Radiation and Durvalumab Immunotherapy As Neoadjuvant Treatment for MIBC

Exclusion Criteria

• •6. Clinical stage T2-T4a N0 M0 TCC/UC, as evaluated by CT, MRI and/or PET (per standard local imaging practices) within 4 weeks prior to randomization.
• •7. Fit and planned for cystectomy (according to local guidelines).
• •8. Ineligible for neoadjuvant cisplatin-based chemotherapy OR patient declines to receive neoadjuvant cisplatin-based chemotherapy
• •a) Ineligibility for chemotherapy include any of: i) Poor renal function (GFR \< 50 ml/min) ii) Poor performance status (ECOG PS ≥ 2) iii) Significant (grade ≥2) neuropathy iv) Significant (grade ≥2) hearing loss v) Heart failure (NYHA-class-III/IV) OR b) Declining to receive neoadjuvant cisplatin regimen is documented by consultation with medical oncologist
• •9. Deemed by investigator to be medically fit (at the time of enrollment) for:
• •1. Radiotherapy to pelvis
• •2. Immunotherapy with durvalumab
• •3. Radical cystectomy
• •10. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (blocks preferred) or at least 15 unstained slides, with an associated pathology report
• •11. ECOG performance status of 0-1
• •12. Adequate hematologic and end-organ function tests.
• •1. Hemoglobin ≥9.0 g/dL
• •2. Absolute neutrophil count ≥1.5×109/L
• •3. Platelet count ≥100×109/L
• •4. Serum bilirubin ≤1.5×the upper limit of normal (ULN).
• •i) This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed after discussion with the study sponsor / medical monitor.
• •e) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0×ULN f) CrCl \>40 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or measured by 24-hour urine collection for determination. In cases where both are performed, measured 24- hour urine collection will be used to determine eligibility, providing an adequate collection was performed.
• •13. Must have a life expectancy of at least 12 weeks at enrollment
• •14. Patients of childbearing / reproductive potential should use highly effective birth control methods, as defined by the investigator, during the study treatment period and for a period of at least 90 days after the last dose of durvalumab. A highly effective method of birth control (as defined in Section 8.7.2) are those that result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
• •15. Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test at the time of screening. WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, females under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level \> 40 mIU/mL to confirm menopause.
• •16. Females must not be breastfeeding at time of enrollment until at least 90 days after last dose of durvalumab
• •17. Male patients should agree to not donate sperm during the study until at least 90 days after the last dose of durvalumab
• •1. Evidence of suspected metastatic lymph node(s) (defined as short axis measurement of ≥10 mm as per IV contrast-enhanced CT or MRI scan) and/or PET-CT scan
• •2. Extravesical TCC/UC that invades the pelvic and/or abdominal wall for bladder cancer (T4b)
• •3. Distantly metastatic TCC/UC
• •4. Primary non-bladder (ie, ureter, urethral, or renal pelvis) TCC/UC
• •5. Inoperable tumor(s) with fixation to the pelvic wall on clinical exam
• •6. History of allogeneic organ transplantation that requires use of immunosuppressive agents. Patients with a history of allogenic stem cell transplantation are also excluded.
• •7. Malignancies other than TCC/UC within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA \< 10 ng/mL undergoing active surveillance and treatment naive).
• •8. Any history of autoimmune disease or connective tissue disorder 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, glomerulonephritis, or scleroderma.
• •a) The following are exceptions to this criterion: i) Patients with vitiligo or alopecia ii) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on thyroid replacement iii) Any chronic skin condition that does not require systemic therapy iv) Patients with celiac disease controlled by diet alone may be included after consultation the study sponsor and medical monitor v) Patients without active autoimmune disease in the last 5 years may be included after consultation with the study sponsor and medical monitor
• •9. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B virus \[HBV\] surface antigen \[HBsAg\] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).