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

• ClinicalTrials.gov Identifier: NCT01386632
• Recruitment Status: Completed
• First Posted: July 1, 2011
• Results First Posted: June 14, 2017
• Last Update Posted: October 27, 2020
• Sponsor: Sanford Health
• Information provided by (Responsible Party): Sanford Health

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Squamous Cell Carcinoma of the Head and Neck	Drug: DCA (dichloroacetate); Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 2011
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: June 1, 2020

Arms and Interventions

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Who Experienced Adverse Events During Treatment. [ Time Frame: 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. ]
   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

Secondary Outcome Measures :

1. Two-year Progression-free Survival Rate in Locally Advanced Head and Neck Squamous Cell Carcinoma in Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: Year 2 ]

   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.

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. [ Time Frame: Year 5 ]
   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.
3. Local Response Rate for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: 3 months ]
4. Local Response Rate for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: 1 year ]
5. Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: 1 year ]
6. Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: 2 years ]
7. Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: 5 year ]
8. Health-related Quality of Life Among Study Patients by Treatment Arm. [ Time Frame: Completion of Treatment ]
9. Health-related Quality of Life Among Study Patients by Treatment Arm . [ Time Frame: 1 year ]
10. Health-related Quality of Life Among Study Patients by Treatment Arm. [ Time Frame: 2 year ]
11. Health-related Quality of Life Among Study Patients by Treatment Arm . [ Time Frame: 5 year ]
12. Immune Response and Correlate These Findings With Toxicity and Outcome (Exploratory Analysis). [ Time Frame: 3 months ]
13. HPV Status- Correlate These Findings With Toxicity and Outcome (Exploratory Analysis). [ Time Frame: 3 months ]
14. Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: 2 years ]
15. Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: 3 months ]
16. Relative Toxicities During Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: End of treatment ]
17. Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. [ Time Frame: 5 years ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, North Dakota

Sanford Roger Maris Cancer Center

Fargo, North Dakota, United States, 58122

United States, South Dakota

Sanford Hematology and Oncology

Sioux Falls, South Dakota, United States, 57104

Sponsors and Collaborators

Sanford Health

Investigators

• Study Chair: Steven F Powell, MD; Sanford Health

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sanford Health
• ClinicalTrials.gov Identifier: NCT01386632
• Other Study ID Numbers: DCA 2010
• First Posted: July 1, 2011
• Results First Posted: June 14, 2017
• Last Update Posted: October 27, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Sanford Health:

Stage III-IV Squamous Cell Carcinoma

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Head and Neck Neoplasms; Neoplasms by Site