Description:
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.
Title
- Brief Title: Study to Evaluate Pharmacokinetics and Pharmacodynamics of Evolocumab in rHGG
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
Pro00108375
- NCT ID:
NCT04937413
Conditions
- Malignant Glioma
- Glioblastoma
Interventions
Drug | Synonyms | Arms |
---|
Evolocumab | Repatha | Single dose of evolocumab |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Single dose of evolocumab | Experimental | 420 mg of evolocumab subcutaneous injection 7-14 days before scheduled surgery for malignant glioma | |
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 21 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 21 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 7 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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Presence of evolocumab in surgical tumor tissue and tissue from a matched control group |
Time Frame: | At time of surgical resection |
Safety Issue: | |
Description: | Determined by mass spectrometry |
Secondary Outcome Measures
Measure: | Level of lipid metabolism within the surgical tumor tissue and tissue from a matched control group |
Time Frame: | At time of surgical resection |
Safety Issue: | |
Description: | Determined by fluorescence-activated cell sorting (FACS) |
Measure: | Major histocompatibility complex-1 (MHC-I) expression within the surgical tumor tissue and tissue from a matched control group |
Time Frame: | At time of surgical resection |
Safety Issue: | |
Description: | Determined by FACS |
Measure: | Correlation between serum and surgical tumor tissue levels of evolocumab |
Time Frame: | 2 weeks |
Safety Issue: | |
Description: | Using serum taken before receiving evolocumab (7-14 days before surgery) and serum taken at the time of surgery |
Details
Phase: | Early Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | Duke University |
Trial Keywords
- Pro00108375
- Khasraw
- PCSK9i
- Evolocumab
- Glioma
- Glioblastoma
Last Updated
June 28, 2021