478P - A phase I open-labelled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumours

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Clinical Research
Basic Scientific Principles
Presenter QUincy Siu-chung Chu
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors Q.S. Chu1, R. Sangha1, J. Spratlin1, L.J. Vos1, J.R. Mackey1, A.J.B. McEwan1, P. Venner1, E.D. Michelakis2
  • 1Oncology, University of Alberta, Cross Cancer Institute, T6G1Z2 - Edmonton/CA
  • 2Medicine, Cardiology, University of Alberta, Edmonton/CA



Altered glucose metabolism and suppression of apoptosis in cancer can be modified by dichloroacetate (DCA). This phase I study aimed to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and pharmacokinetics (PK) of oral DCA administered twice daily (BID) in patients with advanced solid tumors.


24 patients were enrolled using a standard 3 + 3 design at a starting dose of 6.25mg/kg BID. Treatment was continued until progression, toxicity or withdrawal of consent. Serial plasma samples for PK analysis were obtained on day 1 and 15 of cycle 1 and day 1 of subsequent 28 day cycles.


23 evaluable patients, with a median age of 60 years (12F/11M), were treated with DCA at two doses: 6.25mg/kg and 12.5mg/kg BID (median 2 cycles for both). The most common malignancies were colorectal (6), lung (5), breast (3), and head and neck (3). There were no dose-limiting toxicities (DLTs) in the 6.25mg/kg BID cohort. 3 of 7 patients had DLTs (fatigue, vomiting and/or diarrhea) at the 12.5mg/kg BID dose level. 13 additional patients were treated at dose-expansion of 6.25mg/kg BID, which was established as the MTD and RP2D for DCA. Common toxicities of any grade were fatigue (34.8%), peripheral neuropathy (34.8%), and nausea (17.4%). Although there were no responses by RECIST criteria, 8 patients had stable disease for a median duration of 7.9 weeks. The PK profile of 10 patients was consistent with previously published data. The mean peak concentration on day 15 was higher than that of day 1 and for patients at the 6.25mg/kg BID dose was 430 µM (range: 38-733 µM) and at the 12.5mg/kg BID dose was 808 µM (range: 211-1441 µM). Within a given dose, there was progressive increase in trough DCA levels with time, compatible with published data that DCA inhibits its own metabolism with time.


The MTD and RP2D of oral DCA is 6.25mg/kg BID. This results in peak serum levels within the range known to inhibit pyruvate dehydrogenase kinase (the target enzyme of DCA). However, the short duration of exposure of this cohort to DCA may produce inadequate trough levels. Trial designs and enrolment criteria that would allow for longer exposure may be required to evaluate efficacy of DCA.


All authors have declared no conflicts of interest.