Neutron Radiation Therapy and Pembrolizumab in Treating Participants With Advanced Urothelial Carcinoma

Study Overview
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Brief Summary
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This phase II trial studies how well neutron radiation therapy and pembrolizumab work in treating participants with urothelial carcinoma that has spread to other places in the body. Neutron radiation therapy uses high energy neutrons to kill tumor cells and shrink tumors. 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. Giving radiation therapy and pembrolizumab may work better than radiation alone in treating participants with urothelial carcinoma that has spread to other places in the body.

Detailed Description
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OUTLINE: Participants receive pembrolizumab intravenously (IV) on days 1 and 22. On day 23, participants may undergo an optional tumor biopsy and receive 3-5 treatments of neutron radiation therapy over 2 weeks on days 23-42. Participants receive pembrolizumab IV on day 43 and continue per standard of care in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up every 3 months.

Official Title
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Phase II Trial of Neutron Radiotherapy With Concurrent Checkpoint Inhibitor Immunotherapy (Pembrolizumab) in Patients With Advanced Urothelial Carcinoma

Conditions
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Urothelial Carcinoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Biological: Pembrolizumab
* Radiation: Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically proven (either histologic or cytologic) diagnosis of urothelial carcinoma At least two sites of disease that are measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria Eligible for checkpoint inhibitor immunotherapy (pembrolizumab) per standard of care No history of autoimmune disease requiring systemic therapy (e.g. steroids or biologic agents) Absolute neutrophil count (ANC) ≥ 1500 /mcL Platelets ≥ 100,000/mcL Hemoglobin > 9 g/dL Creatinine ≤ 1.5 x upper limit of normal (ULN) OR ≥ 60 mL/min Total bilirubin ≤ 1.5 ULN OR direct bilirubin ≤ ULN if total bilirubin > 1.5 x ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN OR < 5 x ULN if patient has liver metastasis Albumin >= 2.5 g/dL International normalized ratio (INR) or PT ≤ 1.5 x ULN unless on anticoagulation therapy, in which case prothrombin time (PT) or partial thromboplastin time (PTT) should be in the therapeutic range PTT ≤ 1.5 x ULN unless on anticoagulation therapy, in which case PT or PTT should be in the therapeutic range Eligible for neutron radiation treatment to 1-3 sites of metastatic disease (lesions do not have to be symptomatic) No steroids for at least 2 weeks prior to enrollment, and patient must not be expected to require steroids during the study period Zubrod performance status 0-2 Patient must sign study specific informed consent prior to study entry Patients who are sexually active must use medically acceptable forms of contraception Life expectancy must be > 3 months Exclusion Criteria: Has a known history of active TB (Bacillus tuberculosis) Hypersensitivity to pembrolizumab or any of its excipients Has a known additional malignancy that is progressing or requires active treatment Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator Has known history of, or any evidence of active, non-infectious pneumonitis Has an active infection requiring systemic therapy Has received a live vaccine within 30 days of planned start of study therapy Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided there is no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Pembrolizumab, neutron radiation therapy)<br>Participants receive pembrolizumab IV on days 1 and 22. On day 23, participants may undergo an optional tumor biopsy and receive 3-5 treatments of neutron radiation therapy over 2 weeks on days 23-42. Participants receive pembrolizumab IV on day 43 and continue per standard of care in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Radiation: Radiation Therapy<br>* Undergo neutron radiation therapy<br>* Other names: Therapy, Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate per immune-modified response evaluation criteria in solid tumors | Overall response rate will be calculated as the percentage of patients achieving a partial response or complete response, and will be presented along with the 95% confidence interval (CI). | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | This will be estimated with the Kaplan and Meier method with 95% CI obtained using Greenwood estimates of variance. | Up to 3 years | 
| Progression-free survival | This will be estimated with the Kaplan and Meier method with 95% CI obtained using Greenwood estimates of variance. | Up to 3 years |