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

Plain English Summary

Pembrolizumab Plus CA-4948 for the Treatment of Patients With Progressive Metastatic Urothelial Cancer Despite Prior Immunotherapy is a Phase 1 clinical trial sponsored by National Cancer Institute (NCI) studying Metastatic Urothelial Carcinoma, Unresectable Urothelial Carcinoma. This trial tests a new drug combination (emavusertib plus pembrolizumab) for advanced bladder cancer that has stopped responding to a common type of immunotherapy. It is for adults with metastatic urothelial cancer that has progressed despite prior treatment with immunotherapy and chemotherapy or a specific targeted therapy. Participants will receive the study drugs and undergo regular tests, including imaging scans and blood draws. Standard treatments for advanced bladder cancer include chemotherapy, immunotherapy, and targeted therapies, depending on the specific characteristics of the cancer. The trial aims to enroll 27 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with a confirmed diagnosis of urothelial cancer that has spread or cannot be removed surgically. Patients must have previously received treatment with a PD-1 or PD-L1 inhibitor and either platinum-based chemotherapy or enfortumab vedotin. Individuals whose cancer has shown resistance to immunotherapy, meaning it did not respond or stopped responding within a specific timeframe after treatment. Patients must have adequate blood counts, kidney, liver, and heart function, and a general health status that allows them to participate in the trial. This trial is studying Metastatic Urothelial Carcinoma, Unresectable Urothelial Carcinoma, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcomes measure the highest dose of the new drug that can be safely given and any side effects that occur, helping to determine if this combination is safe enough for further testing. The specific primary outcome measures are: Dose limiting toxicities (DLTs) (Up to completion of cycle 1); Recommended phase 2 dose (RP2D) (Up to completion of cycle 1); Incidence of AEs (Up to 30 days after last dose of study treatment). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial addresses a critical need for new treatments in patients with advanced bladder cancer who have become resistant to current immunotherapy options, a growing challenge in the field. This research targets Metastatic Urothelial Carcinoma, Unresectable Urothelial Carcinoma, where improved treatment options are needed.

Investor Insight

This Phase 1 trial is an early-stage investigation, but success could lead to a new treatment option for a difficult-to-treat cancer, potentially impacting a significant market for urothelial cancer t Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of this new combination therapy compared to other available treatments. Understand that you will need to attend regular appointments for drug administration, monitoring, and tests, which may include biopsies. Be prepared for potential side effects and discuss any new or worsening symptoms with your healthcare team immediately. This trial is currently recruiting participants. The trial is being conducted at 11 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 27 participants

Interventions

• PROCEDURE: Biopsy Procedure — Undergo tumor biopsy
• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• PROCEDURE: Computed Tomography — Undergo CT
• BIOLOGICAL: Emavusertib — Given PO
• PROCEDURE: Magnetic Resonance Imaging — Undergo MRI

Primary Outcomes

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

Secondary Outcomes

• 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)

Full Eligibility 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 wi

Trial Locations

• City of Hope Comprehensive Cancer Center, Duarte, California, United States
• UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care, Irvine, California, United States
• UC San Diego Moores Cancer Center, La Jolla, California, United States
• UC Irvine Health/Chao Family Comprehensive Cancer Center, Orange, California, United States
• University of Miami Miller School of Medicine-Sylvester Cancer Center, Miami, Florida, United States
• Emory University Hospital Midtown, Atlanta, Georgia, United States
• Emory University Hospital/Winship Cancer Institute, Atlanta, Georgia, United States
• Emory Saint Joseph's Hospital, Atlanta, Georgia, United States
• Mount Sinai Hospital, New York, New York, United States
• NYP/Weill Cornell Medical Center, New York, New York, United States
• ...and 1 more locations

Frequently Asked Questions

Related Conditions

• Bladder Cancer
• Urothelial Carcinoma
• Metastatic Cancer
• Kidney Cancer
• Prostate Cancer
• Immunotherapy Resistance
• Kinase Inhibitors
• Oncology
• Genitourinary Cancers
• Neoadjuvant Therapy

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