Oral Cavity Neoplasm, Oropharyngeal Neoplasm, Stage 0 Oral Cavity Squamous Cell Carcinoma American Joint Committee on Cancer (AJCC) v6 and v7, Stage 0 Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7, Stage III Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage II Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage II Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7, Stage I Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage I Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7, Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7
Conditions
Brief summary
This randomized phase IIb trial studies how well ACTOplus met extended release (XR) works in treating in patients with stage I-IV oral cavity or oropharynx cancer that are undergoing definitive treatment. Chemoprevention is the use of drugs to keep oral cavity or oropharynx cancer from forming or coming back. The use of ACTOplus met XR may slow disease progression in patients with oral cavity or oropharynx cancer.
Detailed description
PRIMARY OBJECTIVES: I. To determine whether 10-21 days of treatment with ACTOplus met XR will result in a decrease in proliferation index (Ki-67) expression in oral cavity/oropharyngeal tumor tissue as compared to placebo. SECONDARY OBJECTIVES: I. Compare differences in proliferation index (Ki-67) expression from baseline to post-exposure in visually normal appearing oral cavity/oropharyngeal tissue. II. Compare immunohistochemical differences in the apoptosis biomarker cleaved caspase 3 from baseline to post-exposure in oral cavity/oropharyngeal adjacent visually normal appearing tissue and tumor tissue samples. III. Compare immunohistochemical differences from baseline to post-exposure in oral cavity/oropharyngeal tumor tissue samples with regard to cyclin D1, p21 and biguanide or PPAR gamma associated pathway biomarkers; prospective biomarkers on the panel will include phosphorylated (p)AKT, pAMPK, pS6 (metformin), and PPAR gamma. IV. Compare immunohistochemical differences from baseline to post-exposure of oral cavity/oropharyngeal tumor tissue samples with regard to tumor infiltrating immune cells (effector CD8 \[CD8+\]), regulatory CD4 T regulatory (Treg) (CD4+Foxp3+), tumor associated myeloid cells (CD68), PD1 and PD-L1. V. Compare and correlate pre- and post-ACTOplus met XR treatment human ribonucleic acid (RNA)-sequencing (seq) gene analysis on total RNA samples from oral cavity/oropharyngeal adjacent visually normal appearing tissue and tumor tissue pre-and post-study treatment. VI. Determine human papillomavirus (HPV) status in pre-treatment tumor tissue using p16 immunohistochemistry. EXPLORATORY OBJECTIVES I. Compare pre- and post-study treatment fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) scans with regard to standardized uptake value (SUV) of FDG and tumor burden using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 in those participants with a preintervention standard of care staging FDG-PET/CT. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP I: Patients receive ACTOplus met XR orally (PO) once daily (QD) for 10-21 days in the absence of disease progression or unacceptable toxicity. Patients may continue ACTOplus met XR PO QD for a maximum of 25 days if end of treatment biopsy/surgical treatment is delayed beyond day 22. GROUP II: Patients receive placebo PO QD daily for 10-21 days.
Interventions
Correlative studies
Given PO
Correlative studies
Given PO
Sponsors
Study design
Eligibility
Inclusion criteria
* Participant has a newly diagnosed, histologically confirmed, stage I-IV squamous cell carcinoma or squamous cell carcinoma in situ of the oral cavity or oropharynx and will be undergoing definitive surgical, radiotherapy, or chemoradiation treatment; patients who are NOT candidates for localized treatment (surgery, radiation or chemoradiation) with curative intent (i.e.patients with distant metastasis or contra-indication to localized treatment) are not eligible OR * Participant has a lesion in the oral cavity or oropharynx that is not yet biopsied but is highly suspicious for cancer; (randomization will be placed on hold until the presence of cancer is histologically confirmed, and a treatment plan is established; if the presence of cancer is not confirmed, the participant will be considered a screen failure) * The participant's primary tumor is accessible for the collection of 4 mm samples of tumor and adjacent visually normal appearing tissue for biomarker analysis and the participant is willing to have these samples collected at baseline and at the end of study visit. (The protocol requires the collection of fresh tissue for biomarker analysis) * Patients who have not yet had a diagnostic biopsy: * The tissue samples for biomarker analysis may be collected in conjunction with the patient's standard of care diagnostic biopsy but not until after the patient has signed informed consent and it has been determined that they meet all of the eligibility criteria for this protocol with the exception of normal organ and marrow function as defined by the clinical laboratory test results listed for that criterion. In this situation, because the patient would be having a biopsy regardless of whether or not they were participating in this study, it is not required to obtain these results prior to conducting the biopsy. It is however, required to confirm normal organ and marrow function prior to randomization. * Patients who are scheduled for a direct operative laryngoscopy with biopsy (DL biopsy) for diagnostic purposes may be candidates for this study provided the following criteria are met: * The lesion to be biopsied is within the anatomic confines of the oropharynx (i.e. above the epiglottis). * Tissue samples for biomarker analysis of the required 4 mm size are able to be obtained from both the lesion and an area of visually normal appearing tissue adjacent to but 1 cm distant from the lesion. In this situation, randomization will be placed on hold until the following criteria are met: * Normal organ and marrow function is confirmed. * There is histologic confirmation of squamous cell carcinoma. * It has been determined that surgical excision will be the first line standard of care treatment and the end of study tissue samples will be obtained in conjunction with that surgery. Because these patient's lesions are not accessible to end of study tissue sample collection in the outpatient clinic setting, the only way to obtain those samples is in conjunction with standard of care surgical excision of the lesion. If the first line of treatment will be non-surgical, the patient will be considered a screen failure. Under no circumstances will DL biopsy be used for the sole purpose of collecting tissue samples for biomarker analysis. * Patients who have already had a diagnostic biopsy: * The baseline tissue samples for biomarker analysis will be collected in the outpatient clinic setting as a for research purposes only procedure. The samples may not be collected until it has been determined that the participant meets all eligibility criteria for this protocol. * End of study tissue sample collection: * If surgical excision will be the patient's first line treatment, the end of study tissue samples for biomarker analysis will be collected in conjunction with that surgery. If, for any reason, the patient's surgery is delayed beyond Day 26, the end of study tissue samples may be collected in the outpatient clinic setting. * If the patient's first line of treatment will not be surgical excision, the end of study tissue samples for biomarker analysis will be collected in the outpatient clinic setting prior to initiation of the non-surgical treatment. * Participant is able to complete a minimum of 10 days of study agent dosing prior to initiation of definitive treatment for their cancer * Participant is scheduled for an end of study biopsy within 22 days of starting study agent and within 52 days of their study screening visit; (if the participant is scheduled for surgical excision of the tumor and the surgery is delayed for any reason after the participant has started taking the study agent, study agent dosing may be extended up to a maximum of 25 days without compromising the evaluability of the end of study biomarkers) * Eastern Cooperative Oncology Group (ECOG) performance status = 0 or 1 * Life expectancy is \> 6 months * Body mass index (BMI) is \>= 18.5 * Hemoglobin \>= 10 g/dl * White blood cells \>= 3,000/microliter * Platelets \>= 100,000/microliter * Total bilirubin =\< 1.2 x institutional upper limit of normal * With the exception of candidates with a diagnosis of Gilbert's disease in which case the total bilirubin may extend up to 1.5 x institutional upper limit of normal * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 1.2 x institutional upper limit of normal * Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 1.2 x institutional upper limit of normal * Glucose, serum \< 200 mg/dL * Estimated glomerular filtration rate (eGFR) \> 45 mL/min (if eGFR is not included on the clinical lab report, the chronic kidney disease epidemiology \[CKD-EPI\] creatinine calculator may be used) * Participant is able to swallow a tablet whole * Participant is willing and able to participate for the duration of the study * Participant of childbearing potential agrees to use adequate contraception (a hormonal method that has been in continual use for a minimum of 3 months prior to the study screening visit, a barrier method, or abstinence) for the duration of their study participation. (Therapy with pioglitazone may result in ovulation in some premenopausal anovulatory women. In addition, the effects of ACTOplus Met XR on the developing human fetus at the recommended therapeutic dose are unknown. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.) * Note: Due to the risks associated with hormonal methods of birth control, participants should not start hormonal therapy for the purpose of meeting the eligibility criteria for this protocol. * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Participant has received or will receive some form of treatment for their cancer prior to completing a minimum of 10 days of study agent dosing; (a biopsy is not considered a form of treatment) * Participant has a concurrent diagnosis of type I or type II diabetes that is being treated with insulin or an oral antidiabetic agent; (participants whose type II diabetes is controlled with diet and/or exercise alone are eligible provided they meet all other eligibility criteria) * Participant has taken any of the following medications within the past 3 months: * A thiazolidinedione (e.g. pioglitazone \[Actos\] or rosiglitazone \[Avandia\]), * A biguanide (e.g. metformin \[Glucophage, Glumetza, Fortamet, Riomet\] or proguanil \[Paludrine\]) * A combination drug containing one of the agents above (brand names include: ACTOplus Met, Avandamet, Avandaryl, Duetact, Glucovance, Invokamet, Janumet, Jentadueto, Komboglyze, Metaglip, PrandiMet, Synjardy, Xigudo) * Participant is currently taking a strong CYP2C8 inhibitor (e.g. gemfibrozil \[Lopid\]) * Participant is currently taking an enzyme inducer of CYP2C8 (carbamazepine \[Carbatrol, Epitol, Equetro, Tegretol\] cortisol \[Hydrocortisone\]; dexamethasone \[Decadron\]; phenobarbital \[Luminal Sodium\]; phenytoin \[Dilantin, Phenytek, Novaplus Phenytoin Sodium\]; primidone \[Mysoline\]; rifampin \[Rifadin, Rimactane\]; rifapentine \[Priftin\]; secobarbital \[Seconal\]) * Participant is currently taking topiramate (Topamax) commonly used in epilepsy or to prevent migraines or other carbonic anhydrase inhibitors (e.g. zonisamide \[Zonegran\]; acetazolamide \[Diamox Sequels\]; or dichlorphenamide \[Keveyis, Daranide\]) * Participant is currently taking a cationic drug or multidrug and toxin extrusion \[MATE\] inhibitor (e.g. amiloride \[Midamor\]; cimetidine \[Tagamet\]; digoxin \[Lanoxin, Digitek, Digox\]; dolutegravir \[Tivicay\]; morphine \[Roxanol, Duramorph, Kadian, MS Contin\]; procainamide \[Pronestyl, Procanbid\]; quinidine \[Quinidex, Cardioquin, Quin-G, Quinora\]; quinine \[Qualaquin, Quinamm, Quiphile\]; ranitidine \[Zantac, Deprizine, Gabitidine\]; ranolazine \[Ranexa\]; triamterene \[Dyrenium)\] trimethoprim \[Proloprim, Trimpex, Primsol\]; vancomycin \[Vancocin, Vancoled\]; or vandetanib \[Calpresa\]) * Participants is taking another investigational agent * Participant has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ACTOplus Met XR * Participant has a contraindication to biopsy * Participants with a history of congestive heart failure or New York Heart Association (NYHA) class III or IV functional status are excluded * Participant has a history of liver disease * Participant has \> Common Terminology Criteria for Adverse Events (CTCAE) grade 1 limb edema (5 - 10% inter-limb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection) * Participant has a history of hypoglycemia * Participant is an active alcoholic or consumes excessive amounts of alcohol per the following definitions: * Female: More than 3 drinks on any day or a total of more than seven drinks in a week * Male: More than 4 drinks on any day or a total of more than 14 drinks in a week * 1 drink = * Beer: 12 oz. (1 standard size can or bottle) * Wine: 5 oz. (one standard glass) * Spirits: 6 oz. (one mixed drink or one 1.5 fluid oz. shot) * Participant has a history of macular edema * Participant has a history of bladder cancer (including in situ bladder cancer) * Participant has a history of invasive cancer (other than non-melanoma skin cancer or cervical cancer in situ) active within 18 months prior to the baseline study visit; (participants who have a history of cancer that was curatively treated without evidence of recurrence in the 18 months prior to the baseline study visit are considered eligible) * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Participant is pregnant, breast feeding or planning to become pregnant; (all participants of childbearing potential regardless of method of birth control must have a negative pregnancy test at baseline; a woman is considered not to be of childbearing potential if she has had a hysterectomy, bilateral oophorectomy, or if she is \> 55 years of age with \>= 2 years of amenorrhea) * Breastfeeding should be discontinued if the mother is treated with ACTOplus met XR
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Proliferation Index (Ki-67) Expression, Assessed in Tumor Tissue by Immunohistochemistry | Baseline to days 11-22 | Baseline, post-exposure, absolute change in Ki-67, and difference in absolute change between the ACTOplus met XR and placebo subjects will all be summarized with descriptive statistics. Ki-67 is a semi-quantitative immune-histochemistry analysis in which a computer generates an analysis based on the staining within tumor and normal cells leading to a score which is an indirect measure of cellular proliferation. Will compare the difference in absolute change in Ki-67 between the ACTOplus met XR and placebo arms using a two sided two-sample Student's t-test or Wilcoxon rank-sum test, as appropriate, at a significance level of 0.05. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry | Baseline to days 11-22 | Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test. |
| Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Baseline to days 11-22 | Cleaved Caspase 3 is a semi-quantitative immune-histochemistry analysis in which a computer generates an analysis based on the staining within tumor and normal cells leading to a score which is a direct measure of cellular apoptosis. Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test. |
| Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Baseline to days 11-22 | Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test. |
| Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Baseline to days 11-22 | Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test. |
| Genes With Significant Changes From Baseline to Days 11-22 for Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | Baseline to days 11-22 | Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test. |
| Genes With Significant Changes From Baseline to Days 11-22 for Tumor-Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | Baseline to days 11-22 | The plan was to summarize for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test. |
| Human Papillomavirus Status Assessed in Tumor Tissue by p16 by Immunohistochemistry | Baseline | Human papillomavirus status will be assessed in tumor tissue by p16 by immunohistochemistry. |
| Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | Baseline to days 11-22 | Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Tumor Fluorodeoxyglucose Uptake/Metabolism Assess by Treatment Positron Emission Tomography/Computed Tomography | Baseline to days 11-22 | Tumor fluorodeoxyglucose uptake/metabolism assess by treatment positron emission tomography/computed tomography. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled from Johns Hopkins University - Sidney Kimmel Comprehensive Cancer Center, UW Hospital and Clinics, and University of Minnesota - Masonic Cancer Center between May 31, 2018 and August 2, 2019.
Pre-assignment details
16 people were consented and 10 people were subsequently determined to be ineligible. 6 participants were randomized to study.
Participants by arm
| Arm | Count |
|---|---|
| Group I (ACTOplus Met XR) Patients receive ACTOplus met XR PO QD for 10-21 days in the absence of disease progression or unacceptable toxicity. Patients may continue ACTOplus met XR PO QD for a maximum of 25 days if end of treatment biopsy/surgical treatment is delayed beyond day 22.
Laboratory Biomarker Analysis: Correlative studies
Metformide Hydrochloride/Pioglitazone Hydrochloride Extended-Release Tablet: Given PO
Pharmacological Study: Correlative studies | 4 |
| Group II (Placebo) Patients receive placebo PO QD daily for 10-21 days.
Laboratory Biomarker Analysis: Correlative studies
Pharmacological Study: Correlative studies
Placebo: Given PO | 2 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Group II (Placebo) | Group I (ACTOplus Met XR) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 1 Participants | 3 Participants |
| Body Mass Index (BMI) | 29.68 kilograms per meter squared | 28.70 kilograms per meter squared | 30.17 kilograms per meter squared |
| Diastolic Blood Pressure | 82.00 mmHg | 86.00 mmHg | 80.00 mmHg |
| ECOG Performance Status 0 (Fully Active) | 6 Participants | 2 Participants | 4 Participants |
| ECOG Performance Status 1 (Restricted) | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 174.32 centimeters | 180.00 centimeters | 171.48 centimeters |
| History or Baseline Presence of Abnormality or Disease Breasts | 0 Participants | 0 Participants | 0 Participants |
| History or Baseline Presence of Abnormality or Disease Cardiovascular | 4 Participants | 1 Participants | 3 Participants |
| History or Baseline Presence of Abnormality or Disease Dermatologic | 2 Participants | 2 Participants | 0 Participants |
| History or Baseline Presence of Abnormality or Disease Endocrine / Metabolic | 4 Participants | 2 Participants | 2 Participants |
| History or Baseline Presence of Abnormality or Disease Gastrointestinal | 6 Participants | 2 Participants | 4 Participants |
| History or Baseline Presence of Abnormality or Disease Genitourinary | 4 Participants | 0 Participants | 4 Participants |
| History or Baseline Presence of Abnormality or Disease Head, Eyes, Ears, Nose, Throat | 6 Participants | 2 Participants | 4 Participants |
| History or Baseline Presence of Abnormality or Disease Hematopoietic / Lymph | 1 Participants | 0 Participants | 1 Participants |
| History or Baseline Presence of Abnormality or Disease Musculoskeletal | 5 Participants | 2 Participants | 3 Participants |
| History or Baseline Presence of Abnormality or Disease Neck | 1 Participants | 0 Participants | 1 Participants |
| History or Baseline Presence of Abnormality or Disease Neurologic | 2 Participants | 1 Participants | 1 Participants |
| History or Baseline Presence of Abnormality or Disease Respiratory | 4 Participants | 0 Participants | 4 Participants |
| Pulse | 70.34 beats per minute | 79.00 beats per minute | 66.00 beats per minute |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 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 | 6 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United States | 6 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 3 Participants |
| Systolic Blood Pressure | 139.50 mmHg | 135.00 mmHg | 141.75 mmHg |
| Temperature | 97.96 degrees Fahrenheit (F) | 98.05 degrees Fahrenheit (F) | 97.92 degrees Fahrenheit (F) |
| Weight | 90.32 kilograms | 93.67 kilograms | 88.64 kilograms |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 2 |
| other Total, other adverse events | 4 / 4 | 2 / 2 |
| serious Total, serious adverse events | 0 / 4 | 0 / 2 |
Outcome results
Absolute Change in Proliferation Index (Ki-67) Expression, Assessed in Tumor Tissue by Immunohistochemistry
Baseline, post-exposure, absolute change in Ki-67, and difference in absolute change between the ACTOplus met XR and placebo subjects will all be summarized with descriptive statistics. Ki-67 is a semi-quantitative immune-histochemistry analysis in which a computer generates an analysis based on the staining within tumor and normal cells leading to a score which is an indirect measure of cellular proliferation. Will compare the difference in absolute change in Ki-67 between the ACTOplus met XR and placebo arms using a two sided two-sample Student's t-test or Wilcoxon rank-sum test, as appropriate, at a significance level of 0.05.
Time frame: Baseline to days 11-22
Population: 1 sample in the treatment group was not analyzed because site misplaced the sample.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group I (ACTOplus Met XR) | Absolute Change in Proliferation Index (Ki-67) Expression, Assessed in Tumor Tissue by Immunohistochemistry | baseline | 20.40 proliferation index expression |
| Group I (ACTOplus Met XR) | Absolute Change in Proliferation Index (Ki-67) Expression, Assessed in Tumor Tissue by Immunohistochemistry | Day 11-22 | 17.57 proliferation index expression |
| Group I (ACTOplus Met XR) | Absolute Change in Proliferation Index (Ki-67) Expression, Assessed in Tumor Tissue by Immunohistochemistry | absolute change from baseline | -2.68 proliferation index expression |
| Group II (Placebo) | Absolute Change in Proliferation Index (Ki-67) Expression, Assessed in Tumor Tissue by Immunohistochemistry | baseline | 13.69 proliferation index expression |
| Group II (Placebo) | Absolute Change in Proliferation Index (Ki-67) Expression, Assessed in Tumor Tissue by Immunohistochemistry | Day 11-22 | 36.96 proliferation index expression |
| Group II (Placebo) | Absolute Change in Proliferation Index (Ki-67) Expression, Assessed in Tumor Tissue by Immunohistochemistry | absolute change from baseline | 24.82 proliferation index expression |
Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry
Cleaved Caspase 3 is a semi-quantitative immune-histochemistry analysis in which a computer generates an analysis based on the staining within tumor and normal cells leading to a score which is a direct measure of cellular apoptosis. Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.
Time frame: Baseline to days 11-22
Population: 1 sample in the treatment group was not analyzed because site misplaced the sample.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (ACTOplus Met XR) | Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Post-Exposure Normal Tissue | 0.000 percent positive cells | Standard Deviation 0 |
| Group I (ACTOplus Met XR) | Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Baseline Normal Tissue | 0.000 percent positive cells | Standard Deviation 0 |
| Group I (ACTOplus Met XR) | Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Baseline Tumor Tissue | 1.000 percent positive cells | Standard Deviation 1 |
| Group I (ACTOplus Met XR) | Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Post-Exposure Tumor Tissue | 3.333 percent positive cells | Standard Deviation 4.041 |
| Group II (Placebo) | Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Post-Exposure Tumor Tissue | 4.000 percent positive cells | — |
| Group II (Placebo) | Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Baseline Normal Tissue | 0.000 percent positive cells | Standard Deviation 0 |
| Group II (Placebo) | Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Post-Exposure Normal Tissue | 0.000 percent positive cells | — |
| Group II (Placebo) | Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry | Baseline Tumor Tissue | 1.000 percent positive cells | Standard Deviation 0 |
Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry
Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.
Time frame: Baseline to days 11-22
Population: 1 sample in the treatment group was not analyzed because site misplaced the sample.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated S6 Day 11-22 | 0.282 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in Cyclin D1 from Baseline | -0.0066 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | P21 Baseline | 0.090 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in phosphorylated S6 from Baseline | 0.029 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Cyclin D1 Day 11-22 | 0.050 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | P21 Day 11-22 | 0.068 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in P21 from Baseline | -0.0093 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated AKT Baseline | 0.00018 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated AKT Day 11-22 | 0.00048 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in phosphorylated AKT from baseline | 0.00031 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated AMPK at Baseline | 0.079 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated AMPK Day 11-22 | 0.131 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in phosphorylated AMPK from baseline | 0.052 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | PPAR gamma at Baseline | 0.0547 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | PPAR gamma Day 11-22 | 0.0061 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in PPAR gamma from baseline | -0.022 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated S6 at Baseline | 0.284 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Cyclin D1 Baseline | 0.051 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in phosphorylated AMPK from baseline | -0.333 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Cyclin D1 Day 11-22 | 0.033 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated S6 at Baseline | 0.188 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in Cyclin D1 from Baseline | 0.0019 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in phosphorylated AKT from baseline | 0.00016 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | P21 Baseline | 0.112 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | P21 Day 11-22 | 0.052 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated AKT Day 11-22 | 0.00042 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated S6 Day 11-22 | 0.071 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | PPAR gamma at Baseline | 0.0138 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in phosphorylated S6 from Baseline | -0.028 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Cyclin D1 Baseline | 0.020 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated AMPK at Baseline | 0.363 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in PPAR gamma from baseline | 0.019 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated AMPK Day 11-22 | 0.030 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Absolute change in P21 from Baseline | -0.0605 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | PPAR gamma Day 11-22 | 0.0200 percent positive cells |
| Group II (Placebo) | Change in Cyclin D1, p21 and Biguanide or Phosphorylated AKT, Phosphorylated AMPK, Phosphorylated S6 (Metformin), and PPAR Gamma Expression, Assessed by Immunohistochemistry | Phosphorylated AKT Baseline | 0.00013 percent positive cells |
Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry
Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.
Time frame: Baseline to days 11-22
Population: 1 sample in the treatment group was not analyzed because site misplaced the sample.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group I (ACTOplus Met XR) | Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry | baseline | 17.58 proliferation index expression |
| Group I (ACTOplus Met XR) | Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry | Day 11-22 | 11.81 proliferation index expression |
| Group I (ACTOplus Met XR) | Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry | absolute change from baseline | -5.77 proliferation index expression |
| Group II (Placebo) | Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry | baseline | 14.52 proliferation index expression |
| Group II (Placebo) | Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry | Day 11-22 | 26.05 proliferation index expression |
| Group II (Placebo) | Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry | absolute change from baseline | 17.25 proliferation index expression |
Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry
Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.
Time frame: Baseline to days 11-22
Population: 1 sample in the treatment group was not analyzed because site misplaced the sample.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD68 Day 11-22 | 0.10 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in CD68 from Baseline | -0.033 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD4 Baseline | 0.193 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD68 Baseline | 0.11 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | PD1 Baseline | 0.0520 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | PD1 Day 11-22 | 0.0088 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in PD1 from Baseline | -0.045 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | PD-L1 Baseline | 0.0632 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | PD-L1 Day 11-22 | 0.0494 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in PD-L1 from Baseline | -0.012 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD8 Baseline | 0.244 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD8 Day 11-22 | 0.095 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in CD8 from Baseline | -0.218 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD4 Day 11-22 | 0.159 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in CD4 from Baseline | 0.043 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | FoxP3 Baseline | 0.027 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | FoxP3 Day 11-22 | 0.020 percent positive cells |
| Group I (ACTOplus Met XR) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in FoxP3 from Baseline | 0.0034 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD4 Day 11-22 | 0.074 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD68 Day 11-22 | 0.23 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in PD-L1 from Baseline | 0.012 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | PD1 Day 11-22 | 0.0721 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in PD1 from Baseline | 0.050 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in CD8 from Baseline | 0.086 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in FoxP3 from Baseline | 0.0235 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD8 Baseline | 0.141 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD68 Baseline | 0.190 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in CD68 from Baseline | 0.068 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | Absolute Change in CD4 from Baseline | -0.128 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | PD1 Baseline | 0.0356 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD8 Day 11-22 | 0.189 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | FoxP3 Day 11-22 | 0.038 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | CD4 Baseline | 0.195 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | PD-L1 Baseline | 0.0086 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | FoxP3 Baseline | 0.057 percent positive cells |
| Group II (Placebo) | Change in Regulatory T Cell, T4, T8, Tumor-associated Macrophage-CD68 Positive, PD1, PD-L1 Expression, Assessed in Tumor Tissue by Immunohistochemistry | PD-L1 Day 11-22 | 0.0136 percent positive cells |
Genes With Significant Changes From Baseline to Days 11-22 for Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples
Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.
Time frame: Baseline to days 11-22
Population: Pre- and post-treatment RNA-seq data was available in four ACTOplus treated participants and one placebo treated participant. Because of this, a comparison between the treatment arms was not deemed to be possible or useful. What was attempted was an analysis of change from baseline values for the ACTOplus met® XR arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group I (ACTOplus Met XR) | Genes With Significant Changes From Baseline to Days 11-22 for Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | 1.0060 raw counts of RNA sequencing reads | Standard Deviation 0.006 |
| Group II (Placebo) | Genes With Significant Changes From Baseline to Days 11-22 for Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | 2.0135 raw counts of RNA sequencing reads | — |
Genes With Significant Changes From Baseline to Days 11-22 for Tumor-Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples
The plan was to summarize for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.
Time frame: Baseline to days 11-22
Population: Pre- and post-treatment RNA-seq data was available in four ACTOplus treated participants and one placebo treated participant. Because of this, a comparison between the treatment arms was not deemed to be possible or useful. What was attempted was an analysis of change from baseline values for the ACTOplus met® XR arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (ACTOplus Met XR) | Genes With Significant Changes From Baseline to Days 11-22 for Tumor-Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000232479 | 1.0013 raw counts of RNA sequencing reads | Standard Deviation 0.0072 |
| Group I (ACTOplus Met XR) | Genes With Significant Changes From Baseline to Days 11-22 for Tumor-Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000233163 | 1.0037 raw counts of RNA sequencing reads | Standard Deviation 0.0193 |
| Group I (ACTOplus Met XR) | Genes With Significant Changes From Baseline to Days 11-22 for Tumor-Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000249245 | -1.0098 raw counts of RNA sequencing reads | Standard Deviation 0.005 |
| Group II (Placebo) | Genes With Significant Changes From Baseline to Days 11-22 for Tumor-Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000232479 | -1.0087 raw counts of RNA sequencing reads | — |
| Group II (Placebo) | Genes With Significant Changes From Baseline to Days 11-22 for Tumor-Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000233163 | -1.0003 raw counts of RNA sequencing reads | — |
| Group II (Placebo) | Genes With Significant Changes From Baseline to Days 11-22 for Tumor-Normal Tissue: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000249245 | 0.0000 raw counts of RNA sequencing reads | — |
Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples
Will be summarized for baseline, post-exposure, and absolute change by treatment arm using the appropriate descriptive statistics, and will be evaluated with Student's t-test or Wilcoxon rank-sum test.
Time frame: Baseline to days 11-22
Population: Pre- and post-treatment RNA-seq data was available in four ACTOplus treated participants and one placebo treated participant. Because of this, a comparison between the treatment arms was not deemed to be possible or useful. What was attempted was an analysis of change from baseline values for the ACTOplus met® XR arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group I (ACTOplus Met XR) | Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000249245 | -1.0098 raw counts of RNA sequencing reads | Standard Deviation 0.005 |
| Group I (ACTOplus Met XR) | Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000229822 | 1.0011 raw counts of RNA sequencing reads | Standard Deviation 0.024 |
| Group I (ACTOplus Met XR) | Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000230585 | -1.0217 raw counts of RNA sequencing reads | Standard Deviation 0.0257 |
| Group I (ACTOplus Met XR) | Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000261792 | 1.0007 raw counts of RNA sequencing reads | Standard Deviation 0.0063 |
| Group II (Placebo) | Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000261792 | 0.0000 raw counts of RNA sequencing reads | — |
| Group II (Placebo) | Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000249245 | 0.0000 raw counts of RNA sequencing reads | — |
| Group II (Placebo) | Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000230585 | -3.0108 raw counts of RNA sequencing reads | — |
| Group II (Placebo) | Genes With Significant Changes From Baseline to Days 11-22 in Tumor Tissue in Treated Participants: Change in Whole Transcriptome Gene Analysis on Total Ribonucleic Acid Samples | ENSG00000229822 | -5.0023 raw counts of RNA sequencing reads | — |
Human Papillomavirus Status Assessed in Tumor Tissue by p16 by Immunohistochemistry
Human papillomavirus status will be assessed in tumor tissue by p16 by immunohistochemistry.
Time frame: Baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group I (ACTOplus Met XR) | Human Papillomavirus Status Assessed in Tumor Tissue by p16 by Immunohistochemistry | Positive | 2 Participants |
| Group I (ACTOplus Met XR) | Human Papillomavirus Status Assessed in Tumor Tissue by p16 by Immunohistochemistry | Not Tested | 2 Participants |
| Group II (Placebo) | Human Papillomavirus Status Assessed in Tumor Tissue by p16 by Immunohistochemistry | Positive | 0 Participants |
| Group II (Placebo) | Human Papillomavirus Status Assessed in Tumor Tissue by p16 by Immunohistochemistry | Not Tested | 2 Participants |
Change in Tumor Fluorodeoxyglucose Uptake/Metabolism Assess by Treatment Positron Emission Tomography/Computed Tomography
Tumor fluorodeoxyglucose uptake/metabolism assess by treatment positron emission tomography/computed tomography.
Time frame: Baseline to days 11-22
Population: No one consented to this aspect of the study, no data is available.