A Phase 1 interventional study of Biopsy Procedure and Biospecimen Collection in Metastatic Urothelial Carcinoma and Unresectable Urothelial Carcinoma, sponsored by National Cancer Institute (NCI). Recruiting at 11 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-21.
Sponsored by National Cancer Institute (NCI) · Phase 1, Interventional, and Treatment
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.
PRIMARY OBJECTIVES:
I. To determine the recommended phase 2 dose of the combination of CA-4948 plus pembrolizumab in patients with immune checkpoint blockade (ICB)-resistant metastatic urothelial cancer (Dose Escalation Cohort).
II. To determine the safety of the combination of CA-4948 plus pembrolizumab in patients with ICB-resistant metastatic urothelial cancer (Dose Escalation Cohort and Dose Expansion Cohort).
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To measure the objective response (complete response [CR] or partial response [PR]) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at 9 weeks and the best overall response (CR or PR) as defined by RECIST 1.1 at any time while on study.
III. To determine progression-free survival, overall survival, and duration of response.
IV. To assess whether CA-4948 plus pembrolizumab leads to on-treatment increases in 2IR scores (as defined by ribonucleic acid [RNA] sequencing) in paired tumor biopsies.
EXPLORATORY OBJECTIVES:
I. To assess the clinical benefit rate with pembrolizumab plus CA-4948 therapy. II. To assess the "C-reactive protein (CRP) response rate" as defined by the proportion of patients achieving a ≥ 1.5 fold reduction in CRP at 9 weeks.
III. To explore the association between the 2IR score as defined by bulk-ribonucleic acid (RNA) sequencing of pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival.
IV. To explore whether CA-4948 plus pembrolizumab leads to on-treatment changes in the cellular and/or molecular composition of the tumor microenvironment (TME).
V. To explore the association between the quantity and spatial localization of SPP1+ monocytes-macrophages (MoMacs) defined by multiplex immunohistochemistry on pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival.
VI. To explore the association between the cellular and molecular composition of the TME defined by spatial RNA sequencing on pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival.
VII. To explore on-treatment changes in high-sensitivity (hs) CRP and cytokines and chemokines in peripheral blood and their association with objective response rate, clinical benefit rate, progression-free survival, and/or overall survival.
VIII. To explore the association between PD-L1 expression on pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival.
IX. To explore the association between the CXCL9:SPP1 ratio as defined by bulk-RNA sequencing of pre-treatment tumor tissue and objective response rate, clinical benefit rate, progression-free survival, and/or overall survival.
X. To assess whether CA-4948 plus pembrolizumab leads to on-treatment increases in the CXCL9:SPP1 ratio (as defined by RNA sequencing) in paired tumor biopsies.
OUTLINE: This is a dose-escalation study of CA-4948 in combination with pembrolizumab followed by a dose-expansion study.
Patients receive CA-4948 orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) throughout the study. Additionally, patients may undergo a tumor biopsy on study.
After completion of study treatment, patients are followed up every 3 months for 2 years.
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Age ≥ 18 years
Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L
Creatinine \< 1.5 × institutional ULN or creatinine clearance of ≥ 30 mL/min for patient with creatine levels ≥ 1.5 x institutional ULN
Must have received at least one of the following (may have been administered concurrently or sequentially with PD-1/PD-L1 inhibitor):
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:
For patients who received single-agent PD-1/PD-L1 blockade in the metastatic setting:
For patients who received single-agent PD-1/PD-L1 blockade in the switch-maintenance setting:
For patients who received an antibody-drug conjugate or cytotoxic chemotherapy plus PD-1/PD-L1 blockade combination
Exclusion Criteria:
Patients receive CA-4948 orally PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, CT, MRI, or PET throughout the study. Additionally, patients may undergo a tumor biopsy on study.
Procedure: Biopsy Procedure · Procedure: Biospecimen Collection · Procedure: Computed Tomography · Biological: Emavusertib · Procedure: Magnetic Resonance Imaging · Biological: Pembrolizumab · Procedure: Positron Emission Tomography
Undergo tumor biopsy
Also known as: Biopsy, BIOPSY_TYPE, Bx
Undergo blood sample collection
Also known as: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo CT
Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography
Given PO
Also known as: AU 4948, AU-4948, CA 4948, CA-4948, CA4948, Interleukin-1 Receptor-associated Kinase 4 Inhibitor CA-4948, IRAK4 Inhibitor CA-4948
Undergo MRI
Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI
Given IV
Also known as: BCD-201, GME 751, GME751, Keytruda, Lambrolizumab, MK 3475, MK-3475, MK3475, Pembrolizumab Biosimilar BCD-201, Pembrolizumab Biosimilar GME751, Pembrolizumab Biosimilar QL2107, Pembrolizumab Biosimilar RPH-075, Pembrolizumab Biosimilar SB27, QL2107, RPH 075, RPH-075, RPH075, SB 27, SB-27, SB27, SCH 900475, SCH-900475, SCH900475
Undergo PET
Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT
Dose limiting toxicities (DLTs)
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.
Time frame: Up to completion of cycle 1
Recommended phase 2 dose (RP2D)
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.
Time frame: Up to completion of cycle 1
Incidence of AEs
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.
Time frame: Up to 30 days after last dose of study treatment
Objective response rate (ORR)
ORR will be defined as the proportion of patients achieving a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria at 9 weeks. The number of confirmed responses will be reported along with a corresponding two-sided 95% Wilson confidence interval (CI) and p-value will be reported from Binomial exact test.
Time frame: At 9 weeks
Progression-free survival (PFS)
PFS will be defined as the time from initial treatment to any progression or death from any cause, whichever occurs first. Kaplan-Meier estimates of median PFS time will be presented together with two-sided 95% CIs calculated according to Brookmeyer and Crowley. The frequency (number and percentage) of participants with an event (progression or death) and censoring reasons will be presented (alive, withdrawal of consent, lost to follow-up).
Time frame: At initial treatment to progression or death up to 2 years after last dose of study treatment
Overall survival (OS)
OS will be defined as the duration from the first date of study treatment to the date of death. Kaplan-Meyer estimates of median OS will be presented together with two-sided 95% CIs calculated according to Brookmeyer and Crowley. the frequency of participants with an event and censoring reasons will be presented.
Time frame: At start of study treatment to death up to 2 years after last dose of study treatment
Duration of response (DOR)
DOR will be defined as the time from date of the first documentation of response to the first documentation of progression of disease or death due to any cause in the absence of documented progression of disease. Kaplan-Meier estimates of median DOR time will be presented together with two-sided 95% CIs calculated according to Brookmeyer and Crowley. The frequency of participants with an event and censoring reasons will be presented.
Time frame: At first response to progression or death up to 2 years after last dose of study treatment
2IR scores
The 2IR score will be calculated using the mean expression levels of the adaptive immune response and pro-tumorigenic inflammation gene signatures from the baseline and on-treatment transcriptome profile derived for each subject. A paired t-test will be used to test whether there is an increase in 2IR score from baseline to on-treatment time points. Univariable logistic regression models will be fitted for response variables with either 2IR score at baseline and change in 2IR score as continuous covariates. Proportional hazard (PH) Cox regression models for PFS and OS will also be fitted with 2IR score either at baseline or as time-dependent continuous covariates.
Time frame: At baseline and up to 2 years after last dose of study treatment
Clinical benefit rate (CBR)
CBR will be defined as the proportion of patients achieving a CR or PR per RECIST 1.1 criteria at 9 weeks or stable disease at 9 weeks accompanied by a 1.5 or greater reduction in hrCRP. CBR will be reported along with a corresponding two-sided 95% Wilson CI and p-value will be reported from Binomial exact test.
Time frame: At 9 weeks
High-sensitivity C-reactive protein (hsCRP)
CRP response rate will be defined as achieving a ≥ 1.5 fold reduction in CRP at 9 weeks. The CRP response rate will be reported along with a corresponding two-sided 95% Wilson CI and p-value will be reported from Binomial exact test. Linear mixed models will also be fitted for comparisons between patients achieving and not achieving an objective response and between patients achieving and not achieving clinical benefit. Random effects with autoregressive model of order 1 will be incorporated to describe the correlation of repeated measures. Univariable PH Cox regression models for PFS and OS will also be fitted with hsCRP levels either at baseline or as a time-dependent continuous covariate.
Time frame: At 9 weeks
Cytokines and chemokines
Linear mixed models will also be used for comparisons between patients achieving and not achieving an objective response and between patients achieving and not achieving clinical benefit. Random effects with autoregressive model of order 1 will be incorporated to describe the correlation of repeated measures. Residual plots will be used to check model assumptions. Univariable PH Cox regression models for PFS and OS will also be fitted with cytokine and chemokine levels either at baseline or as time-dependent continuous covariates. Schoenfeld residuals will be used to check PH assumption. P-values will be adjusted by false discovery rate of 5%.
Time frame: At baseline and up to 2 years after last dose of study treatment
Multiplex immunohistochemistry markers
A paired t-test will be used to test whether there are a reduction of SPP1+ MoMacs and an increase in intra-tumoral T cells from baseline to on-treatment time points. Univariable logistic regression models will be fitted for ORR and CBR as response variables with either marker levels at baseline or change in marker levels as continuous covariates. PH Cox regression models for PFS and OS will also be fitted with marker levels either at baseline or as time-dependent continuous covariates. Schoenfeld residuals will be used to check PH assumption. P-values will be adjusted by false discovery rate of 5%.
Time frame: At baseline and up to 2 years after last dose of study treatment
PD-L1 expression
Univariable logistic regression models will be fitted for ORR and CBR as response variables with PD-L1 expression as continuous covariate. Univariable PH Cox regression models for PFS and OS will be fitted with PD-L1 expression as continuous covariate. Schoenfeld residuals will be used to check PH assumption.
Time frame: Up to 2 years after last dose of study treatment
Tumor microenvironment (TME) markers
A paired t-test will be used to test whether there are a decrease in SPP1+ CD68+ cells and an increase in C1QC+ CD68+ cells from baseline to on-treatment time points. Univariable logistic regression models will be fitted for ORR and CBR as response variables with either TME markers at baseline or change in TME marker levels as continuous covariates. PH Cox regression models for PFS and OS will be fitted with TME markers either at baseline or as time-dependent continuous covariates. Schoenfeld residuals will be used to check PH assumption. P-values will be adjusted by false discovery rate of 5%.
Time frame: At baseline and up to 2 years after last dose of study treatment
Cytometry by time of flight
Will be analyzed using state of the art techniques developed at National Institute of Health and Mount Sinai focused on modeling variance and cellular abundance of these cell populations. The hierarchical nature of the classification and identification of cell types will allow to characterize and identify what populations are affected by treatment and associated with response in the periphery, in contrast with the data obtained at the tumor site (locally), which is identified with spatial assays.
Time frame: At week 1 of cycles 1-3
Extracellular vesicles and particles (EVPs)
Will be analyzed using linear mixed models for longitudinal comparisons, univariable logistic regression for associations with ORR and CBR, and proportional hazards Cox models (including time-dependent covariates) for PFS and OS. Model assumptions will be evaluated using residual diagnostics, including Schoenfeld residuals for PH models. False discovery rate adjustment at 5% will be applied for multiple testing correction. EVP-derived molecular signatures (also known as the secretome) may provide complementary, non-redundant insights beyond those captured by Olink, immunohistochemistry, and spatial transcriptomics, and may identify circulating surrogates of treatment response or resistance.
Time frame: At week 1 of cycles 1-3
Plan to share: Yes — NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
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