Recruiting

Phase 1

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

Sponsor:

National Cancer Institute (NCI)

Code:

NCT06439836

Conditions

Metastatic Urothelial Carcinoma

Unresectable Urothelial Carcinoma

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Biopsy Procedure

Biospecimen Collection

Computed Tomography

Emavusertib

Magnetic Resonance Imaging

Study Details

Brief summary:

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.

Conditions

Metastatic Urothelial Carcinoma

Unresectable Urothelial Carcinoma

Study ID

NCT06439836

Start date

May 5, 2025

Status verified date

Aug, 2026

Completion date

Jun 1, 2027

Anticipated

Primary completion date

Jun 1, 2027

Anticipated

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

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)

Study Design

Enrollment

27 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Treatment (CA-4948, pembrolizumab)

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.

Interventions

Biopsy Procedure

Undergo tumor biopsy

Biospecimen Collection

Undergo blood sample collection

Computed Tomography

Undergo CT

Emavusertib

Given PO

Magnetic Resonance Imaging

Undergo MRI

Pembrolizumab

Given IV

Positron Emission Tomography

Undergo PET

Primary outcome measure

Dose limiting toxicities (DLTs) [ Time Frame: Up to completion of cycle 1 ]
Recommended phase 2 dose (RP2D) [ Time Frame: Up to completion of cycle 1 ]
Incidence of AEs [ Time Frame: Up to 30 days after last dose of study treatment ]

Central Contacts and Locations

Locations

City of Hope Comprehensive Cancer Center

Recruiting

Duarte, California, United States, 91010

Contacts

Site Public Contact

800-826-4673 becomingapatient@coh.org

Principal Investigator:

Abhishek Tripathi

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Recruiting

Irvine, California, United States, 92612

Contacts

Site Public Contact

877-827-8839 ucstudy@uci.edu

Principal Investigator:

Nataliya Mar

UC San Diego Moores Cancer Center

Recruiting

La Jolla, California, United States, 92093

Contacts

Site Public Contact

858-822-5354 cancercto@ucsd.edu

Principal Investigator:

Tyler Stewart

UC Irvine Health/Chao Family Comprehensive Cancer Center

Recruiting

Orange, California, United States, 92868

Contacts

Site Public Contact

877-827-8839 ucstudy@uci.edu

Principal Investigator:

Nataliya Mar

University of Miami Miller School of Medicine-Sylvester Cancer Center

Recruiting

Miami, Florida, United States, 33136

Contacts

Site Public Contact

305-243-2647

Principal Investigator:

Jaime R. Merchan

Emory University Hospital Midtown

Recruiting

Atlanta, Georgia, United States, 30308

Contacts

Site Public Contact

888-946-7447

Principal Investigator:

Jacqueline T. Brown

Emory University Hospital/Winship Cancer Institute

Recruiting

Atlanta, Georgia, United States, 30322

Contacts

Site Public Contact

404-778-1868

Principal Investigator:

Jacqueline T. Brown

Emory Saint Joseph's Hospital

Recruiting

Atlanta, Georgia, United States, 30342

Contacts

Site Public Contact

404-851-7115

Principal Investigator:

Jacqueline T. Brown

Mount Sinai Hospital

Recruiting

New York, New York, United States, 10029

Contacts

Site Public Contact

212-824-7309 CCTO@mssm.edu

Principal Investigator:

Matthew D. Galsky

NYP/Weill Cornell Medical Center

Recruiting

New York, New York, United States, 10065

Contacts

Site Public Contact

212-746-1848

Principal Investigator:

Rohit Jain

UT Southwestern/Simmons Cancer Center-Dallas

Recruiting

Dallas, Texas, United States, 75390

Contacts

Site Public Contact

214-648-7097 canceranswerline@UTSouthwestern.edu

Principal Investigator:

Waddah Arafat

More Information

Sponsor

National Cancer Institute (NCI)

Last update posted

Aug 31, 2026

Last verified

Aug, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by National Cancer Institute (NCI) on 2026-08-31.