Iowa, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Ohio State University Medical Center Division of H
🇺🇸Columbus, Ohio, United States
Hospital Saint Louis
🇫🇷Paris Cedex 10, France
Hopital Europeen Georges Pompidou (Hegp)
🇫🇷Paris Cedex 15, France
Azienda Ospedaliera Universitaria Integrata Verona (Ospedale Borgo Roma)
🇮🇹Verona, Italy
L Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi
🇮🇹Bologna, Italy
Universita Campus Bio Medico Di Roma
🇮🇹Roma, Italy
Istituto Di Ricovero E Cura A Carattere Scientifico (Irccs) Ospedale San Raffaele
🇮🇹Milano, Italy