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Influence of Exceptional Patient Characteristics on Everolimus Exposure (INPRES)

Primary Purpose

Breast Neoplasms

Status
Completed
Phase
Phase 4
Locations
Netherlands
Study Type
Interventional
Intervention
everolimus dose escalation
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Breast Neoplasms focused on measuring Breast Neoplasms, everolimus, pharmacokinetics, elderly patients, obese patients

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • Maasziekenhuis Pantein
  • Spaarne Gasthuis
  • Maastricht University Medical Center
  • St. Antonius Ziekenhuis
  • Radboud university medical center
  • Bernhoven Ziekenhuis
  • Isala Klinieken

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

standard care

everolimus dose escalation

Arm Description

everolimus dose is continued independently of everolimus AUC

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
September 13, 2013
Last Updated
December 5, 2018
Sponsor
Radboud University Medical Center
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT01948960
Brief Title
Influence of Exceptional Patient Characteristics on Everolimus Exposure
Acronym
INPRES
Official Title
Influence of Exceptional Patient Characteristics on Everolimus Exposure
Study Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
August 2013 (undefined)
Primary Completion Date
January 15, 2018 (Actual)
Study Completion Date
January 15, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
Collaborators
Novartis

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Neoplasms
Keywords
Breast Neoplasms, everolimus, pharmacokinetics, elderly patients, obese patients

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
56 (Actual)

8. Arms, Groups, and Interventions

Arm Title
standard care
Arm Type
No Intervention
Arm Description
everolimus dose is continued independently of everolimus AUC
Arm Title
everolimus dose escalation
Arm Type
Active Comparator
Arm Description
patients with an AUC below mean will have dose escalation of everolimus based on their AUC
Intervention Type
Drug
Intervention Name(s)
everolimus dose escalation
Intervention Description
patients with an AUC below mean will have dose escalation of everolimus based on their AUC
Primary Outcome Measure Information:
Title
everolimus AUC
Description
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).
Time Frame
day 14 after start treatment
Secondary Outcome Measure Information:
Title
correlation between early metabolic response and PFS
Description
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.
Time Frame
within 90 days after start of treatment
Title
correlation between early metabolic response and AUC
Description
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.
Time Frame
15 days after start of treatment
Title
effect dose escalation on metabolic respons
Description
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.
Time Frame
within 36 days after start of treatment
Title
correlation between AUC and frequency of adverse event
Description
To explore, quantify and describe the correlation between everolimus exposure and the frequency of adverse events as graded with CTCAE v4.0.
Time Frame
4 months after start of treatment

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carla van Herpen, MD, PhD
Organizational Affiliation
Radboud university medical center, department of medical oncology
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nielka van Erp, PharmD, PhD
Organizational Affiliation
Radboud university medical center, department of Pharmacy
Official's Role
Principal Investigator
Facility Information:
Facility Name
Maasziekenhuis Pantein
City
Boxmeer
Country
Netherlands
Facility Name
Spaarne Gasthuis
City
Hoofddorp
Country
Netherlands
Facility Name
Maastricht University Medical Center
City
Maastricht
Country
Netherlands
Facility Name
St. Antonius Ziekenhuis
City
Nieuwegein
Country
Netherlands
Facility Name
Radboud university medical center
City
Nijmegen
Country
Netherlands
Facility Name
Bernhoven Ziekenhuis
City
Uden
Country
Netherlands
Facility Name
Isala Klinieken
City
Zwolle
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
30259313
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.
Results Reference
derived
Links:
URL
https://www.ncbi.nlm.nih.gov/pubmed/30259313
Description
Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane

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Influence of Exceptional Patient Characteristics on Everolimus Exposure

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