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
Overview
- Phase
- Phase 2
- Intervention
- Everolimus
- Conditions
- Estrogen Receptor-positive Breast Cancer
- Sponsor
- Emory University
- Enrollment
- 2
- Locations
- 2
- Primary Endpoint
- Incidence of Stomatitis
- Status
- Terminated
- Last Updated
- 9 years ago
Overview
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 Description
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.
Investigators
R. Donald Harvey, PharmD
Principal Investigator
Emory University
Eligibility Criteria
Inclusion Criteria
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Confirmed diagnosis of:
- •Postmenopausal advanced hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer after failure of treatment with letrozole or anastrozole
- •Progressive neuroendocrine tumors of pancreatic origin (PNET) that is unresectable, locally advanced or metastatic
- •Advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib
- •Histologically confirmed, measurable or evaluable disease. Patients should have at least one measurable lesion.
- •Adequate bone marrow function as indicated by the following:
- •Absolute neutrophil count (ANC) \> 1,500/μL
- •Platelets ≥ 100,000/μL
- •Hemoglobin \> 10 g/dL
Exclusion Criteria
- •Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of everolimus (including chemotherapy, radiation therapy, antibody based therapy, etc., but not including somatostatin analogues, e.g., octreotide)
- •Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
- •Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
- •Uncontrolled diabetes mellitus as defined by HbA1c \>8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary.
- •Patients who have any severe and/or uncontrolled medical conditions such as:
- •Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease
- •Symptomatic congestive heart failure of New York Heart Association Class III or IV
- •Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e. quantifiable hepatitis B virus \[HBV\]-DNA and/or positive HbsAg, quantifiable hepatitis C virus \[HCV\]-RNA)
- •Known severely impaired lung function (spirometry and diffusing capacity of the lung for carbon monoxide \[DLCO\] 50% or less of normal and O2 saturation 88% or less at rest on room air)
- •Active, bleeding diathesis
Arms & Interventions
Supportive care (real-time pharmacokinetic TDM of everolimus)
Patients receive everolimus 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 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.
Intervention: Everolimus
Outcomes
Primary Outcomes
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.
Secondary Outcomes
- Downstream Markers of Mammalian Target of Rapamycin (mTOR) Function Measured in Peripheral Blood Mononuclear Cells(Up to day 15 of course 1)
- Percentage of Days on Therapy(Up to 6 months)
- Dose Interruptions and Adjustments(Up to 6 months)
- Frequency of Treatments for Stomatitis(Up to 6 months)
- Type of Treatments for Stomatitis(Up to 6 months)
- Response Rate Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria(Up to 24 weeks)
- Progression Free Survival (PFS)(6 months)