Neoadjuvant Immunotherapy With Durvalumab and Tremelimumab for Bladder Cancer Patients Ineligible for Cisplatin (NITIMIB)

This is an interventional treatment trial for Muscle-invasive Bladder Cancer focused on measuring Muscle-invasive Bladder Cancer, Ineligible for Cisplatin-based Chemotherapy, Durvalumab, Tremelimumab Read More

Inclusion Criteria:

• Age ≥ 18 years
• Signed Informed Consent Form
• ECOG performance status of 0 or 1
• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder (T2-T4 and/or N+). Patients with mixed histologies are required to have a dominant transitional cell pattern.
• Measurable disease according to RECIST v1.1 criteria
• Representative fresh tumor specimen; TURB (transurethral resection of bladder ) specimens must contain a muscle invasive component (at least T2)

• Ineligible to receive cisplatin-based neoadjuvant chemotherapy based on at least one of the following criteria:

  • Creatinin clearance less than 60ml/min (24h urine)
  • CTCAE Gr ≥ 2 hearing loss
  • CTCAE Gr ≥ 2 neuropathy
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Body weight >30 kg
• Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior the first study treatment:
• Absolute neutrophil count (ANC) ≥ 1500 cells/µl
• WBC counts > 2500/µl
• Platelet count ≥ 100,000/µl
• Hemoglobin ≥ 9.0 g/dL
• AST, ALT and alkaline phosphatase ≤ 2.5 times the upper limit of normal (ULN)
• Serum bilirubin ≤ 1.5 x ULN
• INR and aPTT ≤ 1.5 x ULN
• Serum creatinine clearance (CrCl) ≥ 40 mL/min using the Cockcroft-Gault equation
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for premenopausal female. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.

Exclusion Criteria:

• Known metastatic disease
• Intravesical chemo- or biological/immune (BCG) therapy within 6 weeks of first treatment dose
• Prio treatment with immune checkpoint blockade therapies like anti-CTLA-4, anti-PD1 and anti-PD-L1 therapeutic antibodies, including durvalumab and tremelimumab
• 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 anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are eligible for this study
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational drug.
• Female patients who are pregnant or breast feeding as well as male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy.
• Known allergy or hypersensitivity to any of the investigational study drugs or any of the study excipients.
• Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
• Uncontrolled intercurrent illness, including but limited to, ongoing infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• 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 prior allogeneic stem cell or solid organ transplantation
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan
• Positive test for HIV
• Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen test at screening) or hepatitis C.
• Active tuberculosis
• Administration of a living, attenuated vaccine within 4 weeks prior to treatment start
• Severe infection within 4 weeks prior to cycle 1, day 1
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior treatment start or anticipated requirement for systemic immunosuppressive medications during the trial. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids, and mineralocorticoids is allowed
• Known allergy or hypersensitivity to any of the study drugs or any of the study excipients.