An Open-Label, Randomized, Phase 2, Study of Various Therapies for Participants With Muscle-Invasive bladder cancer who are not eligible for Cisplatin or Refuse Cisplatin Therapy and are having bladder removal. (Optimus)

Phase 1

Conditions: Muscle-Invasive Urothelial Carcinoma of the Bladder Who Are Cisplatin-Ineligible or Refuse Cisplatin Therapy and Undergoing Radical Cystectomy
MedDRA version: 20.0Level: LLTClassification code 10064467Term: Urothelial carcinomaSystem Organ Class: 100000004864
MedDRA version: 20.0Level: LLTClassification code 10046714Term: Urothelial carcinoma bladderSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2020-002244-23-FR

Lead Sponsor: Incyte Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 45

Inclusion Criteria

1. Ability to comprehend and willingness to sign a written ICF for the study.
2. Men or women aged 18 years or older.
3. Histologically confirmed transitional cell urothelial carcinoma.
4. Clinical stage T2-T3b, N0, M0 muscle invasive urothelial carcinoma by CT (or MRI) + PET/CT (Stage II-IIIA per AJCC 2018).
a. Concomitant upper tract tumors should be excluded.
5. Ineligible for cisplatin therapy per modified Galsky criteria with exclusion of ECOG PS 2 participants
a. Participants with CTCAE v4 = Grade 2 audiometric hearing loss (Galsky Criteria).
b. Participants with CTCAE v4 = Grade 2 peripheral neuropathy (Galsky Criteria).
c. Creatinine clearance of < 60 mL/min but = 30 mL/min (measured by the
Cockcroft-Gault formula or 24-hour urine).
d. New York Heart Association Class III heart failure.
6. Participants who refuse cisplatin-based therapy.
7. Eligible for radical cystectomy by the following:
a. Fit and planned for radical cystectomy according to local guidelines.
b. Able to receive a minimum of 4 weeks of neoadjuvant treatment on study before date of scheduled radical cystectomy.
c. Willing and able to delay surgery by a maximum of 12 weeks, if necessary.
8. Residual disease after TURBT
9. ECOG PS 0 or 1.
10. Pretreatment tumor biopsy must be a tumor block or 20 unstained slides from biopsy of primary tumor containing at least 20% tumor.
11. Willingness to avoid pregnancy or fathering children based on the criteria below.
a. Male participants with childbearing potential must agree to take appropriate
precautions to avoid fathering children (with at least 99% certainty) from screening through 90 days after the last dose of study drug and must refrain from donating sperm during this period.
b. Women participants with childbearing potential must have a negative serum and/or pregnancy test at screening and before the first dose of study drug on Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) and from donating oocytes from screening through 90 days after last dose of study drug.
c. Women participants without childbearing potential (ie, surgically sterile with a
hysterectomy and/or bilateral oophorectomy OR = 12 months of amenorrhea).
d. Women participants without childbearing potential should refrain from donating oocytes from screening through 90 days after the last dose of study drug.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 23
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 22

Exclusion Criteria

1. 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.
2. 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).
3. Evidence of measurable nodal or metastatic disease.
4. Concurrent anticancer therapy
5. Has had major surgery within 4 weeks before enrollment (C1D1).
6. Has had known additional malignancy other than miUBC that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, or cancers from which the participant has been disease-free for > 1 year, after treatment with curative intent.
7. 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.
8. Participants with laboratory values at screening defined in the protocol
9. Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent).
10. Has known active hepatitis B or C (defined as follows) or HIV, HBV, HCV, or hepatitis D virus coinfection:
a. Active hepatitis B infection is defined by positive HBsAg and positive total anti-HBc results.
b. Active hepatitis C is defined by a positive hepatitis C antibody result and
quantitative HCV RNA results greater than lower limits of detection of the assay.
11. Participants who are known to be HIV-positive, unless all of the following criteria are met:
a. CD4+ count = 300/µL.
b. Undetectable viral load.
c. Receiving antiretroviral therapy that is not a potential risk for a drug-drug interaction with the assigned study drugs.
12. Has known carcinomatous meningitis.
13. Active infection requiring systemic antibiotics = 14 days from first dose of study drug.
14. Participants with known or suspected COVID-19 infection.
15. Use of probiotics within 28 days from first dose of study drug.
16. Current use of prohibited medication
17. Has not recovered to = Grade 1 from toxic effects of previous therapy and/or
complications from previous surgical intervention before starting study therapy.
18. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful.
19. History of a gastrointestinal condition (eg, inflammatory bowel disease, Crohn disease, ulcerative colitis) that may affect oral drug absorption.
20. Has received a live vaccine within 30 days of planned start of study therapy.
21. Participants with impaired cardiac function or clinically significant cardiac disease:
a. New York Heart Association Class III or IV cardiac disease, including preexisting
clinically significant ventricular arrhythmia, congestive heart failure, or
cardiomyopathy
b. Unstable angina pectoris.
c. Acute myocardial infarction = 6 months before study participation.
d. Other clinically significant heart disease (eg, = Grade 3 hypertension).
22. Inability or unlikeliness to comply with the dose schedule and study evaluations, in the opinion of

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine biologic response in participants with muscle-invasive cisplatin-ineligible or those refusing cisplatin therapy, urothelial carcinoma of<br>the bladder.;Secondary Objective: To evaluate the safety and tolerability of each of the treatment groups.<br>To evaluate the preliminary efficacy of each of the treatment groups.;Primary end point(s): For each treatment group, the primary endpoint is the change from baseline in CD8+ lymphocytes within resected tumor.;Timepoint(s) of evaluation of this end point: Safety will be performed throughout the study and the primary end point will be evaluated at the time of radical cystectomy

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Safety and tolerability assessed by monitoring the frequency and severity of AEs, including delay in cystectomy due to AEs<br>•pCR rate, defined as percentage of participants with ypT0N0 in each treatment<br>group.<br>• Major pathological response, defined as residual ypT0/1/a/isN0M0.;Timepoint(s) of evaluation of this end point: Safety will be performed throughout the study and the primary end point will be evaluated at the time of radical cystectomy