Clinical trial NCT01948960: Influence of Exceptional Patient Characteristics on Everolimus Exposure
Official title: Influence of Exceptional Patient Characteristics on Everolimus Exposure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Breast Neoplasms
Keywords: Breast Neoplasms
everolimus
pharmacokinetics
elderly patients
obese patients
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2013-09-24
Enrollment: 56
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

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.


Eligibility criteria: 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

Primary outcomes:
measure: everolimus AUC
timeFrame: day 14 after start treatment
Secondary outcomes:
measure: correlation between early metabolic response and PFS
timeFrame: within 90 days after start of treatment
measure: correlation between early metabolic response and AUC
timeFrame: 15 days after start of treatment
measure: effect dose escalation on metabolic respons
timeFrame: within 36 days after start of treatment
measure: correlation between AUC and frequency of adverse event
timeFrame: 4 months after start of treatment
Other outcomes:
Locations:
city: Boxmeer
country: Netherlands
facility: Maasziekenhuis Pantein
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nieuwegein
country: Netherlands
facility: St. Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Radboud university medical center
city: Uden
country: Netherlands
facility: Bernhoven Ziekenhuis
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: Radboud university medical center, department of medical oncology
name: Carla van Herpen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud university medical center, department of Pharmacy
name: Nielka van Erp, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Willemsen AECAB, de Geus-Oei LF, de Boer M, Tol J, Kamm Y, de Jong PC, Jonker MA, Vos AH, Grootjans W, de Groot JWB, Mulder SF, Aarntzen EHJG, Gerritsen WR, van Herpen CML, van Erp NP. Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane. Target Oncol. 2018 Oct;13(5):641-648. doi: 10.1007/s11523-018-0596-8.