Durvalumab and Vicineum in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)
Condition: Urinary Bladder Neoplasms
MeSH terms: Urinary Bladder Neoplasms; Non-Muscle Invasive Bladder Neoplasms
Intervention: Durvalumab; Vicineum; Acetaminophen; Antihistamine; Bladder Biopsy; TURBT; Cystoscopy; Urine cytology; Electrocardiogram; CT; MRI
Intervention description: Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that, participant is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.; Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.; Acetaminophen or equivalent medications per institutional standard may be administered at the discretion of the investigator.; Antihistamine (e.g., diphenhydramine) or equivalent medications per institutional standard may be administered at the discretion of the investigator.; Bladder biopsy at screening and every 3 months before each cystoscopy per schema.; Transurethral resection of a bladder tumor (TURBT) at screening and every 3 months before each cystoscopy per schema.; Urine cytology at screening and every 3 months before each cystoscopy per schema.; Urine cytology at baseline and every 3 months before each cystoscopy per schema.; Electrocardiogram (ECG) at screening, pre-durvalumb infusion and as clinically indicated during the trial.; Computed tomography (CT) at screening and every 12 months while on study.; Magnetic resonance imaging (MRI) at screening and every 12 months while on study.
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Durvalumab; Histamine H1 Antagonists; Histamine Antagonists
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Carcinoma-in-situ; High-grade Ta or T1 disease; Papillary Tumors

Summary:

      Background:

      Non-muscle-invasive bladder cancer is in the early stages. But it usually comes back after
      treatment. The drugs Vicineum and Durvalumab may help the immune system find and destroy
      cancer cells.

      Objective:

      To test if the drugs Durvalumab and Vicineum together are safe and effective to treat people
      with bladder cancer that has not spread to the muscle in the bladder.

      Eligibility:

      People ages 18 and older who have bladder cancer that has not spread to the muscle in the
      bladder and was treated unsuccessfully with Bacillus Calmette-Guerin

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Blood and urine tests

      Tumor sample from previous surgery. If one is not available, they will have a biopsy: A small
      piece of tumor is removed.

      Cystoscopy to examine the inside of the bladder. This may include a biopsy or removing
      tumors.

      Computed tomography (CT) or magnetic resonance imaging (MRI): They lie in a machine that
      takes pictures of the body.

      Electrocardiogram to test heart function

      Participants will receive Durvalumab and Vicineum in 2 phases:

      First phase: Durvalumab every 4 weeks and Vicineum once a week for 3 months

      Second phase: Durvalumab every 4 weeks and Vicineum once every other week

      Participants will have tumor samples taken every 3 months. They will have blood and urine
      tests throughout the study.

      Participants will continue treatment for up to 2 years.

      Participants will have a visit about 30 days after their last treatment. This includes blood
      and urine tests. It may include a cytoscopy or additional biopsies.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed by National Cancer
             Institute (NCI) Laboratory of Pathology as high-grade non-muscle invasive urothelial
             (transitional cell carcinoma) of the bladder as follows:

               -  Carcinoma-in-situ (CIS) with or without papillary tumors

               -  High-grade Ta or T1 disease based on a biopsy/transurethral resection of bladder
                  tumor (TURBT) performed within 12 weeks of the initial dose of study treatment.
                  If multiple bladder biopsies/TURBTs are required to confirm eligibility, the
                  timing of the last bladder biopsy to the initial dose of study treatment must be
                  within 12 weeks.

               -  Patients with persistent T1 high grade disease on TURBT following a single
                  induction course of BCG (Bacillus Calmette-Guerin) (at least 5 of 6 doses) may
                  also be eligible for this trial provided that the patient is surgically unfit for
                  cystectomy as deemed by the investigator or the patient declines cystectomy.

          -  Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology
             and the Food and Drug Administration (FDA): Subjects must have received at least two
             courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of
             3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat
             induction course). Please note exception above for persistent T1 disease. There is no
             upper limit on the amount of prior BCG a subject may have received.

          -  Patients who have met eligibility criterion above must have received last BCG dose
             within a year of enrollment.

          -  The investigator must document that he/she believes the subject would not benefit from
             additional BCG treatment at the time of study entry.

          -  Age >= 18 years at time of signing the informed consent form (ICF). Because no dosing
             or adverse event data are currently available on the use of Vicineum in combination
             with durvalumab in patients <18 years of age, children are excluded from this study,
             but will be eligible for future pediatric trials. Furthermore, non-muscle invasive
             bladder cancer (NMIBC) does not occur in children.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

          -  Adequate organ and marrow function as defined below:

               -  Hemoglobin >= 9.0 g/dL

               -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3)

               -  Platelet count >= 75 x 10^9/L (>75,000 per mm^3)

               -  Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal
                  (ULN).

               -  Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase
                  (SGOT)/alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase
                  (SGPT) less than or equal to 2.5 x institutional ULN

               -  Creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)
                  or by 24-hour urine collection for determination of creatinine clearance:

                    -  Males: Creatinine CL (mL/min) = (Weight (kg) x (140 - Age))/72 x serum
                       creatinine (mg/dL)

                    -  Females: Creatinine CL (mL/min) = (Weight (kg) x (140 - Age) x 0.85)/72 x
                       serum creatinine (mg/dL)

          -  Female subjects must either be of non-reproductive potential (i.e., post-menopausal as
             described below) OR history of surgical sterilization (hysterectomy, bilateral tubal
             ligation, or bilateral oophorectomy) or must have a negative serum pregnancy test upon
             study entry.

               -  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

               -  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, or had
                  chemotherapy-induced menopause with last menses >1 year ago

          -  The effects of Vicineum and durvalumab on the developing human fetus are unknown. For
             this reason, all sexually active subjects agree to use barrier contraception (i.e.,
             condoms) while receiving study treatment and for 120 days following their last dose of
             study treatment. Female subjects of child-bearing potential and male subjects whose
             sexual partners are women of childbearing potential (WOCBP) agree to use barrier
             contraception and a second form of contraception while receiving study treatment and
             for 4 months following their last dose of study treatment. Should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately.

          -  Written informed consent obtained from the subject prior to performing any protocol-
             related procedures

          -  Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

          -  Body weight > 30 kg

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  QT interval corrected for heart rate using Fridericia's formula the corrected QT
             interval by Fridericia (QTcF) >=470 ms. (Any clinically significant abnormalities
             detected require triplicate ECG results and a mean QT interval corrected for heart
             rate using Fridericia's formula (QTcF) >=470 ms calculated from 3 ECGs.)

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to Vicineum or durvalumab or other agents used in the study.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements. Urinary tract infections (UTIs) are excluded from being an
             exclusion criterion for treatment unless they are grade 3 or higher.

          -  Pregnant women are excluded from this study because it is unknown whether Vicineum
             and/or durvalumab have any teratogenic effects. In nursing mothers, breastfeeding
             should be discontinued as these medications may have the potential risk for adverse
             events in nursing infants secondary to treatment of the mother.

          -  Any previous treatment with a programmed cell death 1 (PD-1) or programmed
             death-ligand 1 (PD-L1) inhibitor, including durvalumab

          -  Evidence of non-bladder urothelial (transitional cell) carcinoma by biopsy, cytology,
             or radiological imaging within the past 2 years of treatment (e.g., upper tract
             transitional cell carcinoma, urethral urothelial carcinoma).

          -  Subjects with hydronephrosis, except for those subjects where hydronephrosis has been
             longstanding (i.e., predates the diagnosis of the CIS (carcinoma in situ), Ta, or T1
             by more than 2 years) and diagnostic evaluation at screening shows no evidence of
             tumor causing the hydronephrosis.

          -  Any other anticancer therapy (e.g., chemotherapy, biologic therapy, immunotherapy,
             targeted therapy, endocrine therapy, radiation therapy, intravesical therapy,
             investigational agent) within 28 days of the first dose of study therapy (and within 6
             weeks for nitrosourea or mitomycin C) other than a single dose of intravesical
             chemotherapy which is permitted between 28 days and 14 days prior to the first dose of
             study treatment.

          -  The subject has a diagnosis of another malignancy within 2 years before the first dose
             of study treatment, except for superficial skin cancer, localized prostate cancer on
             active surveillance, or localized solid tumors deemed cured by surgery and not treated
             with systemic anticancer therapy and not expected to require anticancer therapy in the
             next 2 years i.e., while the subject may be taking study treatment.

          -  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.

          -  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, Grave's disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
             criterion:

               -  Subjects with vitiligo or alopecia

               -  Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormonal replacement

               -  Any chronic skin condition that does not require systemic therapy

               -  Subjects without active disease in the last 5 years may be included but only
                  after consultation with the Principal Investigator

               -  Subjects with celiac disease controlled by diet alone

          -  History of primary immunodeficiency.

          -  History of allogeneic organ transplant.

          -  History of hypersensitivity to durvalumab or any excipient

          -  History of hypersensitivity to Vicineum or its components

          -  Active infection with tuberculosis (clinical evaluation that includes clinical
             history, physical examination, and radiographic findings, and purified protein
             derivative (PPD) testing if indicated), hepatitis B (known positive HBV surface
             antigen (HBsAg) result, hepatitis C, or human immunodeficiency virus (positive HIV 1/2
             antibodies). Patients with HIV are excluded from participating on this clinical trial
             because their immunodeficiency would confound the evaluation of adverse events which
             would hinder meeting the primary objective. Subjects with a past or resolved HBV
             infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
             of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible
             only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).

          -  History of leptomeningeal carcinomatosis

          -  Receipt of live attenuated vaccination within 30 days prior to the first dose of
             Vicineum or durvalumab

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

          -  Subjects with uncontrolled seizures

          -  Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria
             for Adverse Events (CTCAE) Grade >=2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria

               -  Subjects with Grade >=2 neuropathy will be evaluated on a case-by-case basis
                  after consultation with the Principal Investigator.

               -  Subjects with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab may be included only after consultation with the
                  Principal Investigator.