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

NCT02917629 | Terminated Phase 2 Results DMC FDA Drug

• 6 other identifiers: NCI-2016-01407UW16110N01-CN-2012-00033UWI2016-07-01N01CN00033P30CA014520
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 4

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.

Conditions

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 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 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

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline to days 11-22

Secondary Outcomes (8)

• Change in Ki-67 Expression in Visually Normal Appearing Tissue, Assessed by Immunohistochemistry

  Baseline to days 11-22

• Change in Cleaved Caspase 3 Expression in Visually Normal Appearing Tissue and Tumor Tissue Samples, Assessed by Immunohistochemistry

  Baseline to days 11-22

• 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

• 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

• 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

Other Outcomes (1)

• Change in Tumor Fluorodeoxyglucose Uptake/Metabolism Assess by Treatment Positron Emission Tomography/Computed Tomography

  Baseline to days 11-22

Study Arms (2)

Group I (ACTOplus met XR)

EXPERIMENTAL

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.

Other: Laboratory Biomarker Analysis; Drug: Metformide Hydrochloride/Pioglitazone Hydrochloride Extended-Release Tablet; Other: Pharmacological Study

Group II (placebo)

PLACEBO COMPARATOR

Patients receive placebo PO QD daily for 10-21 days.

Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Other: Placebo

Interventions

Laboratory Biomarker Analysis OTHER

Correlative studies

Group I (ACTOplus met XR); Group II (placebo)

Metformide Hydrochloride/Pioglitazone Hydrochloride Extended-Release Tablet DRUG

Given PO

Also known as: ACTOplus Met XR, Metformide HCl/Pioglitazone HCl ER Tablet

Group I (ACTOplus met XR)

Pharmacological Study OTHER

Correlative studies

Group I (ACTOplus met XR); Group II (placebo)

Placebo OTHER

Given PO

Also known as: placebo therapy, PLCB, sham therapy

Group II (placebo)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, 55455, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

MeSH Terms

Conditions

Mouth Neoplasms; Oropharyngeal Neoplasms; Squamous Cell Carcinoma of Head and Neck

Condition Hierarchy (Ancestors)

Head and Neck Neoplasms; Neoplasms by Site; Neoplasms; Mouth Diseases; Stomatognathic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Otorhinolaryngologic Diseases; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Results Point of Contact

• Title: Dr. Howard Bailey
• Organization: UW Carbone Cancer Center

clinicaltrials@cancer.wisc.edu

800-622-8922

Study Officials

• Frank G Ondrey

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2016
• First Posted: September 28, 2016
• Study Start: May 31, 2018
• Primary Completion: August 28, 2019
• Study Completion: August 28, 2019
• Last Updated: March 8, 2023
• Results First Posted: March 8, 2023

Record last verified: 2023-02

Locations

US (4)