ADAPT-BLADDER: Modern Immunotherpy in BCG-Relapsing Urothelial Carcinoma of the Bladder

Randomization:

Prior to commencing accrual, each study site will be required to self-identify their site as
a site with external beam radiation therapy (EBRT+) or without (EBRT-) the capacity to
provide radiation therapy as specified in the durvalumab + EBRT arm. The radiation therapy
status of each site will remain fixed throughout the course of the trial.

Subjects enrolled in cohort 1 of Phase 1 of the protocol will receive durvalumab monotherapy
with no randomization. For all other study cohorts in both Phase 1 and Phase 2 of the
protocol, subjects registered at self-identified EBRT+ study sites will be randomized 1:1
between all actively accruing study arms while subjects registered at self-identified EBRT-
study sites will be randomized 1:1 between all actively accruing study arms except the
durvalumab + EBRT arm.

Subgroup Enrollment Caps:

Both men and women of all races and ethnic groups are eligible for this trial.

Treatment Plan:

Phase I:

Upon successful screening and registration, enrollment to durvalumab monotherapy (cohort 1)
will begin. If DLT criteria are exceeded with durvalumab monotherapy (cohort 1), the study
will close. Provided the safety of durvalumab monotherapy is established, enrollment to
durvalumab plus BCG (cohort 2a) and durvalumab plus external beam radiation therapy (cohort
2b) will proceed.

Within the durvalumab plus BCG arm (cohort 2a), treatment will begin at full-dose BCG. If the
safety of durvalumab plus full-dose BCG (cohort 2a) is established, enrollment to durvalumab
plus full-dose BCG will continue in Phase 2 of the study. If DLT criteria are exceeded with
durvalumab plus full-dose BCG (cohort 2a), a one level dose reduction of BCG will be
implemented. If DLT criteria are exceeded with durvalumab plus reduced-dose BCG (cohort 2a),
the durvalumab plus reduced-dose BCG arm will not proceed to Phase 2 of the study. Similarly,
if DLT criteria are exceeded within the durvalumab plus EBRT arm (cohort 2b), no radiation
dose reductions are planned and the durvalumab plus EBRT arm will not proceed to Phase 2 of
the study. Due to the prolonged half-life of antibody therapies, no dose adjustments are
planned for durvalumab in any of the study arms.

Durvalumab Monotherapy (cohort 1):

Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles. Infuse over 60 minutes (± 5
minutes).

Durvalumab plus BCG (cohort 2a):

Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles. Infuse over 60 minutes (± 5
minutes).

BCG re-treatment intravesical weekly x 6 doses. BCG maintenance to be administered according
to SWOG 8507 schedule.

Durvalumab plus External Beam Radiotherapy (EBRT) (cohort 2b) Durvalumab 1120 mg
intravenously Day 1 every 21 days x 8 cycles. Infuse over 60 minutes (± 5 minutes).

EBRT 6 Gy x 3; Cycle 1 Day 1, 3, and 5.

Dose limiting toxicity (DLT):

Dose limiting toxicity (DLT) will be examined within each arm within Phase 1 of the study.

Recommended Phase 2 Dose (RP2D):

Each arm examined within Phase 1 will establish the RP2D for use in Phase 2 of the study
according to the following parameters:

- Within the durvalumab monotherapy arm (cohort 1), subjects will be enrolled in a 3+3
design starting at dose level 0 (Table 2). If < 1 out of 3 subjects experience DLT, dose
level 0 will be declared the RP2D for durvalumab monotherapy. If 1 out of 3 subjects
experience DLT, an additional 3 subjects will be enrolled at dose level 0. If < 2 out of
6 subjects experience DLT, dose level 0 will be declared the RP2D for durvalumab
monotherapy. If > 2 out of 6 subjects experience DLT, a RP2D will not be established and
the study will close.

Within the durvalumab plus BCG arm (cohort 2a), subjects will be enrolled in a 6+3+3 design
starting at dose level 0. If < 2 out of 6 subjects experience DLT, an additional 3 subjects
will be enrolled at dose level 0. If < 4 out of 9 subjects experience DLT, an additional 3
subjects will be enrolled. If < 5 out of 12 patients experience DLT, dose level 0 will be
declared the RP2D for durvalumab plus BCG. If > 2 out of 6, > 4 out of 9, or > 5 out of 12
subjects experience DLT, an additional group of durvalumab plus BCG patients will be enrolled
at dose level -1. If < 2 out of 6 subjects experience DLT, an additional 3 subjects will be
enrolled at dose level -1. If < 4 out of 9 subjects experience DLT, an additional 3 subjects
will be enrolled at dose level -1. If < 5 out of 12 patients experience DLT, dose level -1
will be declared the RP2D for durvalumab plus BCG. If > 2 out of 6, > 4 out of 9, or > 5 out
of 12 subjects experience DLT, a RP2D will not be established and the durvalumab plus BCG arm
will not proceed to Phase 2 of the study.

Within the durvalumab plus EBRT arm (cohort 2b), subjects will be enrolled in a 6+3+3 design
starting at dose level 0. If < 2 out of 6 subjects experience DLT, an additional 3 subjects
will be enrolled at dose level 0. If < 4 out of 9 subjects experience DLT, an additional 3
subjects will be enrolled. If < 5 out of 12 patients experience DLT, dose level 0 will be
declared the RP2D for durvalumab plus EBRT. If > 2 out of 6, > 4 out of 9, or > 5 out of 12
subjects experience DLT, a RP2D will not be established and the durvalumab plus EBRT arm will
not proceed to Phase 2 of the study.

Phase 2:

If either of the durvalumab plus BCG (cohort 2a) or the durvalumab plus EBRT (cohort 2b)
establishes a RP2D in Phase 1 of the study, enrollment to Phase 2 of the study will proceed.
Upon successful screening and registration, Phase 2 subjects will be randomized to one of the
treatment arms. Randomization will occur amongst the arms that are open to accrual at the
time of subject registration. With the exception of patients assigned to BCG re-treatment,
treatment of Phase 2 subjects will be administered at the RP2D's established for each regimen
within Phase 1 of the study. Given the established safety profile of BCG therapy, patients
assigned to BCG re-treatment within Phase 2 of the study will be treated with full dose BCG
(dose level 0).

It is anticipated that individual treatment arms will be closed and added during the conduct
of the study as arms complete accrual, individual arm safety data is analyzed, and new arms
are added. Initially, three arms are proposed in Phase 2: durvalumab plus BCG, durvalumab
plus EBRT, and BCG re-treatment. Enrollment to Phase 2 arms will not begin until at least one
arm has successfully completed the Phase 1 safety evaluation and deemed safe to proceed to
the Phase 2 portion of the trial.

Cross-over to Durvalumab Monotherapy Option:

Phase 2 patients assigned initially to BCG re-treatment who are noted to have persistent or
recurrent high grade NMIBC (Tis, Ta, or T1) at any post-treatment study evaluation have
converted their disease status from BCG-relapsing to BCG-unresponsive. Such patients continue
to meet study eligibility criteria, they may cross-over to durvalumab monotherapy treatment.

All Trial Phases:

Cycle Length: A treatment cycle is defined as 21 days in all arms.

Duration of Therapy:

Regardless of the study arm a patient is assigned, study treatment will continue for a
maximum of 24 weeks (8 cycles) from the cycle 1 day 1 date. For patients on BCG-containing
arms, standard of care maintenance BCG treatment according to the SWOG 8507 schedule will
continue for a maximum of 36 months.

Intravesical BCG Administration:

Induction BCG Administration:

In all arms incorporating BCG therapy, induction intravesical BCG will be administered weekly
x 6 doses starting on Cycle 1 Day 1 in the form of 1 freeze-dried/lyophilized vial (TheraCys®
or TICE®) reconstituted in approximately 50 mL normal saline instilled via foley catheter
into an empty bladder and maintained in the bladder for 1-2 hours before voiding. Treatment
will begin at full-dose BCG. A one level dose reduction will be implemented if certain DLT
criteria are met.

Maintenance BCG Administration:

In all arms incorporating BCG therapy, BCG maintenance according to the SWOG 8507 schedule is
considered standard therapy following the initial 6-week study therapy induction portion
(65). All patients on BCG-containing arms that have not relapsed in follow up should receive
maintenance BCG weekly for 3 consecutive weeks given 3, 6, 12, 18, 24, 30, and 36 months
after their initial BCG treatment. On BCG maintenance treatment days, BCG therapy will be
administered in the form of 1 freeze-dried/lyophilized vial (TheraCys® or TICE®)
reconstituted in approximately 50 mL normal saline instilled via foley catheter into an empty
bladder and maintained in the bladder for 1-2 hours before voiding. Any decision to alter,
abbreviate, or modify the standard BCG maintenance schedule is at the treating urologist's
discretion. Any deviations from the standard BCG maintenance schedule will be recorded in the
study database.

External Beam Radiation Therapy Administration:

All subjects receiving durvalumab + EBRT will begin radiation therapy within 56 days
following the TURBT. Radiation therapy will consist of three individual 6 Gy fractions
planned approximately on Days 1, 3, and 5 of Cycle 1 only. To accommodate regional variations
in the proximity and scheduling complexities of multi-disciplinary clinics required for
therapy, radiation therapy may be delivered on Day 1 ± 1 day and Day 3 ± 1 day provided the
Day 1 and Day 3 fractions are separated by 1 day. Similarly, radiation therapy may be
delivered on Day 5 ± 2 days provided the Day 3 and Day 5 fractions are separated by 1 day.
This will give a total dose to the gross bladder of 18 Gy. Simulation and treatment on the
same day is permitted. The overall schema is for small field pelvic irradiation given by 3D
conformal irradiation to the entire bladder and prostatic urethra (in men). No radiation dose
reductions are planned.

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 42 days of registration.

- 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/mm^3

- Absolute neutrophil count (ANC) ≥ 1.5 K/mm^3

- Platelets ≥ 100 K/mm^3

- 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 Cockcroft-Gault equation,
see formula below:

- CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if subject
is female multiply the above by 0.85)

- 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 listed 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:

- Prior treatment with 2 or more adequate courses of BCG (at least 5 of 6 induction
installations and at least 2 of 3 maintenance installations for subjects on
maintenance therapy)

- Persistent T1 high-grade disease at the initial 3-month cystoscopy/TURBT
assessment in subjects who received 5 of 6 inductions BCG installations

- Relapsed NMIBC within 6 months of last exposure to BCG

- Prostatic urethra involvement of NMIBC

Inclusion Criteria (Phase 2 Only):

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

Intermediate or high-risk NMIBC defined according to modified EORTC risk criteria
summarized as follows:

- 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).

- Documented recurrence within 15 months of last exposure to intravesical
therapy.

- Recurrence after 1 prior induction course of intravesical BCG.

Inclusion Criteria (Phase 2 Patients with Persistent or Relapsed NMIBC who Cross-Over to
Durvalumab Only):

- In addition to the inclusion criteria described of all patients listed above, the
following inclusion criteria are also required of patients originally enrolled in
Phase 2 of the study who are noted to have NMIBC in follow up and opt to cross-over to
durvalumab monotherapy.

- Subjects with BCG-unresponsive disease defined by any of the following:

- Prior treatment with 2 or more adequate courses of BCG (at least 5 of 6
induction installations and at least 2 of 3 maintenance installations for
subjects on maintenance therapy).

- Persistent T1 high-grade disease at the initial 3-month cystoscopy/TURBT
assessment in subjects who received 5 of 6 inductions BCG installations.

- Relapsed NMIBC within 6 months of last exposure to BCG

- Prostatic urethra involvement of NMIBC

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 28 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 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 or PD-L1 directed agents.

- Subjects who have had any prior radiation to the prostate or pelvis.

- 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.

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

- Women of child-bearing potential, who are biologically able to conceive, and not
employing two forms of highly effective contraception or abstinence. Highly effective
contraception or abstinence must be used from the time of informed consent, throughout
the trial and up to 180 days after the last dose of durvalumab (e.g. male condom with
spermicidal; diaphragm with spermicide; intra-uterine device). Women of child-bearing
potential are defined as sexually mature women who have not undergone a hysterectomy
or who have not been naturally postmenopausal for at least 12 consecutive months
(i.e., who has had menses any time in the preceding 12 consecutive months). Women will
be considered post-menopausal if they have been amenorrheic for 12 months without an
alternative medical cause. The following age-specific requirements apply:

- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).

- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).

- Fertile males not willing to use contraception or abstinence, as stated above.
Contraception or abstinence must be followed from screening through 180 days after
receipt of the final dose of durvalumab therapy.

- Subjects unwilling or unable to comply with the protocol.

- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.

- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.

Exclusion Criteria (Phase 1 Only):

- In Phase 1 of the study, there are no additional exclusion criteria beyond those
described of all patients in the section listed above.

Exclusion Criteria (Phase 2 Only):

- In addition to the exclusion criteria described of all patients listed above, the
following exclusion criteria apply to patients enrolling to Phase 2 of the study.

- Subjects with BCG-unresponsive disease defined by any of the following:

- Prior treatment with 2 or more adequate courses of BCG (at least 5 of 6 induction
installations and at least 2 of 3 maintenance installations for subjects on
maintenance therapy).

- Persistent T1 high-grade disease at the initial 3-month cystoscopy/TURBT
assessment in subjects who received 5 of 6 inductions BCG installations.

- Relapsed NMIBC within 6 months of last exposure to BCG.

- Prostatic urethra involvement of NMIBC.

- Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) non-invasive
urothelial carcinoma.

Exclusion Criteria (Phase 2 Patients with Persistent or Relapsed NMIBC who Cross-Over to
Durvalumab Only):

- In addition to the exclusion criteria described of all patients listed above, the
following exclusion criteria apply to patients enrolling to the cross-over to
durvalumab portion of the Phase 2 study.

- Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis)
non-invasive urothelial carcinoma.