Metastatic Urothelial CarcinomaPhase 1NCT06439836
Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy
A Phase 1 study testing Biopsy Procedure, Biospecimen Collection and Computed Tomography in people with Metastatic Urothelial Carcinoma and Unresectable Urothelial Carcinoma, run by National Cancer Institute (NCI) at 11 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Urothelial Carcinoma, Unresectable Urothelial Carcinoma
- What is being tested?
- Biopsy Procedure, Biospecimen Collection and Computed Tomography
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 11 sitesUnited States
- Study dates
- 5 May 2025to 1 Jun 2027
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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)
Trial locations and contacts
11 sites in 1 country. Contact the study team or a site near you to ask about taking part.
11 sites in 1 country
United States11 sites, 11 recruiting
- Recruiting
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Site Public Contact, 888-946-7447
Jacqueline T. Brown
- Recruiting
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Site Public Contact, 404-778-1868
Jacqueline T. Brown
- Recruiting
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342
Site Public Contact, 404-851-7115
Jacqueline T. Brown
- Recruiting
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
Site Public Contact, 214-648-7097, canceranswerline@UTSouthwestern.edu
Waddah Arafat
- Recruiting
City of Hope Comprehensive Cancer Center
Duarte, California, 91010
Site Public Contact, 800-826-4673, becomingapatient@coh.org
Abhishek Tripathi
- Recruiting
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612
Site Public Contact, 877-827-8839, ucstudy@uci.edu
Nataliya Mar
- Recruiting
UC San Diego Moores Cancer Center
La Jolla, California, 92093
Site Public Contact, 858-822-5354, cancercto@ucsd.edu
Tyler Stewart
- Recruiting
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136
Site Public Contact, 305-243-2647
Jaime R. Merchan
- Recruiting
Mount Sinai Hospital
New York, New York, 10029
Site Public Contact, 212-824-7309, CCTO@mssm.edu
Matthew D. Galsky
- Recruiting
NYP/Weill Cornell Medical Center
New York, New York, 10065
Site Public Contact, 212-746-1848
Rohit Jain
- Recruiting
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
Site Public Contact, 877-827-8839, ucstudy@uci.edu
Nataliya Mar
About this study
Official title: Phase 1 Trial of CA-4948 in Combination With Pembrolizumab to Overcome Resistance to PD-1/PD-L1 Blockade in Metastatic Urothelial Cancer
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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:
- 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).
- 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.
- 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.
- Being tested
- Biopsy Procedure, Biospecimen Collection, Computed Tomography, Emavusertib, Magnetic Resonance Imaging
- Medical subject headings
- Carcinoma, Transitional Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo tumor biopsy
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo blood sample collection
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
EmavusertibBiological
Also called AU 4948, AU-4948, CA 4948, CA-4948
Given PO
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
PembrolizumabBiological
Also called BCD-201, GME 751, GME751, Keytruda
Given IV
Positron Emission TomographyProcedure or surgery
Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)
Undergo PET
| Study group | Role | What they receive |
|---|---|---|
| Treatment (CA-4948, pembrolizumab) | Experimental | 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. Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Emavusertib; Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Procedure: Positron Emission Tomography |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: Up to 30 days after last dose of study treatment
Secondary outcomes (5)
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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: At baseline and up to 2 years after last dose of study treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jun 2024
- Study start5 May 2025
- Primary completion1 Jun 2027 (estimated)
- Study completion1 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Urothelial CarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 27 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Matthew D Galsky, Principal investigator, MOUNT SINAI HOSPITAL
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06439836
- Sponsor's protocol ID
- NCI-2024-04436
- Other IDs
- NCI-2024-04436, 10636, 10636
- Status last verified
- Sep 2026
- First submitted
- 31 May 2024
- Last updated
- 21 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- 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.