Radiation and Durvalumab Immunotherapy As Neoadjuvant Treatment for MIBC

Inclusion Criteria:

1. Patient is willing and able to provide written informed consent
2. Patient is willing and able to comply with the protocol
3. Age ≥ 18 years
4. Body weight >30 kg.
5. Histopathologically confirmed transitional cell carcinoma/urothelial carcinoma (TCC/UC).
6. Patients with mixed transitional/non-transitional cell histologies (adenocarcinoma, squamous cell) or variant transitional histology (eg,micropapillary, plasmacytoid, sarcomatoid, nested variant, lymphoepithelioid,nested variant) are eligible.
7. Patients with pure non-transitional cell variant histologies and/or any componentof small cell histology are not eligible.
8. Clinical stage T2-T4a N0 M0 TCC/UC, as evaluated by CT, MRI and/or PET (per standardlocal imaging practices) within 4 weeks prior to randomization.
9. Fit and planned for cystectomy (according to local guidelines).
10. Ineligible for neoadjuvant cisplatin-based chemotherapy OR patient declines to receiveneoadjuvant cisplatin-based chemotherapy a) Ineligibility for chemotherapy include any of: i) Poor renal function (GFR < 50ml/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 isdocumented by consultation with medical oncologist
11. Deemed by investigator to be medically fit (at the time of enrollment) for:
12. Radiotherapy to pelvis
13. Immunotherapy with durvalumab
14. Radical cystectomy
15. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (blockspreferred) or at least 15 unstained slides, with an associated pathology report
16. ECOG performance status of 0-1
17. Adequate hematologic and end-organ function tests.
18. Hemoglobin ≥9.0 g/dL
19. Absolute neutrophil count ≥1.5×109/L
20. Platelet count ≥100×109/L
21. Serum bilirubin ≤1.5×the upper limit of normal (ULN). i) This will not apply to patients with confirmed Gilbert's syndrome, who will beallowed 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) ormeasured by 24-hour urine collection for determination. In cases where both areperformed, measured 24- hour urine collection will be used to determine eligibility,providing an adequate collection was performed.
22. Must have a life expectancy of at least 12 weeks at enrollment
23. Patients of childbearing / reproductive potential should use highly effective birthcontrol methods, as defined by the investigator, during the study treatment period andfor a period of at least 90 days after the last dose of durvalumab. A highly effectivemethod of birth control (as defined in Section 8.7.2) are those that result in lowfailure rate (i.e. less than 1% per year) when used consistently and correctly.
24. 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 hasexperienced menarche and who has not undergone surgical sterilization (hysterectomy orbilateral oophorectomy or bilateral salpingectomy) and is not postmenopausal.Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in theabsence of other biological or physiological causes. In addition, females under theage of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40mIU/mL to confirm menopause.
25. Females must not be breastfeeding at time of enrollment until at least 90 days afterlast dose of durvalumab
26. Male patients should agree to not donate sperm during the study until at least 90 daysafter the last dose of durvalumab

Exclusion Criteria:

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 immunosuppressiveagents. Patients with a history of allogenic stem cell transplantation are alsoexcluded.
7. Malignancies other than TCC/UC within 5 years prior to Cycle 1, Day 1, with theexception of those with a negligible risk of metastasis or death and treated withexpected curative outcome (such as adequately treated carcinoma in situ of the cervix,basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgicallywith curative intent) or localized prostate cancer treated with curative intent andabsence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatmentnaive).
8. Any history of autoimmune disease or connective tissue disorder including but notlimited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren'ssyndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, glomerulonephritis,or scleroderma. a) The following are exceptions to this criterion: i) Patients with vitiligo oralopecia ii) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable onthyroid replacement iii) Any chronic skin condition that does not require systemictherapy iv) Patients with celiac disease controlled by diet alone may be includedafter consultation the study sponsor and medical monitor v) Patients without activeautoimmune disease in the last 5 years may be included after consultation with thestudy sponsor and medical monitor
9. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis testing inline with local practice), hepatitis B (known positive hepatitis B virus [HBV] surfaceantigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as thepresence 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 polymerasechain reaction is negative for HCV ribonucleic acid (RNA).
10. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria a) Patients with irreversible toxicity not reasonably expected to be exacerbated bytreatment with durvalumab may be included only after discussion with the study sponsor / medical monitor.
11. History of idiopathic pulmonary fibrosis
12. History of active primary immunodeficiency
13. Evidence of significant uncontrolled concomitant disease that could affect compliancewith the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder)
14. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 6 months prior to enrolment,unstable arrhythmias, or unstable angina.
15. Severe infections within 4 weeks prior to enrolment in the study including but notlimited to hospitalization for complications of infection, bacteraemia, or severepneumonia.
16. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need fora major surgical procedure during the course of the study other than for diagnosis.
17. History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins
18. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamsterovary cells or any component of the durvalumab formulation
19. History of any illness or disease that would significant compromise patient ability toreceive radiation or any reason that would preclude a patient from radiation therapyas delivered by this study design
20. Prior systemic treatment for TCC/UC a) Prior local intravesical chemotherapy or immunotherapy (e.g. BCG) is allowed ifcompleted at least 6 weeks prior to initiation of study treatment
21. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer- related conditions (eg, hormonereplacement therapy) is acceptable.
22. Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette Guerin [BCG]), including but not limited to other anti-CTLA-4, anti-PD-1, anti-PD-L1, oranti-PD-L2 antibodies.
23. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and upto 30 days after the last dose of IP.
24. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab. The following are exceptions to this criterion:
25. Intranasal, inhaled, topical steroids, or local steroid injections (eg,intra-articular injection)
26. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent
27. Prior pelvic radiotherapy treatment
28. Treatment with any other investigational agent or participation in another clinicaltrial with therapeutic intent within 28 days prior to enrolment
29. Concurrent enrollment in another clinical study unless it is non- interventional orduring the follow-up period of an interventional study