ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 46 of 2060 for:    Oral Cancer | NIH

ACTOplus Met XR in Treating Patients With Stage I-IV Oral Cavity or Oropharynx Cancer Undergoing Definitive Treatment

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02917629
Recruitment Status : Recruiting
First Posted : September 28, 2016
Last Update Posted : March 5, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

September 27, 2016
September 28, 2016
March 5, 2018
August 14, 2017
June 10, 2019   (Final data collection date for primary outcome measure)
Absolute change in proliferation index (Ki-67) expression, assessed in tumor tissue by immunohistochemistry [ Time Frame: Baseline to day 26 ]
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. 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.
Absolute change in proliferation index (Ki-67) expression, assessed in tumor tissue by immunohistochemistry (IHC) [ Time Frame: Baseline to day 26 ]
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. 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.
Complete list of historical versions of study NCT02917629 on ClinicalTrials.gov Archive Site
  • Change in Ki-67 expression in visually normal appearing tissue, assessed by immunohistochemistry [ Time Frame: Baseline to day 26 ]
    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 [ Time Frame: Baseline to day 26 ]
    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 [ Time Frame: Baseline to day 26 ]
    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 [ Time Frame: Baseline to day 26 ]
    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 whole transcriptome gene analysis on total ribonucleic acid samples from visually normal appearing tissue and tumor tissue [ Time Frame: Baseline to day 26 ]
    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.
  • Human papillomavirus status assessed in tumor tissue by p16 by immunohistochemistry [ Time Frame: Baseline ]
    Human papillomavirus status will be assessed in tumor tissue by p16 by immunohistochemistry.
  • Change in tumor fluorodeoxyglucose uptake/metabolism assess by treatment positron emission tomography/computed tomography [ Time Frame: Baseline to day 26 ]
    Tumor fluorodeoxyglucose uptake/metabolism assess by treatment positron emission tomography/computed tomography.
  • Change in cleaved caspase 3 expression in visually normal appearing tissue and tumor tissue samples, assessed by IHC [ Time Frame: Baseline to day 26 ]
    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 pAKT, pAMPK, pS6 (metformin), and PPAR gamma expression, assessed by IHC [ Time Frame: Baseline to day 26 ]
    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 Ki-67 expression in visually normal appearing tissue, assessed by IHC [ Time Frame: Baseline to day 26 ]
    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 treg, T4, T8, tumor-associated macrophage-CD68 positive, PD1, PD-L1 expression, assessed in tumor tissue by IHC [ Time Frame: Baseline to day 26 ]
    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 tumor FDG uptake/metabolism assess by treatment PET/CT [ Time Frame: Baseline to day 26 ]
  • Change in whole transcriptome gene analysis on total RNA samples from visually normal appearing tissue and tumor tissue [ Time Frame: Baseline to day 26 ]
    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.
  • HPV status assessed in tumor tissue by p16 by IHC [ Time Frame: Baseline ]
Not Provided
Not Provided
 
ACTOplus Met XR in Treating Patients With Stage I-IV Oral Cavity or Oropharynx Cancer Undergoing Definitive Treatment
Phase IIB Randomized, Placebo-Controlled Trial of ACTOplus Met® XR in Subjects With Stage I-IV Squamous Cell Carcinoma of the Oral Cavity or Oropharynx Prior to Definitive Treatment
This randomized phase IIb trial studies how well ACTOplus met 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.

PRIMARY OBJECTIVES:

I. To determine whether 14-21 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+IFNg+]), 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.

VII. Compare pre- and post-study treatment positron emission tomography (PET)/computed tomography (CT) scans to determine any change in tumor fluorodeoxyglucose (FDG) uptake/metabolism.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive ACTOplus met XR orally (PO) once daily (QD) for 14-21 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 14-21 days.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
  • Oral Cavity Neoplasm
  • Oropharyngeal Neoplasm
  • Stage I Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7
  • Stage I Oropharyngeal Squamous Cell Carcinoma AJCC v6 and v7
  • Stage II Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7
  • Stage II 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 IV Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7
  • Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC 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
  • Stage IVC Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7
  • Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Metformide Hydrochloride/Pioglitazone Hydrochloride Extended-Release Tablet
    Given PO
    Other Names:
    • ACTOplus Met XR
    • Metformide HCl/Pioglitazone HCl ER Tablet
  • Other: Pharmacological Study
    Correlative studies
  • Other: Placebo
    Given PO
    Other Names:
    • placebo therapy
    • PLCB
    • sham therapy
  • Experimental: Group I (ACTOplus met XR)
    Patients receive ACTOplus met XR PO QD for 14-21 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.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Drug: Metformide Hydrochloride/Pioglitazone Hydrochloride Extended-Release Tablet
    • Other: Pharmacological Study
  • Placebo Comparator: Group II (placebo)
    Patients receive placebo PO QD daily for 14-21 days.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Other: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
39
Same as current
June 10, 2019
June 10, 2019   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Participant has a newly diagnosed, histologically confirmed, stage I-IV squamous cell carcinoma of the oral cavity or oropharynx and will be undergoing definitive surgical, radiotherapy, or chemoradiation treatment 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, a standard of care staging PET/CT scan is completed 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 to biopsy in the outpatient clinic setting and the participant is willing to have baseline and end of study (day 15-26) 4 mm punch biopsies of tumor and adjacent visually normal appearing tissue for biomarker analysis

    • If the participant has a biopsy-confirmed cancer, the baseline biopsy to collect tissue for biomarker analysis will be in addition to the pre-study diagnostic biopsy
    • If the participant is having surgical treatment, the end of study biopsies may be collected at the time of surgery unless surgery is delayed beyond day 26
    • If the participant is not having surgical treatment, the end of study biopsies will be collected prior to initiation of non-surgical treatment
  • Participant is able to complete a minimum of 14 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 36 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)
  • A standard of care staging PET/CT scan has been or will be performed prior to randomization
  • Participant is willing and able to have another FDG PET/CT performed within 36 hours of their day 15-26 end of study biopsy
  • 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 within normal institutional limits

    • 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]) within normal institutional limits
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) within normal institutional limits
  • Glucose, serum < 200 mg/dL
  • Estimated glomerular filtration rate (eGFR) > 45 mL/min using Cockcroft-Gault calculator
  • 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; (should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately)

    • NOTE: 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 14 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 (e.g. amiloride [Midamor]; cimetidine [Tagamet]; digoxin [Lanoxin, Digitek, Digox]; morphine [Roxanol, Duramorph, Kadian, MS Contin]; procainamide [Pronestyl, Procanbid]; quinidine [Quinidex, Cardioquin, Quin-G, Quinora]; quinine [Qualaquin, Quinamm, Quiphile]; ranitidine [Zantac, Deprizine, Gabitidine]; triamterene [Dyrenium]; trimethoprim [Proloprim, Trimpex, Primsol]; or vancomycin [Vancocin, Vancoled])
  • 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 is 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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
United States
 
 
NCT02917629
NCI-2016-01407
NCI-2016-01407 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00033
UWI2016-07-01 ( Other Identifier: University of Wisconsin Hospital and Clinics )
UWI2016-07-01 ( Other Identifier: DCP )
N01CN00033 ( U.S. NIH Grant/Contract )
P30CA014520 ( U.S. NIH Grant/Contract )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Frank Ondrey University of Wisconsin, Madison
National Cancer Institute (NCI)
February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP