Pembrolizumab Plus CA-4948 for Metastatic Urothelial Cancer
This study is testing a combination of two drugs, emavusertib (CA-4948) and pembrolizumab, for patients with urothelial cancer that has spread (metastatic) or cannot be removed by surgery, and has not responded to prior immunotherapy. Emavusertib (CA-4948) is a kinase inhibitor that may help stop cancer cell growth, while pembrolizumab is an immunotherapy that helps your immune system fight the cancer. Researchers want to find the safest and most effective dose of this combination, understand its side effects, and see if it shrinks tumors. The study aims to enroll 27 adult patients aged 18 or older with this specific type of cancer. The study is looking at how well the treatment works and how long patients live without their cancer getting worse.
- Study design
- This is an interventional study, meaning participants will receive a specific treatment. It aims to enroll 27 participants.
- What's involved
- You would undergo a tumor biopsy, blood sample collection, CT scans, and MRI scans. You would also take emavusertib (CA-4948) by mouth.
- Compensation
- Not stated in the trial record.
- Follow-up
- Side effects will be monitored for up to 30 days after your last dose of study treatment.
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NCT06439836
Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy
Recruiting
PHASE1Ages 18+InterventionalTreatmentNational Cancer Institute (NCI)Government-funded
~27 participants
Updated 2026-08-06 on ClinicalTrials.gov
What's tested:Biopsy ProcedureBiospecimen CollectionComputed TomographyEmavusertibMagnetic Resonance ImagingPembrolizumab
At a glance
Recruiting sites
11 of 11 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Dose limiting toxicities (DLTs)
Measured over Up to completion of cycle 1
+2 more outcomes measured
Conditions
Where it's being run
11 sites across 5 statesCalifornia4
Georgia3
New York2
Florida1
Texas1
Study leadership
- Matthew D Galsky · PRINCIPAL_INVESTIGATOR · MOUNT SINAI HOSPITAL
Who to contact
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Do you actually qualify for this trial?
Add a private profile and we'll compare every criterion below against your situation — and tell you which ones are met, uncertain, or excluding.
Eligibility criteria
Inclusion
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
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)
What this trial measures
- Dose limiting toxicities (DLTs)Up to completion of cycle 1
Adverse events (AEs) will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Occurrence of DLTs along with count and percentage of subjects experiencing DLTs will be summarized. Safety of the combination regimen will be summarized by the number of adverse events as well as by the number and percentage of subjects experiencing the adverse events in both dose escalation and expansion cohorts. The safety summary will include count and percentage for overall and by AE type, seriousness, severity, attribution, anticipated or not. Furthermore, toxicity index will be calculated as a summary index for each patient to summarize multiple AEs.
- Recommended phase 2 dose (RP2D)Up to completion of cycle 1
The RP2D may be determined to be the highest dose level, the maximum tolerated dose, or it may be a lower dose based on the consensus of the investigators, Cancer Therapy Evaluation Program and pharmaceutical company collaborators.
- Incidence of AEsUp to 30 days after last dose of study treatment
AEs will be graded using NCI CTCAE v 5.0. Safety will be summarized by the number of AEs as well as by the number and percentage of subjects experiencing the AEs in both the dose escalation and dose expansion phases of the study. The safety summary will include count and percentage for overall and by AE type, seriousness, severity, attribution, anticipated or not. Toxicity will be calculated as a summary index for each patient to summarize multiple AEs.