Phase 2 Durvalumab (Medi4736) for Bacillus Calmette-Guérin (BCG) Refactory Urothelial Carcinoma in Situ of the Bladder
Condition: Carcinoma in Situ of Bladder; Bladder Cancer
MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Carcinoma in Situ
Intervention: Durvalumab; Cystoscopy with Biopsy
Intervention description: Durvalumab will be given every 4 weeks at 1500 mg/kg IV for total of 12 months/13 doses.; Cystoscopy with biopsy and transurethral resection of the bladder tumor (TURBT) (if indicated) will be performed at baseline, month 3, 6, 9, 12, 18, and 24. The month 6 and 24 cystoscopy will be done in the operating room with mapping biopsy. Rest of the cystoscopic exam with biopsy will be performed in the out-patient office setting and if clinically indicated will be repeated in the operating room. Participants will be off study if any of the biopsies document muscle invasive (T2 or above) urothelial carcinoma. Participants will also be off study if their month 6, 9, 12, 18 biopsies show persistent (month 6) or recurrent CIS or invasive (T1 or above) urothelial carcinoma. Otherwise, participants will remain on study until after the month 24 mapping biopsy.
Intervention MeSH terms: Durvalumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: BCG refractory CIS; Urothelial CIS of bladder; Carcinoma in situ (CIS); Bacillus Calmette-Guérin (BCG); Medi4736; Durvalumab; CIS of the bladder; Bladder cancer; BCG Vaccine; Bladder diseases; Urothelial diseases

Summary:

      The purpose of this study is to test if an experimental drug called Durvalumab (Medi4736)
      given by intravenous (IV) infusion is effective in treating carcinoma in situ (CIS) of the
      bladder that no longer responds to Bacillus Calmette-Guérin (BCG) and to collect information
      on the safety of these drugs and whether they cause any side effects.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must have pathologically confirmed urothelial carcinoma in situ (CIS) of the bladder
             that meet one of the following criteria: 1. Persistence of high-grade CIS at 6 months
             following an adequate course of BCG; OR - 2. Stage/grade progression at 3 months after
             induction BCG; OR - 3. Recurrence of high-grade CIS after achieving a disease-free
             state (i.e., CR) following induction of an adequate course of BCG that occurs < 9
             months after the last exposure to BCG; OR - 4. Persistent CIS noted on the bladder
             biopsies within 3 months of completing at least 2 induction BCG (minimum of five
             weekly instillations). An adequate course of BCG should be defined as at least one
             course of induction (minimum of five weekly instillations) and one maintenance (two of
             three instillations) in a 6 months period, with an exception for any patient with
             grade/stage progression after induction BCG (minimum of five weekly instillations).

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          -  Adequate organ and marrow function.

          -  Written informed consent and any locally required authorization (e.g., HIPAA in the
             USA, EU Data Privacy Directive in the EU) obtained from the subject prior to
             performing any protocol-related procedures, including screening evaluations.

          -  Females must not be pregnant, or breast feeding and must have a negative urine or
             serum pregnancy test within 28 days prior to treatment on day 1. Females of
             childbearing potential who are sexually active with a nonsterilized male partner must
             use a highly effective method of contraception from the time of screening, and must
             agree to continue using such precautions for 90 days after the final dose of
             Durvalumab. They must also refrain from egg cell donation for 90 days after the final
             dose of Durvalumab.

          -  Nonsterilized males who are sexually active with a female partner of childbearing
             potential must use a highly effective method of contraception and refrain from sperm
             donation from Day 1 through 90 days after receipt of the final dose of Durvalumab.

        Exclusion Criteria:

          -  Muscle invasive (T2 or above) urothelial carcinoma or urothelial carcinoma outside the
             bladder.

          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site) or previous enrolment in the present study.

          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.

          -  History of another primary malignancy except for: Malignancy treated with curative
             intent and with no known active disease ≥5 years before the first dose of study drug
             and of low potential risk for recurrence; Adequately treated non-melanoma skin cancer
             or lentigo maligna without evidence of disease; Adequately treated carcinoma in situ
             without evidence of disease e.g., cervical cancer in situ.

          -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
             endocrine therapy, tyrosine kinase inhibitor, biologic therapy, tumor embolization,
             monoclonal antibodies, other investigational agent) ≤ 30 days prior to the first dose
             of study drug and within 6 weeks for nitrosourea, mitomycin C or intravesical
             therapy).

          -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             electrocardiograms (ECGs) using Frediricia's Correction.

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid.

          -  Any unresolved toxicity (CTCAE grade 2 or above) from previous anti-cancer therapy.
             [Potential participants with irreversible toxicity that is not reasonably expected to
             be exacerbated by the investigational product may be included (e.g., hearing loss,
             peripherally neuropathy)].

          -  Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1.

          -  Active or prior documented autoimmune disease within the past 2 years. NOTE: Potential
             participants with vitiligo, Grave's disease, or psoriasis not requiring systemic
             treatment (within the past 2 years) are not excluded.

          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis).

          -  History of primary immunodeficiency.

          -  History of allogeneic organ transplant.

          -  History of pneumonitis.

          -  History of hypersensitivity to durvalumab or any excipient.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
             bleeding diatheses including any participant known to have evidence of acute or
             chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
             illness/social situations that would limit compliance with study requirements or
             compromise the ability of the participant to give written informed consent.

          -  Known history of previous clinical diagnosis of tuberculosis.

          -  History of leptomeningeal carcinomatosis.

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving durvalumab.

          -  Females who are pregnant, breast-feeding or males or females of reproductive potential
             who are not employing an effective method of birth control.

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results.

          -  Uncontrolled seizures.

          -  Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
             of but not limited to surgery, radiation and/or corticosteroids.