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

Inclusion Criteria (All Patients):

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 followinglaboratory 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

Inclusion Criteria (Phase 1 Only):

In addition to the inclusion criteria required of all patients above, the following inclusion criteria are also required of patients enrolling to Phase 1 of the study.

• BCG-unresponsive disease defined by any of the following:

• Persistent or recurrent CIS with or without the presence of concurrent Ta or T1tumors within 12 months of completion of adequate BCG therapy

• Recurrent high-grade Ta or T1 tumors within 6 months of completion of adequate BCGtherapy.

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- monthpost-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 3doses of maintenance therapy

• At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 6doses of a second induction course.

NOTE: Patients with concurrent non-muscle invasive tumors (CIS, Ta, T1) in the prostatic urethra and/or concurrent non-invasive tumors (CIS, Ta) in the upper urinary tracts (ureter, renal pelvis) are permitted to enroll in Phase 1 of the study. Patients with concurrent T1 tumors in the upper urinary tracts (ureter, renal pelvis) are not eligible to enroll in Phase 1 of the study. Patients who have met the BCG-unresponsive criteria at any time point in their treatment history are permitted to enroll in Phase 1 of the study regardless of the time frame between their most recent BCG treatment administration and study registration dates.

Inclusion Criteria (Phase 2 Only):

In addition to the inclusion criteria required of all patients above, the following inclusion criteria are also required of patients enrolling to Phase 2 of the study.

• High-risk NMIBC defined according to modified EORTC risk criteria summarized as follows:

NOTE: Intermediate- and Low-risk tumors as defined below are not eligible. NOTE: Patients with concurrent non-muscle invasive tumors (CIS, Ta, T1) in the prostatic urethra are permitted to enroll in Phase 2 of the study. At least half of the subjects enrolled to each cohort must have a component of CIS present.

• Low-risk Tumors: Initial or recurrent tumor > 12 months after resection with all ofthe following:

--- Solitary tumor

--- Low-grade

• < 3 cm

• No CIS

• Intermediate-Risk Tumors

--- All tumors not defined in the two adjacent categories (between the category oflow and high risk)

• High-risk Tumors. Any of the following:

• T1 tumor

• High-grade

• CIS

• Multiple and recurrent and large (> 3 cm) Ta low-grade tumors (all conditionsmust be met for this point on Ta low-grade tumors) • BCG-unresponsive, BCG-relapsing, BCG-persistent, or high-risk BCG-naïve NMIBCdefined as follows:

NOTE: Patients enrolling to phase 2 will enroll separately into a maximum of three expanded cohorts defined by the BCG exposure population eligibility criteria defined below (BCG-unresponsive, BCG-relapsing, BCG-persistent, and high-risk BCG-naïve). The three possible cohorts for each regimen expanded to phase 2 enrollment will be: BCG-unresponsive, BCG-relapsing and/or BCG-persistent (combined within a single cohort), and high-risk BCG-naïve. It is not anticipated that all three possible phase 2 expansion cohort populations will be pursued for every regimen entering phase 2 expansion. Questions regarding phase 2 expansion cohort populations and patient eligibility should be directed to the study chair. The individual eligibility for phase 2 expanded cohorts according to BCG exposure history are summarized below.

o BCG-unresponsive NMIBC phase 2 expanded cohort. BCG-unresponsive NMIBC is defined by any of the following:

• Persistent or recurrent CIS with or without the presence of concurrent Ta or T1tumors within 12 months of completion of adequate BCG therapy

• Recurrent high-grade Ta or T1 tumors within 6 months of completion of adequate BCGtherapy.

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 high-grade 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-monthpost-treatment evaluation) following an adequate BCG induction course

• Prostatic urethra involvement of NMIBC o Adequate BCG therapy is defined as at leastone of the following:

• At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 3 dosesof maintenance therapy

• At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 6 dosesof a second induction course

• BCG-relapsing and/or BCG-persistent NMIBC phase 2 expanded Cohort.BCG-relapsing and/or BCG-persistent NMIBC is defined by either of thefollowing: • BCG-relapsing NMIBC is defined as recurrent high-risk NMIBC after achievementof a complete response to BCG induction therapy which does not meet any of theBCG-unresponsive criteria outlined in the protocol.

• BCG-persistent NMIBC is defined as persistent high-risk NMIBC at the firstdisease evaluation after initial BCG induction therapy (with no interveningachievement of complete response) for which a second course of BCG inductiontherapy is considered a standard of care (e.g. CIS or high grade Ta tumors)which does not meet any of the BCG-unresponsive criteria outlined in theprotocol.

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

Primary Exclusion Criteria:

Exclusion Criteria (All Patients):

• Subjects with muscle-invasive (i.e. T2, T3, T4) locally advanced unresectable, ormetastatic urothelial carcinoma as assessed on baseline radiographic imagingobtained within 60 days prior to study registration. The required radiographicimaging includes:

• Abdomen/Pelvis - CT scan

• Chest - chest x-ray or CT scan

• Subjects with another active second malignancy other than non-melanoma skin cancersand biochemical relapsed prostate cancer. Subjects that have completed all necessarytherapy and are considered to be at less than 30% risk of relapse are not consideredto have an active second malignancy and are eligible for enrollment.

• Subjects who have received the last administration of an anti-cancer therapyincluding chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior tostarting study drug, or who have not recovered from the side effects of suchtherapy.

• Any unresolved toxicity NCI CTCAE v4.03 for Cohorts 1-3 and v5.0 for cohorts 4-6Grade ≥ 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 basisafter consultation with the sponsor-investigator.

• Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab may be included only after consultation with thesponsor-investigator.

• Subjects who have received prior therapy with PD-1, PD-L1, or CTLA-4 directedagents.

• 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 orintra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior tostarting study drug, or subjects who have had minor procedures (i.e. TURBT),percutaneous biopsies or placement of vascular access device ≤ 1 week prior tostarting study drug, or who have not recovered from side effects of such procedureor injury

• Subjects with any of the following concurrent severe and/or uncontrolled medicalconditions 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 BypassGraft (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 mmHg, 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 ofhepatitis B core antibody [anti-HBc] and absence of HbsAg) are eligible --- Hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligibleonly if polymerase chain reaction is negative for HCV RNA. --- Known diagnosis of human immunodeficiency virus (HIV/positive HIV 1/2antibodies) infection (HIV testing is not mandatory)

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory 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.]). Thefollowing are exceptions to this criterion: --- Patients with vitiligo or alopecia --- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement --- Any chronic skin condition that does not require systemic therapy --- Patients without active disease in the last 5 years may be included butonly 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 causeunacceptable safety risks or compromise compliance with the protocol

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

• Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatmentof osteoarthritis and uric acid synthesis inhibitors for the treatment of goutare permitted. For questions, please consult the sponsor-investigator.

• Pregnant or breast-feeding women. Women of child-bearing potential must have anegative serum test ≤ 14 days prior to starting study drug.

• Women of child-bearing potential, who are biologically able to conceive, and notemploying 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.