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 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

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 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.

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 of
the following:

--- Solitary tumor

--- Low-grade

- < 3 cm

- No CIS

- Intermediate-Risk Tumors

--- All tumors not defined in the two adjacent categories (between the category of
low 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 conditions
must be met for this point on Ta low-grade tumors)

• BCG-unresponsive, BCG-relapsing, BCG-persistent, or high-risk BCG-naïve NMIBC
defined 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 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 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-month
post-treatment evaluation) following an adequate BCG induction course

- Prostatic urethra involvement of NMIBC o 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

- BCG-relapsing and/or BCG-persistent NMIBC phase 2 expanded Cohort.
BCG-relapsing and/or BCG-persistent NMIBC is defined by either of the
following:

• BCG-relapsing NMIBC is defined as recurrent high-risk NMIBC after achievement
of a complete response to BCG induction therapy which does not meet any of the
BCG-unresponsive criteria outlined in the protocol.

- BCG-persistent NMIBC is defined as persistent high-risk NMIBC at the first
disease evaluation after initial BCG induction therapy (with no intervening
achievement of complete response) for which a second course of BCG induction
therapy 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 the
protocol.

- 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)

Primary Exclusion Criteria:

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.