Clinical Trials /

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

NCT03601455

Description:

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.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Radiation Therapy and Durvalumab With or Without Tremelimumab in Treating Participants With Unresectable, Locally Advanced, or Metastatic Bladder Cancer
  • Official Title: Phase II Study of Radiation Therapy and Anti-PD-L1 Checkpoint Inhibitor (Durvalumab) With or Without Anti-CTLA-4 Inhibition (Tremelimumab) in Patients With Unresectable, Locally Advanced, or Metastatic Urothelial Bladder Cancer That Are Ineligible or Refusing Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: 17-001894
  • SECONDARY ID: NCI-2018-01415
  • SECONDARY ID: 17-001894
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT03601455

Conditions

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

Interventions

DrugSynonymsArms
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Regimen A (radiation therapy and durvalumab)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabRegimen B (radiation therapy, durvalumab, tremelimumab)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety profile of radiation therapy (RT) and durvalumab with or without
      tremelimumab. (Safety lead-in cohort) II. To determine the median progression-free survival
      with RT and durvalumab with or without tremelimumab. (Expansion cohort)

      SECONDARY OBJECTIVES:

      I. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of local
      control of irradiated bladder tumor.

      II. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of
      pathologic complete response (CR) rate of irradiated bladder tumor.

      III. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms
      overall response rate.

      IV. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of
      abscopal response rate.

      V. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of
      duration of response.

      VI. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of
      disease specific survival.

      VII. To assess the efficacy of RT and durvalumab with or without tremelimumab in terms of
      overall survival.

      VIII. To further determine the safety and tolerability of RT + durvalumab with or without
      tremelimumab (expansion cohorts).

      EXPLORATORY OBJECTIVES:

      I. To explore the immunologic changes associated with the combination of durvalumab and RT
      +/- tremelimumab.

      OUTLINE: Participants are randomized to 1 of 2 regimens.

      REGIMEN A: Participants receive durvalumab intravenously (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 external beam radiation therapy (EBRT) for 5
      fractions beginning on day 8 of course 1.

      REGIMEN B:

      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.

      After completion of study treatment, participants are followed up at 8 weeks and then every
      12 and 16 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Regimen A (radiation therapy and durvalumab)ExperimentalParticipants 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.
  • Durvalumab
Regimen B (radiation therapy, durvalumab, tremelimumab)ExperimentalParticipants 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.
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)

          -  Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)

          -  Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). This will not
             apply to subjects with confirmed Gilbert?s syndrome (persistent or recurrent
             hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
             hepatic pathology), who will be allowed only in consultation with their physician.

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal unless liver metastases are present, in
             which case it must be =< 5 x ULN

          -  Serum creatinine clearance (CL) > 30 mL/min by the Cockcroft-Gault formula or by
             24-hour urine collection for determination of creatinine clearance.

          -  Female subjects must either be of non-reproductive potential (ie, post-menopausal by
             history: >= 60 years old and no menses for 1 year without an alternative medical
             cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history
             of bilateral oophorectomy) or must have a negative serum pregnancy test upon study
             entry. Evidence of post-menopausal status or negative urinary or serum pregnancy test
             for female pre-menopausal patients. Women will be considered post-menopausal if they
             have been amenorrheic for 12 months without an alternative medical cause. The
             following age-specific requirements apply:

               -  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 or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  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, had
                  chemotherapy-induced menopause with last menses > 1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy)

          -  Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visit and examinations and follow-up.

        Exclusion Criteria:

          -  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.

          -  Current enrollment/participation in another clinical study, unless it is an
             observational (noninterventional) clinical study or during the follow-up period of an
             interventional study.

          -  Prior radiation therapy to the abdomen or pelvis, including radiation therapy to the
             bladder, prostate, or rectum.

          -  Any concurrent systemic chemotherapy, biologic, or hormonal therapy for cancer
             treatment. Concurrent use of hormonal therapy for non-cancer related conditions (i.e.
             hormonal replacement therapy) is acceptable. Prior systemic therapies are allowed with
             a washout period of >= 45 days.

          -  Major surgical procedure (as defined by the investigator) within 28 days prior to the
             first dose of IP. Note biopsy and transurethral resection of the bladder tumor (TURBT)
             of the primary tumor is acceptable.

          -  History of another primary malignancy except for:

               -  Malignancy treated with curative intent and with no known active disease >= 3
                  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 eg, cervical
                  cancer in situ >> (Optional criteria that are dependent on the patient population
                  under investigation.)

                    -  Note: Patients with incidental finding of early stage prostate cancer will
                       not be eligible.

          -  QT interval corrected for heart rate using Fridericia?s formula (QTcF) >= 470 ms
             calculated. Any clinically significant abnormalities detected require triplicate
             electrocardiography (ECG) results and a mean QT interval corrected for heart rate
             using Fridericia?s formula (QTcF) >= 470 ms calculated from 3 ECGs).

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or tremelimumab, 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.

          -  History of primary immunodeficiency.

          -  History of allogeneic organ transplant.

          -  History of hypersensitivity to durvalumab, tremelimumab, or any excipient.

          -  History of hypersensitivity to the combination therapy of durvalumab and tremelimumab.

          -  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 subject 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 subject to give written informed consent.

          -  Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination, and radiographic findings, and tuberculosis [TB]
             testing in line with local practice).

          -  History of leptomeningeal carcinomatosis.

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving durvalumab or tremelimumab.

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results.

          -  Brain metastases or spinal cord compression unless the patient?s condition is stable
             (asymptomatic, no evidence of new or emerging brain metastases) and off steroids for
             at least 14 days prior to the start of study treatment. Following radiotherapy and/or
             surgery, patients with suspected brain metastases at screening should have a magnetic
             resonance imaging (MRI)(preferred)/CT, preferably with IV contrast.

          -  Subjects with uncontrolled seizures.

          -  Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 180 days after the last dose of durvalumab + tremelimumab combination
             therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the
             longer time period.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.03 criteria (Safety lead-in cohort)
Time Frame:Up to 90 days after last dose of investigation product
Safety Issue:
Description:Observed toxicities will be tabulated using frequencies and percentages based on the CTCAE v 4.03.

Secondary Outcome Measures

Measure:Local control at the primary irradiate site determined by RECIST v 1.1
Time Frame:Up to 3 years
Safety Issue:
Description:The stratified Kaplan Meier method will be used to describe local control for each arm along with their median.
Measure:Pathologic complete rate (CR) of primary irradiated tumor
Time Frame:Up to 3 years
Safety Issue:
Description:The point estimate and its 95% confidence interval will be obtained for the pathologic CR rate of the primary irradiated tumor for each arm and for localized patients and metastatic patients separately within each arm. A two-sample proportion test will be used to test if there is significant difference in pathologic CR (pCR) rates between two arms and the CochranMantel-Haenszel test will be used when accounting for the stratified design.
Measure: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
Time Frame:Up to 3 years
Safety Issue:
Description:The point estimate and its 95% confidence interval of ORR will be obtained by arm and for localized patients and metastatic patients separately within each arm. A two-sample proportion test will be used to test if there is significant difference in ORR rates between two arms and the Cochran-Mantel-Haenszel test will be used when accounting for the stratified design.
Measure: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
Time Frame:Up to 3 years
Safety Issue:
Description:The point estimate and its 95% confidence interval will be obtained by arm and for localized patients and metastatic patients separately within each arm. Furthermore, a two-sample proportion test will be used to test if there is significant difference between two arms and the Cochran-Mantel-Haenszel test will be used when accounting for the stratified design.
Measure:Duration of response
Time Frame:From date of the first documented response until the first date of documented progression or death, assessed up to 3 years
Safety Issue:
Description:The stratified Kaplan Meier method will be used to describe the duration of response for each arm along with their median.
Measure:Disease-specific survival
Time Frame:From the date of randomization to the date of death related to treatment and/or disease determined, assessed up to 3 years
Safety Issue:
Description:The stratified Kaplan Meier method will be used to describe disease-specific survival for each arm along with their median.
Measure:Overall survival
Time Frame:From the date of randomization to the date of to the date of death due to any cause, assessed up to 3 years
Safety Issue:
Description:The stratified Kaplan Meier method will be used to describe overall survival for each arm along with their median.
Measure:Incidence of adverse events assessed by National Cancer Institute CTCAE v4.0
Time Frame:Up to 3 years
Safety Issue:
Description:Will be summarized according to the subjects? baseline grade and maximum grade for each cycle of therapy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

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