Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy
Phase 1 Trial of CA-4948 in Combination With Pembrolizumab to Overcome Resistance to PD-1/PD-L1 Blockade in Metastatic Urothelial Cancer
2 other identifiers
interventional
27
1 country
11
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_1
Started May 2025
Typical duration for phase_1
11 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 31, 2024
CompletedFirst Posted
Study publicly available on registry
June 3, 2024
CompletedStudy Start
First participant enrolled
May 5, 2025
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 1, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
June 1, 2027
April 13, 2026
February 1, 2026
2.1 years
May 31, 2024
April 9, 2026
Conditions
Outcome Measures
Primary Outcomes (3)
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.
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.
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.
Up to 30 days after last dose of study treatment
Secondary Outcomes (5)
Objective response rate (ORR)
At 9 weeks
Progression-free survival (PFS)
At initial treatment to progression or death up to 2 years after last dose of study treatment
Overall survival (OS)
At start of study treatment to death up to 2 years after last dose of study treatment
Duration of response (DOR)
At first response to progression or death up to 2 years after last dose of study treatment
2IR scores
At baseline and up to 2 years after last dose of study treatment
Other Outcomes (8)
Clinical benefit rate (CBR)
At 9 weeks
High-sensitivity C-reactive protein (hsCRP)
At 9 weeks
Cyotkines and chemokines
At baseline and up to 2 years after last dose of study treatment
- +5 more other outcomes
Study Arms (1)
Treatment (CA-4948, pembrolizumab)
EXPERIMENTALPatients 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
Undergo PET
Undergo tumor biopsy
Undergo blood sample collection
Undergo CT
Given IV
Undergo MRI
Given PO
Eligibility Criteria
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
- +30 more criteria
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)
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (11)
City of Hope Comprehensive Cancer Center
Duarte, California, 91010, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612, United States
UC San Diego Moores Cancer Center
La Jolla, California, 92093, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136, United States
Emory University Hospital Midtown
Atlanta, Georgia, 30308, United States
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322, United States
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342, United States
Mount Sinai Hospital
New York, New York, 10029, United States
NYP/Weill Cornell Medical Center
New York, New York, 10065, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Matthew D Galsky
MOUNT SINAI HOSPITAL
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
May 31, 2024
First Posted
June 3, 2024
Study Start
May 5, 2025
Primary Completion (Estimated)
June 1, 2027
Study Completion (Estimated)
June 1, 2027
Last Updated
April 13, 2026
Record last verified: 2026-02
Data Sharing
- IPD Sharing
- Will share
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.