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Trial of Dichloroacetate (DCA) in Glioblastoma Multiforme (GBM)

Primary Purpose

Glioblastoma Multiforme

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dichloroacetate (DCA)
Genotype
Sponsored by
University of Florida
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma Multiforme

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Study subjects will be male and female adults, aged 18 through 80 years, previously diagnosed with a GBM who have experienced tumor recurrence as determined by neuroimaging and some degree of symptomatology (e.g., headache, mental status change, seizure) and have clinically indicated tumor debulking surgery planned.
  • All subjects will have completed initial, standard- therapy with surgical debulking, followed by radiation and temozolomide (TMZ) and will, therefore, be considered treatment failures.
  • Patients will be recruited and studied at the 11 ABTC clinical sites. The DCA liquid formulation is on file with the FDA, is identical to that administered in our Phase I trial of brain tumor patients and can be given by mouth or feeding tube. Patients may retain whatever medications they are receiving for other conditions (e.g., hypertension, seizures), except patients requiring insulin or sulfonylurea therapy (see below).
  • The probability of adverse drug-drug interactions is extremely low, for the following reasons. First, DCA is the only pharmaceutical in clinical use that is metabolized by GSTZ1. Second, DCA is not known to be metabolized by any other drug metabolizing enzyme system, thus precluding competition with other agents for biotransformation. Third, the results of both open label and randomized controlled trials of orally or parenterally administered DCA in the treatment of children and/or adults have never shown evidence of adverse drug-drug interactions (34). Thus, from decades of clinical investigations of use of DCA in various acutely or chronically ill populations, there is nothing to suggest adverse drug-drug interactions should be anticipated in this trial.

Exclusion Criteria:

  • Patients considered pre-terminal (life expectancy ≤ 2 months)
  • Those who are pregnant will be excluded.
  • DCA inhibits gluconeogenesis and lowers blood glucose levels in patients with type 2 diabetes. Therefore, in subjects who are receiving either insulin or a sulfonylurea, coadministration of DCA could lead to symptomatic hypoglycemia and those patients will be excluded from the trial.
  • DCA is dialyzable and its clearance diminishes in patients with end stage renal failure (GFR ≤ 30 ml/min); such patients will be excluded from participating.
  • DCA is metabolized by hepatic GSTZ1, so patients with severe liver insufficiency (total bilirubin > 2.0 mg/dl or ALT or AST > 3 x ULN) will be excluded.

Sites / Locations

  • University of Alabama - Birmingham
  • Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsRecruiting
  • Wake Forest UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Pre-Surgical Dichloroacetate (DCA)

No Pre-Surgical Dichloroacetate (DCA)

Arm Description

Study medication begins in subjects randomized to preoperative DCA. All subjects will be given the 12.5 mg/kg/12 hour DCA for pre-surgical dosing. Post-surgery the GSTZ1 haplotype will be utilized to dose all patients.

Subject randomized to start DCA after surgery will do so 12-24 hours postoperatively, depending on their ability to safely receive medication.

Outcomes

Primary Outcome Measures

The efficacy will be measured between the groups by using the Observer Reported Outcome (ObsRO) measure of health.
The efficacy of dichloroacetate will be determined by applying a novel Observer Reported Outcome (ObsRO) measure of health. The ObsRO scores will be graded on a Likert Scale from 0-4. (0 being absent and 4 being extremely severe).

Secondary Outcome Measures

Full Information

First Posted
November 2, 2021
Last Updated
August 31, 2023
Sponsor
University of Florida
Collaborators
Food and Drug Administration (FDA)
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1. Study Identification

Unique Protocol Identification Number
NCT05120284
Brief Title
Trial of Dichloroacetate (DCA) in Glioblastoma Multiforme (GBM)
Official Title
Trial of Dichloroacetate (DCA) in Glioblastoma Multiforme (GBM)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 1, 2022 (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
University of Florida
Collaborators
Food and Drug Administration (FDA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Conduct a multicenter, open label Phase IIA trial of oral DCA in 40 surgical patients with recurrent GBM who have clinically indicated debulking surgery planned. No patients will be recruited at UF. Patients will be genotyped to establish safe dosing regimens and will be randomized to receive DCA (N=20) or no DCA (N=20) for one week prior to surgery. Deidentified blood and tumor tissue obtained at surgery will be assessed at UF for biochemical markers of DCA dynamics.
Detailed Description
Evaluate effects of dichloroacetate (DCA) on tumor PDC phosphorylation.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
subsequent ordered and alternating patients
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Pre-Surgical Dichloroacetate (DCA)
Arm Type
Active Comparator
Arm Description
Study medication begins in subjects randomized to preoperative DCA. All subjects will be given the 12.5 mg/kg/12 hour DCA for pre-surgical dosing. Post-surgery the GSTZ1 haplotype will be utilized to dose all patients.
Arm Title
No Pre-Surgical Dichloroacetate (DCA)
Arm Type
Active Comparator
Arm Description
Subject randomized to start DCA after surgery will do so 12-24 hours postoperatively, depending on their ability to safely receive medication.
Intervention Type
Drug
Intervention Name(s)
Dichloroacetate (DCA)
Other Intervention Name(s)
Sodium Dichloroacetate
Intervention Description
Study medication DCA is a liquid formulation mixed with an artificial sweetener containing aspartame and strawberry extract (50mg/mL) Participants will be genotyped to determine GSTZ1 (glutathione S-transferase Zeta-1) haplotype status, which will stratify this group into 1 of 2 dose regimens: EGT carriers will receive 12-14 mg/kg/12hr DCA. EGT non-carriers will receive 6-7 mg/kg/12 hr.
Intervention Type
Genetic
Intervention Name(s)
Genotype
Intervention Description
Participants will be genotyped to determine GSTZ1 haplotype status.
Primary Outcome Measure Information:
Title
The efficacy will be measured between the groups by using the Observer Reported Outcome (ObsRO) measure of health.
Description
The efficacy of dichloroacetate will be determined by applying a novel Observer Reported Outcome (ObsRO) measure of health. The ObsRO scores will be graded on a Likert Scale from 0-4. (0 being absent and 4 being extremely severe).
Time Frame
9 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Study subjects will be male and female adults, aged 18 through 80 years, previously diagnosed with a GBM who have experienced tumor recurrence as determined by neuroimaging and some degree of symptomatology (e.g., headache, mental status change, seizure) and have clinically indicated tumor debulking surgery planned. All subjects will have completed initial, standard- therapy with surgical debulking, followed by radiation and temozolomide (TMZ) and will, therefore, be considered treatment failures. Patients will be recruited and studied at the 11 ABTC clinical sites. The DCA liquid formulation is on file with the FDA, is identical to that administered in our Phase I trial of brain tumor patients and can be given by mouth or feeding tube. Patients may retain whatever medications they are receiving for other conditions (e.g., hypertension, seizures), except patients requiring insulin or sulfonylurea therapy (see below). The probability of adverse drug-drug interactions is extremely low, for the following reasons. First, DCA is the only pharmaceutical in clinical use that is metabolized by GSTZ1. Second, DCA is not known to be metabolized by any other drug metabolizing enzyme system, thus precluding competition with other agents for biotransformation. Third, the results of both open label and randomized controlled trials of orally or parenterally administered DCA in the treatment of children and/or adults have never shown evidence of adverse drug-drug interactions (34). Thus, from decades of clinical investigations of use of DCA in various acutely or chronically ill populations, there is nothing to suggest adverse drug-drug interactions should be anticipated in this trial. Patients who are diabetic must have a screening hemoglobin A1c (Hgb A1c) level of at least 6.0. Exclusion Criteria: Patients considered pre-terminal (life expectancy ≤ 2 months) Those who are pregnant will be excluded. DCA inhibits gluconeogenesis and lowers blood glucose levels in patients with type 2 diabetes. Therefore, in subjects who are receiving either insulin or a sulfonylurea, coadministration of DCA could lead to symptomatic hypoglycemia and those patients will be excluded from the trial. DCA is dialyzable and its clearance diminishes in patients with end stage renal failure (GFR ≤ 30 ml/min); such patients will be excluded from participating. DCA is metabolized by hepatic GSTZ1, so patients with severe liver insufficiency (total bilirubin > 2.0 mg/dl or ALT or AST > 3 x ULN) will be excluded. Patients with Hgb A1c level less than 6.0 at screening
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Peter W Stacpoole, PhD, MD
Phone
352-273-9023
Email
pws@ufl.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Tom Franklin, BA
Phone
352--273-9023
Email
tomfranklin@ufl.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Stacpoole, PhD, MD
Organizational Affiliation
University of Florida
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama - Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Burt Nabors, MD
Facility Name
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States
Individual Site Status
Recruiting
Facility Name
Wake Forest University
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27587
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roy Strowd, MD

12. IPD Sharing Statement

Plan to Share IPD
No
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Trial of Dichloroacetate (DCA) in Glioblastoma Multiforme (GBM)

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