Durvalumab and Standard Chemotherapy for the Treatment of Lymph Node Positive Bladder Cancer
This is a phase II randomized study of standard of care (SOC) neo-adjuvant cisplatin chemotherapy (NAC) versus NAC plus durvalumab in patients with either clinical or pathologic intra-pelvic node-positive urothelial carcinoma of the bladder. Patients with cTanyN1-3M0 via American Joint Committee on Cancer (AJCC) 8th edition staging30 will be considered tor enrollment in this trial. We plan to enroll 60 patients. Patients will be randomized 2:1 to the intervention arm with durvalumab plus NAC vs SOC NAC. In patients randomized to receive, durvalumab will be continued as maintenance every 4 weeks until either relapse or 1 year, whichever event occurs first. Tissue collection will occur as a biopsy prior to initiation of neo-adjuvant therapy via both transurethral biopsy of bladder and lymph node biopsy. Tissue will again be collected at the time of radical cystectomy or, in patients who are no longer surgical candidates, in the form of biopsy as standard of care. Blood and urine will be collected at baseline, week 2, week 6, week 16, and at the 6 week-post surgery visit for analysis of correlative studies.
• Patients must have histological diagnosis of urothelial carcinoma of the bladder and must meet criteria for stage cTanyN1-3M0 disease via AJCC 8th edition staging criteria30
• Patients must provide tissue by agreeing to transurethethral biopsy of the bladder and the lymph node prior to initiating treatment. If patient is unable or unwilling to undergo biopsy at screening and tissue is available, patient may be eligibile per PI discretion.
• Patients must be ≥18 years of age.
• Patients must have pelvic lymph node amenable for biopsy as assessed by treating MD and interventional radiologist.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Patients must have a life expectancy of at least 12 weeks.
• Patients must have body weight \>30 kg.
• Left ventricular ejection fraction ≥ 50%.
• Adequate organ function as defined below:
‣ Hematological i. Absolute neutrophil count (ANC) ≥ 1,500/mcL. ii. Platelets ≥100,000 / mcL. iii. Hemoglobin ≥9 g/dL
⁃ Renal iv. Creatinine clearance \> 50 ml/min as calculated by the Cockgroft Gault formula as:
‣ 1\. CLCR = {\[(140-age) × weight)\]/(72 x SCR) × 0.85 (if female), where CLCR (creatinine clearance) is measured in mL/min, age is expressed in years, weight in kilograms (kg), and SCR (serum creatinine) in mg/dL.
⁃ Hepatic v. Serum total bilirubin ≤1.5xULN OR Direct bilirubin ≤ULN for subjects with total bilirubin levels \>1.5xULN. vi. AST and ALT ≤2.5xULN OR ≤5xULN for subjects with liver metastases.
⁃ Coagulation vii. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. viii. Activated Partial Thromboplastin Time (aPTT) ≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• Women of child-bearing potential MUST have a negative serum or urine HCG test unless prior tubal ligation (\>/= 1 year before screening), total hysterectomy or menopause (defined as 12 consecutive months of amenorrhea). Patients should not become pregnant or breastfeed while on this study. Sexually active patients must agree to use dual contraception for the duration of study participation and for 90 days after receipt of last drug on active treatment.
• Ability to understand and willingness to sign informed consent from prior to initiation of the study and any study procedures.
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.