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

Recruiting now · Phase 1

Conditions studied: Metastatic Urothelial Carcinoma, Unresectable Urothelial Carcinoma

In brief

This phase I trial tests the safety, side effects, best dose, and effectiveness of emavusertib (CA-4948) in combination with pembrolizumab in treating patients with urothelial cancer that has spread from where it first started to other places in the body (metastatic) and that has a resistance to PD-1/PD-L1 immune checkpoint inhibitors. CA-4948, a kinase inhibitor, may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving CA-4948 in combination with pembrolizumab may be safe, tolerable and/or effective in treating patients with metastatic urothelial cancer that is resistant to PD-1/PD-L1 immune checkpoint inhibitors.

Key facts

Study ID: NCT06439836
Run by: National Cancer Institute (NCI)
People needed: 27
Starts: 2025-05-05
Expected to finish: 2027-06-01
Last updated by the study team: 2026-08-06

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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:

You may not qualify if…

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)

Where it is running

City of Hope Comprehensive Cancer Center — Duarte, California, United States (enrolling)
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care — Irvine, California, United States (enrolling)
UC San Diego Moores Cancer Center — La Jolla, California, United States (enrolling)
UC Irvine Health/Chao Family Comprehensive Cancer Center — Orange, California, United States (enrolling)
University of Miami Miller School of Medicine-Sylvester Cancer Center — Miami, Florida, United States (enrolling)
Emory University Hospital Midtown — Atlanta, Georgia, United States (enrolling)
Emory University Hospital/Winship Cancer Institute — Atlanta, Georgia, United States (enrolling)
Emory Saint Joseph's Hospital — Atlanta, Georgia, United States (enrolling)
Mount Sinai Hospital — New York, New York, United States (enrolling)
NYP/Weill Cornell Medical Center — New York, New York, United States (enrolling)
UT Southwestern/Simmons Cancer Center-Dallas — Dallas, Texas, United States (enrolling)

Full record on ClinicalTrials.gov

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