Influence of Exceptional Patient Characteristics on Everolimus Exposure

Phase 4

Completed

Brief Summary: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
everolimus dose escalation	everolimus dose escalation	patients with an AUC below mean will have dose escalation of everolimus based on their AUC

Primary Outcome Measures

Name	Time	Method
everolimus AUC	day 14 after start treatment	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).

Secondary Outcome Measures

Name	Time	Method
correlation between early metabolic response and PFS	within 90 days after start of treatment	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.
correlation between early metabolic response and AUC	15 days after start of treatment	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.
effect dose escalation on metabolic respons	within 36 days after start of treatment	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.
correlation between AUC and frequency of adverse event	4 months after start of treatment	To explore, quantify and describe the correlation between everolimus exposure and the frequency of adverse events as graded with CTCAE v4.0.

Locations (7): Maasziekenhuis Pantein
🇳🇱
Boxmeer, Netherlands
Maastricht University Medical Center
🇳🇱
Maastricht, Netherlands
St. Antonius Ziekenhuis
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Nieuwegein, Netherlands
Spaarne Gasthuis
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Hoofddorp, Netherlands
Radboud university medical center
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Nijmegen, Netherlands
Bernhoven Ziekenhuis
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Uden, Netherlands
Isala Klinieken
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Zwolle, Netherlands