Mouth Neoplasms
Conditions
Keywords
Calcitriol, Celecoxib, Immunotherapy
Brief summary
The poor survival of Veterans with oral cancer underscores the significance of identifying new treatment approaches. The proposed studies will test a new 2 pronged immunotherapeutic approach for oral cancer patients which lessen the immune inhibitory environment while maturing cells that can stimulate T cell reactivity against oral cancer cells.
Detailed description
The hypothesis of this study is beneficial T cell reactivity in oral squamous cell carcinoma (OSCC) tumors can be synergistically stimulated by blocking suppressor endothelial cells and their induction of other inhibitory cell populations while also maturing immune inhibitory CD34+ cells into antigen-presenting dendritic cells. To test this hypothesis, newly diagnosed OSCC patients will be administered the cyclooxigenase 2 inhibitor celecoxib and/or Calcitriol for the 3 week duration between cancer diagnosis and surgical treatment. The following aims will test the immunological and clinical effectiveness of the combination treatment: * 1\. To block the suppressive activity of endothelial cells and increase the levels of dendritic that are stimulatory to T cell reactivity, thereby synergistically increasing intratumoral T cell reactivity. These functional immune analyses will use OSCC tissues removed from untreated patients or patients treated with celecoxib and/or Calcitriol. * 2\. To reduce development of OSCC recurrences by synergistically stimulating intratumoral T cell reactivity with celecoxib to block suppressor endothelial cell activity and Calcitriol to mature CD34+ suppressor cells into T cell stimulatory dendritic cells.
Interventions
DRUGCelecoxib
Celecoxib (400 mg twice daily)
DRUGCalcitriol
3 week pre-surgical enteral treatment of Calcitriol (1,25-dihydroxyvitamin D3) (3 cycles of 4 microg Calcitriol 3 for each of 3 sequential days followed by 4 days of no treatment)
DRUGCelecoxib plus Calcitriol
3 week pre-surgical enteral treatment of Calcitriol (1,25-dihydroxyvitamin D3) (3 cycles of 4 microg Calcitriol for each of 3 sequential days followed by 4 days of no treatment) plus Celecoxib (400 mg twice daily)
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* locoregional OSCC (T stage II-IV) of the oral cavity, oropharynx, larynx, or hypopharynx without evidence of distant metastases * greater than or equal to 18 years of age * the OSCC treatment plan includes surgical resection * performance status of 0 or 1 * recovered from any prior surgery * must be willing to use appropriate contraception if of child-bearing potential * give signed informed consent prior to the initiation of therapy
Exclusion criteria
* prior immunotherapy * chemotherapy or radiation therapy within three weeks * concurrent NSAID treatments while undergoing treatment * women pregnant or lactating * HIV positive * have an active infection requiring antibiotic therapy, or concomitant malignancies * history of idiopathic urinary calcium stone disease, chronic hypercalcemia, or gastrointestinal malabsorptive conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in IL-2 Levels | baseline and 3 weeks | Change in IL-2 stimulatory cytokine levels within tumor tissue. |
| Change in IFN-gamma Levels | baseline and 3 weeks | Change in IFN-gamma stimulatory cytokine levels within tumor tissue. |
| Change in GM-CSF | baseline and 3 weeks | Change in GM-CSF stimulatory cytokine levels within tumor tissue. |
| Change in IL-6 Levels. | baseline and 3 weeks | Change in levels of immune inhibitory/inflammatory mediator IL-6 in tumor tissue. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Celecoxib Celecoxib:
Celecoxib (400 mg twice daily) oral cancer patients receiving new immunotherapy prior to surgery | 6 |
| Arm 2: Calcitriol Calcitriol Calcitriol (1,25-dihydroxyvitamin D3): 3 week pre-surgical enteral treatment of Calcitriol (3 cycles of 4 microg Calcitriol for each of 3 sequential days followed by 4 days of no treatment) | 6 |
| Arm 3: Celecoxib Plus Calcitriol Celecoxib + Calcitriol 3 week pre-surgical enteral treatment of Calcitriol (3 cycles of 4 microg 1,25-dihydroxyvitamin D3) for each of 3 sequential days followed by 4 days of no treatment) plus Celecoxib (400 mg twice daily) | 4 |
| Arm 4: No Treatment oral cancer patients receiving no immunotherapy prior to surgery | 5 |
| Total | 21 |
Baseline characteristics
| Characteristic | Arm 1: Celecoxib | Arm 2: Calcitriol | Arm 3: Celecoxib Plus Calcitriol | Arm 4: No Treatment | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 3 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 6 Participants | 3 Participants | 3 Participants | 5 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 5 |
Outcome results
Primary
Change in GM-CSF
Change in GM-CSF stimulatory cytokine levels within tumor tissue.
Time frame: baseline and 3 weeks
Population: Patients with head and neck squamous cell carcinoma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Celecoxib | Change in GM-CSF | 3.8 pg/100 gm protein | Standard Error 1.4 |
| Arm 2: Calcitriol | Change in GM-CSF | 8.1 pg/100 gm protein | Standard Error 1.9 |
| Arm 3: Celecoxib Plus Calcitriol | Change in GM-CSF | 14.3 pg/100 gm protein | Standard Error 3.4 |
| Arm 4: No Treatment | Change in GM-CSF | 3.2 pg/100 gm protein | Standard Error 0.9 |
p-value: <0.05t-test, 2 sided
Primary
Change in IFN-gamma Levels
Change in IFN-gamma stimulatory cytokine levels within tumor tissue.
Time frame: baseline and 3 weeks
Population: Patients with head and neck squamous cell carcinoma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Celecoxib | Change in IFN-gamma Levels | 1.9 pg/100 gm protein | Standard Error 0.6 |
| Arm 2: Calcitriol | Change in IFN-gamma Levels | 2.8 pg/100 gm protein | Standard Error 1.1 |
| Arm 3: Celecoxib Plus Calcitriol | Change in IFN-gamma Levels | 6.3 pg/100 gm protein | Standard Error 2.2 |
| Arm 4: No Treatment | Change in IFN-gamma Levels | 2.0 pg/100 gm protein | Standard Error 0.3 |
p-value: <0.05t-test, 2 sided
Primary
Change in IL-2 Levels
Change in IL-2 stimulatory cytokine levels within tumor tissue.
Time frame: baseline and 3 weeks
Population: Patients with head and neck squamous cell carcinoma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Celecoxib | Change in IL-2 Levels | 1.8 pg/100 gm protein | Standard Error 0.3 |
| Arm 2: Calcitriol | Change in IL-2 Levels | 4.0 pg/100 gm protein | Standard Error 0.4 |
| Arm 3: Celecoxib Plus Calcitriol | Change in IL-2 Levels | 7.9 pg/100 gm protein | Standard Error 1.2 |
| Arm 4: No Treatment | Change in IL-2 Levels | 2.1 pg/100 gm protein | Standard Error 0.2 |
p-value: <0.05t-test, 2 sided
Primary
Change in IL-6 Levels.
Change in levels of immune inhibitory/inflammatory mediator IL-6 in tumor tissue.
Time frame: baseline and 3 weeks
Population: Patients with head and neck squamous cell carcinoma.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Celecoxib | Change in IL-6 Levels. | 39 pg/100 gm protein | Standard Error 18 |
| Arm 2: Calcitriol | Change in IL-6 Levels. | 46 pg/100 gm protein | Standard Error 21 |
| Arm 3: Celecoxib Plus Calcitriol | Change in IL-6 Levels. | 29 pg/100 gm protein | Standard Error 8 |
| Arm 4: No Treatment | Change in IL-6 Levels. | 132 pg/100 gm protein | Standard Error 46 |
p-value: <0.05t-test, 2 sided