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The PCSK9i Inhibitor Evolocumab - a Surgical Trial of Pharamcodynamics and Kinetics Evaluation

Primary Purpose

Malignant Glioma, Glioblastoma

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Evolocumab

About this trial

This is an interventional basic science trial for Malignant Glioma focused on measuring Pro00108375, Khasraw, PCSK9i, Evolocumab, Glioma, Glioblastoma, PEskE

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Adult patients ≥ 18 years old
Newly diagnosed or recurrent high grade glioma (HGG) or glioblastoma (GBM) (if recurrent, prior pathology report indicating HGG or GBM)
Adequate hematologic function within 14 days prior to starting evolocumab defined as follows:
1. Hemoglobin ≥ 10 g/dl (Note: the use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable)
2. Leukocytes ≥ 1,500/mm3
3. Absolute Neutrophil Count (ANC) ≥ 1,000/mm3
4. Platelets ≥ 100,000/mm3
Adequate renal function within 14 days prior to starting evolocumab defined as calculated creatinine clearance (CrCL) of ≥ 30 mL/min/1.73m2 by the Cockcroft-Gault formula
Adequate hepatic function within 14 days prior to starting evolocumab defined as follows:
1. Total bilirubin ≥ 1.5 x institutional upper limit of normal (ULN) (Note: Patients with known Gilbert disease without other clinically significant liver abnormalities are not excluded.)
2. AST(SGOT) and ALT(SGPT) ≥ 1.5 × ULN
Negative serum pregnancy test (in females of childbearing potential) within 48 hours of starting evolocumab.

Exclusion Criteria:

Any patient with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in evolocumab
Patients with severe hepatic impairment outside of the range defined in the inclusion criteria within 7 days of starting evolocumab.
History or evidence of central nervous system bleeding as defined by stroke or intraocular bleed (including embolic stroke) not associated with any antitumor surgery within 6 months before enrollment
Infection requiring intravenous antibiotics that was completed < 1 week of study enrollment (day 1) with the exemption of prophylactic antibiotics for long line insertion or biopsy
Females of reproductive potential and males who are unwilling to practice an acceptable method(s) of effective birth control while on study through 1 month (2 half-lives) after receiving the last dose of study drug.

Sites / Locations

Duke University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single dose of evolocumab

Arm Description

420 mg of evolocumab subcutaneous injection 7-14 days before scheduled surgery for malignant glioma

Outcomes

Primary Outcome Measures

Presence of evolocumab in surgical tumor tissue and tissue from a matched control group

Determined by mass spectrometry

Secondary Outcome Measures

Level of lipid metabolism within the surgical tumor tissue and tissue from a matched control group

Determined by fluorescence-activated cell sorting (FACS)

Major histocompatibility complex-1 (MHC-I) expression within the surgical tumor tissue and tissue from a matched control group

Determined by FACS

Correlation between serum and surgical tumor tissue levels of evolocumab

Using serum taken before receiving evolocumab (7-14 days before surgery) and serum taken at the time of surgery

Full Information

NCT ID

NCT04937413

First Posted

June 16, 2021

Last Updated

October 13, 2022

Sponsor

Duke University

1. Study Identification

Unique Protocol Identification Number

NCT04937413

Brief Title

The PCSK9i Inhibitor Evolocumab - a Surgical Trial of Pharamcodynamics and Kinetics Evaluation

Official Title

PEskE: A Phase 0/Surgical Window-of-opportunity Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Evolocumab in Patients With Recurrent High-grade Glioma or Glioblastoma

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Recruiting

Study Start Date

October 8, 2021 (Actual)

Primary Completion Date

June 2025 (Anticipated)

Study Completion Date

June 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Duke University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This Phase 0 surgical window of opportunity trial seeks to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of an FDA-approved proprotein convertase/ kexin type 9 serine protease inhibitor (PCSK9i) in patients with primary and recurrent World Health Organization (WHO) grade IV malignant glioma. The investigators intend to evaluate whether a clinically licensed PCSK9i called evolocumab (also known as Repatha) can be repurposed as a potential immunotherapeutic for high grade glioma by testing its ability to access the intracranial space. The primary objective is to evaluate whether evolocumab crosses the blood brain barrier (BBB) and is measurable in the resected tumor specimens of patients with primary and recurrent high grade glioma or glioblastoma.

Detailed Description

A maximum of 10 participants will receive 420 mg (the maximum single dose) of evolocumab subcutaneously into their thigh, abdomen or upper arm 7-14 days prior to surgical de-bulking of their tumor. After de-bulking, leftover tissue not required for histological analysis will be collected, and the level of evolocumab will be quantified. At two time points, prior to injection of evolocumab and at time of their surgery, participants will have peripheral blood drawn to analyze serum levels of the drug (for comparison to levels found in their leftover tissue). The investigators will follow-up with participants about 2 weeks after surgery at their post-operative visit. A matched cohort of resected tumor specimens from patients who were not treated with evolocumab from the Duke Brain Tumor Center Biorepository will be used as a comparison for the primary objective and 2 of the 3 secondary objectives of this study comparing brain tumor tissue specimens of patients who did and did not receive evolocumab with respect to lipid metabolism and tumor cells expressing MHC-I.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malignant Glioma, Glioblastoma

Keywords

Pro00108375, Khasraw, PCSK9i, Evolocumab, Glioma, Glioblastoma, PEskE

7. Study Design

Primary Purpose

Basic Science

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Single dose of evolocumab

Arm Type

Experimental

Arm Description

420 mg of evolocumab subcutaneous injection 7-14 days before scheduled surgery for malignant glioma

Intervention Type

Drug

Intervention Name(s)

Evolocumab

Other Intervention Name(s)

Repatha

Intervention Description

Evolocumab subcutaneous injection

Primary Outcome Measure Information:

Title

Presence of evolocumab in surgical tumor tissue and tissue from a matched control group

Description

Determined by mass spectrometry

Time Frame

At time of surgical resection

Secondary Outcome Measure Information:

Title

Level of lipid metabolism within the surgical tumor tissue and tissue from a matched control group

Description

Determined by fluorescence-activated cell sorting (FACS)

Time Frame

At time of surgical resection

Title

Major histocompatibility complex-1 (MHC-I) expression within the surgical tumor tissue and tissue from a matched control group

Description

Determined by FACS

Time Frame

At time of surgical resection

Title

Correlation between serum and surgical tumor tissue levels of evolocumab

Description

Using serum taken before receiving evolocumab (7-14 days before surgery) and serum taken at the time of surgery

Time Frame

2 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Adult patients ≥ 18 years old Newly diagnosed or recurrent high grade glioma (HGG) or glioblastoma (GBM) (if recurrent, prior pathology report indicating HGG or GBM) Adequate hematologic function within 14 days prior to starting evolocumab defined as follows: Hemoglobin ≥ 10 g/dl (Note: the use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable) Leukocytes ≥ 1,500/mm3 Absolute Neutrophil Count (ANC) ≥ 1,000/mm3 Platelets ≥ 100,000/mm3 Adequate renal function within 14 days prior to starting evolocumab defined as calculated creatinine clearance (CrCL) of ≥ 30 mL/min/1.73m2 by the Cockcroft-Gault formula Adequate hepatic function within 14 days prior to starting evolocumab defined as follows: Total bilirubin ≥ 1.5 x institutional upper limit of normal (ULN) (Note: Patients with known Gilbert disease without other clinically significant liver abnormalities are not excluded.) AST(SGOT) and ALT(SGPT) ≥ 1.5 × ULN Negative serum pregnancy test (in females of childbearing potential) within 48 hours of starting evolocumab. Exclusion Criteria: Any patient with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients in evolocumab Patients with severe hepatic impairment outside of the range defined in the inclusion criteria within 7 days of starting evolocumab. History or evidence of central nervous system bleeding as defined by stroke or intraocular bleed (including embolic stroke) not associated with any antitumor surgery within 6 months before enrollment Infection requiring intravenous antibiotics that was completed < 1 week of study enrollment (day 1) with the exemption of prophylactic antibiotics for long line insertion or biopsy Females of reproductive potential and males who are unwilling to practice an acceptable method(s) of effective birth control while on study through 1 month (2 half-lives) after receiving the last dose of study drug.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Mustafa Khasraw, MBChB, MD, FRCP, FRACP

Phone

9196845301

dukebrain1@dm.duke.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Erin Severance, BA

Phone

9196845301

dukebrain1@dm.duke.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mustafa Khasraw, MBChB, MD, FRCP, FRACP

Organizational Affiliation

Duke University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Duke University Medical Center

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Mustafa Khasraw, MBChB, MD, FRCP, FRACP

Phone

9196845301

dukebrain1@dm.duke.edu

First Name & Middle Initial & Last Name & Degree

Erin Severance, BA

Phone

9196845301

dukebrain1@dm.duke.edu

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

https://tischbraintumorcenter.duke.edu/

Description

The Preston Robert Tisch Brain Tumor Center at Duke

URL

http://www.dukehealth.org/clinical-trials

Description

Duke Health

Learn more about this trial

The PCSK9i Inhibitor Evolocumab - a Surgical Trial of Pharamcodynamics and Kinetics Evaluation

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