Clinical Trials /

Durvalumab and Vicinium in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)

NCT03258593

Description:

Background: Non-muscle-invasive bladder cancer is in the early stages. But it usually comes back after treatment. The drugs Vicinium and Durvalumab may help the immune system find and destroy cancer cells. Objective: To test if the drugs Durvalumab and Vicinium 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. CT or MRI: They lie in a machine that takes pictures of the body. Electrocardiogram to test heart function Participants will receive Durvalumab and Vicinium in 2 phases: First phase: Durvalumab every 4 weeks and Vicinium once a week for 3 months Second phase: Durvalumab every 4 weeks and Vicinium 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.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab and Vicinium in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)
  • Official Title: A Phase I Single-Arm Study of the Combination of Durvalumab (MEDI4736) and Vicinium (Oportuzumab Monatox, VB4-845) in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With BCG

Clinical Trial IDs

  • ORG STUDY ID: 170157
  • SECONDARY ID: 17-C-0157
  • NCT ID: NCT03258593

Conditions

  • Urinary Bladder Neoplasms

Interventions

DrugSynonymsArms
Durvalumab1/Run In
Vicinium1/Run In

Purpose

Background: Non-muscle-invasive bladder cancer is in the early stages. But it usually comes back after treatment. The drugs Vicinium and Durvalumab may help the immune system find and destroy cancer cells. Objective: To test if the drugs Durvalumab and Vicinium 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. CT or MRI: They lie in a machine that takes pictures of the body. Electrocardiogram to test heart function Participants will receive Durvalumab and Vicinium in 2 phases: First phase: Durvalumab every 4 weeks and Vicinium once a week for 3 months Second phase: Durvalumab every 4 weeks and Vicinium 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. ...

Detailed Description

      Background:

      In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390
      deaths associated with bladder cancer. Bladder cancer is associated with the highest costs
      among all types of cancer, due to the need for lifelong routine monitoring and treatment.
      Approximately 70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and
      are treated by transurethral resection of bladder tumor (TURBT) followed by intravesical
      treatment with BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of high
      grade disease, these therapies can become ineffective over time in up to two-thirds of
      patients and disease progression to muscle invasive bladder cancer (MIBC) can occur. In
      patients who present with CIS (carcinoma in situ) rates of progression are greater than 50%.
      Progression to MIBC portends a poor outcome as only 50% of patients will survive five years
      despite undergoing radical cystectomy. Clearly, there is a large unmet need in therapeutic
      options for NMIBC that recurs or progresses.

      Vicinium is a recombinant fusion protein, VB4-845, that contains a humanized single-chain
      antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked
      to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed on
      the surface of urothelial carcinoma cells and therefore represents a good target for Vicinium
      to bind to. In a previous phase II study in BCG refractory or BCG intolerant patients with
      high grade bladder cancer, 16% of patients treated with induction and maintenance therapy
      with Vicinium remained disease-free at 1 year. As a result, Vicinium is currently being
      evaluated as a single agent in a phase III trial.

      Pre-clinical work with a drug called Proxinium, an earlier version of Vicinium, demonstrated
      an abscopal effect and synergy with the use of a checkpoint blockade inhibitor. Although it
      was done in a NSCLC model, the results were impressive in causing tumor shrinkage. Durvalumab
      is a human monoclonal antibody (MAb) that inhibits binding of programmed cell death ligand 1
      (PD-L1) (B7 homolog 1 [B7-H1], cluster of differentiation [CD]274) to programmed cell death 1
      (PD-1; CD279) and CD80 (B7-1). Durvalumab has been demonstrated to have activity against
      advanced metastatic urothelial bladder cancer whose tumor has progressed during or after one
      standard platinum-based regimen in a phase I trial.

      Therefore, this trial will take two agents with single agent activity against urothelial
      cancer and combine them in a Phase I trial for patients with high-grade NMIBC Previously
      Treated with BCG.

      Objectives:

      Primary Objectives:

      -To evaluate the safety and tolerability of durvalumab and Vicinium when administered in
      combination to subjects with BCG-refractory high-grade NMIBC

      Eligibility:

        -  Subjects must have a histologically-confirmed high-grade non-muscle invasive urothelial
           carcinoma (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/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.

        -  Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology
           and the 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). See exception
           below for persistent T1 disease below. There is no upper limit on the amount of prior
           BCG a subject may have received.

        -  Patients with persistent T1 high grade disease on TURBT following a single induction
           course of BCG (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

      Design:

      This is a Phase I, open-label study of the combination of durvalumab and Vicinium in subjects
      with high-grade NMIBC previously treated with BCG.

        -  All subjects will receive Vicinium intravesically and durvalumab systemically at the
           standard doses for both drugs as determined by Phase II trials for each drug, as no
           synergy or additive effect is expected for adverse events.

        -  Vicinium 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, Vicinium is administered once weekly for 12 weeks. During the
           Maintenance Phase, Vicinium is administered every other week. The dose of Vicinium is 30
           mg in 50 mL of saline.

        -  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 patient 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.

        -  Vicinium will be given as monotherapy for 1 week followed by treatment with the
           combination of Vicinium and durvalumab starting week 2.

        -  In the initial six patients, three subjects at a time will enroll at these doses and
           schedules. Dose-liming toxicity (DLT) for each subject will be determined during the
           initial 6-week period that the subject is on treatment (i.e., the DLT period). When all
           subjects in the initial cohort have been on treatment through the DLT period, all
           available safety data will be considered in decisions to enroll additional subjects at
           this dose level, or to de-escalate the dose(s) of study drug(s), based on a standard 3 +
           3 design. There will be no dose escalations in this study. The dose of durvalumab will
           remain at 1500 mg every 4 weeks, and the dose of each intravesical Vicinium treatment
           can be reduced to 20 mg if the initial doses in combination induce DLTs.

        -  After the first six patients, an additional 18 subjects will be enrolled at the initial
           doses or at the reduced doses (if DLTs resulted in the first 6 patients) in order to
           obtain additional safety data, biomarker data and preliminary anti-tumor activity.

      Each subject s course will consist of the following periods:

        -  Screening/Baseline Period: The subject is consented and undergoes screening assessments
           to determine eligibility for the study.

        -  Treatment Period: The subject is treated and monitored for safety. Biomarker data will
           be obtained prior to treatment and at periodic intervals during treatment. Subjects who
           remain free of high-grade NMIBC after 12 months of study treatment may continue to
           receive treatment for an additional 12 months until they develop recurrent high-grade
           disease, disease progression, or intolerable toxicity, or meet another withdrawal
           criterion (e.g., consent withdrawal, pregnancy).

        -  Post-Treatment. The subject will return to the study site montly for up to 90 days after
           the last dose of immunotherapy for end-of-treatment assessments. Subjects with ongoing
           clinically significant related AEs or SAEs will have additional follow-up after the
           initial post-treatment visit.
    

Trial Arms

NameTypeDescriptionInterventions
1/Run InExperimentalDurvalumab + Vicinium, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 subjects
  • Durvalumab
  • Vicinium
2/ExpansionExperimentalDurvalumab + Vicinium, at the MTD. Up to 24 subjects
  • Durvalumab
  • Vicinium

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed by 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/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 (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 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 Vicinium 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, NMIBC does not occur in
             children.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

          -  Adequate normal 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).

               -  AST (SGOT)/ALT (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 Vicinium 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 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 (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.)

          -  Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to Vicinium 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 Vicinium
             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 PD1 or 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, 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, Graves 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 Vicinium or its components

          -  Active infection with tuberculosis (clinical evaluation that includes clinical
             history, physical examination, and radiographic findings, and PPD testing if
             indicated), hepatitis B (known positive HBV surface antigen (HBsAg) result, hepatitis
             C, or human immunodeficiency virus (positive HIV 1/2 antibodies). 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 RNA.

          -  History of leptomeningeal carcinomatosis

          -  Receipt of live attenuated vaccination within 30 days prior to the first dose of
             Vicinium 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 NCI 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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:safety and tolerability
Time Frame:one year
Safety Issue:
Description:List of adverse event frequency

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Carcinoma-in-situ
  • High-grade Ta or T1 disease
  • Papillary Tumors

Last Updated