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Back|NCT06439836Recruiting
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

Phase
Phase 1
Sponsor
National Cancer Institute (NCI)
Enrollment
27
Timeline
May 2025 → Jun 2027
About This Study

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.

Eligibility Criteria

Inclusion Criteria

  • 1Patients must have histologically confirmed urothelial cancer that is metastatic or unresectable and must have had the prior treatments outlined
  • 2Age ≥ 18 years
  • 3Because 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
  • 4Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%) within 28 days prior to registration
  • 5Leukocytes ≥ 3,000/mcL
  • 6Absolute neutrophil count (ANC) ≥ 1,500/mcL
  • 7Platelets ≥ 100,000/mcL
  • 8Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L
  • 9Criteria 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)
  • 10Creatine phosphokinase (CPK) \< grade (Gr) 2 ( \</= 2.5 upper limit of normal \[ULN\])
  • 11Creatinine \< 1.5 × institutional ULN or creatinine clearance of ≥ 30 mL/min for patient with creatine levels ≥ 1.5 x institutional ULN
  • 12Creatinine clearance (CrCl) should be calculated per institutional standard
  • 13Total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)
  • 14Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) ≤ 3 x ULN
  • 15Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x ULN
  • 16International 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
  • 17Activated 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
  • 18Ability 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)
  • 19Measurable metastatic or unresectable disease
  • 20Must have received prior treatment with a PD-1 or PD-L1 inhibitor
  • 21Must have received at least one of the following (may have been administered concurrently or sequentially with PD-1/PD-L1 inhibitor):
  • 22Platinum-based chemotherapy
  • 23Enfortumab vedotin
  • 24Primary resistance to PD-1/PD-L1 blockade as defined by Society for Immunotherapy of Cancer (SITC) consensus definitions:
  • 25For patients who received single-agent PD-1/PD-L1 blockade in the adjuvant setting:
  • 26Must have received ≥ 6 weeks of treatment with PD-1/PD-L1 blockade
  • 27Recurrence while on treatment or within ≤ 3 months after completion of therapy
  • 28For patients who received single-agent PD-1/PD-L1 blockade in the metastatic setting:
  • 29Must have received ≥ 6 weeks of treatment with PD-1/PD-L1 blockade
  • 30Progression within ≤ 6 months of initiating treatment with single-agent PD-1/PD-L1 blockade with best response of stable disease
  • 31For patients who received single-agent PD-1/PD-L1 blockade in the switch-maintenance setting:
  • 32Must have received ≥ 6 weeks of treatment with PD-1/PD-L1 blockade
  • 33Progression within ≤ 6 months of initiating treatment with single-agent PD-1/PD-L1 blockade
  • 34For patients who received an antibody-drug conjugate or cytotoxic chemotherapy plus PD-1/PD-L1 blockade combination
  • 35Must have received ≥ 6 weeks of treatment with PD-1/PD-L1 blockade
  • 36Progression within ≤ 12 months of initiating treatment
  • 37An 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)
  • 38Female 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
  • 39Male 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
  • 40HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • 41Patients who have received messenger ribonucleic acid (mRNA) COVID-19 and influenza vaccines will be allowed
  • 42Patients 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
  • 43Patients 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
  • 44Patients should be willing and able to swallow pills
  • 45Ability 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

  • 1Patients 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
  • 2Diagnosis 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
  • 3Grade ≥ 3 immune related adverse event with prior PD-1/PD-L1 blockade
  • 4History of allergic reactions attributed to compounds of similar chemical or biologic composition to CA-4948 and/or pembrolizumab
  • 5Patients 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
  • 6Patients who are receiving any other investigational agents
  • 7Patients with carcinomatous meningitis
  • 8Patients with malabsorption syndrome or other conditions that would interfere with intestinal absorption
  • 9Has 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
  • 10Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • 11Has 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
  • 12Has received a live vaccine within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted
  • 13Pregnant 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
  • 14Has 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)
  • 15Has a known history of active tuberculosis (TB)

Locations

9 sites participating in this study

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia 30322

Recruiting

Jacqueline T. Brown

City of Hope Comprehensive Cancer Center

Duarte, California 91010

Recruiting

Abhishek Tripathi

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Irvine, California 92612

Recruiting

Nataliya Mar

Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →