Study of DCA (Dichloroacetate) in Combination With Cisplatin and Definitive Radiation in Head and Neck Carcinoma

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

This will be a randomized masked placebo-controlled single-center study to evaluate the effects of Dichloroacetate (DCA) versus placebo given in combination with Cisplatin and radiation treatment in patients with Stage III-IV Squamous Cell Carcinoma of the Head and Neck (SCCHN). Fifty subjects will be enrolled and randomly assigned on a 1:1 ratio to DCA or matching placebo given with standard of care treatment consisting of Cisplatin and radiation treatment.

Patients will receive DCA/placebo PO or per G-tube twice a day for 8 weeks. The first 6 patients of the total study population will represent a safety lead-in cohort. The results of the safety lead-in of DCA/placebo in combination with Cisplatin and radiation therapy will be evaluated after the 6th patient has completed 8 weeks of therapy. Recruitment of patients will be withheld during safety data analysis.

Study Overview

• Status: Completed
• Conditions: Squamous Cell Carcinoma of the Head and Neck
• Intervention / Treatment: Drug: DCA (dichloroacetate); Drug: Placebo

Detailed Description

Doses for Cisplatin will be based on actual body weight taken on each day of Cisplatin therapy. DCA doses will be calculated at baseline according to actual body weight and will not change during the 8 weeks of therapy.

A careful description of the extent of the primary lesion and nodal spread will be recorded.

Dental Evaluation: Prior to treatment, patients will be evaluated by the dental service and a prophylactic cleaning/fluoride regimen instituted. A delay of at least 14 days from major surgery, including dental extractions, will be required prior to Day 1 treatment.

Airway Patency: Significant laryngeal edema has been described after the use of cisplatin containing regimens. Patients with laryngeal tumors should be considered for a prophylactic tracheostomy prior to the initiation of chemotherapy, if any possibility of airway compromise exists. Patients with laryngeal tumors experiencing respiratory stridor or compromise shortly after chemotherapy/radiotherapy administration should be rapidly evaluated for tracheostomy.

Alimentation: Significant stomatitis, mucositis and dysphagia are expected with these treatment regimens. Hospitalization may be required for symptomatic management. Pronounced weight loss is common, and adequate alimentation needs to be maintained. Early, if not pre-emptive, enteral tube feedings should be considered if difficulty is anticipated.

Compliance: The complexity of these treatment regimes and their attendant toxicity are such that compliance is of major concern. Patients expected to pose compliance problems should not be entered on this study. Patients will need to be seen at least weekly during therapy so that the toxicities can be monitored and treated.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Roger Maris Cancer Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Hematology and Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have histologically, cytologically confirmed and previously untreated stage 3 or 4 HNSC that recommended treatment would be concurrent cisplatin and radiation.
• Age ≥ 18 years
• ECOG performance status ≤ 2 or Karnofsky ≥70%
• Life expectancy of greater than 12 weeks.

• 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
• 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.
• Repeat biopsy is not mandatory, but is strongly suggested. Should be performed between Day 8 and Day 15 treatments.

Exclusion Criteria:

• 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.(Cetuximab)
• Due to the possibility of peripheral sensorimotor neuropathy from DCA, the presence of grade 2 or higher peripheral neuropathy due to a 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.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes mellitus, 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 or breast-feeding 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.
• Five 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: DCA (dichloroacetate) Treatment; DCA orally 12.5mg/kg or per G-tube BID daily for 8 weeks in conjunction with Cisplatin 100 mg/m^2 IV over 30-60 minutes every 3wks X 3(Days 1, 22, and 43 of RT)and RT 70 Gy/35 -200 cGy/d x 7 weeks (35 Fractions)	Drug: DCA (dichloroacetate); DCA orally 12.5mg/kg PO or per G-tube BID daily for 8 weeks in conjunction with Cisplatin 100 mg/m^2 IV over 30-60minutes every 3wks X 3(Days 1, 22, and 43 of RT)and RT 70 Gy/35 -200 cGy/d x 7 weeks (35 Fractions); Other Names: dichloroacetate
Placebo Comparator: Placebo; Placebo orally or per G-tube BID for 8 weeks in conjunction with Cisplatin 100 mg/m^2 IV over 30-60 minutes every 3wks X 3(Days 1, 22, and 43 of RT)and RT 70 Gy/35 -200 cGy/d x 7 weeks (35 Fractions)	Drug: Placebo; Placebo PO or per G-tube twice a day for 8 weeks given in combination with Cisplatin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experienced Adverse Events During Treatment.	Percentage of Participants Who Experienced Adverse Events During Treatment including but are not limited to mucositis, leucopenia, neuropathy, and treatment breaks. This will be done according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0	Adverse events (AE) will be assessed from the time the subject begins the study until the 30-days after receiving the last dose of the study medication.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Two-year Progression-free Survival Rate in Locally Advanced Head and Neck Squamous Cell Carcinoma in Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.	Outcome of tumor change will be compared in two separate ways. First, change in measured tumor size at 8 weeks and 3 months will be compared using standard linear models methods (using appropriate transformation to reduce statistical skew). Progression was determined using RECIST 1.1 definition of 20% increase in the sum of the diameters of target lesions, in either primary or nodal lesions or the appearance of one or more new lesion(s) and/or unequivocal progression of existing non-target lesions.	Year 2
Two-year and Five-year Progression-free Survival Rate in Locally Advanced Head and Neck Squamous Cell Carcinoma in Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.	Progression will be determined using RECIST 1.1 definition of 20% increase in the sum of the diameters of target lesions, in either primary or nodal lesions or the appearance of one or more new lesion(s) and/or unequivocal progression of existing non-target lesions.	Year 5
Local Response Rate for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		3 months
Local Response Rate for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		1 year
Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		1 year
Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		2 years
Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		5 year
Health-related Quality of Life Among Study Patients by Treatment Arm.		Completion of Treatment
Health-related Quality of Life Among Study Patients by Treatment Arm .		1 year
Health-related Quality of Life Among Study Patients by Treatment Arm.		2 year
Health-related Quality of Life Among Study Patients by Treatment Arm .		5 year
Immune Response and Correlate These Findings With Toxicity and Outcome (Exploratory Analysis).		3 months
HPV Status- Correlate These Findings With Toxicity and Outcome (Exploratory Analysis).		3 months
Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		2 years
Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		3 months
Relative Toxicities During Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		End of treatment
Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.		5 years

Collaborators and Investigators

• Sponsor: Sanford Health
• Investigators: Study Chair: Steven F Powell, MD, Sanford Health

Publications and helpful links

General Publications

• Powell SF, Mazurczak M, Dib EG, Bleeker JS, Geeraerts LH, Tinguely M, Lohr MM, McGraw SC, Jensen AW, Ellison CA, Black LJ, Puumala SE, Reed VJ, Miskimins WK, Lee JH, Spanos WC. Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma. Invest New Drugs. 2022 Jun;40(3):622-633. doi: 10.1007/s10637-022-01235-5. Epub 2022 Mar 21.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: May 23, 2011
• First Submitted That Met QC Criteria: June 30, 2011
• First Posted (Estimate): July 1, 2011

Study Record Updates

• Last Update Posted (Actual): October 27, 2020
• Last Update Submitted That Met QC Criteria: October 2, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Stage III-IV Squamous Cell Carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
• Other Study ID Numbers: DCA 2010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No