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Essai clinique du CA-4948 ajouté à la chimiothérapie standard pour traiter le cancer du pancréas métastatique ou non résécable

31 octobre 2026 mis à jour par: National Cancer Institute (NCI)

Un essai clinique de phase I du CA-4948 en association avec la gemcitabine et le nab-paclitaxel dans le carcinome canalaire pancréatique métastatique ou non résécable

This phase I trial tests the safety, side effects, and best dose of emavusertib (CA-4948) in combination with gemcitabine and nab-paclitaxel in treating patients with pancreatic ductal adenocarcinoma that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable). CA-4948 is in a class of medications called kinase inhibitors. It works by blocking the action of abnormal proteins called interleukin-1 receptor-associated kinase 4 (IRAK4) and FMS-like tyrosine kinase 3 (FLT3) that signal cells to multiply. This may help keep cancer cells from growing. The usual approach for patients with pancreatic ductal adenocarcinoma is treatment with chemotherapy drugs gemcitabine and nab-paclitaxel. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill cancer cells. Paclitaxel is in a class of medications called anti-microtubule agents. It stops cancer cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Giving CA-4948 in combination with gemcitabine and nab-paclitaxel may shrink or stabilize metastatic or unresectable pancreatic ductal adenocarcinoma.

Aperçu de l'étude

Statut

Suspendu

Les conditions

Intervention / Traitement

Description détaillée

PRIMARY OBJECTIVE:

I. To assess dose limiting toxicities and determine the recommended phase 2 dose of emavusertib (CA--4948) in combination with chemotherapy in patients with pancreatic ductal adenocarcinoma.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To evaluate the safety and tolerability of the combination of CA-4948 and chemotherapy.

III. To determine preliminary signals of efficacy, as measured by objective response rate (ORR), CA-4948 response, progression free survival (PFS), and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To evaluate pharmacodynamic effect of CA-4948 in combination with chemotherapy.

II. To evaluate pharmacokinetics of CA-4948 in combination with chemotherapy. III. To explore biomarkers and genomic alterations associated with treatment response.

OUTLINE: This is a dose-escalation study of CA-4948 in combination with fixed-dose gemcitabine and nab-paclitaxel followed by a dose-expansion study.

Patients receive CA-4948 orally (PO) twice daily (BID) on days 1-21 or 1-28 of each cycle, gemcitabine intravenously (IV) over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT), tumor biopsies, and blood sample collection throughout the trial.

After completion of study treatment, patients are followed every 3 months for 1 year.

Type d'étude

Interventionnel

Inscription (Estimé)

43

Phase

  • La phase 1

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

  • États-Unis
    • California
      • Duarte, California, États-Unis, 91010
        • City of Hope Comprehensive Cancer Center
      • Irvine, California, États-Unis, 92612
        • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
      • Orange, California, États-Unis, 92868
        • UC Irvine Health/Chao Family Comprehensive Cancer Center
    • Colorado
      • Aurora, Colorado, États-Unis, 80045
        • UCHealth University of Colorado Hospital
    • Illinois
      • Chicago, Illinois, États-Unis, 60611
        • Northwestern University
      • Shiloh, Illinois, États-Unis, 62269
        • Memorial Hospital East
    • Kentucky
      • Lexington, Kentucky, États-Unis, 40536
        • University of Kentucky/Markey Cancer Center
    • Maryland
      • Baltimore, Maryland, États-Unis, 21287
        • Johns Hopkins University/Sidney Kimmel Cancer Center
      • Bethesda, Maryland, États-Unis, 20892
        • National Institutes of Health Clinical Center
      • Bethesda, Maryland, États-Unis, 20892
        • National Cancer Institute Developmental Therapeutics Clinic
    • Missouri
      • City of Saint Peters, Missouri, États-Unis, 63376
        • Siteman Cancer Center at Saint Peters Hospital
      • Creve Coeur, Missouri, États-Unis, 63141
        • Siteman Cancer Center at West County Hospital
      • St Louis, Missouri, États-Unis, 63110
        • Washington University School of Medicine
      • St Louis, Missouri, États-Unis, 63129
        • Siteman Cancer Center-South County
      • St Louis, Missouri, États-Unis, 63136
        • Siteman Cancer Center at Christian Hospital
    • New York
      • Mineola, New York, États-Unis, 11501
        • NYU Langone Hospital - Long Island
      • New York, New York, États-Unis, 10032
        • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
      • New York, New York, États-Unis, 10016
        • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • North Carolina
      • Chapel Hill, North Carolina, États-Unis, 27599
        • UNC Lineberger Comprehensive Cancer Center
    • Ohio
      • Cincinnati, Ohio, États-Unis, 45219
        • University of Cincinnati Cancer Center-UC Medical Center
      • Columbus, Ohio, États-Unis, 43210
        • Ohio State University Comprehensive Cancer Center
      • West Chester, Ohio, États-Unis, 45069
        • University of Cincinnati Cancer Center-West Chester
    • Oklahoma
      • Oklahoma City, Oklahoma, États-Unis, 73104
        • University of Oklahoma Health Sciences Center
    • Pennsylvania
      • Pittsburgh, Pennsylvania, États-Unis, 15232
        • UPMC Hillman Cancer Center
    • Wisconsin
      • Madison, Wisconsin, États-Unis, 53792
        • University of Wisconsin Carbone Cancer Center - University Hospital
      • Madison, Wisconsin, États-Unis, 53718
        • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans et plus (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed adenocarcinoma of the pancreas that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
  • Patients must have had disease progression on or after fluorouracil (5-FU)-based therapy for metastatic or unresectable pancreatic ductal adenocarcinoma (PDAC). If received gemcitabine-based regimen as adjuvant therapy, then gemcitabine and nab-paclitaxel (if used) should be >12 months from study enrollment. Prior use of gemcitabine/nab-paclitaxel for metastatic or unresectable disease is not allowed
  • Age >= 18 years. Because no dosing or adverse event data are currently available on the use of CA-4948 in combination with gemcitabine and nab-paclitaxel in patients < 18 years of age, children are excluded from this study
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
  • Glomerular filtration rate (GFR) >= 60 mL/min (based on the calculated Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] glomerular filtration rate estimation)
  • Creatine phosphokinase (CPK) elevation at the screening < grade 2 (creatine phosphokinase [CPK] =< 2.5 ULN)
  • Patients on a cholesterol lowering statin must be on a stable dose with no dose changes within 3 weeks prior to study start
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial as long as their anti-retroviral therapy does not have the potential for drug-drug interactions as judged by the treating investigator
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Patients with treated brain metastases are eligible if follow-up brain imaging after at least 4 weeks following central nervous system (CNS)-directed therapy shows no evidence of progression
  • 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 are eligible for this trial
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
  • Patients must have lesions amenable to research biopsy for those enrolling to the expansion cohort. The biopsy should be deemed feasible and safe for pre-biopsy lesion assessment criteria
  • The effects of CA-4948, nab-paclitaxel, and gemcitabine on the developing human fetus are unknown. For this reason and because gemcitabine is known to be teratogenic, embryotoxic, and fetotoxic in mice and rabbits, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 90 days after completion of CA-4948, nab-paclitaxel, and gemcitabine administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of CA-4948, nab-paclitaxel, and gemcitabine administration
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible
  • Patients must have measurable disease per Response Evaluable Criteria in Solid Tumors (RECIST) 1.1

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
  • Patients who have not recovered from clinically significant adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of neuropathy, which should resolve to grade 2, or alopecia
  • History of other malignancy with the exception of 1) malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease; 2) or known indolent malignancies that do not require treatment and will likely not alter the course of treatment of disease under treatment
  • History of allogeneic organ or stem cell transplant
  • Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment
  • Patients who are receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to CA-4948 or other agents used in study
  • Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible due to CA-4948 and nab-paclitaxel. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • Patients with uncontrolled intercurrent illness
  • Pregnant women are excluded from this study because gemcitabine is nucleoside analogue 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 gemcitabine, breastfeeding should be discontinued if the mother is treated with gemcitabine. These potential risks may also apply to other agents used in this study
  • Prolonged Fridericia's correction formula (QTcF) (> 470 in females, > 450 in males) on screening electrocardiogram (ECG)
  • Gastrointestinal condition which could impair absorption of CA-4948 or inability to ingest CA-4948
  • Severe obstructive pulmonary disease or interstitial lung disease
  • History of rhabdomyolysis or elevated creatine phosphokinase (CPK)

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: N / A
  • Modèle interventionnel: Affectation à un seul groupe
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: Treatment (CA-4948, gemcitabine, nab-paclitaxel)

Patients receive CA-4948 PO BID on days 1-21 or 1-28 of each cycle, gemcitabine IV over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, tumor biopsies, and blood sample collection throughout the trial.
Procédure: Biospecimen Collection

Undergo blood sample collection

Autres noms:
  • Collecte d'échantillons biologiques
  • Spécimen biologique collecté
  • Collecte de spécimens
  • Collection d'échantillons
Médicament: Gemcitabine Hydrochloride

Given IV

Autres noms:
  • Gemzar
  • dFdCyd
  • Chlorhydrate de difluorodésoxycytidine
  • Gemcitabine HCI
  • LY-188011
  • LY188011
  • LY 188011
Procédure: Computed Tomography

Undergo a CT scan

Autres noms:
  • TDM
  • CHAT
  • Scanner
  • Tomographie axiale informatisée
  • Tomographie assistée par ordinateur
  • Tomodensitométrie
  • tomographie
  • Tomographie axiale informatisée (procédure)
  • Tomodensitométrie (TDM)
  • Scan de chat diagnostique
  • Type de service de scan de chat diagnostique
Procédure: Biopsy Procedure

Undergo tumor biopsies

Autres noms:
  • Bx
  • BIOPSIE_TYPE
  • Biopsie
Médicament: Nab-paclitaxel

Given IV

Autres noms:
  • ABI-007
  • Abraxane
  • Paclitaxel lié à l'albumine
  • ABI 007
  • Paclitaxel à nanoparticules stabilisées à l'albumine
  • Paclitaxel lié à l'albumine de nanoparticules
  • Paclitaxel à nanoparticules
  • Paclitaxel Albumine
  • formulation de nanoparticules stabilisées à l'albumine de paclitaxel
  • Paclitaxel lié aux protéines
  • ABI007
  • Paclitaxel Nanoparticules liées à l'albumine
  • Navéruclif
Biologique: Emavusertib

Given PO

Autres noms:
  • CA-4948
  • AU 4948
  • AU-4948
  • CA 4948
  • CA4948
  • Inhibiteur de la kinase 4 associée au récepteur de l'interleukine-1 CA-4948
  • Inhibiteur IRAK4 CA-4948

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
Dose limiting toxicity rate
Délai: Up to 1 year

Done to determine the maximum tolerated dose for the combination of CA-4948 and gemcitabine/nab-paclitaxel chemotherapy backbone. Data analysis of the study will be descriptive in nature. Demographic and clinical characteristics of the sample, toxicity by severity, as well as loss to follow-up will be summarized using descriptive statistics. Safety endpoints will be listed for each dose level.
Up to 1 year

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Incidence of adverse events
Délai: Up to 1 year

Tabulations of adverse events will be produced by severity and by relationship to study drug.
Up to 1 year
Overall response rate (ORR)
Délai: Up to 1 year

For efficacy data in the expansion cohort, ORR and its 95% confidence interval will be calculated.
Up to 1 year
Progression-free survival (PFS)
Délai: From start of study treatment to time of progression or death, whichever occurs first, assessed up to 1 year

Will be described using Kaplan-Meier product limit methods.
From start of study treatment to time of progression or death, whichever occurs first, assessed up to 1 year
Overall survival (OS)
Délai: Up to 1 year

Will be described using Kaplan-Meier product limit methods.
Up to 1 year

Autres mesures de résultats

Mesure des résultats
Description de la mesure
Délai
Pharmacodynamic effect of CA-4948 in combination with chemotherapy
Délai: Up to 1 year

Pharmacodynamic indices from biopsies obtained from expansion cohorts will be summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point and the change will be compared by paired t-test or Wilcoxon rank-sum test as appropriate.
Up to 1 year
Pharmacokinetics (PK) of both CA-4948 and nab-paclitaxel
Délai: Cycle 1 day 1 (C1D1) (pre-dose, 0.5, 1, 2, 4, 6, 8 hours [h]), C1D8 (pre-dose), C2D1 (pre-dose, 0.5, 1, 2, 4, 6, 8h), C2D2: (24h post C2D1 dose), C2D8 (pre-dose), C3D1 (pre-dose), C3D17 (+/- 3 d)

Done to confirm whether a clinically relevant drug-drug interaction occurs. Plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied in the Phoenix WinNonlin Professional software package. Exposure obtained by noncompartmental methods will also be compared to toxicity and efficacy outcomes using graphical and statistical programs. A formal population PK or exposure-response analyses may be conducted based on these initial findings.
Cycle 1 day 1 (C1D1) (pre-dose, 0.5, 1, 2, 4, 6, 8 hours [h]), C1D8 (pre-dose), C2D1 (pre-dose, 0.5, 1, 2, 4, 6, 8h), C2D2: (24h post C2D1 dose), C2D8 (pre-dose), C3D1 (pre-dose), C3D17 (+/- 3 d)

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

National Cancer Institute (NCI)

Les enquêteurs

  • Chercheur principal: Patrick Grierson, Yale University Cancer Center LAO

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude (Réel)

12 juin 2023

Achèvement primaire (Estimé)

30 avril 2027

Achèvement de l'étude (Estimé)

30 avril 2027

Dates d'inscription aux études

Première soumission

13 janvier 2023

Première soumission répondant aux critères de contrôle qualité

13 janvier 2023

Première publication (Réel)

17 janvier 2023

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Réel)

3 novembre 2026

Dernière mise à jour soumise répondant aux critères de contrôle qualité

31 octobre 2026

Dernière vérification

1 septembre 2026

Plus d'information

Termes liés à cette étude

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • NCI-2022-08984
  • UM1CA186689 (Subvention/contrat des NIH des États-Unis)
  • NCI-2022-08984 (Identificateur de registre: CTRP (Clinical Trial Reporting Program))
  • 10522 (Autre identifiant: CTEP)
  • 202304010
  • 10522 (Autre identifiant: Yale University Cancer Center LAO)

Plan pour les données individuelles des participants (IPD)

Prévoyez-vous de partager les données individuelles des participants (DPI) ?

OUI

Description du régime IPD

"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."

Informations sur les médicaments et les dispositifs, documents d'étude

Étudie un produit pharmaceutique réglementé par la FDA américaine

Oui

Étudie un produit d'appareil réglementé par la FDA américaine

Non

Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .

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