Trial of Dichloroacetate in Glioblastoma

Glioblastoma Clinical Trial

— DCA  

Official title:

Phase IIA Trial of Dichloroacetate in Glioblastoma

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05173623
• Other study ID #: 2189
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: January 10, 2022
• Est. completion date: January 10, 2027

Study information

• Verified date: December 2021
• Source: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Contact: Peter Stacpoole, Phd, MD
• Phone: 352-273-9599
• Email: pws[@]ufl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Dichloroacetate (DCA), the prototypic PDK inhibitor, readily crosses the blood-brain barrier and represents an entirely new class of small molecule metabolic modulators that act in mitochondria to reset cellular homeostasis in various congenital and acquired metabolic disorders. Indeed, pharmacological inhibition of PDK in cancer cells by DCA restores PDC activity, reverses the Warburg effect and induces a caspase-mediated selective apoptosis of tumors. The central hypothesis is that patients treated with DCA prior to surgery will have a significant (p ≤ 0.05) mean decrease in phosphorylated PDC protein expression in tumor tissue, compared to tissue from patients who are not treated before surgery.

Description:

Primary Objective: 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.

Secondary Objectives: (1) Compare intratumoral biochemical correlates in tumor tissue excised from DCA-treated and DCA-non- treated subjects. Based on the patients' initial tumor resection, MGMT promoter status will be known; however, in this small study, such information will only be used in exploratory post hoc comparisons. (2) Determine two (or longer) year survival in all post- surgical subjects receiving DCA. Subjects will be followed in clinic every two months with standard of care brain imaging and laboratory studies, including plasma trough DCA levels and a clinical neurological exam.

Forty study participants, ages 18-80 years, previously diagnosed with a glioblastoma multiforme (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. Study participants will be recruited throughout the United States.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: January 10, 2027
• Est. primary completion date: December 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Patient must be 18-80 years old

2. Patients must have histologically confirmed WHO grade IV glioma that is progressive or recurrent following at least one prior TMZ plus radiation therapy regimen

3. Patients must have recurrent GBM as determined by neuroimaging and some degree of symptomatology (e.g., headache, mental status change, seizure), and have clinically indicated tumor debulking surgery planned

4. Patients must have recovered (<CTCAE grade 2 or baseline) from severe toxicity of prior therapy. Patient may have unlimited prior therapies. The following intervals from previous treatments are required to be eligible:

• 12 weeks from the completion of radiation.

• 6 weeks from a nitrosourea chemotherapy

• 3 weeks from a non-nitrosourea chemotherapy

• 4 weeks from any investigational (not FDA-approved) agents

• 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.)

5. Must have completed Standard of Care RT and TMZ. Patients must have received at least 80% of planned TMZ/RT treatment?

6. Patients must have a Karnofsky Performance (KPS) Status >/= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).

7. Patients may retain whatever medications they are receiving for other conditions (e.g., hypertension, seizures), except patients requiring insulin or sulfonylurea therapy, these patients will not be eligible.

8. Women of childbearing potential must have a negative serum pregnancy test within 7 days of dosing. Women of childbearing potential and men must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for at 30 days after the last dose of study drug.

9. Patients must have the following organ and marrow function:

(1) Absolute neutrophil count >1,500/ µL (2) Platelets =100,000/ µL (3) Hemoglobin = 9 g/dL (4) Total bilirubin = 2mg/dl (5) AST (SGOT)/ALT (SGPT) =3 × institutional upper limit of normal (6) GFR > 30ml/min

10. Patients must be able to undergo MRI of the brain with gadolinium. Patients must be maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 5 days) prior to this baseline MRI.

12. Patients must be able to provide written informed consent.

13. Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with prior malignancies must be disease-free for >/= 3 years.

14. Patients must be able to swallow liquid

Exclusion Criteria:

1. Patients receiving any other investigational agents for brain tumor are ineligible.

2. Patients who have not recovered to <CTCAE grade 2 toxicities apart from alopecia related to prior therapy are ineligible.

3. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.

4. Pregnant women are excluded from this study because the effects of DCA on a fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DCA, breastfeeding should be discontinued if the mother is treated with DCA.

5. Patients who require insulin or sulfonylurea therapy.

Related Conditions & MeSH terms

• Glioblastoma

Intervention

Drug:
• Dichloroacetate
Dichloroacetate (DCA), the prototypic PDK inhibitor, readily crosses the blood-brain barrier and represents an entirely new class of small molecule metabolic modulators that act in mitochondria to reset cellular homeostasis in various congenital and acquired metabolic disorders.

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Food and Drug Administration (FDA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Level of phosphorylated PDC protein expression in tumor tissue	To compare phosphorylated PDC protein expression level in tumor tissue between patients with rGBM who were treated with or without DCA one week prior to surgical resection of the tumor. Patients will go to surgery and have tumor removed for evaluation.	7 days