NeoplasmsPhase 1DCANCT00566410
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
A Phase 1 study testing Dichloroacetate in people with Neoplasms, run by AHS Cancer Control Alberta at 1 site in Canada.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Neoplasms
- What is being tested?
- Dichloroacetate
- Type of treatment
- Pill or oral medicine
- How many people
- 23 participants
- Where
- 1 siteCanada
- Study dates
- Dec 2007to Mar 2013
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have histologically or cytologically confirmed recurrent or metastatic solid tumours. All patients will have no meaningful therapies available to them including hormone therapy, chemotherapy and targeted therapies. For the malignancies that have no proven therapy, they can be enrolled without any prior systemic therapy.
- Four weeks must have elapsed since prior chemotherapy, hormonal therapy, targeted therapy, or radiation therapy. There is no restriction in the amount of bone marrow previously radiated.
- Recovery to baseline or, at most, grade 1 of all drug-related toxicities due to prior chemotherapy, radiation, hormonal therapy, or molecular targeted therapy, except for alopecia.
- Age ≥ 18 years.
- ECOG performance status ≤ 2 (Karnofsky ≥70%, see Appendix A).
- Life expectancy of greater than 12 weeks.
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- Patients must have normal organ 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) ≤2.5 X ULN or ≤ 5 X ULN in the presence of liver metastases
- creatinine ≤1.5 X institutional upper limit of normal
- Cardiac ejection fraction by MUGA scan or echocardiogram must be >50% for patients at baseline.
- The effects of DCA on the developing human fetus are unknown. For this reason and because DCA can be teratogenic, 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.
- Ability to understand the purpose of the study and the willingness to sign a written informed consent document.
Who cannot join
- Patients who have had chemotherapy, hormonal therapy, 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 may not be receiving any other investigational agents, chemotherapy, immunotherapy, radiotherapy, or molecular targeted agents.
- Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that could confound the evaluation of neurologic and other adverse events.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to DCA.
- Due to the possibility of peripheral sensorimotor neuropathy from DCA, the presence of grade 2 or higher peripheral neuropathy due to prior medical condition (such as multiple sclerosis), medications, or other etiologies.
- Any psychological, familial, sociological, or geographical conditions that do not permit medical follow-up and compliance with the study protocol.
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- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Specifically, for patients who are taking either or both oral hypoglycemics and insulin for diabetes mellitus will not be eligible as DCA in combination with these agents may increase the risk of clinically significant hypoglycemia, compromising patient safety.
- Pregnant women are excluded from this study because DCA is an agent with the potential for teratogenic or abortifacient effects. 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.
- 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 infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
- 5 years must have elapsed since the initial curative procedure for other malignancies, except for in situ cervical cancer, basal cell carcinoma of the skin, and localized prostate cancer after curative therapy such as surgery, or radiation.
- History of malabsorption syndrome or substantial amount of small bowels or stomach removed that may impair absorption of DCA.
- Patients taking warfarin. Low dose or therapeutic dose of heparin or low molecular weight heparin is allowed.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the detailed description
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.
- Conditions
- Neoplasms
- Being tested
- Dichloroacetate
- Keywords
- DCA, Phase I, Dose Escalation, Solid Tumours, Dichloroacetate, Pharmacokinetic
- Medical subject headings
- Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DichloroacetateDrug
Continuous daily oral dosage (bid).
What is being measured
The primary outcome is the main question the study is designed to answer.
To assess safety and tolerability of oral DCA
Measured: Trial Completion
To determine the dose-limiting toxicity (DLT) and phase II dose
Measured: Trial completion
To characterize pharmacokinetic (PK) profile
Measured: Trial Completion
Secondary outcomes (3)
To evaluate the effect of oral DCA
Measured: Trial Completion
To evaluate the clinical response rate
Measured: Trial completion
To evaluate the change in standard uptake value by FDG-PET scans before and after treatment with DCA
Measured: Trial completion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Dec 2007 (estimated)
- Study startDec 2007
- Primary completionMar 2013
- Study completionMar 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for NeoplasmsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- AHS Cancer Control Alberta
- Sponsor type
- University, hospital or other
- Collaborators
- Cross Cancer Institute
- Responsible party
- Sponsor
- Investigators
- Peter Venner, M.D., Principal investigator, AHS Cancer Control AlbertaEvangelos Michelakis, M.D., Principal investigator, University of Alberta
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00566410
- Sponsor's protocol ID
- 23596
- Acronym
- DCA
- Status last verified
- Mar 2016
- First submitted
- 29 Nov 2007
- Last updated
- 11 Mar 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 11 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT00566410
- Acronym / sponsor ID
- DCA / 23596
- Conditions
- Neoplasms
- Keywords
- DCA, Phase I, Dose Escalation, Solid Tumours, Dichloroacetate, Pharmacokinetic
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- AHS Cancer Control AlbertaUniversity, hospital or other
- Collaborators
- Cross Cancer Institute
- Study start
- Dec 2007
- Primary completion
- Mar 2013 (actual)
- Study completion
- Mar 2013 (actual)
- First posted
- 3 Dec 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Patients must have histologically or cytologically confirmed recurrent or metastatic solid tumours. All patients will have no meaningful therapies available to them including hormone therapy, chemotherapy and targeted therapies. For the malignancies that have no proven therapy, they can be enrolled without any prior systemic therapy.
- Four weeks must have elapsed since prior chemotherapy, hormonal therapy, targeted therapy, or radiation therapy. There is no restriction in the amount of bone marrow previously radiated.
- Recovery to baseline or, at most, grade 1 of all drug-related toxicities due to prior chemotherapy, radiation, hormonal therapy, or molecular targeted therapy, except for alopecia.
- Age ≥ 18 years.
- ECOG performance status ≤ 2 (Karnofsky ≥70%, see Appendix A).
Key exclusion criteria (12 listed)
- Patients who have had chemotherapy, hormonal therapy, 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 may not be receiving any other investigational agents, chemotherapy, immunotherapy, radiotherapy, or molecular targeted agents.
- Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that could confound the evaluation of neurologic and other adverse events.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to DCA.
- Due to the possibility of peripheral sensorimotor neuropathy from DCA, the presence of grade 2 or higher peripheral neuropathy due to prior medical condition (such as multiple sclerosis), medications, or other etiologies.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DichloroacetateContinuous daily oral dosage (bid). | Drug | – |
Primary outcome
To assess safety and tolerability of oral DCA
Time frame: Trial Completion
To determine the dose-limiting toxicity (DLT) and phase II dose
Time frame: Trial completion
To characterize pharmacokinetic (PK) profile
Time frame: Trial Completion
3 secondary outcomes
To evaluate the effect of oral DCA
Time frame: Trial Completion
To evaluate the clinical response rate
Time frame: Trial completion
To evaluate the change in standard uptake value by FDG-PET scans before and after treatment with DCA
Time frame: Trial completion
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Mar 2016.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Venner, M.D. principal investigator
AHS Cancer Control Alberta
Evangelos Michelakis, M.D. principal investigator
University of Alberta
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Dichloroacetate in people with Neoplasms, run by AHS Cancer Control Alberta at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To assess safety and tolerability of oral DCA (time frame: Trial Completion). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Mar 2016.