CA-4948 Added to Standard Chemotherapy to Treat Metastatic or Unresectable Pancreatic Cancer

April 6, 2024 updated by: National Cancer Institute (NCI)

A Phase I Clinical Trial of CA-4948 in Combination With Gemcitabine and Nab-Paclitaxel in Metastatic or Unresectable Pancreatic Ductal Carcinoma

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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), gemcitabine intravenously (IV), and nab-paclitaxel IV on study. Patients undergo magnetic resonance imaging (MRI), computed tomography (CT) scan, positron emission tomography (PET) scan, and/or x-ray imaging throughout the trial. Patients also undergo tumor biopsies and blood sample collection during screening and on study.

Study Type

Interventional

Enrollment (Estimated)

36

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Duarte, California, United States, 91010
        • Recruiting
        • City of Hope Comprehensive Cancer Center
        • Contact:
        • Principal Investigator:
          • Vincent Chung
      • Orange, California, United States, 92868
        • Recruiting
        • UC Irvine Health/Chao Family Comprehensive Cancer Center
        • Contact:
        • Principal Investigator:
          • Farshid Dayyani
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • UCHealth University of Colorado Hospital
        • Contact:
          • Site Public Contact
          • Phone Number: 720-848-0650
        • Principal Investigator:
          • Robert W. Lentz
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Recruiting
        • Yale University Cancer Center LAO
        • Contact:
        • Principal Investigator:
          • Patrick Grierson
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Recruiting
        • Northwestern University
        • Principal Investigator:
          • Mary F. Mulcahy
        • Contact:
      • Shiloh, Illinois, United States, 62269
        • Recruiting
        • Memorial Hospital East
        • Contact:
        • Principal Investigator:
          • Patrick Grierson
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • Recruiting
        • University of Kentucky/Markey Cancer Center
        • Contact:
          • Site Public Contact
          • Phone Number: 859-257-3379
        • Principal Investigator:
          • Reema A. Patel
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Recruiting
        • Johns Hopkins University/Sidney Kimmel Cancer Center
        • Principal Investigator:
          • Ana D. De Jesus Acosta
        • Contact:
      • Bethesda, Maryland, United States, 20892
        • Recruiting
        • National Institutes of Health Clinical Center
        • Contact:
          • Site Public Contact
          • Phone Number: 800-411-1222
        • Principal Investigator:
          • Naoko Takebe
      • Bethesda, Maryland, United States, 20892
        • Recruiting
        • National Cancer Institute Developmental Therapeutics Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 800-411-1222
        • Principal Investigator:
          • Naoko Takebe
    • Missouri
      • Creve Coeur, Missouri, United States, 63141
        • Recruiting
        • Siteman Cancer Center at West County Hospital
        • Contact:
        • Principal Investigator:
          • Patrick Grierson
      • Saint Louis, Missouri, United States, 63110
        • Recruiting
        • Washington University School of Medicine
        • Contact:
        • Principal Investigator:
          • Patrick Grierson
      • Saint Louis, Missouri, United States, 63129
        • Recruiting
        • Siteman Cancer Center-South County
        • Contact:
        • Principal Investigator:
          • Patrick Grierson
      • Saint Louis, Missouri, United States, 63136
        • Recruiting
        • Siteman Cancer Center at Christian Hospital
        • Contact:
        • Principal Investigator:
          • Patrick Grierson
      • Saint Peters, Missouri, United States, 63376
        • Recruiting
        • Siteman Cancer Center at Saint Peters Hospital
        • Contact:
        • Principal Investigator:
          • Patrick Grierson
    • New York
      • Mineola, New York, United States, 11501
        • Recruiting
        • NYU Winthrop Hospital
        • Principal Investigator:
          • Kristen R. Spencer
        • Contact:
      • New York, New York, United States, 10032
        • Recruiting
        • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
        • Principal Investigator:
          • Gulam A. Manji
        • Contact:
      • New York, New York, United States, 10016
        • Recruiting
        • Laura and Isaac Perlmutter Cancer Center at NYU Langone
        • Principal Investigator:
          • Kristen R. Spencer
        • Contact:
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • Recruiting
        • UNC Lineberger Comprehensive Cancer Center
        • Contact:
        • Principal Investigator:
          • Ashwin Somasundaram
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • Recruiting
        • University of Cincinnati Cancer Center-UC Medical Center
        • Contact:
        • Principal Investigator:
          • Davendra P. Sohal
      • Columbus, Ohio, United States, 43210
        • Recruiting
        • Ohio State University Comprehensive Cancer Center
        • Principal Investigator:
          • Shafia Rahman
        • Contact:
      • West Chester, Ohio, United States, 45069
        • Recruiting
        • University of Cincinnati Cancer Center-West Chester
        • Contact:
        • Principal Investigator:
          • Davendra P. Sohal
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Recruiting
        • University of Oklahoma Health Sciences Center
        • Contact:
        • Principal Investigator:
          • Susanna V. Ulahannan
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15232
        • Recruiting
        • University of Pittsburgh Cancer Institute (UPCI)
        • Contact:
          • Site Public Contact
          • Phone Number: 412-647-8073
        • Principal Investigator:
          • Janie Y. Zhang
    • Wisconsin
      • Madison, Wisconsin, United States, 53792
        • Recruiting
        • University of Wisconsin Carbone Cancer Center
        • Principal Investigator:
          • Monica A. Patel
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

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 6 months 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 3 months 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

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 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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (CA-4948, gemcitabine, nab-paclitaxel)
Patients receive CA-4948 orally (PO), gemcitabine intravenously (IV), and nab-paclitaxel IV on study. Patients undergo magnetic resonance imaging (MRI), computed tomography (CT) scan, positron emission tomography (PET) scan, and/or x-ray imaging throughout the trial. Patients also undergo tumor biopsies and blood sample collection during screening and on study.
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
  • MRI
  • Magnetic Resonance
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI Scan
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • Magnetic Resonance Imaging (MRI)
  • sMRI
  • Magnetic resonance imaging (procedure)
  • MRIs
  • Structural MRI
Drug: Nab-paclitaxel
Given IV
Other Names:
  • ABI-007
  • Abraxane
  • Albumin-bound Paclitaxel
  • ABI 007
  • Albumin-Stabilized Nanoparticle Paclitaxel
  • Nanoparticle Albumin-bound Paclitaxel
  • Nanoparticle Paclitaxel
  • Paclitaxel Albumin
  • paclitaxel albumin-stabilized nanoparticle formulation
  • Protein-bound Paclitaxel
  • Paclitaxel Protein-Bound
  • Paclitaxel Nanoparticle Albumin-bound
Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • Gemzar
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemcitabine HCI
  • LY-188011
  • LY188011
Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
Procedure: Computed Tomography
Undergo a CT scan
Other Names:
  • CT
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT Scan
  • tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography (CT) scan
Procedure: X-Ray Imaging
Undergo an x-ray
Other Names:
  • Conventional X-Ray
  • Diagnostic Radiology
  • Medical Imaging, X-Ray
  • Radiographic Imaging
  • Radiography
  • RG
  • Static X-Ray
  • X-Ray
  • Plain film radiographs
  • Radiographic imaging procedure (procedure)
Procedure: Positron Emission Tomography
Undergo a PET scan
Other Names:
  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging
  • PT
  • Positron emission tomography (procedure)
Procedure: Biopsy
Undergo a tumor biopsy
Other Names:
  • Bx
  • BIOPSY_TYPE
Biological: Emavusertib
Given PO
Other Names:
  • CA-4948
  • AU 4948
  • AU-4948
  • CA 4948
  • CA4948
  • Interleukin-1 Receptor-associated Kinase 4 Inhibitor CA-4948
  • IRAK4 Inhibitor CA-4948

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose limiting toxicity rate
Time Frame: 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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of adverse events
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: Up to 1 year
Will be described using Kaplan-Meier product limit methods.
Up to 1 year

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacodynamic effect of CA-4948 in combination with chemotherapy
Time Frame: 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
Time Frame: Up to 1 year
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.
Up to 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Patrick Grierson, Yale University Cancer Center LAO

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 12, 2023

Primary Completion (Estimated)

March 15, 2025

Study Completion (Estimated)

March 15, 2025

Study Registration Dates

First Submitted

January 13, 2023

First Submitted That Met QC Criteria

January 13, 2023

First Posted (Actual)

January 17, 2023

Study Record Updates

Last Update Posted (Actual)

April 9, 2024

Last Update Submitted That Met QC Criteria

April 6, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2022-08984 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • UM1CA186689 (U.S. NIH Grant/Contract)
  • 10522 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

"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."

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Stage III Pancreatic Cancer AJCC v8

Clinical Trials on Magnetic Resonance Imaging

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Indonesia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe