Clinical Trial: Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Phase II Evaluation of Real-Time, Pharmacokinetically Guided Everolimus in Patients With Hormone Receptor Positive Breast Cancer, Pancreatic Neuroendocrine Tumors (PNET), and Renal Cell Carcinoma

Brief Summary: This phase II trial studies how well real-time pharmacokinetic therapeutic drug monitoring works in preventing stomatitis from developing in patients with hormone receptor positive breast cancer, pancreatic neuroendocrine tumors, or kidney cancer that are receiving a type of cancer drug called everolimus. Stomatitis is a common side effect of everolimus that causes inflammation of the mouth, with or without oral ulcers, and frequently leads to patients discontinuing the medication. Monitoring the blood levels of everolimus and making adjustments in a patient's dose may be able to decrease the incidence of stomatitis, while maintaining the effectiveness of everolimus to treat the cancer.

Detailed Summary:

PRIMARY OBJECTIVE:

To determine frequency of any grade of stomatitis at day 29 (cycle 2, day 1) in patients receiving dose-adjusted everolimus.

SECONDARY OBJECTIVES:

  1. Progression-free survival rates at 6 months.
  2. Pharmacodynamic (PD)-inhibition of downstream mammalian target of rapamycin (mTOR) effectors in peripheral blood.
  3. Number of dose adjustments required.
  4. Percentage of days on therapy.
  5. Average minimum concentration (Cmin) values.
  6. Frequency and type of treatments for stomatitis.
  7. Genetic predictors of stomatitis development in selected outlier patients.

OUTLINE:

Patients receive everolimus orally (PO) daily on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo real-time pharmacokinetic therapeutic drug monitoring (TDM) on days 4, 8, and 15 of course 1. Dosing adjustments of everolimus will be performed on day 8, if necessary. If the everolimus dose is adjusted, patients will continue to undergo real-time pharmacokinetic TDM weekly until goal concentrations are achieved on 2 consecutive measures. Patients whose everolimus dose is not adjusted undergo real-time pharmacokinetic TDM on day 1 of courses 2-6.

After completion of study treatment, patients are followed up every 12 weeks.


Sponsor: Emory University

Current Primary Outcome: Incidence of Stomatitis [ Time Frame: Day 29 ]

Stomatitis graded rates and severity will be evaluated and recorded per World Health Organization and Common Terminology Criteria for Adverse Events criteria in the study population.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Progression Free Survival (PFS) [ Time Frame: 6 months ]
    PFS will be evaluated based on rates of cancer progression and time to progression in the population. Progression will be determined using standard RECIST criteria. The median PFS for this study will be estimated by Kaplan-Meier method along with 95% confidence interval.
  • Downstream Markers of Mammalian Target of Rapamycin (mTOR) Function Measured in Peripheral Blood Mononuclear Cells [ Time Frame: Up to day 15 of course 1 ]
    Pharmacodynamics will be evaluated for phosphorylated and non-phosphorylated ribosomal protein S6 kinase, protein kinase B, and eukaryotic translation initiation factor 4E-binding protein 1.
  • Percentage of Days on Therapy [ Time Frame: Up to 6 months ]
    Percentage of days on therapy will be calculated using the formula: (expected - actual days)/expected x 100.
  • Dose Interruptions and Adjustments [ Time Frame: Up to 6 months ]
    Dose interruptions and adjustments will be made on a per subject basis and total for the population.
  • Frequency of Treatments for Stomatitis [ Time Frame: Up to 6 months ]
    Frequency of treatments for stomatitis will be collection of prescription and non-prescription interventions.
  • Type of Treatments for Stomatitis [ Time Frame: Up to 6 months ]
    Type of treatments for stomatitis will be collection of prescription and non-prescription interventions.
  • Response Rate Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria [ Time Frame: Up to 24 weeks ]
    Response rate will be measured at different time points, e.g. 8, 16, and 24 weeks, and will be summarized as percentage of stable disease, complete remission or partial remission along with 95% confidence interval.


Original Secondary Outcome:

  • Progression Free Survival (PFS) [ Time Frame: 6 months ]
    PFS will be evaluated based on rates of cancer progression and time to progression in the population. Progression will be determined using standard RECIST criteria. The median PFS for this study will be estimated by Kaplan-Meier method along with 95% confidence interval.
  • Pharmacodynamic downstream markers of mTOR function measured in peripheral blood mononuclear cells [ Time Frame: Up to day 15 of course 1 ]
    Pharmacodynamics will be evaluated for phosphorylated and non-phosphorylated ribosomal protein S6 kinase, protein kinase B, and eukaryotic translation initiation factor 4E-binding protein 1.
  • Percentage of Days on Therapy [ Time Frame: Up to 6 months ]
    Percentage of days on therapy will be calculated using the formula: (expected - actual days)/expected x 100.
  • Dose Interruptions and Adjustments [ Time Frame: Up to 6 months ]
    Dose interruptions and adjustments will be made on a per subject basis and total for the population.
  • Frequency of Treatments for Stomatitis [ Time Frame: Up to 6 months ]
    Frequency of treatments for stomatitis will be collection of prescription and non-prescription interventions.
  • Type of Treatments for Stomatitis [ Time Frame: Up to 6 months ]
    Type of treatments for stomatitis will be collection of prescription and non-prescription interventions.
  • Response rate assessed using RECIST criteria [ Time Frame: Up to 24 weeks ]
    Response rate will be measured at different time points, e.g. 8, 16, and 24 weeks, and will be summarized as percentage of stable disease, complete remission or partial remission along with 95% confidence interval.


Information By: Emory University

Dates:
Date Received: October 22, 2014
Date Started: November 2014
Date Completion:
Last Updated: December 9, 2016
Last Verified: December 2016