Modern Immunotherapy in BCG-Unresponsive, BCG-Relapsing and High Risk BCG-Naive Non-Muscle Invasive Urothelial Carcinoma of the Bladder

Inclusion Criteria

• •Subject must meet all of the following applicable criteria to participate in this study:
• •Histologically confirmed non-muscle invasive urothelial carcinoma of the bladder (Ta, T1, or Tis stage) on TURBT obtained within 60 days of registration.
• •NOTE: Mixed histologies are permitted, provided a component of urothelial carcinoma is present. Patients with histologically confirmed non- muscle invasive urothelial carcinoma of the bladder (Ta, T1, or Tis stage) on prior TURBT who undergo re-resection of the tumor base to confirm the diagnosis and/or exclude the presence of muscle-invasive disease (T2 or greater) who do not have appreciable tumor in the re-resection TURBT are eligible to enroll provided their re-resection was obtained within 60 days of registration and they meet all other eligibility criteria.
• •ECOG (WHO) performance status 0 or 1
• •Age ≥ 18 years old at time of consent
• •Adequate hematologic, hepatic, and renal function as defined by the following laboratory parameters:
• •* White blood cell count (WBC) \> 3.0 K/mm3
• •* Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
• •* Platelets ≥ 100 K/mm3
• •* Hemoglobin (Hgb) ≥ 9 g/dL
• •* Serum total bilirubin: ≤ 1.5 x ULN
• •* ALT and AST ≤ 2.5 x ULN
• •* Serum creatinine clearance (CrCl) ≥ 30 mL/min using the modified Cockcroft- Gault equation
• •Subjects who give a written informed consent obtained according to local guidelines
• •BCG-unresponsive disease defined by any of the following:
• •Persistent or recurrent CIS with or without the presence of concurrent Ta or T1 tumors within 12 months of completion of adequate BCG therapy
• •Recurrent high-grade Ta or T1 tumors within 6 months of completion of adequate BCG therapy.
• •NOTE: In recognition of the fact that procedure scheduling factors beyond the control of the patient or treating physician may cause unintended delays in disease evaluations, patients with pure papillary tumors (Ta or T1) with no components of CIS with recurrence documented within 9 months of completion of adequate BCG therapy who meet all other eligibility criteria may be considered for enrollment after consultation with the study chair.
• •Persistent T1 high-grade tumors at the first disease evaluation (e.g. 3- month post-treatment evaluation) following an adequate BCG induction course
• •Prostatic urethra involvement of NMIBC
• •Adequate BCG therapy is defined as at least one of the following:
• •* At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 3 doses of maintenance therapy
• •* At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 6 doses of a second induction course.
• •High-risk NMIBC defined according to modified EORTC risk criteria summarized as follows:
• •* Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by- case basis after consultation with the sponsor-investigator.
• •* Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the sponsor-investigator.
• •Subjects who have received prior therapy with PD-1, PD-L1, or CTLA-4 directed agents.
• •Subjects who have had any prior radiation to the prostate or pelvis.
• •NOTE: The exclusion of patients who have had any prior radiation to the prostate or pelvis applies to both phase 1 and 2 of the trial only within radiation containing study regimens. Patients with a prior history of prostate or pelvic radiation who meet all other eligibility criteria may be considered for phase 1 and phase 2 enrollment to non-radiation containing study regimens after consultation with the study chair.
• •Subjects who have undergone major surgery (e.g. intra-thoracic, intra- abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or subjects who have had minor procedures (i.e. TURBT), percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
• •Subjects with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
• •* Clinically significant cardiac diseases, including any of the following:
• •* History or presence of serious uncontrolled ventricular arrhythmias
• •* Clinically significant resting bradycardia
• •* Any of the following within 3 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)
• •* Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s)
• •* Cirrhosis
• •* Active Infection (includes chronic active and chronic persistent) --- Tuberculosis --- Hepatitis B (known positive HBV surface antigen (HbsAg). 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
• •\--- Hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• •\--- Known diagnosis of human immunodeficiency virus (HIV/positive HIV 1/2 antibodies) infection (HIV testing is not mandatory)
• •* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion:
• •\--- Patients with vitiligo or alopecia
• •\--- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• •\--- Any chronic skin condition that does not require systemic therapy
• •\--- Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• •\--- Patients with celiac disease controlled by diet alone
• •* Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
• •Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
• •* Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• •* Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• •* Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
• •* Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted. For questions, please consult the sponsor-investigator.
• •Pregnant or breast-feeding women. Women of child-bearing potential must have a negative serum test ≤ 14 days prior to starting study drug.
• •Women of child-bearing potential, who are biologically able to conceive, and not employing contraception as described in the protocol.
• •Fertile males not willing to use contraception, as stated in the protocol.
• •Subjects unwilling or unable to comply with the protocol
• •Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
• •NOTE: Patients, if enrolled, should not receive live vaccine whilst receiving study drugs and up to 30 days after the last dose of study drug.
• •Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.