Symptoms and General Pathology

All Conditions

Hypoxia

Signs and Symptoms, Respiratory

Antineoplastic Agents

All Drugs and Chemicals

Etanidazole

PET Scan

Carbogen

Dichloroacetate

Dr. Billy W. Loo Jr. M.D. Ph.D.

Hypoxia, meaning a lack of oxygen, has been associated strongly with a wide range of human cancers. Hypoxia occurs when tumor growth exceeds the ability of blood vessels to supply the tumor with oxygenated blood. It is currently understood that hypoxic tumors are more aggressive. Current methods for measuring hypoxia include invasive procedures such as tissue biopsy, or insertion of an electrode into the tumor. EF5-PET may be a non-invasive way to measure tumor hypoxia.

To establish PET imaging with the tracer EF5 as an accurate and reliable method for measuring the oxygen content of a tumor and to establish the measurement of secreted markers in blood as an accurate and reliable method for measuring the oxygen content of a tumor.

Imaging and Biomarkers of Hypoxia in Solid Tumors

Stanford University

Associate Professor of Radiation Oncology

Neoplasms

Recurrence

Head and Neck Neoplasms

25 mg/kg/day, 37.5 mg/kg, or 50 mg/kg/day oral DCA.

Daniel T Chang

The purpose of this study is to study the effect of the drug DCA (dichloroacetate) on recurrent head and neck cancers. Part of this study will also use EF5 PET scan to study tumor hypoxia.

Metabolic Reprogramming Therapy for Treatment of Recurrent Head and Neck Cancers

Phase I Trial of Metabolic Reprogramming Therapy for Treatment of Recurrent Head and Neck Cancers

Daniel T. Chang

Assistant Professor of Radiation Oncology

Peter Venner, M.D.

Evangelos Michelakis, M.D.

Dichloroacetate (DCA) is a small molecule that has been used for years to treat lactic acidosis and rare metabolic disorders in humans. Further testing now shows that it may suppress the growth of human cancer cells. Tests of DCA on human cells cultured outside of the body found that it killed lung, breast, and brain cancer cells, without affecting human normal cells. Tumors in rats that were infected with human tumors also shrank considerably. Most cancers are characterized by a resistance to apoptosis (cell death that removes abnormal cells) that makes them more likely to grow as well as be resistant to most cancer treatments. Plus, many current cancer treatments kill both cancerous and healthy cells and are highly toxic. DCA works by reversing the damage to the mitochondria that is present in cancer cells, thus reactivating the apoptosis (cell death) mechanism in them. The result is the death of the cancer cells. This mitochondrial reactivation presents an entirely new approach to treating cancer.

DCA is known to be relatively well tolerated with few significant side effects and its selectivity, effectiveness and ease of delivery (oral) make it an attractive opportunity. It is hoped that one day this treatment may become a safe and effective treatment, either along or in conjunction with other treatments, for many forms of cancer.

As cancer cells have a hyperpolarized mitochondrial membrane and deficiency in Kv channel expression, it was postulated that the reversal of this observation may increase apoptosis and inhibit tumor growth. Bonnet and colleagues reported that the administration of DCA led to the switch from glycolysis to oxidative phosphorylation in the Krebs Cycle through inhibition of PDHK. This was associated with an increase in the production of reactive oxygen species and a decrease in hyperpolarization of the inner mitochondrial membrane, leading to efflux of proapoptotic proteins and apoptosis as measured by increased in TUNEL-positive cells. In addition, DCA also decreased the expression of survivin, an anti-apoptotic protein. DCA upregulated the expression of Kv channels in cancer cells, leading to efflux of potassium ions and further increased the proapoptotic effect of DCA. Such change in energy metabolism and apoptosis was not observed in normal cells. DCA was also shown to inhibit tumor growth both in vitro and in vivo. Thus, inhibition of PDHK by DCA represents a novel anti-cancer therapy target with reasonable toxicities to normal tissue. It is therefore of interest to study DCA in refractory cancer patients.

Although the bioavailability was only 50-60% in normal subjects treated with 2.5 microgram/kg of DCA , in a study using clinically relevant dose of DCA at 50 mg/kg, the bioavailability was 100% in health volunteers. DCA administered at 50 mg/kg/day can achieve plasma concentrations above those require for inhibition of PHDK, the target enzyme for at least 24 hours, without exceeding the concentration for maximal lactate lowering. There was a high incidence of peripheral neuropathy in adults with MELAS after administration of DCA at 50 mg/kg/day for 6 months, but peripheral neuropathy is part of the MELAS syndrome, and many adult patients with MELAS develop diabetes mellitus, which commonly presents with peripheral neuropathy. In the contrary, no peripheral neuropathy was observed in children with congenital acidosis after prolonged treatment with DCA at 50 mg/kg/day up to 2 years. Therefore, with exclusion of patients with any grade 2 or higher peripheral neuropathy and with careful monitoring of peripheral neuropathy using monofilaments, the likelihood of developing severe peripheral neuropathy in adult cancer patients should be minimized. Given the presence of significant neuropathy in adult patients with MELAS after treatment with DCA at 25 mg/kg/day, it is judged to be safe and reasonable to establish the starting dose at 12.5 mg/kg/day in adult cancer patients.

A Phase I, Open-Labeled, Single-Arm, Dose Escalation, Clinical and Pharmacology Study of Dichloroacetate (DCA) in Patients With Recurrent and/or Metastatic Solid Tumours

Cross Cancer Institute

AHS Cancer Control Alberta

Nervous System Diseases

Rare Diseases

Glioblastoma

Glioma

Brain Neoplasms

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

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

Newly diagnosed disease with no previous therapy

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

Dichloroacetate (DCA)

Kenneth Petruk, MD co-PI

Evangelos D Michelakis, MD co-PI

Connor Maguire MD, investigator

Linda Webster, NP manager

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.

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

A Phase II Open-labeled, Double-arm Clinical Study of Dichloroacetate (DCA) in Malignant Gliomas and Glioblastome Multiforme (GBM) Patients

Capital Health, Canada

University of Alberta

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Subjects are given a dose of Dichloroacetate 4mg/kg twice a day for 30 days

Subjects are given a dose of Dichloroacetate 12.5mg/kg twice a day for 30 days

Subjects after passing the inclusion criteria are given a dose of dichloroacetate 4mg/kg bid for thirty days. While in the clinical research center they participate in a breath test where they exhale through a straw into a glass tube. This will measure CO2. They are monitored every two weeks for side effects and return to the clinical research center for evaluation in thirty days. They undergo another breath test and if all health parameters are within normal limits they are given a month's supply of dichloroacetate. The cycles continue unless a serious adverse event occurs or the PI judges the side effects preclude another 30 days of medication

Erin M. Dunbar, MD

Peter W. Stacpoole, PhD, MD

The purpose of this study is to evaluate the safety and tolerability of oral Dichloroacetate (DCA) in the treatment of recurrent malignant brain tumors (RMBTs). RMBTs are defined as either: 1) malignant tumors, originating in the brain, that have recurred at least once or 2) malignant tumors originating elsewhere in the body that have spread to the brain at least once. Otherwise, there are no limitations to the number of prior recurrences. There are no limitations to the number or types of prior therapies.

Malignant brain tumors are defined as any World Health Organization grade III-IV glioma and any solid tumor metastasis (spread) to the brain. Recurrent malignant brain tumors (RMBTs) are defined as either: 1) malignant tumors, originating in the brain, that have recurred at least once or 2) malignant tumors originating elsewhere in the body that have spread to the brain at least once. They share an increasing incidence, clinical and radiographic characteristics, lack of effective therapies, tendency to recur, and poor outcome. Importantly, recurrent malignant brain tumor's shared characteristics may be usefully exploited by an emerging class of biologic agents called metabolic modulators of which Dichloroacetate (DCA) is the drug in the class most thoroughly investigated clinically. DCA's mechanism of action and tolerability have been extensively demonstrated in the treatment of chronic metabolic disorders. Furthermore, the preciseness of DCA's mechanism of action appears to target abnormal tumor cell metabolism.

Study of the Safety and Efficacy of Dichloroacetate (DCA) in Glioblastoma and Other Recurrent Brain Tumors

Phase 1, Open-Label, Single-Arm, Clinical and Metabolomics Study of Dichloroacetate (DCA) in Adults With Recurrent Malignant Brain Tumors

Oral DCA will be administered until intolerance, toxicity, radiographic progression, or death. Safety and tolerance will be assessed by reviewing available standardized clinical, radiographic, and quality of life (QOL) criteria. The safety and tolerance will also be assessed by reviewing available plasma, urine, and brain tumor tissue for metabolites of the tumor and the effects of DCA thereon.

We postulate that the metabolism of RMBTs and the effects of DCA thereon will help investigators understand RMBTs, how DCA works on them, and how to design future treatment studies.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Imaging and Biomarkers of Hypoxia in Solid Tumors	NCT01123005	Neoplasms	PET Scan EF5 Carbogen Dichloroacetate	18 Years -	Stanford University
Imaging and Biomarkers of Hypoxia in Solid Tumors	NCT01123005	Neoplasms	PET Scan EF5 Carbogen Dichloroacetate	18 Years -	Stanford University
Metabolic Reprogramming Therapy for Treatment of Recurrent Head and Neck Cancers	NCT01163487	Head and Neck C... Head and Neck C...	Dichloroacetate EF5	18 Years -	Stanford University
A Phase I, Open-Labeled, Single-Arm, Dose Escalation, Clinical and Pharmacology Study of Dichloroacetate (DCA) in Patients With Recurrent and/or Metastatic Solid Tumours	NCT00566410	Neoplasms	Dichloroacetate	18 Years -	AHS Cancer Control Alberta
The Safety and Efficacy of DCA for the Treatment of Brain Cancer	NCT00540176	Malignant Gliom...	Dichloroacetate...	18 Years -	University of Alberta
Study of the Safety and Efficacy of Dichloroacetate (DCA) in Glioblastoma and Other Recurrent Brain Tumors	NCT01111097	Brain Tumor Glioblastoma	Dichloroacetate	21 Years - 90 Years	University of Florida

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