Phase II Randomized Trial of Immunotherapy Versus Immunotherapy and Radiation Therapy for Platinum Ineligible/Refractory Metastatic Urothelial Cancer (IMMORTAL)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 83
- 主要终点
- Tumor Response
研究概览
简要总结
This phase II trial compares the effect of adding radiation therapy to an immunotherapy drug called pembrolizumab versus pembrolizumab alone in treating patients with urothelial cancer that has spread from where it first started (primary site) to other places in the body (metastatic). The addition of radiation to immunotherapy may shrink the cancer, but it could also cause side effects. Immunotherapy with monoclonal antibodies such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy (SBRT) is a type of radiation therapy that uses high energy x-rays to kill tumor cells and shrink tumors. This method uses special equipment to position a patient and precisely deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and may cause less damage to normal tissue than conventional radiation therapy. The combination of pembrolizumab and radiation therapy may be more efficient in killing tumor cells.
详细描述
PRIMARY OBJECTIVE:
I. To compare the overall response rates by 6 months in patients with advanced urothelial carcinoma when treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site.
SECONDARY OBJECTIVES:
I. To compare the response rates using immune related Response Evaluation Criteria in Solid Tumors (iRECIST) as assessed by central review.
II. To compare progression-free survival (PFS) and overall survival (OS) for patients treated with immunotherapy and immunotherapy plus radiotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed metastatic urothelial carcinoma
- •Patients must be either ineligible for platinum treatment or platinum refractory as defined below:
- •Platinum-ineligible: If patients meet any one of the following criteria:
- •Impaired renal function (creatinine clearance [CrCl] of < 30 mL/min)
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of > 2
- •Grade > 2 peripheral neuropathy
- •New York Heart Association (NYHA) Heart Failure of > 3
- •Platinum-refractory: If patients meet any one of the following criteria:
- •Prior platinum-based perioperative chemotherapy within 12 months of relapse
- •Prior platinum-based chemotherapy for metastatic disease
- •Patients must have at least one measurable site >= 1 cm in diameter per RECIST 1.1 and a site targetable for radiotherapy. Measurable site must not overlap with radiated site such that measurable site cannot receive > 2 Gy per fraction
- •Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions)
- •Men and women, ages >= 18 years of age
- •ECOG performance status =< 2
- •Leukocytes >= 2,500/mm^3
- •Absolute neutrophil count >= 1,500/mm^3
- •Platelets >= 100,000/mm^3
- •Hemoglobin >= 8 g/dL
- •Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x upper limit of normal (ULN)
- •AST and/or ALT =< 5 x ULN for patients with liver involvement
- •Alkaline phosphatase =< 2.5 x ULN
- •=< 5 x ULN for patients with documented liver involvement or if due to bone metastases primarily in absence of liver disease, no limitation
- •No prior allogeneic bone marrow transplantation or prior solid organ transplantation
- •No prior radiotherapy to targetable site or measurable site
- •No chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier. However, the following therapies are allowed:
- •Hormone-replacement therapy or oral contraceptives
- •Palliative radiotherapy for bone metastases > 2 weeks prior to registration
- •No prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- •No treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
- •No prior treatment with any other investigational agent within 4 weeks prior to registration
- •No prior treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks prior to registration
- •Any prior systemic therapy is permitted except therapy with PD1/PDL1 inhibitor
- •Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
- •The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
- •No active tuberculosis (TB)
- •No known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- •Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:
- •Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:
- •Evaluable or measurable disease outside the CNS
- •No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
- •No history of intracranial hemorrhage or spinal cord hemorrhage
- •No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted
- •No neurosurgical resection or brain biopsy within 28 days prior to registration
- •Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:
- •Radiographic demonstration of improvement upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS directed therapy and the screening radiographic study
- •No stereotactic radiation or whole-brain radiation within 28 days prior to registration
- •Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
- •No active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- •Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
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排除标准
- 未提供
研究组 & 干预措施
Arm A (pembrolizumab)
Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm A (pembrolizumab)
Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Bone Scan (Procedure)
Arm A (pembrolizumab)
Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Computed Tomography (Procedure)
Arm A (pembrolizumab)
Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm A (pembrolizumab)
Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Pembrolizumab (Biological)
Arm A (pembrolizumab)
Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Arm A (pembrolizumab)
Patients receive pembrolizumab IV over 25-40 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Questionnaire Administration (Other)
Arm B (pembrolizumab, SBRT)
Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT QD every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Biospecimen Collection (Procedure)
Arm B (pembrolizumab, SBRT)
Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT QD every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Bone Scan (Procedure)
Arm B (pembrolizumab, SBRT)
Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT QD every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Computed Tomography (Procedure)
Arm B (pembrolizumab, SBRT)
Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT QD every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm B (pembrolizumab, SBRT)
Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT QD every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Pembrolizumab (Biological)
Arm B (pembrolizumab, SBRT)
Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT QD every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Arm B (pembrolizumab, SBRT)
Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT QD every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Questionnaire Administration (Other)
Arm B (pembrolizumab, SBRT)
Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT QD every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.
干预措施: Stereotactic Body Radiation Therapy (Radiation)
结局指标
主要结局
Tumor Response
时间窗: Up to 6 months from randomization
Will be defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.
次要结局
- Tumor Response(Up to 3 years from randomization)
- Progression-free Survival(Time from randomization until disease progression as assessed by the treating physician using RECIST 1.1 or death due to any cause, assessed up to 3 years)
- Overall Survival(Time from randomization until death due to any cause. Patients who are not known to be dead at time of analysis will be censored at the time of their last follow-up, assessed up to 3 years)
- Rate of Treatment Discontinuation(At 1 year)
- Incidence of Adverse Events(Up to 3 years from randomization)