Immunotherapy With or Without Radiation Therapy for Metastatic Urothelial Cancer

Study Overview
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Brief Summary
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This phase II trial compares the effect of adding radiation therapy to an immunotherapy drug called atezolizumab vs. atezolizumab alone in treating patients with urothelial cancer that has spread 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 atezolizumab, 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 atezolizumab and radiation therapy may be more efficient in killing tumor cells.

Detailed Description
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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. III. To compare the rates of treatment discontinuation at 1 year. IV. To assess adverse events experienced by patients treated with immunotherapy and immunotherapy plus radiotherapy via the Common Terminology Criteria for Adverse Events (CTCAE) and Patient Reported Outcome (PRO)-CTCAE. IV. To determine whether treatment effects are similar for key subgroups including those defined by the stratification variables. QUALITY OF LIFE CORRELATIVE STUDY OBJECTIVES: I. To compare patient-reported fatigue as assessed by the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue 8a from baseline through 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site. II. To compare health-related quality of life (HRQOL) as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core (C)30 from baseline through 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site. III. To compare urinary symptoms as assessed by the EORTC QLQ-BLM30 from baseline through 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site. IV. To compare patient-reported diarrhea, shortness of breath and pain as assessed by the EORTC QLQ-C30 from baseline through 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site. V. To compare health utilities and quality-adjusted survival between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site. VI. To compare other scale scores of the EORTC QLQ-C30 (global health status and quality of life; physical, role, emotional, cognitive, and social function; symptoms) and EORTC QLQ-BLM30 (urostomy problems, catheter problems, future perspectives, abdominal bloating and flatulence, body image, sexual function) at 45 days, and at 6, 12, and 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), bone scan, positron emission tomography (PET) scan, and blood sample collection throughout the study. ARM B: Patients receive atezolizumab as in Arm A. Patients also undergo stereotactic body radiation therapy (SBRT) for 3 fractions over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, PET scan, and blood sample collection throughout the study. After completion of study treatment, patients are followed up within 12 weeks and then every 3 months for 3 years following registration.

Official Title
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Phase II Randomized Trial of Immunotherapy Versus Immunotherapy and Radiation Therapy for Platinum Ineligible/Refractory Metastatic Urothelial Cancer (IMMORTAL)

Conditions
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Metastatic Urothelial Carcinoma, Platinum-Resistant Urothelial Carcinoma, Stage IV Bladder Cancer AJCC v8

Intervention / Treatment
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* Biological: Atezolizumab
* Procedure: Biospecimen Collection
* Procedure: Bone Scan
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Procedure: Positron Emission Tomography
* Other: Questionnaire Administration
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PRE-REGISTRATION INCLUSION 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 tissue available for central PD-L1 determination stratification OR agree to undergo a biopsy for additional tissue 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) REGISTRATION INCLUSION 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 Creatinine clearance (CrCl) of 30 to 59 mL/min 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 bone metastases Institutional normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose 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 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 No known history of, or any evidence of active, non-infectious pneumonitis or colitis No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies No history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins No known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease No history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted No significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina No other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications No history of leptomeningeal disease No uncontrolled tumor-related pain Patients requiring pain medication must be on a stable regimen at study entry Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment No uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations Rash must cover less than 10% of body surface area (BSA) Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids) No 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 No active infections requiring systemic antibiotics within 2 weeks prior to registration. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible No major surgical procedure within 28 days prior to registration or anticipation of need for a major surgical procedure during the course of the study No administration of a live, attenuated vaccine within 30 days before registration or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab Patients who have received live attenuated vaccines within 30 days of the first dose of trial treatment are eligible at the discretion of the investigator. All seasonal influenza vaccines and vaccines intended to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) are allowed Exclusion Criteria: Physicians should consider whether any of the following may render the patient inappropriate for this protocol: Patients with life expectancy of less than 6 months Psychiatric illness which would prevent the patient from giving informed consent Medical conditions such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Patients with a currently active second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for >= 3 years. Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study and for 5 months (150 days) after the last dose of study agent due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom). 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. A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). REGISTRATION EXCLUSION 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (atezolizumab)<br>Patients receive atezolizumab IV over 30-60 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, PET scan, and blood sample collection throughout the study. | Biological: Atezolizumab<br>* Given IV<br>* Other names: Tecentriq;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Bone Scan<br>* Undergo bone scan<br>* Other names: Bone Scintigraphy;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo PET scan<br>* Other names: PT;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm B (atezolizumab, SBRT)<br>Patients receive atezolizumab as in Arm A. Patients also undergo SBRT for 3 fractions over 2 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, PET scan, and blood sample collection throughout the study. | Biological: Atezolizumab<br>* Given IV<br>* Other names: Tecentriq;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Bone Scan<br>* Undergo bone scan<br>* Other names: Bone Scintigraphy;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo PET scan<br>* Other names: PT;Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response | 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 (v) 1.1 criteria. | Up to 6 months from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response | Will be assessed by immune modified (i)RECIST. | Up to 3 years from randomization | 
| Progression-free survival (PFS) | Stratified Cox models will be used to compare the outcomes between the two treatment groups. | 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 (OS) | Stratified Cox models will be used to compare the outcomes between the two treatment groups. | 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 | The proportion of patients who discontinue their protocol directed treatment prior to one year from date of study registration will be determined. Patients who stop their protocol directed treatment for any reason prior to one year from study registration will be considered to have discontinued their treatment. | At 1 year | 
| Incidence of adverse events | Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be summarized with frequencies and relative frequencies. | Up to 3 years from randomization |