Bintrafusp Alfa (M7824) and PDS01ADC Alone and in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Metastatic Non-Prostate Genitourinary Malignancies

* INCLUSION CRITERIA:
* Participants must have histologically or cytologically confirmed diagnosis of a metastatic non-prostate genitourinary tumor.
* Participants must have metastatic disease defined as new or progressive lesions on cross-sectional imaging. Radiological evaluation should occur within 21 days prior to enrollment.
* Participants must have evaluable or measurable disease, per RECIST 1.1.
* Participants in Arms 2 and 3 must have at least one site of disease that is amenable to irradiation (irradiation of up to 4 different sites is permitted)
* Participants must have at least one measurable site of disease (according to RECIST criteria) that will not be irradiated.
* Participants may have been previously treated with cytotoxic chemotherapy regimen or targeted agent. Participants may have received any number of prior cytotoxic agents.
* Participants may have been previously treated with radiation therapy. However, re-irradiation of a previously irradiated site is not permitted unless explicitly discussed with protocol PI and treating radiation oncologist.
* Participants may have had prior immunomodulating therapy including therapy with a checkpoint inhibitor but excluding prior treatment with M7824 and/or PDS01ADC.
* Participants with locally advanced/metastatic clear cell renal cell cancer must have previously received, refused or been ineligible for either axitinib plus pembrolizumab, cabozantinib plus nivolumab, levantinib plus pembrolizumab, axitinib plus avelumab, nivolumab plus ipilumumab, cabozantinib, pazopanib, sunitinib or axitinib.
* Participants with locally advanced or mestastatic germ cell tumors must have received, refused or been ineligible for prior bleomycin plus etoposide plus cisplatin, etoposide plus cisplatin, etoposide plus ifosfamide plus cisplatin, vinblastine plus ifosfamide plus cisplatin, paclitaxel plus ifosfamide plus cisplatin or autologous hematopoietic cell transplantation.
* Participants with locally advanced/metastatic urothelial cancer must have previously received, refused or been ineligible for platinum chemotherapy and/or single agent PD-1/PD-L1 inhibitor.
* Pre-treatment tissue availability for PD-L1 expression testing is mandatory for enrollment. If tissue is determined to be of insufficient/unsuitable quality/quantity, a pre-treatment biopsy prior to initiation of study therapy will be required.
* Male and female participants who are at least 18 years of age on the day of signing the informed consent will be enrolled in the study.
* ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%)
* Participants must have adequate organ and marrow function as defined below:

  * leukocytes greater than or equal to 2500mcL
  * absolute neutrophil count greater than or equal to 1500/mcL
  * platelets greater than or equal to 100,000/mcL
  * Aspartate Aminotransferase (AST)/ Alanine Aminotransferase (ALT) less than or equal to 1.5 X institutional upper limit of normal (ULN)
  * Hemoglobin (Hgb) greater than or equal to 9g/dL (Packed red blood cells (pRBC) transfusions are allowed to achieve acceptable Hgb)
* Participants may have mild to moderate hepatic impairment with total bilirubin less than or equal to 3.0 x ULN.
* For participants with liver involvement in their tumor, we allow the following: AST less than or equal to 5.0 x ULN, ALT less than or equal to 5.0 x ULN, and bilirubin less than or equal to 3.0 x ULN.
* Calculated Creatinine clearance greater than or equal to 20 mL/min (using either CKD-EPY equation)
* The effects of M7824 and/or PDS01ADC on the developing human fetus are unknown. For this reason, individuals of child-bearing potential (IOCBP) and individuals able to father a child must agree to use strict and effective contraception during treatment and after the last dose of M7824 administration - at least 65 days after for IOCBP and 125 days after for individuals able to father a child. Should IOCBPs become pregnant or suspect they are pregnant while they or their partner are participating in this study, they should inform their treating physician immediately.
* Human Immunoodeficiency Virus (HIV)-positive participants are eligible if on stable dose of highly active antiretroviral therapy (HAART), CD4 counts are greater than 350 cells/mm3 and viral load is undetectable.
* Participants with previously treated brain or central nervous system (CNS) metastases are eligible provided that the participant has recovered from any acute effects of radiotherapy and is not requiring steroids, and any whole brain radiation therapy was completed at least 2 weeks prior to M7824 administration, or any stereotactic radiosurgery was completed at least 2 weeks prior to M7824 administration.
* Hepatitis B Virus (HBV) positive participants are eligible-they must have been treated and on a stable dose of antivirals \[eg, entecavir, tenofovir, or lamivudine; (adefovir or interferon are not allowed)\] at study entry and with planned monitoring and management according to appropriate labeling guidance.
* Hepatitis B Virus (HCV) positive participants are eligible if participants are on active HCV therapy at study entry and must be on a stable dose without documented clinically significant impaired liver function test or hematologic abnormalities and with planned monitoring and management according to appropriate labeling guidance.
* Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

* History of allergic reactions attributed to compounds of similar chemical or biologic composition to M7824 and/or PDS01ADC investigational agents used in the study.
* Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Participants with a history of bleeding diathesis or recent clinically significant bleeding events considered by the Investigator as high risk for investigational drug treatment are also excluded with the exception of hematuria.
* Participants unwilling to accept blood products as medically indicated
* Pregnant individuals are excluded from this study because M7824 and/or PDS01ADC are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M7824 and/or PDS01ADC, nursing should be discontinued if the nursing individual is treated with these agents.
* Participants with any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required treatment with either systemic corticosteroids (\> 10 mg daily prednisone equivalent) or immunosuppressive medications. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Participants with inflammatory bowel disease that have been in remission for at least 5 years whether or not they are currently on immunosuppressive therapy provided that they are not on systemic corticosteroids (\> 10mg daily prednisone equivalent) are eligible.
* Participants with any active or recent history of inflammatory bowel disease, active lupus or scleroderma or other medical conditions (i.e., pneumonits with planned SBRT to lung lesion) or genetic radiosensitivity syndromes will be excluded from the study unless deemed eligible by Principal Investigator because these diseases make the participant unsafe or ineligible for radiation therapy with SBRT.
* Participants with a "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ or incidental organ-confined prostate cancer found on cystoprostatectomy (provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score \<= 3+4, Prostate-Specific Antigen (PSA) undetectable). Participants are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for \>= 2 years and currently do not require systemic therapy.
* Participants having tumor lesion(s) in the liver or chest which are 10 cm or larger.