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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00540176
Recruitment Status : Completed
First Posted : October 5, 2007
Last Update Posted : October 13, 2014
Sponsor:
Collaborator:
Capital Health, Canada
Information provided by (Responsible Party):
University of Alberta

Tracking Information
First Submitted Date  ICMJE October 4, 2007
First Posted Date  ICMJE October 5, 2007
Last Update Posted Date October 13, 2014
Study Start Date  ICMJE October 2007
Actual Primary Completion Date August 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 4, 2007)
  • To determine the therapeutic response to oral Dichloroacetate (DCA) in patients with malignant gliomas, utilizing standard criteria for the objective response of tumor size to treatment (CT and/or MRI).
  • To evaluate the safety and tolerability of oral (DCA) in patients with gliomas.
  • To determine the progression-free survival (PFS) and overall survival achieved with oral DCA in patients with gliomas.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 4, 2007)
  • • To evaluate the in vitro effects of DCA on cell proliferation/apoptosis and mitochondrial function in malignant glioma tissues taken from enrolled patients at the time of surgery and correlate them with clinical data.
  • • To evaluate glucose uptake using 18F-FDG Positron Emission Tomography (PET) scanning as a biological marker for predicting subsequent therapeutic response to oral DCA in patients with malignant gliomas.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Safety and Efficacy of DCA for the Treatment of Brain Cancer
Official Title  ICMJE A Phase II Open-labeled, Double-arm Clinical Study of Dichloroacetate (DCA) in Malignant Gliomas and Glioblastome Multiforme (GBM) Patients
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malignant Gliomas, Glioblastoma Multiforme
Intervention  ICMJE Drug: Dichloroacetate (DCA)
Oral DCA given twice daily for the 24 week period of the study. Continuation of therapy will be indefinite if efficacious.
Study Arms  ICMJE
  • Experimental: Cohort A
    Recurrent disease with previous surgery, radiation therapy and/or chemotherapy
    Intervention: Drug: Dichloroacetate (DCA)
  • Experimental: Cohort B
    Newly diagnosed disease with no previous therapy
    Intervention: Drug: Dichloroacetate (DCA)
Publications * Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007 Jan;11(1):37-51.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 10, 2014)
40
Original Estimated Enrollment  ICMJE
 (submitted: October 4, 2007)
50
Actual Study Completion Date  ICMJE August 2009
Actual Primary Completion Date August 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00540176
Other Study ID Numbers  ICMJE DCA 10002
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Alberta
Study Sponsor  ICMJE University of Alberta
Collaborators  ICMJE Capital Health, Canada
Investigators  ICMJE
Principal Investigator: Kenneth Petruk, MD co-PI University of Alberta and Capital Health
Principal Investigator: Evangelos D Michelakis, MD co-PI University of Alberta and Capital Health
Principal Investigator: Connor Maguire MD, investigator University of Alberta and Capital Health
Study Director: Linda Webster, NP manager Capital Health, Canada
PRS Account University of Alberta
Verification Date February 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP