Status and phase
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About
This is a multi-site, randomized, prospective, open-label phase II study. Patients in this study will have localized (cT3-cT4), or metastatic bladder cancer with a symptomatic, intact primary bladder tumor. In this study, patients will undergo stereotactic body radiation therapy (SBRT) to the bladder tumor and will receive durvalumab with or without tremelimumab.
Full description
The study will commence with a safety lead-in phase at UCSF in which 6 patients are accrued to Regimen A1 (RT + durvalumab). If this is not tolerated then an alternative Regimen A2, containing a lower total radiation dose will accrue 6 patients. If either A1 or A2 is tolerated then patients will be accrued to Regimen B1 (durvalumab, tremelimumab x 2 doses, and RT dose determined from Regimen A) following a 3+3 design for safety. If Regimen B1 is not tolerated an alternative Regimen B2 (durvalumab, tremelimumab x 1 dose, and RT dose determined from regimen A) will accrue following a 3+3 design for safety.
After the safety lead-in for each group is completed, an expansion cohort will accrue patients. In this expansion cohort, patients will be randomized 1:1 to be treated with either regimen A or regimen B dose selected from the safety lead-in stratified by patient population (localized patients and metastatic patients).
Sex
Ages
Volunteers
Inclusion criteria
Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
Locally advanced (cT3 or cT4) or metastatic (N+ or M+) urothelial bladder cancer. Mixed histologies with predominant urothelial pattern are allowed
If metastatic disease present patients must have an intact, symptomatic bladder tumor, appropriate for palliative RT to the bladder.
Measurable metastatic disease according to RECIST v1.1 criteria. Thus, patients with metastatic disease must have at least 1 lesion, not previously irradiated, that can be accurately measured at baseline as at least 10 mm in the longest diameter (except lymph nodes which must have a short axis greater than or equal to 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.
Age greater than or equal to 18 years at time of study entry
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Life expectancy of at least 12 weeks
Patients with non-metastatic bladder cancer must be ineligible for cystectomy in the opinion of the treating investigator.
Patients must be ineligible for cisplatin-based chemotherapy. The reason for cisplatin ineligibility must be documented. Cisplatin ineligibility is defined as meeting 1 of the following criteria:
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.
Adequate normal organ and marrow function as defined below:
Males:
Creatinine CL (mL/min) = [Weight (kg) x (140 - Age)] / [72 x serum creatinine (mg/dL)]
Females:
Creatinine CL (mL/min) = 0.85 x [Weight (kg) x (140 - Age)] / [72 x serum creatinine (mg/dL)]
Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: At least 60 years old and no menses for at least 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:
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
Upper tract-only or urethral-only urothelial cancer
Prior cystectomy or definitive RT to the bladder.
Prior systemic chemotherapy for bladder cancer
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:
Patients with HIV, active hepatitis B (HBV) or active hepatitis C (HCV)
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 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 exposure to immune-mediated therapy, including but not limited to, durvalumab, tremelimumab, other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, and therapeutic anticancer vaccines. Prior BCG or intravestical immune therapy (ie interferon) is not an exclusion to study participation.
Prior radiation therapy to the abdomen or pelvis.
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.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note biopsy and TURBT of the primary tumor is acceptable.
History of another primary malignancy except for:
QT interval corrected for heart rate using Fridericia's formula (QTcF) greater than or equal to 470 ms calculated. Any clinically significant abnormalities detected require triplicate ECG results and a mean QT interval corrected for heart rate using Fridericia's formula (QTcF) greater than or equal to 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
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 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 an 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
Primary purpose
Allocation
Interventional model
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0 participants in 6 patient groups
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Data sourced from clinicaltrials.gov
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