Trimodal Therapy Plus Atezolizumab in Muscle-invasive Bladder Cancer

Inclusion criteria

* 18 years old or older
* Histologic diagnosis of urothelial carcinoma of the bladder. Focal differentiation allowed other than small cell histology.
* Stage T2-T4a N0M0 (AJCC-TNM version 6) based on trans-urethral resection of bladder tumor (TURBT), CT imaging, +/- bimanual examination under anaesthesia (EUA).
* CT scan of chest/abdomen/pelvis within 8 weeks from the start of treatments, showing no evidence of metastatic disease.
* Attempt of complete TURBT within 56 days (8 weeks) prior to the start of chemoradiation. If TURBT was performed \> 8 weeks ago but a recent cystoscopy show no residual disease, then a repeat TURBT is not necessary.
* Life Expectancy greater than 6 months
* ECOG performance status of 2 or better
* Another primary cancer is allowed only if treated with curative intent at least 3 years prior to enrollment without evidence of recurrence or if the untreated cancer is clinical indolent (eg lower risk prostate cancer).
* Adequate hematologic reserve: Platelet count ≥ 150,000/ul, WBC ≥ 4000/ul. Anemia will be corrected to minimum hemoglobin of 100 g/L with red cell transfusions, if necessary.
* Adequate liver function with a bilirubin ≤ 1.5 ULN\[27\] and SGOT/SGPT \< 1.5 X the upper normal limit
* Patients must be considered able to tolerate systemic chemosensitizer combined with pelvic IMRT by the joint agreement of the participating radiation oncologist and medical oncologist.
* Able and willing to give written informed consent.

Exclusion criteria

* Prior systemic therapy for other urothelial tumors. Neoadjuvant chemotherapy can be considered a component of the trimodal therapy and is allowed. Superficial bladder treatments including BCG and mitomycin C are permitted if completed 6 weeks prior to therapy.
* Hypersensitive to Gemcitabine or to any ingredient in the formulation or component of the container.
* Prior RT to the pelvis
* Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug, whichever is longer, prior to enrollment
* Malignancies other than urothelial cancer within 5 years prior to Cycle 1, Day 1:

Patients with localized lower risk prostate cancer (defined as Stage ≤T2b, Gleason score ≤ 7, and PSA at prostate cancer diagnosis ≤ 20 ng/mL\[if measured\]) treated with radical prostatectomy and without prostate-specific antigen (PSA) recurrence are eligible.

Patients with lower risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 7 and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.

Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of metastasis or death \<5% at 5 years) are eligible provided they meet all of the following criteria:

Malignancy treated with expected curative intent (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated surgically with curative intent) No evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers

* Pre-existing medical conditions precluding treatment (e.g. previous history of immune-related adverse reactions, pneumonitis, colitis, etc.)
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
* History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.
* Active tuberculosis
* Pregnancy or lactating mothers. Women of childbearing age must use contraception during treatment and for 5 months after the last dose of Atezolizumab. Acceptable methods are: oral contraceptives, hormonal implants, hormonal patches, IDU, Diaphragm with spermicides, cervical cape with spermicide, and condom with spermicide.
* Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor \[TNFR\] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
* Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
* Active autoimmune disease that has required systemic treatment in past 2 years
* Received or will receive a live vaccine within 4 weeks prior to first dose of study drug. Influenza vaccination should be given during influenza season only (approximately October through May in the Northern Hemisphere and approximately April through September in the Southern Hemisphere). Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to randomization, during treatment or within 5 months following the last dose of atezolizumab (for patients randomized to atezolizumab)
* History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
* Serum albumin \< 2.5 g/dL
* Active infection requiring IV systemic therapy
* Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
* Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction \< 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
* Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
* Prior allogeneic stem cell or solid organ transplant
* Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
* Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
* Patients with active Hepatitis B virus (HBV) or Hepatitis C virus (HCV)
* Not willing or unable to sign a consent form