Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy

Inclusion Criteria: * Patients must have histologically confirmed urothelial cancer that is metastatic or unresectable and must have had the prior treatments outlined * Age ≥ 18 years * Because no dosing or adverse event data are currently available on the use of CA-4948 in combination with pembrolizumab in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%) within 28 days prior to registration * Leukocytes ≥ 3,000/mcL * Absolute neutrophil count (ANC) ≥ 1,500/mcL * Platelets ≥ 100,000/mcL * Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L * Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stable dose of erythropoietin (≥ approximately 3 months) * Creatine phosphokinase (CPK) \< grade (Gr) 2 ( \</= 2.5 upper limit of normal \[ULN\]) * Creatinine \< 1.5 × institutional ULN or creatinine clearance of ≥ 30 mL/min for patient with creatine levels ≥ 1.5 x institutional ULN * Creatinine clearance (CrCl) should be calculated per institutional standard * Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) ≤ 3 x ULN * Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x ULN * International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants * Activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * Ability to provide at least 20 unstained slides or formalin-fixed paraffin-embedded (FFPE) block plus 1 hematoxylin and eosin (H\&E) slide from prior archival invasive urothelial cancer specimen (and/or ability to undergo baseline tumor biopsy in patients in the expansion cohort) * Measurable metastatic or unresectable disease * Must have received prior treatment with a PD-1 or PD-L1 inhibitor * Must have received at least one of the following (may have been administered concurrently or sequentially with PD-1/PD-L1 inhibitor): * Platinum-based chemotherapy * Enfortumab vedotin * Primary resistance to PD-1/PD-L1 blockade as defined by Society for Immunotherapy of Cancer (SITC) consensus definitions: * For patients who received single-agent PD-1/PD-L1 blockade in the adjuvant setting: * Must have received ≥ 6 weeks of treatment with PD-1/PD-L1 blockade * Recurrence while on treatment or within ≤ 3 months after completion of therapy * For patients who received single-agent PD-1/PD-L1 blockade in the metastatic setting: * Must have received ≥ 6 weeks of treatment with PD-1/PD-L1 blockade * Progression within ≤ 6 months of initiating treatment with single-agent PD-1/PD-L1 blockade with best response of stable disease * For patients who received single-agent PD-1/PD-L1 blockade in the switch-maintenance setting: * Must have received ≥ 6 weeks of treatment with PD-1/PD-L1 blockade * Progression within ≤ 6 months of initiating treatment with single-agent PD-1/PD-L1 blockade * For patients who received an antibody-drug conjugate or cytotoxic chemotherapy plus PD-1/PD-L1 blockade combination * Must have received ≥ 6 weeks of treatment with PD-1/PD-L1 blockade * Progression within ≤ 12 months of initiating treatment * An eligibility form will be developed to include documentation of the dates of prior PD-1/PD-L1 blockade and a redacted radiology report confirming best response of stable disease for \< 6 months or progressive disease) * Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female patients of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient * Male patients of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * Patients who have received messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) and influenza vaccines will be allowed * Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either magnetic resonance imaging \[MRI\] or computed tomography \[CT\] scan, for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen * Patients should be willing and able to swallow pills * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants Exclusion Criteria: * Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) Note: Patients with grade ≤ 2 neuropathy or grade ≤ 2 alopecia are an exception to this criterion and may qualify for the study. Note: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy * Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug * Grade ≥ 3 immune related adverse event with prior PD-1/PD-L1 blockade * History of allergic reactions attributed to compounds of similar chemical or biologic composition to CA-4948 and/or pembrolizumab * Patients with uncontrolled intercurrent illness, including but not limited to interstitial lung disease or active, non-infectious pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia that would limit compliance with study requirements * Patients who are receiving any other investigational agents * Patients with carcinomatous meningitis * Patients with malabsorption syndrome or other conditions that would interfere with intestinal absorption * Has an 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 * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator * Has received a live vaccine within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted * Pregnant women are excluded from this study because pembrolizumab is a monoclonal antibody 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 pembrolizumab, breastfeeding should be discontinued if the mother is treated with pembrolizumab. These potential risks may also apply to other agents used in this study * Has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] RNA \[qualitative\] is detected) * Has a known history of active tuberculosis (TB)