American Head & Neck Society
Translational Research Meeting

April 21-22, 2015

AHNS Annual Meeting
April 22-23, 2015 during the
Combined Otolaryngology Spring Meetings

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Preliminary Results of a Phase II Randomized Trial of DCA (Dichloroacetate) in Combination With Cisplatin and Definitive Radiation in Stage III-IV Squamous Cell Carcinoma of the Head and Neck

Presentation: S008
Topic: Experimental Therapeutics/Molecular Targets
Type: COSM
Date: Wednesday, April 22, 2015
Session: 11:30 AM - 12:15 PM Scientific Session #2
Authors: Steven F Powell, MD, William C Spanos, MD, Andrew Terrell, MD, Miroslaw Mazurczak, MD, Michael Keppen, MD, Sana Jeffreys, MD, Elie Dib, MD, Mark Gitau, MD, Keely Hack, MD, Steven McGraw, MD, Michelle Lohr, MD, Ashley Jensen, Susan Puumala, PhD, Keith Miskimins, PhD, Lora Black, RN, Kimberly Lee, BS, John Lee, MD
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Institution(s): Sanford Health
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BACKGROUND:  Concurrent chemoradiotherapy (CRT) is heavily utilized in the definitive management of stage III-IVA squamous cell carcinoma of the head and neck (SCCHN).  Novel approaches are needed to improve responses and reduce toxicity.  Immunotherapies are emerging as promising treatment options, however the tumor microenvironment may limit their efficacy.  Agents that modulate this microenvironment are appealing options to augment therapy.  Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase (PDK) and thus decreases lactic acid production in the tumor microenvironment.  In an in vivo mouse model evaluating DCA in combination with CRT, immune clearance of SCCHN was enhanced through this mechanism.   As a result, we performed a clinical trial to evaluate the safety and efficacy of DCA in combination with standard high-dose cisplatin based CRT.

METHODS:  A randomized, double-blinded, placebo-controlled multi-site study of DCA versus placebo given in combination with high-dose bolus cisplatin (100 mg/m2 on days 1, 22, and 43) in combination with radiation treatment (70 cGy) in patients with Stage III-IV Squamous Cell Carcinoma of the Head and Neck (SCCHN) was conducted.  DCA (dichloroacetate) or placebo was given PO or per G-tube twice a day during radiation therapy.  DCA was given at a dose of 12.5mg/kg.  Comparison of safety (based on CTCAE version 4.0) between the two groups was the primary outcome.  The secondary outcome of efficacy was evaluated by 2- and 5-year progression-free survival (PFS) rate, overall response rate (ORR) per RECIST 1.1, and median overall survival (OS).  Correlative studies included health-related quality of life (HRQOL) comparison between groups and correlation of HPV status with secondary outcome measures.

RESULTS:  A total of 50 patients enrolled in the study from May 2011 through April 2014.  25 were randomized to DCA and 25 were randomized to placebo.  A total of 133 adverse events (AEs) were analyzed during the study. There was a difference in the distribution of grades of several AEs.  Higher grades in alopecia, headache, tinnitus and vomiting were seen in those treated with in placebo group when compared to DCA. ).  Higher grades in hypotension and decreased platelet counts were seen in those treated with in DCA. Efficacy analysis is still underway.  For evaluable patients, ORRs did not significantly differ between groups.  However, in patients who were assessed   8/18(44%) patient in placebo showed complete response versus 12/15(80%) had completed response in DCA group on the end of treatment imaging studies (day 100 post-radiation completion).  6-month PFS and OS data are being analyzed and will be available by the time of the meeting.

CONCLUSION: The addition of DCA to definitive CRT did not add significant, serious toxicity.  Response rates were not statistically different between the two groups.  However,  100 day complete response favored those who received DCA .  Future data regarding PFS and OS will help determine the potential of this agent for future use in clinical trials.  Data from our study suggests that metabolic inhibitors can be safely incorporated into the management of SCCHN patients undergoing treatment with standard CRT.


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