Clinical Trials /

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

NCT03317158

Description:

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 NMIBC population. In phase 2, BCG-relapsing 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 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.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ADAPT-BLADDER: Modern Immunotherapy in BCG-Relapsing Urothelial Carcinoma of the Bladder
  • Official Title: PhAse 1/2 StuDy of Modern ImmunotherApy in BCG-RelaPsing UroThelial Carcinoma of the BLADDER - (ADAPT-BLADDER) HCRN GU16-243

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU16-243
  • NCT ID: NCT03317158

Conditions

  • Urothelial Carcinoma
  • Bladder Cancer

Interventions

DrugSynonymsArms
DurvalumabImfinziPhase 1: (cohort 1):
Bacillus Calmette-Guérin (BCG)Phase 1: (cohort 2a) & (cohort 2b):

Purpose

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 NMIBC population. In phase 2, BCG-relapsing 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 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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1: (cohort 1):ExperimentalDurvalumab monotherapy (cohort 1)
  • Durvalumab
Phase 1: (cohort 2a) & (cohort 2b):Experimental(cohort 2a) - Durvalumab plus BCG (cohort 2b) - Durvalumab plus External Beam Radiotherapy (EBRT)
  • Durvalumab
  • Bacillus Calmette-Guérin (BCG)
Phase 2: (cohort 2a), (cohort 2b), & (BCG re-treatment)Experimental(cohort 2a) - Durvalumab plus BCG (cohort 2b) - Durvalumab plus External Beam Radiotherapy (EBRT) (BCG re-treatment) - Cross-over to Durvalumab Monotherapy
  • Durvalumab
  • Bacillus Calmette-Guérin (BCG)

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Determine the recommended phase 2 dose (RP2D) of immunotherapy doublet combinations
Time Frame:6 months
Safety Issue:
Description:durvalumab plus BCG, durvalumab plus radiation

Secondary Outcome Measures

Measure:Phase 1: Characterize the 6-month relapse-free survival (RFS) rate of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) subjects treated with immunotherapy monotherapy or doublet combinations
Time Frame:6 months
Safety Issue:
Description:durvalumab monotherapy, durvalumab plus BCG, durvalumab plus radiation
Measure:Assess the safety profile of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) subjects treated with immunotherapy monotherapy or doublet combinations by reporting the highest grade adverse event per patient, as assessed by CTCAE v4.0.
Time Frame:up to 24 months
Safety Issue:
Description:durvalumab monotherapy, durvalumab plus BCG, durvalumab plus radiation
Measure:Phase 2: Determine the 24-month relapse-free survival (RFS) rates of BCG-relapsing non-muscle invasive bladder cancer (NMIBC) subjects treated with immunotherapy doublet combinations or BCG re-treatment
Time Frame:up to 24 months
Safety Issue:
Description:durvalumab plus BCG, durvalumab plus radiation, BCG monotherapy
Measure:Phase 2: Identify significant associations between 6- and 24-month RFS rates and baseline tumor immunohistochemistry staining patterns of PD-L1 and other relevant mechanism of action targets for each drug studied within each study arm.
Time Frame:up to 24 months
Safety Issue:
Description:Determine the relapse-free survival (RFS) rate
Measure:Phase 2: Determine the 6-month relapse-free survival (RFS) rate of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) subjects treated with durvalumab
Time Frame:6 months
Safety Issue:
Description:Determine the 6 month relapse-free survival (RFS) rate
Measure:Phase 2: Determine the 24-month relapse-free survival (RFS) rate of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) subjects treated with durvalumab.
Time Frame:up to 24 months
Safety Issue:
Description:Determine the 24 month relapse-free survival (RFS) rate
Measure:Assess the safety profile of BCG-relapsing non-muscle invasive bladder cancer subjects treated with immunotherapy monotherapy, doublet combinations or BCG re-treatment by reporting the highest grade adverse event per patient as assessed by CTCAE v4.0.
Time Frame:up to 24 months
Safety Issue:
Description:durvalumab plus BCG, durvalumab plus radiation, BCG monotherapy

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Noah Hahn, M.D.

Trial Keywords

  • non-muscle invasive bladder cancer
  • BCG
  • immunotherapy

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