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

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ClinicalTrials.gov Identifier: NCT03317158
Recruitment Status : Recruiting
First Posted : October 23, 2017
Last Update Posted : May 2, 2019
Sponsor:
Collaborators:
AstraZeneca
Hoosier Cancer Research Network
Information provided by (Responsible Party):
Noah Hahn, M.D., Hoosier Cancer Research Network

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Bladder Cancer Drug: Durvalumab Radiation: External Beam Radiotherapy (EBRT) Biological: Bacillus Calmette-Guérin (BCG) Phase 1 Phase 2

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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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 186 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Masking Description: Open-Label
Primary Purpose: Treatment
Official Title: PhAse 1/2 StuDy of Modern ImmunotherApy in BCG-RelaPsing UroThelial Carcinoma of the BLADDER - (ADAPT-BLADDER) HCRN GU16-243
Actual Study Start Date : November 21, 2017
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : September 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer
Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Phase 1: (cohort 1):
Durvalumab monotherapy (cohort 1)
Drug: Durvalumab
Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles.
Other Name: Imfinzi

Experimental: Phase 1: (cohort 2a) & (cohort 2b):

(cohort 2a) - Durvalumab plus BCG

(cohort 2b) - Durvalumab plus External Beam Radiotherapy (EBRT)

Drug: Durvalumab
Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles.
Other Name: Imfinzi

Radiation: External Beam Radiotherapy (EBRT)
EBRT 6 Gy x 3; Cycle 1 Day 1, 3, and 5

Biological: Bacillus Calmette-Guérin (BCG)

Dose level 0 (starting dose) = Full-dose

Dose level-1 = 1/3rd-dose BCG. Dose level -1 is expected to be utilized during the phase II portion of the study due to the ongoing and persistent shortage of BCG in the US.


Experimental: Phase 2: (cohort 2a), (cohort 2b), & (BCG re-treatment)

(cohort 2a) - Durvalumab plus BCG

(cohort 2b) - Durvalumab plus External Beam Radiotherapy (EBRT)

(BCG re-treatment) - Cross-over to Durvalumab Monotherapy

Drug: Durvalumab
Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles.
Other Name: Imfinzi

Radiation: External Beam Radiotherapy (EBRT)
EBRT 6 Gy x 3; Cycle 1 Day 1, 3, and 5

Biological: Bacillus Calmette-Guérin (BCG)

Dose level 0 (starting dose) = Full-dose

Dose level-1 = 1/3rd-dose BCG. Dose level -1 is expected to be utilized during the phase II portion of the study due to the ongoing and persistent shortage of BCG in the US.





Primary Outcome Measures :
  1. Phase 1: Determine the recommended phase 2 dose (RP2D) of immunotherapy doublet combinations [ Time Frame: 6 months ]
    durvalumab plus BCG, durvalumab plus radiation

  2. Phase 2: Determine the 6-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: 6 months ]
    durvalumab plus BCG, durvalumab plus radiation, BCG monotherapy


Secondary Outcome Measures :
  1. 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 ]
    durvalumab monotherapy, durvalumab plus BCG, durvalumab plus radiation

  2. 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 ]
    durvalumab monotherapy, durvalumab plus BCG, durvalumab plus radiation

  3. 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 ]
    durvalumab plus BCG, durvalumab plus radiation, BCG monotherapy

  4. 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 ]
    Determine the relapse-free survival (RFS) rate

  5. 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 ]
    Determine the 6 month relapse-free survival (RFS) rate

  6. 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 ]
    Determine the 24 month relapse-free survival (RFS) rate

  7. 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 ]
    durvalumab plus BCG, durvalumab plus radiation, BCG monotherapy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03317158


Contacts
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Contact: Ahran Lee 317.634.5842 ext 14 alee@hoosiercancer.org
Contact: Noah M. Hahn, MD 443.287.0553 nhahn4@jhmi.edu

Locations
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United States, Arizona
BCG Oncology Recruiting
Phoenix, Arizona, United States, 85032
Contact: Debra Mobley    602-493-6626    Debbi@bcgoncology.com   
Principal Investigator: Donald Lamm, MD         
United States, Indiana
Indiana University Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Nabil Adra, MD    317-948-6942    nadra@iu.edu   
Contact: Yvonne Lafary    317-278-5613    ylafary@iu.edu   
Principal Investigator: Nabil Adra, MD         
Sub-Investigator: Costantine Albany, MD         
Sub-Investigator: Roberto Pili, MD         
Sub-Investigator: Hristos Kaimakliotis, MD         
United States, Iowa
University of Iowa Hospitals and Clinics Recruiting
Iowa City, Iowa, United States, 52242
Contact: Tiffany Kriegel    319-353-4582    tiffany-kriegel@uiowa.edu   
Principal Investigator: Michael A. O'Donnell, MD         
United States, Maryland
Johns Hopkins University: Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21231
Contact: Noah Hahn, M.D.    443-287-0553    nhahn4@jhmi.edu   
Contact: Linnea Smith-Walters    410.502.0017    lsmithw1@jhmi.edu   
United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19111
Contact: Tracy Kradzinski    215-728-1133    Tracy.Kradzinski@fccc.edu   
Principal Investigator: Daniel Geynisman, MD         
Sponsors and Collaborators
Noah Hahn, M.D.
AstraZeneca
Hoosier Cancer Research Network
Investigators
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Study Chair: Noah M. Hahn, MD Hoosier Cancer Research Network

Additional Information:
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Responsible Party: Noah Hahn, M.D., Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT03317158     History of Changes
Other Study ID Numbers: HCRN GU16-243
First Posted: October 23, 2017    Key Record Dates
Last Update Posted: May 2, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Noah Hahn, M.D., Hoosier Cancer Research Network:
non-muscle invasive bladder cancer
BCG
immunotherapy

Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Durvalumab
Antibodies, Monoclonal
BCG Vaccine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic