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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

Phase 1
18 Years
Open (Enrolling)

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Trial Information

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

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.

Inclusion Criteria:

1. 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.

2. 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.

3. 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

4. Age ≥ 18 years.

5. ECOG performance status ≤ 2 (Karnofsky ≥70%, see Appendix A).

6. Life expectancy of greater than 12 weeks.

7. 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

- creatinine ≤1.5 X institutional upper limit of normal

8. Cardiac ejection fraction by MUGA scan or echocardiogram must be >50% for patients at

9. 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.

10. Ability to understand the purpose of the study and the willingness to sign a written
informed consent document.

Exclusion Criteria:

1. 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.

2. Patients may not be receiving any other investigational agents, chemotherapy,
immunotherapy, radiotherapy, or molecular targeted agents.

3. 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

4. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to DCA.

5. 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.

6. Any psychological, familial, sociological, or geographical conditions that do not
permit medical follow-up and compliance with the study protocol.

7. 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.

8. 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

9. 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.

10. 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.

11. History of malabsorption syndrome or substantial amount of small bowels or stomach
removed that may impair absorption of DCA.

12. Patients taking warfarin. Low dose or therapeutic dose of heparin or low molecular
weight heparin is allowed.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To assess safety and tolerability of oral DCA

Outcome Time Frame:

Trial Completion

Safety Issue:


Principal Investigator

Peter Venner, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Alberta Health Services


Canada: Ethics Review Committee

Study ID:




Start Date:

December 2007

Completion Date:

May 2012

Related Keywords:

  • Neoplasms
  • DCA
  • Phase I
  • Dose Escalation
  • Solid Tumours
  • Dichloroacetate
  • Pharmacokinetic
  • Neoplasms