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The Safety and Efficacy of DCA for the Treatment of Brain Cancer

Study Purpose

Malignant gliomas, which include Glioblastoma multiforme (GBM), are the most common and most aggressive types of brain cancer, accounting for approximately 60% of primary brain tumors. These tumors are characterized by diverse molecular abnormalities (within the same tumor), which, along with the difficulties of many standard chemotherapies crossing the blood barrier, contribute to the very poor response to therapy and poor survival. We recently showed that Dichloroacetate (DCA, an inhibitor of the mitochondrial pyruvate dehydrogenase kinase) was able to depolarize cancer (but not normal) mitochondria and induce apoptosis in cancer but not normal tissues. We believe that altering the metabolism of cancers like glioblastoma (DCA switches metabolism from the cytoplasmic glycolysis to the mitochondrial glucose oxidation) we inhibit the resistance to apoptosis that characterizes cancer. Because metabolism (i.e. glycolysis) is the end result of many and diverse molecular pathways, the effects of DCA might be positive in cancers with diverse molecular backgrounds. DCA is also a very small molecule that readily crosses the blood brain barrier. Therefore we hypothesize that DCA will be an effective and relative non-toxic potential therapy for malignant gliomas. We are conducting a phase II trial with 2 parallel arms: a) patients with newly diagnosed malignant gliomas and b) patients with recurrent gliomas or gliomas that have failed standard therapy (which includes surgery, radiotherapy and chemotherapy). All patients need to have a histological diagnosis. DCA will be given orally and patients will be followed for a minimum of 6 months. The tumor size will be followed by standard MRI or CT criteria and glucose uptake (a direct effect of DCA on the tumor) will be measured by FDG-PET imaging. Several clinical parameters and quality of life will be followed. Potential toxicity (particularly peripheral neuropathy) will be closely followed and dose-de-escalation protocols are in place in case of toxicity. In addition, escape protocols for the application of standard therapy (when appropriate) are in place in patients with no evidence of response to DCA. In vitro studies will be performed in the tissues obtained at the time of surgery (where appropriate) and correlated prospectively with clinical data. There is limited ability to accept patients outside of Alberta; this is in part because the visit and testing schedule is intense, requiring residence in Edmonton for at least 6 months.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

 No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

 Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - Patients must have histologically confirmed intracranial malignant glioma / GBM tumors.
  • - All patients enrolled must have measurable with or without evaluable disease, as defined in Section 11.
  • - In the recurrent malignant glioma cohort of patients, four weeks must have elapsed from prior chemotherapy or radiation therapy.
  • - Age 18 years and over.
  • - ECOG (Eastern Cooperative Oncology Group) performance status Grade 0-2 (Karnofsky >70).
  • - Life expectancy of greater than 12 weeks.
  • - Patients must have liver, kidney and marrow function as defined below: - absolute neutrophil count >1,500/mcL.
  • - hemoglobin >90 g/L.
  • - platelets >100,000/mcL.
  • - total bilirubin <1.5 X upper limit of normal (ULN) - AST(SGOT) and ALT(SGPT) <1.5 X ULN.
  • - creatinine <1.5 X ULN.
  • - Recovery to baseline or, at most, grade 1 of all drug-related toxicities due to prior chemotherapy, radiation, or molecular targeted therapy, except for alopecia.
  • - Women of child-bearing potential and men must agree to use adequate contraception (e.g.: hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation.
Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • - Patients must be able to understand and be willing to sign a written informed consent document.
Exclusion Criteria.
  • - Patients who have had chemotherapy, molecular targeted therapy, or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  • - Patients with new onset or increasing dose regimen of steroids for the week prior to enrollment.
  • - Patients cannot be receiving any other investigational therapies.
  • - Patients with grade 2 or higher peripheral neuropathy due to prior medical condition (such as multiple sclerosis, diabetes etc), medications (chemotherapy), or other etiologies.
  • - Greater than 0.8 cm brain midline shift on CT scan or MRI.
  • - Any psychological, familial, sociological, or geographical conditions that do not permit medical follow-up and compliance with the study protocol.
  • - Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes with history of significant hypoglycemic episodes in the past 3 months or psychiatric illness/social situations that would limit compliance with study requirements.
  • - HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with DCA.
In addition, these patients are at increased risk of lethal (and at time intracranial) infections when treated with potentially marrow-suppressive therapy.
  • - History of malabsorption syndrome or substantial amount of small bowels or stomach resection or obstruction that may impair absorption of DCA.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

 NCT00540176
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

 Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

 University of Alberta
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

 Kenneth Petruk, MD co-PIEvangelos D Michelakis, MD co-PIConnor Maguire MD, investigatorLinda Webster, NP manager
Principal Investigator Affiliation University of Alberta and Capital HealthUniversity of Alberta and Capital HealthUniversity of Alberta and Capital HealthCapital Health, Canada
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

 Other
Overall Status Completed
Countries Canada
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

 Malignant Gliomas, Glioblastoma Multiforme
Arms & Interventions

Arms

Experimental: Cohort A

Recurrent disease with previous surgery, radiation therapy and/or chemotherapy

Experimental: Cohort B

Newly diagnosed disease with no previous therapy

Interventions

Drug: - Dichloroacetate (DCA)

Oral DCA given twice daily for the 24 week period of the study. Continuation of therapy will be indefinite if efficacious.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

University of Alberta Hospital, Edmonton, Alberta, Canada

Status

Address

University of Alberta Hospital

Edmonton, Alberta, T6G 2B7

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