Tetra-modality Bladder Preservation Strategies in Muscle-invasive Bladder Cancer: TURBT+ Chemo/Immunotherapy+ Radiation Therapy+ Maintenance Immunotherapy vs. W&W

Inclusion Criteria:

1. Provision of signed and dated informed consent form (ICF) before any trial related procedures.
2. Male or female participant with ≥ 18 years of age at time of consenting.
3. Participant is able and willing to comply with the requirements of trial protocol.
4. Pathologically (histologically or cytologically) and radiologically confirmed newly diagnosed MIBC (T2-T4 N0 M0) or recurrent previously NMIBC.
5. Histologically confirmed transitional cell carcinoma.
6. Participant with ECOG Performance Status (PS) ≤ 1 at screening visit.
7. An estimated life expectancy of more than 6 months.
8. At screening visit, Left Ventricular Ejection Fraction LVEF \>50% by echocardiography, for participants planned to receive DDMVAC.
9. Participant must have adequate laboratory values at screening visit as follow:

   1. Hematologic:

      * Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L
      * Platelet count ≥ 100 × 10\^9/L
      * Hemoglobin ≥ 9 g/dL (may have been transfused)
   2. Hepatic:

      * Total bilirubin level ≤ 1.5 × ULN
      * AST ≤ 2.5 × ULN
      * ALT ≤ 2.5 × ULN
   3. Renal:

      * Estimated creatinine clearance \> 50 mL/min according to the Cockcroft-Gault formula
      * Serum urea ≤ 1.5 x ULN
      * Serum creatinine ≤ 1.5 x ULN.
10. Female participant of childbearing potential must have a negative serum pregnancy test at screening.
11. For female participant of childbearing potential: use one of the following highly effective contraception methods throughout the trial and for 30 days after the last Avelumab treatment administration.

    * combined (estrogen and progesterone) hormonal contraception associated with inhibition of ovulation: either oral, intravaginal or transdermal
    * progesterone-only hormonal contraception associated with inhibition of ovulation: either oral, injectable or implantable
    * intrauterine device (IUD)
    * intrauterine hormone-releasing system (IUS)
    * bilateral tubal occlusion
    * vasectomised partner (provided that partner is the sole sexual partner of the female trial participant and that the vasectomised partner has received medical assessment of the surgical success)
    * sexual abstinence

Exclusion Criteria:

1. Participant with non-muscle invasive bladder cancer or Metastatic disease (M1) and/or lymph node positive.
2. Participant who underwent radical cystectomy or is planned for radical cystectomy.
3. Histologically confirmed squamous cell carcinoma, micropapillary carcinoma, neuroendocrine carcinoma, adenocarcinoma, or mixed histology.
4. Participant had received treatment for urothelial carcinoma, with any of the following anti-cancer therapies prior the first dose of trial treatment: systemic chemotherapy, targeted small molecule therapy, or radiation therapy.
5. Participant had received prior treatment with any drug or antibody (anti-PD-1, anti-PD- L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody) targeting T-cell co-stimulation or checkpoint pathways.
6. Participant who are not eligible to receive DDMVAC or Cisplatin-Gemzar.
7. History of severe hypersensitivity to Avelumab or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI- CTCAE v5.0 Grade ≥ 3).
8. Participant with hydronephrosis.
9. Active infection requiring systemic therapy within 28 days before the first dose of trial treatment (e.g., urinary tract infection).
10. History of testing positive for the human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
11. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening visit (positive Hepatitis B surface antigen (HBsAg) or HCV RNA if anti-HCV antibody screening test is positive).
12. Participant currently using immunosuppressive medication, except for the following:

    * Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection).
    * Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent.
    * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
13. Active autoimmune diseases that might deteriorate upon receiving an immune- stimulatory agent. Conditions such as vitiligo, psoriasis, diabetes type I, or hypo - or hyper-thyroid diseases not requiring immunosuppressive treatment are eligible.
14. Participant has any of the following medical conditions: Addison's disease, thyroiditis/Hashimoto's thyroiditis, systemic lupus erythematosus, Sjogren's syndrome, scleroderma, myasthenia gravis, Goodpasture's syndrome, and Grave's disease.
15. Any psychiatric condition that would prohibit the understanding or rendering of informed consent form.
16. Hepatic insufficiency manifesting as clinical jaundice, hepatic encephalopathy, and/or variceal bleed within 60 days prior to screening.
17. Clinically significant, active cardiovascular disease, such as:

    * Transmural myocardial infarction within 6 months of enrollment
    * Unstable angina
    * Congestive heart failure (New York Heart Association Classification Grade II or greater)
    * Serious cardiac arrhythmia requiring medical treatment
18. Cerebral vascular accident/ stroke within 6 months of enrollment.
19. End-stage renal disease requiring dialysis.
20. Participant has severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior.
21. Prior organ transplantation including allogenic stem-cell transplantation.
22. Treatment with an investigational agent within 28 days before the first dose of trial treatment.
23. Participation in another clinical trial.
24. Participants who are taking prohibited medication.
25. Pregnant or breastfeeding women or who are planned to get pregnant or breastfeed during the trial.
26. Vaccination within 4 weeks of the first dose of Avelumab is prohibited except for administration of inactivated vaccines.
27. Persisting toxicity related to prior therapy with Grade \> 1 (NCI-CTCAE v 5.0); with the exception of: alopecia, sensory neuropathy Grade ≤ 2, or other toxicity with Grade ≤ 2 not constituting a safety risk based on investigator's judgment.