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

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ClinicalTrials.gov Identifier: NCT03258593
Recruitment Status : Recruiting
First Posted : August 23, 2017
Last Update Posted : October 15, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Urinary Bladder Neoplasms Drug: Durvalumab Drug: Vicinium Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 7, 2018
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : July 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: 1/Run In
Durvalumab + Vicinium, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 subjects
Drug: Durvalumab
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.

Drug: Vicinium
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 Maintenance Phase, Vincinium is administered every other week. The dose of Vincinium 30mg in 50 mL of saline.

Experimental: 2/Expansion
Durvalumab + Vicinium, at the MTD. Up to 24 subjects
Drug: Durvalumab
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.

Drug: Vicinium
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 Maintenance Phase, Vincinium is administered every other week. The dose of Vincinium 30mg in 50 mL of saline.




Primary Outcome Measures :
  1. safety and tolerability [ Time Frame: one year ]
    List of adverse event frequency



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03258593


Contacts
Contact: Sonia E Bellfield, R.N. (240) 760-6118 sonia.bellfield@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Piyush K Agarwal, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03258593     History of Changes
Other Study ID Numbers: 170157
17-C-0157
First Posted: August 23, 2017    Key Record Dates
Last Update Posted: October 15, 2018
Last Verified: October 11, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Carcinoma-in-situ
High-grade Ta or T1 disease
Papillary Tumors

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs