Squamous Cell Carcinoma of the Head and Neck
Conditions
Keywords
Stage III-IV Squamous Cell Carcinoma
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.
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.
Interventions
DRUGDCA (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)
DRUGPlacebo
Placebo PO or per G-tube twice a day for 8 weeks given in combination with Cisplatin.
Sponsors
Sanford Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Adverse Events During Treatment. | 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
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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. |
| Local Response Rate for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. | 3 months | — |
| Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. | 1 year | — |
| Health-related Quality of Life Among Study Patients by Treatment Arm. | Completion of Treatment | — |
| Two-year Progression-free Survival Rate in Locally Advanced Head and Neck Squamous Cell Carcinoma in Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. | 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. |
| 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 During Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. | End of treatment | — |
| Health-related Quality of Life Among Study Patients by Treatment Arm . | 1 year | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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)
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) | 25 |
| Placebo Placebo: Placebo PO or per G-tube twice a day for 8 weeks given in combination with Cisplatin. | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | DCA (Dichloroacetate) Treatment | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 60.89 years STANDARD_DEVIATION 9.06 | 59.62 years STANDARD_DEVIATION 8.71 | 58.35 years STANDARD_DEVIATION 8.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 48 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 49 Participants | 24 Participants |
| Region of Enrollment United States | 25 participants | 50 participants | 25 participants |
| Sex: Female, Male Female | 1 Participants | 7 Participants | 6 Participants |
| Sex: Female, Male Male | 24 Participants | 43 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 25 | 25 / 25 |
| serious Total, serious adverse events | 8 / 25 | 6 / 25 |
Outcome results
Primary
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
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DCA (Dichloroacetate) Treatment | Percentage of Participants Who Experienced Adverse Events During Treatment. | 96 percentage of patients |
| Placebo | Percentage of Participants Who Experienced Adverse Events During Treatment. | 96 percentage of patients |
Secondary
Health-related Quality of Life Among Study Patients by Treatment Arm .
Time frame: 1 year
Secondary
Health-related Quality of Life Among Study Patients by Treatment Arm .
Time frame: 5 year
Secondary
Health-related Quality of Life Among Study Patients by Treatment Arm.
Time frame: Completion of Treatment
Secondary
Health-related Quality of Life Among Study Patients by Treatment Arm.
Time frame: 2 year
Secondary
HPV Status- Correlate These Findings With Toxicity and Outcome (Exploratory Analysis).
Time frame: 3 months
Secondary
Immune Response and Correlate These Findings With Toxicity and Outcome (Exploratory Analysis).
Time frame: 3 months
Secondary
Local Response Rate for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.
Time frame: 1 year
Secondary
Local Response Rate for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.
Time frame: 3 months
Secondary
Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.
Time frame: 1 year
Secondary
Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.
Time frame: 2 years
Secondary
Overall Survival for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.
Time frame: 5 year
Secondary
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
Secondary
Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.
Time frame: 3 months
Secondary
Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.
Time frame: 2 years
Secondary
Relative Toxicities for Locally Advanced Head and Neck Squamous Cell Carcinoma Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA.
Time frame: 5 years
Secondary
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.
Time frame: Year 5
Secondary
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.
Time frame: Year 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DCA (Dichloroacetate) Treatment | Two-year Progression-free Survival Rate in Locally Advanced Head and Neck Squamous Cell Carcinoma in Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. | 86.5 percentage of patients |
| Placebo | Two-year Progression-free Survival Rate in Locally Advanced Head and Neck Squamous Cell Carcinoma in Patients Receiving Concurrent Cisplatin, Radiation Therapy, and DCA. | 87.5 percentage of patients |