Mouth Neoplasms, Neoplasms, Oral
Conditions
Brief summary
This phase II trial studies how trametinib effects tumor cells in patients with oral cavity squamous cell carcinoma that can be removed by surgery. Trametinib may shrink the tumor by blocking an enzyme pathway needed for cell growth.
Detailed description
The rationale for this study in oral cavity squamous cell carcinomas rests on pre-clinical findings demonstrating that (a) activation of the ERK1/2 kinases is associated with aggressive features, (b) this aggressive phenotype is directly linked to expression of CD44, a cell surface hyaluronan receptor and (c) this association between activated ERK1/2 and CD44 is also identified in human cell lines and primary tumors. These data suggest that ERK1/2 is targetable biochemical pathway in CD44 expressing cells. These cells represent putative cancer stem cells or tumor initiating cells that have been associated with worse patient outcomes. Thus, the application of GSK1120212 to target OCSCC is a specific translational application of our laboratory findings.
Interventions
DRUGGSK1120212
Trametinib (GSK1120212) is a selective MEK1 and MEK2 inhibitor with selective activity towards BRAF and RAS mutant cancer cell lines and hematopoietic cancer cells from AML and CML origins.
Sponsors
National Comprehensive Cancer Network
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient must have histologically or cytologically confirmed oral cavity squamous cell carcinoma of stage 2, 3, 4a, or 4b. * Patients by definition have disease at the primary tumor site of at least 2 centimeters. * Patient's treatment plan must include primary tumor site biopsy followed by gross excision of the primary tumor site at a separate operative procedure. * Patients with concurrent primary head and neck tumors that will be resected as part of treatment plan are considered eligible * Patients with head and neck cancer recurrence requiring surgery with no history of prior chemotherapy or radiation therapy are considered eligible. * Patient must be ≥ 18 years of age. * Patient must have an ECOG performance status ≤ 1 * Patient must have normal bone marrow and organ function as defined below: * Absolute neutrophil count ≥1,200/mcl * Hemoglobin ≥9.0 g/dL * Platelets ≥100,000/mcl * PT/INR and PTT ≤1.3 x IULN (Subjects on Coumadin are included if their coagulation is within a normal therapeutic range) * LVEF ≥ILLN (by ECHO or MUGA) * Albumin ≥2.5 g/dL * Total bilirubin ≤1.5 x IULN * AST(SGOT)/ALT(SGPT) ≤2.5 x IULN * Creatinine ≤1.5 x IULN OR Creatinine clearance ≥50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, intrauterine device, male partner sterilization, or complete abstinence) prior to study entry, for the duration of study participation, and for at least 4 months after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Patient must have the ability to swallow and retain orally administered medication. * Patient (or legally authorized representative if applicable) must be able to understand and willing to sign an IRB approved written informed consent document. * Both men and women and members of all races and ethnic groups are eligible for this trial.
Exclusion criteria
* Patients must not have had any prior head and neck cancer treatment. * Patient must not have a history of other malignancy ≤ 3 years previous with the exception of previous head and neck cancer treated only by surgery basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix. * Patients must not be receiving any other investigational agents. * Patient must not have a history of retinal vein occlusion (RVO). * Patient must not have known symptomatic leptomeningeal or brain metastases or spinal cord compression. * Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK1120212 or other agents used in the study. * Patient must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. * Patient must not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Patient must not be pregnant and/or breastfeeding. * Patient must not be known to be HIV-positive, hepatitis B-positive, or hepatitis C-positive (with the exception of chronic or cleared HBV or HCV infection, which will be allowed). * Patient must not be taking any herbal supplements during the study (including but not limited to St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, or ginseng). If a potential patient is taking any herbal supplements, s/he must discontinue prior to beginning study treatment. * Patient must not have any history or evidence of cardiovascular risk including any of the following: * QTcB ≥ 480 msec * History or evidence of current clinically significant uncontrolled arrhythmias (exception: subjects with controlled atrial fibrillation for \> 30 days prior to registration are eligible) * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to registration * History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association. * Abnormal cardiac valve morphology (≥ grade 2) documented by echocardiogram (subjects with grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study). Subjects with moderate valvular thickening should not be entered on study. * Treated refractory hypertension defined as a blood pressure of systolic \>140 mmHg and/or diastolic \>90 mmHg which cannot be controlled by antihypertensive therapy. * Intra-cardiac defibrillator or permanent pacemaker * Cardiac metastases * Patient must not have a history of interstitial lung disease or pneumonitis * Current use of a prohibited medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Changes in Putative Tumor Initiating Cell Populations as Defined by Cell Surface CD44 and Intracellular Phospho-ERK1/2 Staining After Treatment With GSK1120212. | Baseline and Day 15 | Pre-post measure of p-EKP expression was measured by change in staining intensity and quartile distribution. |
| Number of Participants With Changes in TumorCell Surface CD44 Expression After Treatment With GSK1120212. | Baseline and Day 15 | Pre-post measure of CD44 expression using IHC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Flow Cytometric Analysis of the Peripheral Blood and Tumor. | Baseline, Day 14, and Day 15 | Peripheral blood - baseline and Day 14 Tumor - baseline and Day 15 |
| Percent Change in Maximum Standard Uptake Value in Oral Cavity Saqumous Cell Carcinoma (OCSCC) Using F18-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT). | Baseline and Day 14 | — |
| Tumor Specific Findings for Pathologic Changes Including Proliferation (Ki-67 Staining), Tumor Vasculature Staining (Microvessel Density), ERK1/2 Mediated Changes in p27 (Kip1) & Flow Cytometric Analysis of the Peripheral Blood & Tumor. | Baseline and Day 15 | — |
| Percent Change in Tumor Size Area | Baseline and Day 15 | — |
| Percent of Participants With Metabolic Changes in OCSCC Using FDG-PET/CT Imaging. | Baseline and Day 14 | Intratumarol metabolic changes were evaluated by changes in in SUVmax in the primary tumor; quantitative analysis SUVmax with the primary tumor site was determined within a volume of interest around the tumor using a Siemens eSoft workstation. |
| Safety of GSK1120212 | 1st 4-6 week follow-up visit | Number of adverse events were monitored for 30 day following last dose of GSK1120212 |
| Percentage of Participants With Clinical Response Induced by GSK1120212, as Determined by Change in Tumor Size. | Baseline and Day 15 | Clinical Response was evaluted by quantitative changes in tumor size based on clinical examination of area of tumor at baseline and after GSK1120212 based on two dimensional measurements. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GSK1120212 GSK1120212 2 mg PO daily for a total of 14 days with the intent of the last pill being the day before surgery.
GSK1120212: Trametinib (GSK1120212) is a selective MEK1 and MEK2 inhibitor with selective activity towards BRAF and RAS mutant cancer cell lines and hematopoietic cancer cells from AML and CML origins. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | constipation | 1 |
Baseline characteristics
| Characteristic | GSK1120212 |
|---|---|
| Age, Customized Median Age (years) | 59.5 years |
| Clinical Stage Stage II | 3 participants |
| Clinical Stage Stage III | 3 participants |
| Clinical Stage Stage IV | 14 participants |
| Gender Female | 1 Participants |
| Gender Male | 19 Participants |
| History of Smoking and/or Alcohol Abuse | 18 participants |
| Oral Cavity Sub-Site Buccal | 1 participants |
| Oral Cavity Sub-Site Floor of Mouth | 7 participants |
| Oral Cavity Sub-Site Retromolar trigone | 5 participants |
| Oral Cavity Sub-Site Tongue | 7 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 20 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 20 |
| serious Total, serious adverse events | 6 / 20 |
Outcome results
Primary
Number of Participants With Changes in Putative Tumor Initiating Cell Populations as Defined by Cell Surface CD44 and Intracellular Phospho-ERK1/2 Staining After Treatment With GSK1120212.
Pre-post measure of p-EKP expression was measured by change in staining intensity and quartile distribution.
Time frame: Baseline and Day 15
Population: Only15 of the 17 participants had sufficient pre- and post-treatment biopsies with sufficient tumor content to be evaluated for this biomarker assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 | Number of Participants With Changes in Putative Tumor Initiating Cell Populations as Defined by Cell Surface CD44 and Intracellular Phospho-ERK1/2 Staining After Treatment With GSK1120212. | Decrease in p-EPK1/2 expression | 7 participants |
| GSK1120212 | Number of Participants With Changes in Putative Tumor Initiating Cell Populations as Defined by Cell Surface CD44 and Intracellular Phospho-ERK1/2 Staining After Treatment With GSK1120212. | Inverse relationship in p-EPK expression | 2 participants |
| GSK1120212 | Number of Participants With Changes in Putative Tumor Initiating Cell Populations as Defined by Cell Surface CD44 and Intracellular Phospho-ERK1/2 Staining After Treatment With GSK1120212. | No change in p-EKP expression | 3 participants |
| GSK1120212 | Number of Participants With Changes in Putative Tumor Initiating Cell Populations as Defined by Cell Surface CD44 and Intracellular Phospho-ERK1/2 Staining After Treatment With GSK1120212. | Increase in p-EKP expression | 3 participants |
Primary
Number of Participants With Changes in TumorCell Surface CD44 Expression After Treatment With GSK1120212.
Pre-post measure of CD44 expression using IHC.
Time frame: Baseline and Day 15
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GSK1120212 | Number of Participants With Changes in TumorCell Surface CD44 Expression After Treatment With GSK1120212. | 3 Participants |
Secondary
Flow Cytometric Analysis of the Peripheral Blood and Tumor.
Peripheral blood - baseline and Day 14 Tumor - baseline and Day 15
Time frame: Baseline, Day 14, and Day 15
Population: There was an insufficient amount of tissue to collected. The data was not collected and the outcome measure was not analyzed.
Secondary
Percentage of Participants With Clinical Response Induced by GSK1120212, as Determined by Change in Tumor Size.
Clinical Response was evaluted by quantitative changes in tumor size based on clinical examination of area of tumor at baseline and after GSK1120212 based on two dimensional measurements.
Time frame: Baseline and Day 15
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GSK1120212 | Percentage of Participants With Clinical Response Induced by GSK1120212, as Determined by Change in Tumor Size. | 76 percentage of participants |
Secondary
Percent Change in Maximum Standard Uptake Value in Oral Cavity Saqumous Cell Carcinoma (OCSCC) Using F18-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT).
Time frame: Baseline and Day 14
Population: Seven patients did not meet protocol-defined tumor size criteria (n=3), withdrew from study (n=3) or declined post GSK1120212 FDG-PET/CT(n=1)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK1120212 | Percent Change in Maximum Standard Uptake Value in Oral Cavity Saqumous Cell Carcinoma (OCSCC) Using F18-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT). | -25 percentage change in SUVmax |
Secondary
Percent Change in Tumor Size Area
Time frame: Baseline and Day 15
Population: Quantitative changes in tumor size based on clinical examination of area of tumor at baseline and after GSK1120212 based on two dimensional measurements.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| GSK1120212 | Percent Change in Tumor Size Area | -46 percent change in tumor size area |
Secondary
Percent of Participants With Metabolic Changes in OCSCC Using FDG-PET/CT Imaging.
Intratumarol metabolic changes were evaluated by changes in in SUVmax in the primary tumor; quantitative analysis SUVmax with the primary tumor site was determined within a volume of interest around the tumor using a Siemens eSoft workstation.
Time frame: Baseline and Day 14
Population: Seven patients did not meet protocol-defined tumor size criteria (n=3), withdrew from study (n=3) or declined post GSK1120212 FDG-PET/CT(n=1)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GSK1120212 | Percent of Participants With Metabolic Changes in OCSCC Using FDG-PET/CT Imaging. | 85 percentage of participants |
Secondary
Safety of GSK1120212
Number of adverse events were monitored for 30 day following last dose of GSK1120212
Time frame: 1st 4-6 week follow-up visit
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1120212 | Safety of GSK1120212 | Neutrophil decrease (Grade 1-2) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Thrombocytopenia(Grade 1-2) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Colitis( Grade 3-4) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Diarrhea (Grade 1-2) | 3 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Mucositis( Grade 3-4) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Nausea (Grade 1-2) | 2 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Doudenal Perforation (Grade 3-4) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Stomach Cramps(Grade 1-2) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Lung Infection (Grade 3-4) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Rash, acneiform (Grade 1-2) | 9 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Pruritis (Grade 1-2) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Fatigue(Grade 1-2) | 2 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Fever (Grade 1-2) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Alkaline Phosphatase (Grade 1-2) | 3 Adverse events |
| GSK1120212 | Safety of GSK1120212 | AST (Grade 1-2) | 4 Adverse events |
| GSK1120212 | Safety of GSK1120212 | ALT (Grade 1-2) | 2 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Blurry Vision (Grade 1-2) | 1 Adverse events |
| GSK1120212 | Safety of GSK1120212 | Hypotension (Grade 1-2) | 1 Adverse events |
Secondary
Tumor Specific Findings for Pathologic Changes Including Proliferation (Ki-67 Staining), Tumor Vasculature Staining (Microvessel Density), ERK1/2 Mediated Changes in p27 (Kip1) & Flow Cytometric Analysis of the Peripheral Blood & Tumor.
Time frame: Baseline and Day 15
Population: There was an insufficient amount of tissue to collected. The data was not collected and the outcome measure was not analyzed.