Influence of Exceptional Patient Characteristics on Everolimus Exposure

Study Overview
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Brief Summary
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A study to determine whether everolimus pharmacokinetics in elderly and obese patients is different compared to control patients. Furthermore the investigators will investigate the relation between metabolic response assessed with [18F] Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) and everolimus exposure and clinical benefit. The investigators will explore whether dose escalation in patients who are hypothetically underexposed will result in an increase in metabolic response.

Official Title
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Influence of Exceptional Patient Characteristics on Everolimus Exposure

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: everolimus dose escalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy. Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer Postmenopausal women Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to enrollment. Progression following a non-steroidal aromatase inhibitor Falling into one of the following categories elderly patients (age ≥ 70 years and BMI < 30 kg/m2); or obese patients (BMI ≥ 30 kg/m2 and age < 70 years); or control patients (BMI < 30 kg/m2 and age < 70 years); Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN Adequate renal function: calculated creatinine clearance, as estimated by GFR using the MDRD formula, is ≥ 30ml/min/1.73m2 Performance status ECOG 0 - 2 (Karnofsky index: 60 - 100) Patient is willing and able to sign the Informed Consent Form prior to screening evaluations Exclusion Criteria: Patients aged ≥ 70 years AND BMI ≥ 30 kg/m2 HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive). Previous treatment with exemestane or mTOR inhibitors. Except for the treatment with exemestane in the adjuvant setting. Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin). Patients with a known history of HIV seropositivity. Any severe and / or uncontrolled medical conditions such as: Unstable angina pectoris, serious uncontrolled cardiac arrhythmia Patients with severe hepatic impairment (Child-Pugh A/B/C) Uncontrolled diabetes mellitus Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) Patients who test positive for hepatitis B or C Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A within the last 5 days prior to enrollment History of non-compliance to medical regimens Patients unwilling to or unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: standard care<br>everolimus dose is continued independently of everolimus AUC | |
| Active Comparator: everolimus dose escalation<br>patients with an AUC below mean will have dose escalation of everolimus based on their AUC | Drug: everolimus dose escalation<br>* patients with an AUC below mean will have dose escalation of everolimus based on their AUC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| everolimus AUC | The primary aim is to show a difference in everolimus exposure (AUC0-24hr) of at least 25% in elderly patients (≥70 years) and obese patients (BMI ≥ 30 kg/m2) compared to the control group (≤ 70 years; BMI ≤ 30 kg/m2), after reaching steady state everolimus pharmacokinetics (day 14, but at least after 7 days of everolimus therapy). | day 14 after start treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| correlation between early metabolic response and PFS | To explore and calculate the predictive value of early metabolic response assessment with clinical benefit (PFS defined as disease progression according to RECIST version 1.1 or death, whichever occurs first) as primary outcome measure. Metabolic response is defined as fractional change (ΔSUV and ΔTLG), comparing the third en second scan with the baseline scan. | within 90 days after start of treatment | 
| correlation between early metabolic response and AUC | To quantify the correlation between early metabolic response and everolimus exposure (AUC0-24hr) on steady-state pharmacokinetics. Metabolic response is defined as fractional change (ΔSUV and ΔTLG), comparing the third en second scan with the baseline scan. | 15 days after start of treatment | 
| effect dose escalation on metabolic respons | To explore, quantify and describe whether dose escalation in patients who are hypothetically underexposed will result in an increase in metabolic response. Metabolic response is defined as fractional change (ΔSUV and ΔTLG), comparing the third en second scan with the baseline scan. | within 36 days after start of treatment | 
| correlation between AUC and frequency of adverse event | To explore, quantify and describe the correlation between everolimus exposure and the frequency of adverse events as graded with CTCAE v4.0. | 4 months after start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Neoplasms, everolimus, pharmacokinetics, elderly patients, obese patients