ADAPT-BLADDER: Modern Immunotherapy in BCG-Relapsing Urothelial Carcinoma of the Bladder
ADAPT-BLADDER: Modern Immunotherapy in BCG-Relapsing Urothelial Carcinoma of the Bladder
A multi-arm multi-stage (MAMS) phase 1/2 study. Phase 1 will be conducted in BCG-unresponsive
 NMIBC patients to establish the safety of durvalumab monotherapy (cohort 1) and durvalumab in
 combination with BCG (cohort 2a) and external beam radiation therapy (EBRT) (cohort 2b).
 Provided safety is demonstrated and recommended phase 2 doses (RP2D) are established in phase
 1, the study will proceed to phase 2 testing. Phase 2 will be conducted in the BCG-relapsing
 or persistent NMIBC population. In phase 2, BCG-relapsing or persistent NMIBC subjects will
 be randomized between treatment arms examining intravesical BCG in combination with novel
 immunotherapy agents (durvalumab), novel immunotherapy in combination with radiation
 (durvalumab + EBRT), or retreatment with intravesical BCG. In addition to providing
 additional safety data on the combination regimens studied, phase 2 will provide preliminary
 efficacy profiles for BCG-relapsing or persistent NMIBC subjects with and without CIS treated
 with each regimen. For regimens demonstrating a tolerable safety profile and encouraging
 clinical activity in this phase 1/2 design, a randomized phase 3 trial of experimental arm
 therapy versus re-treatment with intravesical BCG therapy would be considered.
Patient Assignment in Phase 1

 Prior to commencing accrual, each study site will be required to self-identify their site as
 a site with (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. In phase 1 of the protocol, patients will be assigned to
 study treatment cohorts based on patient slot availability and study site choice of radiation
 therapy arm participation.

 Patient Randomization in Phase 2

 In 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.

 Papillary Subgroup Enrollment Cap

 As described further in the Section 12 enrollment in Phase 2 of patients with papillary only
 (Ta or T1) tumors with no evidence of concurrent CIS within each experimental study arm will
 be capped to ensure adequate representation of patients with CIS for planned efficacy
 analyses.
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:

 -  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 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.

 8. BCG-relapsing NMIBC defined as recurrent intermediate- or high-risk NMIBC
 after achievement of a complete response to initial BCG induction therapy
 which does not meet any of the BCG-unresponsive criteria outlined in section
 3.1.2.

 OR

 BCG-persistent NMIBC defined as persistent intermediate- or 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 section 3.1.2.

 NOTE: Patients who have received additional non-BCG based intravesical therapies (e.g.
 chemotherapy, non-BCG investigational agents) are eligible provided they have received only
 1 prior course of BCG induction therapy and satisfy the above BCG-relapsing or
 BCG-persistent definitions.

 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.