High-risk BCG-naive NMIBC cohort. High-risk BCG-naive NMIBC is defined as high-risk NMIBC in a patient that has never received intravesical BCG therapy. NOTE: Patients who satisfy the above definition of BCG-unresponsive NMIBC continue to be considered BCG-unresponsive regardless of the receipt of any intervening or additional non-BCG based intravesical therapies (e.g. chemotherapy, non-BCG investigational agents)

Exclusion Criteria (All Patients):

    Subjects with muscle-invasive (i.e. T2, T3, T4) locally advanced unresectable, or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 60 days prior to study registration. The required radiographic imaging includes:
        Abdomen/Pelvis - CT scan
        Chest - chest x-ray or CT scan
    Subjects with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer. Subjects that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment.
    Subjects who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.

    Any unresolved toxicity NCI CTCAE v4.03 for Cohorts 1-3 and v5.0 for cohorts 4-6 Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
        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.

3.2.2 Exclusion Criteria (Cohorts 4 and 5 Only)

• Subjects who have received prior intravesical therapy with BOTH gemcitabine and docetaxel

NOTE: Patients who have received either intravesical gemcitabine or intravesical docetaxel (or other taxanes) but not both remain eligible. For example, patients receiving post-TURBT single dose intravesical gemcitabine administration are eligible. Similarly, patients treated with intravesical gemcitabine induction and/or maintenance are eligible. While we typically do not see patients treated with intravesical docetaxel (or other taxanes) monotherapy, if such a patient were identified and screened, they would be eligible. Patients who have received treatment with separate courses of intravesical gemcitabine monotherapy and intravesical docetaxel (or other taxanes) monotherapy are not eligible, unless such therapies occurred more than 24 months ago.

Exclusion Criteria (Phase 1 Only) In Phase 1 of the study, there are no additional exclusion criteria beyond those described of all patients above.

Exclusion Criteria (Phase 2 Only) In addition to the exclusion criteria described of all patients above, the following exclusion criteria apply to patients enrolling to Phase 2 of the study.

• Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) high-grade urothelial carcinoma. NOTE: Subjects with concurrent low-grade non-invasive (Ta) upper urinary tract urothelial carcinoma are eligible. Similarly, patients with a history of high-grade upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.