Clinical trial NCT04586244: An Umbrella Study to Determine the Safety and Efficacy of Various Monotherapy or Combination Therapies in Neoadjuvant Urothelial Carcinoma
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Urothelial Carcinoma
Keywords: Muscle-invasive cisplatin-ineligible
urothelial carcinoma of the bladder
radical cystectomy.
epacadostat
retifanlimab
TIM-3
LAG-3
Lead sponsor: Incyte Corporation
Sponsor class: INDUSTRY
First posted: 2020-10-14
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: Change From Baseline in CD8+ Lymphocytes Within the Resected Tumor
timeFrame: up to 69 days
Secondary outcomes:
measure: Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
timeFrame: up to 159 days
measure: Number of Participants With Any ≥Grade 3 TEAE
timeFrame: up to 159 days
measure: Pathological Complete Response Rate
timeFrame: up to 69 days
measure: Major Pathological Response
timeFrame: up to 69 days
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center Division of H
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Paris Cedex 10
country: France
facility: Hospital Saint Louis
city: Paris Cedex 15
country: France
facility: Hopital Europeen Georges Pompidou (Hegp)
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy
city: Bari
country: Italy
facility: Istituto Tumori Giovanni Paolo Ii Irccs Ospedale Oncologico Bari
city: Bologna
country: Italy
facility: L Azienda Ospedaliero-Universitaria Di Bologna Policlinico S. Orsola - Malpighi
city: Milano
country: Italy
facility: Istituto Di Ricovero E Cura A Carattere Scientifico (Irccs) Ospedale San Raffaele
city: Roma
country: Italy
facility: Universita Campus Bio Medico Di Roma
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona (Ospedale Borgo Roma)
Study officials:
affiliation: Incyte Corporation
name: Diane Hershock, MD
role: STUDY_DIRECTOR
References: