Dichloroacetate for Glioblastoma

(DCA Trial)

Overseen By Peter Stacpoole, Phd, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Insulin, Sulfonylureas

Disqualifiers: Pregnancy, Uncontrolled illness, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You can continue taking your current medications for other conditions, like high blood pressure or seizures, but if you need insulin or sulfonylurea therapy, you won't be eligible for the trial.

What data supports the effectiveness of the drug dichloroacetate for glioblastoma?

Research shows that dichloroacetate can make glioblastoma cells more sensitive to radiotherapy, which is a common treatment for this type of brain cancer. It works by changing the way cancer cells use energy, making them more vulnerable to radiation and potentially improving survival in animal models. ^{1 2 3 4 5}

Is dichloroacetate safe for use in humans?

Dichloroacetate (DCA) has been studied for various conditions and is generally considered safe, though it can cause reversible nerve-related side effects like peripheral neuropathy (nerve damage causing numbness or tingling) and encephalopathy (brain dysfunction). High-dose intravenous DCA has been shown to be safe in both healthy and critically ill patients, and it does not appear to cause genetic mutations. ^{1 2 4 6 7}

How does the drug dichloroacetate work differently for glioblastoma treatment?

Dichloroacetate (DCA) is unique because it targets the metabolism of glioblastoma cells, forcing them to switch from glycolysis (a sugar-based energy process) to oxidative phosphorylation (a more efficient energy process), which makes them more sensitive to radiotherapy. This approach is different from traditional treatments as it focuses on altering the cancer cells' energy production to enhance the effectiveness of radiation. ^{1 2 4 8 9}

What is the purpose of this trial?

This trial tests DCA, a medicine that helps fix cell energy problems, in patients with recurring brain tumors who didn't respond to standard treatments. DCA works by restarting normal cell energy processes to kill cancer cells. DCA has shown activity against several human cancers and has been tested in early research for its potential to treat brain tumors.

Research Team

Stuart Grossman, MD

Principal Investigator

Johns Hopkins/ABTCv2

Eligibility Criteria

Adults aged 18-80 with WHO grade IV glioma that's worsening or returning after treatment, able to care for themselves mostly, and not on insulin/sulfonylurea therapy. They must have adequate organ function, be off certain treatments for specific periods, use effective contraception if applicable, and be scheduled for tumor removal surgery.

Inclusion Criteria

Patients must be able to provide written informed consent

I have recurring brain cancer with symptoms and surgery planned to remove part of the tumor.

I can swallow liquids without difficulty.

Exclusion Criteria

I do not have any severe illnesses that could interfere with the study.

I have recovered from previous cancer treatment side effects, except for hair loss.

Patients receiving any other investigational agents for brain tumor are ineligible

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-surgical Treatment

Dichloroacetate (DCA) is administered orally twice daily for 7 days prior to scheduled surgery

1 week

Daily dosing

Surgery and Recovery

Participants undergo tumor debulking surgery and recover from the procedure

2-4 weeks

Post-surgical Treatment

DCA is administered twice daily continuously for each 60-day cycle

60 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 2 months

Clinic visits every 2 months with standard of care brain imaging and laboratory studies

Treatment Details

Interventions

• Dichloroacetate

Trial Overview The trial is testing Dichloroacetate (DCA), a new type of drug that targets cancer cell metabolism in the brain. It aims to show that DCA can reduce a particular protein in tumors when given before surgery compared to those who don't receive it beforehand.

Participant Groups

Group I: Arm 2 - NO Pre-surgical dosing Experimental Treatment 1 Intervention

Following recovery from surgical resection*, all patients will receive DCA at the determined individual dosing dose "fast" vs "slow". GSTZ1 haplotype analysis, into "fast" (i.e., EGT carriers; 12.5 mg/kg DCA every 12 hours ± 2hrs) or "slow" (i.e., EGT noncarriers; 6.25 mg/kg DCA every 12 hours ± 2hrs) drug metabolizers Post-surgery (upon recovery, within 2-4 weeks, DCA will be administered twice daily continuously for each 60 day cycle. Each dose should be taken 12 hours apart (±2 hours), at approximately the same times each day.

Group II: Arm 1 - Pre-surgical dosing Experimental Treatment 1 Intervention

Dichloroacetate (DCA) will be given orally. Dosing will be 12.5 mg/kg/dose every 12 hours. DCA will be administered twice daily for 7 days prior to scheduled surgery to remove tumor. A final pre-surgical dose should be taken the morning the day before surgery, approximately 12 hours before the surgical procedure begins, i.e. skip evening dose. Following recovery from surgical resection*, all patients will receive DCA at the determined stratification dose "fast" vs "slow". GSTZ1 haplotype analysis, into "fast" (i.e., EGT carriers; 12.5 mg/kg DCA every 12 hours ± 2hrs) or "slow" (i.e., EGT noncarriers; 6.25 mg/kg DCA every 12 hours ± 2hrs) drug metabolizers

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Food and Drug Administration (FDA)

Collaborator

Trials

184

Recruited

1,553,000+

Findings from Research

Sodium dichloroacetate (DCA) has shown the ability to induce programmed cell death in various cancer cells and can also act as a cytostatic agent, stabilizing disease without necessarily causing cell death.

A case study of a 32-year-old male with recurrent metastatic melanoma demonstrated that DCA therapy led to regression and stabilization of the disease for over 4 years with minimal side effects, suggesting its potential as a long-term treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term stabilization of metastatic melanoma with sodium dichloroacetate. Khan, A., Andrews, D., Shainhouse, J., et al.[2020]

Dichloroacetate (DCA) selectively induced apoptosis in pediatric tumor cells but only moderately inhibited growth across 18 different tumor cell lines, suggesting limited efficacy as a standalone treatment.

DCA was found to reduce the effectiveness of cisplatin and doxorubicin in several cell lines, indicating that its use in combination with standard chemotherapy drugs may require careful evaluation to avoid compromising treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs. Heshe, D., Hoogestraat, S., Brauckmann, C., et al.[2022]

Dichloroacetate (DCA) treatment in cancer cells leads to increased autophagy and production of reactive oxygen species (ROS), along with inhibition of the mTOR pathway, which is important for cell growth and metabolism.

After stopping DCA treatment, the metabolic changes, such as lactate excretion and NAD(+)/NADH ratios, returned to normal levels, indicating that the effects of DCA are reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dichloroacetate induces autophagy in colorectal cancer cells and tumours. Lin, G., Hill, DK., Andrejeva, G., et al.[2022]

Intravenous (IV) administration of dichloroacetate sodium (DCA) has shown safety in high doses (up to 100 mg/kg/dose) for both healthy volunteers and critically ill patients, making it a promising option for cancer treatment.

In three cases of patients with recurrent cancers who had failed conventional therapies, IV DCA treatment resulted in clinical, hematological, or radiological responses, suggesting potential efficacy in advanced-stage cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel form of dichloroacetate therapy for patients with advanced cancer: a report of 3 cases. Khan, A., Marier, D., Marsden, E., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Long-term stabilization of metastatic melanoma with sodium dichloroacetate. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Dichloroacetate induces autophagy in colorectal cancer cells and tumours. [2022]

5. Greece pubmed.ncbi.nlm.nih.gov

Metabolic-targeted Combination Therapy With Dichloroacetate and Metformin Suppresses Glioblastoma Cell Line Growth In Vitro and In Vivo. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

A novel form of dichloroacetate therapy for patients with advanced cancer: a report of 3 cases. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Absence of mutagenic effects of sodium dichloroacetate. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Metabolic modulation of glioblastoma with dichloroacetate. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Dichloroacetate is an antimetabolite that antagonizes acetate and deprives cancer cells from its benefits: A novel evidence-based medical hypothesis. [2019]