Phase II Randomized Trial of Atezolizumab Versus Atezolizumab and Radiation Therapy for Platinum Ineligible/Refractory Metastatic Urothelial Cancer (ART)

  • End date
    Apr 30, 2023
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 22 September 2022


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.



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.


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.


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.

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.

After completion of study treatment, patients are followed up within 12 weeks and then every 3 months for 3 years following registration.

Condition Metastatic Urothelial Carcinoma, Platinum-Resistant Urothelial Carcinoma, Stage IV Bladder Cancer AJCC v8
Treatment questionnaire administration, quality-of-life assessment, stereotactic body radiation therapy, Atezolizumab
Clinical Study IdentifierNCT04936230
SponsorNational Cancer Institute (NCI)
Last Modified on22 September 2022


Yes No Not Sure

Inclusion Criteria

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
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
agree to undergo a biopsy for additional tissue
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)
Creatinine clearance (CrCl) of 30 to 59 mL/min
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
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
Institutional normalized ratio (INR) and activated partial thromboplastin time (aPTT)
No prior allogeneic bone marrow transplantation or prior solid organ transplantation
=< 1.5 x ULN
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 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 CD137 agonists or immune checkpoint blockade therapies
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
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
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
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 active autoimmune disease that has required systemic treatment in the past 2 years
No history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
(i.e. with use of disease modifying agents, corticosteroids or
No known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or
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
physiologic corticosteroid replacement therapy for adrenal or pituitary
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
insufficiency, etc.) is not considered a form of systemic treatment
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 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
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

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
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)
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 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
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