Radiation Therapy and Durvalumab With or Without Tremelimumab in Treating Participants With Unresectable, Locally Advanced, or Metastatic Bladder Cancer

NCT03601455 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 17-001894NCI-2018-01415
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies the side effects and how well radiation therapy and durvalumab with or without tremelimumab work in treating participants with bladder cancer that cannot be removed by surgery, has spread to nearby tissue or lymph nodes, or that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving radiation therapy and durvalumab with or without tremelimumab will work better in treating participants with bladder cancer.

Conditions

Bladder Urothelial Carcinoma; Stage IV Bladder Cancer AJCC v8; Stage IVA Bladder Cancer AJCC v8; Stage IVB Bladder Cancer AJCC v8

Outcome Measures

Primary Outcomes (2)

• Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.03 criteria (Safety lead-in cohort)

  Observed toxicities will be tabulated using frequencies and percentages based on the CTCAE v 4.03.

  Up to 90 days after last dose of investigation product

• Progression- free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 (Expansion cohort)

  PFS will be estimated in each study arm by Kaplan-Meier estimate, where PFS is a composite endpoint based on radiologic progression, clinical deterioration or death. A log rank test will be used to test if there is significant difference in PFS between two arms. PFS will be also estimated for localized patients and metastatic patients separately within each arm and stratified log rank test will be used as well.

  From the first day of the treatment to the first occurrence of disease progression or death, assessed up to 3 years

Secondary Outcomes (8)

• Local control at the primary irradiate site determined by RECIST v 1.1

  Up to 3 years

• Pathologic complete rate (CR) of primary irradiated tumor

  Up to 3 years

• Overall response rate (ORR) defined as the number (%) of patients with at least 1 visit response of CR or partial response (PR) determined by RECIST v 1.1

  Up to 3 years

• Abscopal response (in patients with metastatic disease) determined by RECIST v 1.1 with response (PR and CR) sites away from the primary irradiated tumor

  Up to 3 years

• Duration of response

  From date of the first documented response until the first date of documented progression or death, assessed up to 3 years

Other Outcomes (4)

• Immune cell subsets and PD-L1 assessed by immunohistochemistry in tumor biopsies

  Up to 3 years

• Gene signature biomarker

  Baseline

• Circulating immune cell subsets assessed via flow cytometry in peripheral blood mononuclear cell

  Up to 3 years

Study Arms (2)

Regimen A (radiation therapy and durvalumab)

EXPERIMENTAL

Participants receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Participants also undergo EBRT for 5 fractions beginning on day 8 of course 1.

Biological: Durvalumab; Radiation: External Beam Radiation Therapy

Regimen B (radiation therapy, durvalumab, tremelimumab)

EXPERIMENTAL

Participants receive tremelimumab IV over 60 minutes on day 1 for up to 2 courses and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression of unacceptable toxicity. Participants also receive undergo EBRT for 5 fractions beginning on day 8 of course 1.

Biological: Durvalumab; Radiation: External Beam Radiation Therapy; Biological: Tremelimumab

Interventions

Durvalumab BIOLOGICAL

Given IV

Also known as: Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736

Regimen A (radiation therapy and durvalumab); Regimen B (radiation therapy, durvalumab, tremelimumab)

External Beam Radiation Therapy RADIATION

Undergo EBRT

Also known as: Definitive Radiation Therapy, EBRT, External Beam Radiotherapy, External Beam RT, external radiation, External Radiation Therapy, external-beam radiation

Regimen A (radiation therapy and durvalumab); Regimen B (radiation therapy, durvalumab, tremelimumab)

Tremelimumab BIOLOGICAL

Given IV

Also known as: Anti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, Ticilimumab

Regimen B (radiation therapy, durvalumab, tremelimumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
• cT2 - T4 or metastatic (N+ or M+) urothelial bladder cancer. Mixed histologies with predominant urothelial pattern are allowed. Patients with localized disease must either refuse cystectomy or be deemed not ideal cystectomy candidates.
• If metastatic disease present patients must have an intact, symptomatic bladder tumor, appropriate for palliative RT to the bladder.
• Measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria. Thus, patients with metastatic disease must have at least 1 lesion, not previously irradiated, that can be accurately measured at baseline as \>= 10 mm in the longest diameter (except lymph nodes which must have a short axis \>= 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and that is suitable for accurate repeated measurement as per RECIST v1.1 guidelines.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1/
• Life expectancy of \>= 12 weeks.
• Patients must be ineligible for or refuse cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting 1 of the following criteria:
• Creatinine clearance (calculated or measured) \< 60 mL/min
• Common Terminology Criteria for Adverse Events (CTCAE) grade \>= 2 audiometric hearing loss
• CTCAE grade 2 or higher peripheral neuropathy
• New York Heart Association class III heart failure
• Any other criteria deemed by the investigator to make the patient unsuitable for cisplatin-based chemotherapy
• Note: The reason for cisplatin ineligibility must be documented. Patients may refuse cisplatin-based chemotherapy after an informed discussion of the risks and benefits, and the reason for refusal must be documented.
• Subjects must consent to provide an archived tumor specimen from within 12 months prior to study entry (ie, from subject signing consent to participate in the study) for immunologic characterization. If not available, subjects should have at least 1 lesion amenable to biopsy and consent to provide a pre-treatment fresh biopsy. Tumor lesions used for biopsy should not be lesions used as target lesions. Additional archival tissue from beyond 12 months prior to study entry is also requested, if available, to support exploratory analyses.
• Hemoglobin \>= 9.0 g/dL

You may not qualify if:

• ECOG PS 2 or higher.
• Prior cystectomy or definitive RT to the bladder.
• History of autoimmune disease, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegner?s granulomatosis, Sjogren?s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], celiac disease, 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 childhood atopy or asthma, vitiligo, alopecia, Hashimoto syndrome, Grave?s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
• Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are not excluded.
• Patients with controlled type 1 diabetes mellitus on a stable dose of insulin regimen are not excluded.
• Any chronic skin condition that does not require systemic therapy are not excluded.
• Patients without active autoimmune disease in the last 5 years may be included after consultation with the study physician.
• Patients with human immunodeficiency virus (HIV), active hepatitis B (HBV) or active hepatitis C (HCV)
• Patients with past HBV infection or resolved HBV infection, defined as the presence of hepatitis B core antibody (HBc Ab) and absence of hepatitis B surface antigen (HBsAg) are eligible. HBV deoxyribonucleic acid (DNA) must be obtained in these patients prior to day 1 of therapy, but detection of HBV DNA in these patients will not exclude study participation.
• Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Previous investigational product (IP) assignment in the present study.

Sponsors & Collaborators

• Jonsson Comprehensive Cancer Center: lead
• AstraZeneca: collaborator

Study Sites (1)

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

durvalumab; Immunoglobulin G; Disulfides; tremelimumab

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals

Study Officials

• Albert Chang

  UCLA / Jonsson Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2018
• First Posted: July 26, 2018
• Study Start: October 26, 2018
• Primary Completion: January 31, 2026
• Study Completion (Estimated): January 31, 2027
• Last Updated: April 13, 2025

Record last verified: 2025-04

Locations

US (1)