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Combining pembrolizumab and CA-4948 for advanced urothelial cancer treatment

Phase 1 Trial of CA-4948 in Combination With Pembrolizumab to Overcome Resistance to PD-1/PD-L1 Blockade in Metastatic Urothelial Cancer

Phase 1 Interventional National Cancer Institute (NCI) · NCT06439836

This study is testing a new combination of two drugs, pembrolizumab and CA-4948, to see if it can help people with advanced urothelial cancer that hasn't responded to other treatments.

Quick facts

PhasePhase 1
Study typeInterventional
Enrollment27 (estimated)
Ages18 Years and up
SexAll
SponsorNational Cancer Institute (NCI) NIH
Drugs / interventionspembrolizumab, Enfortumab, chemotherapy, Immunotherapy, prednisone
Locations11 sites (Duarte, California and 10 other locations)
Trial IDNCT06439836 on ClinicalTrials.gov

What this trial studies

This phase I trial evaluates the safety and effectiveness of the combination of CA-4948, a kinase inhibitor, and pembrolizumab, an immune checkpoint inhibitor, in patients with metastatic urothelial cancer that has shown resistance to prior immunotherapy. The study aims to determine the recommended dose of this combination and assess its anti-tumor activity, progression-free survival, and overall survival. Patients will undergo various assessments, including tumor biopsies and imaging, to monitor treatment responses and safety. The trial includes both dose escalation and expansion cohorts to gather comprehensive data on the treatment's effects.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with histologically confirmed metastatic or unresectable urothelial cancer that has not responded to standard treatments.

Not a fit: Patients with early-stage urothelial cancer or those who have not received prior immunotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with advanced urothelial cancer who have not responded to existing immunotherapies.

How similar studies have performed: While this approach is novel in combining CA-4948 with pembrolizumab for this specific patient population, similar immunotherapy combinations have shown promise in other cancer types.

Eligibility criteria

Show full inclusion / exclusion criteria 
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)

Where this trial is running

Duarte, California and 10 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Metastatic Urothelial CarcinomaUnresectable Urothelial Carcinoma
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.