ESK981 in Treating Patients With Metastatic Castrate-Resistant Prostate Cancer

June 24, 2023 updated by: Elisabeth Heath, Barbara Ann Karmanos Cancer Institute

An Open-Label, Parallel, Phase II Study of Single-Agent Oral ESK981 in Men With Castrate-Resistant Prostate Cancer (CRPC)

This phase II trials studies the side effects and how well ESK981 works in treating patients with castration-resistant prostate cancer that has spread to other places in the body. ESK981 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Study Overview

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the PSA >= 50% response rate (PSA50) from baseline using the Prostate Cancer Working Group 3 (PCWG3) criteria to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981) as a single agent in men with castration-resistant prostate cancer (CRPC) who have progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor).

II. To assess the safety and tolerability of ESK981 as a single agent.

SECONDARY OBJECTIVES:

I. To determine the time to PSA response to ESK981 in metastatic CRPC patients. II. To determine the duration of PSA response to ESK981 in metastatic CRPC patients.

III. To determine PSA progression rates and PSA progression free survival (PFS), as defined by the PCWG3 criteria.

TERTIARY OBJECTIVES:

I. To assess exploratory biomarkers from blood and tumor biopsies.

OUTLINE:

Patients receive pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 orally (PO) once daily (QD) for 5 days (Monday-Friday). Treatment repeats for up to 8 weeks in the absence of disease progression or unacceptable toxicity. If treatment is successful after 8 weeks, patients may receive up to 6 months of pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.

After completion of study treatment, patients are followed up periodically.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 2

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

    • Michigan
      • Detroit, Michigan, United States, 48201
        • Wayne State University/Karmanos Cancer Institute
    • Washington
      • Seattle, Washington, United States, 98109
        • Seattle Cancer Care Alliance

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:

  • Have signed an informed consent document indicating that the subject understands the purpose of and procedures required for the study and are willing to participate in the study
  • Be willing/able to adhere to the prohibitions and restrictions specified in this protocol
  • Eastern Cooperative Group (ECOG) performance status =< 1
  • Patient must have evidence of castrate resistant prostate cancer as evidenced by a confirmed rising PSA (per PCWG3 criteria) and a castrate serum testosterone level (i.e. =< 50 mg/dL)
  • Documented histologically confirmed adenocarcinoma of the prostate
  • Metastatic prostate cancer (M1) as documented by appropriate medical imaging (i.e. computed tomography [CT]-scan, positron emission tomography [PET] scan or bone scan)
  • Treatment failure of either abiraterone and/or enzalutamide as evidenced by a confirmed rising PSA (per PCWG3 criteria) and a castrate serum testosterone level (i.e. =< 50 mg/dL) while receiving treatment with either abiraterone and/or enzalutamide
  • Willingness to use contraception by a method that is deemed effective by the Investigator throughout the treatment period and for at least 30 days following the last dose of therapy
  • Willingness and ability to comply with study procedures and follow-up examination
  • Able to swallow and retain oral medication

Exclusion Criteria:

  • Current systemic therapy (other than a gonadotrophin releasing hormone [GnRH] agonist/antagonist) for CRPC including:

    • CYP-17 inhibitors (e.g. ketoconazole, abiraterone)
    • Antiandrogens (e.g. bicalutamide, nilutamide)
    • Second generation antiandrogens (e.g. enzalutamide, ARN-509, Galeterone)
    • Immunotherapy (e.g. sipuleucel-T, ipilimumab)
    • Chemotherapy (e.g. docetaxel, cabazitaxel)
  • Greater than 2 lines of prior systemic therapy for CRPC
  • Prior chemotherapy (e.g. docetaxel, cabazitaxel) for CRPC; prior docetaxel administered in the castrate-sensitive space is allowed
  • Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153, etc.) within the past year
  • Have any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements
  • Absolute neutrophil count (ANC) less than 1500/mm^3
  • Platelet count less than 100000/mm^3
  • Hemoglobin less than 9 g/dL
  • Bilirubin greater than 1.5 times the upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2.0 times the ULN in the absence of known hepatic metastases, or ALT or AST greater than 3.0 times the ULN in the presence of known hepatic metastases
  • The patient has a serum creatinine value greater than 1.5 mg/dL
  • The patient has active brain metastases
  • The patient is currently on warfarin or heparin therapy
  • The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria, or gastrointestinal bleeding, and a history of a clinically significant cardiovascular or cerebrovascular event within 12 months prior to study entry
  • The patient has uncontrolled hypertension defined as a blood pressure measurement greater than 150 mm Hg systolic or 90 mm Hg diastolic with medication
  • The patient has received any investigational drug within the past 4 weeks
  • The patient has previously been enrolled in the study or received ESK981
  • The patient has known hypersensitivity to gelatin or lactose monohydrate
  • The patient has taken a medication known to be a potent inducer of CYP1A2, CYP2C8, or CYP3A4 within 4 weeks prior to the first dose of study drug
  • The patient has taken a medication known to be a potent inhibitor of CYP1A2, CYP2C8, or CYP3A4 within 2 weeks prior to the first dose of study drug

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 ESK981
Patients receive pan-VEGFR/TIE2 (Vascular Endothelial Growth Factor Receptor/angopoeitin receptor2) tyrosine kinase inhibitor CEP-11981 PO QD for 5 days (Monday-Friday). Treatment repeats for up to 8 weeks in the absence of disease progression or unacceptable toxicity. If treatment is successful after 8 weeks, patients may receive up to 6 months of pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.
Treatment with ESK981 for patients with metastatic castrate resistant prostate cancer

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PSA Decline of >= 50% (PSA50) From Baseline
Time Frame: Up to 1 year
PSA decline of >= 50% (PSA50) from baseline using Prostate Cancer Working Group 3 (PCWG3) definition with point estimate and (1-sided Wilson type 90% lower) confidence interval (CI) estimates.
Up to 1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Duration of PSA Response (RD)
Time Frame: From start of PSA50 until PSA progression, assessed up to 1 year
Will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for RD will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life table, each one with its respective 80% CI.
From start of PSA50 until PSA progression, assessed up to 1 year
PSA Progression Free Survival (PFS)
Time Frame: Date that a 25% or greater increase and an absolute increase of 2.0 ng/mL or more from the nadir is documented and confirmed by a second value obtained 3 or more weeks later, assessed up to 1 year
Will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for PFS will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life table, each one with its respective 80% CI.
Date that a 25% or greater increase and an absolute increase of 2.0 ng/mL or more from the nadir is documented and confirmed by a second value obtained 3 or more weeks later, assessed up to 1 year
Time to PSA Response
Time Frame: From treatment start until the first documented occurrence of PSA50, assessed up to 1 year
Will be used to summarize the time to PSA response. These descriptives will include sample size (N), median, mean, standard deviation (SD), interquartile range (IQR), minimum, and maximum.
From treatment start until the first documented occurrence of PSA50, assessed up to 1 year

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Immunohistochemistry (IHC) of Protein Markers
Time Frame: Up to 1 year
Ki67, Receptor, CD31, NG2, desmin, PDGFR1/2, VEGFR1/2 immunohistochemistry graded 0, 1, 2, 3
Up to 1 year
Androgen Receptor (AR) Signaling
Time Frame: Up to 1 year
Will examine the association of somatic and germline mutations with exceptional response/resistance to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.
Up to 1 year
Circulating and Disseminated Tumor Cells as Pharmacodynamic Biomarkers
Time Frame: Up to 1 year
Number of Circulating and disseminated tumor cells per 7.5ml as a pharmacodynamic biomarker.
Up to 1 year
ETS/Kinase Gene Fusions
Time Frame: Up to 1 year
Will examine the association of somatic and germline mutations with exceptional response/resistance to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.
Up to 1 year
Metastatic Kinome Activity Profiles as Predictive Biomarkers
Time Frame: Up to 1 year
Description of immunohistochemistry of the kinases, graded 0,1,2,3
Up to 1 year
DNA Sequencing of Prostate Tumor
Time Frame: Up to 1 year
copy number, Loss of heterozygosity, mutation, amplification, graded 0,1
Up to 1 year

Collaborators and Investigators

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

Investigators

  • Principal Investigator: Elisabeth I. Heath, Barbara Ann Karmanos Cancer Institute

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)

March 8, 2018

Primary Completion (Actual)

March 15, 2023

Study Completion (Actual)

May 9, 2023

Study Registration Dates

First Submitted

February 9, 2018

First Submitted That Met QC Criteria

February 28, 2018

First Posted (Actual)

March 7, 2018

Study Record Updates

Last Update Posted (Actual)

July 14, 2023

Last Update Submitted That Met QC Criteria

June 24, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Other Study ID Numbers

  • 2017-065 (Other Identifier: Wayne State University/Karmanos Cancer Institute)
  • P30CA022453 (U.S. NIH Grant/Contract)
  • NCI-2017-02330 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

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.

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