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Influence of Exceptional Patient Characteristics on Everolimus Exposure (INPRES)

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ClinicalTrials.gov Identifier: NCT01948960
Recruitment Status : Completed
First Posted : September 24, 2013
Last Update Posted : April 12, 2018
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Radboud University

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.


Condition or disease Intervention/treatment Phase
Breast Neoplasms Drug: everolimus dose escalation Phase 4

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Influence of Exceptional Patient Characteristics on Everolimus Exposure
Study Start Date : August 2013
Actual Primary Completion Date : January 15, 2018
Actual Study Completion Date : January 15, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: standard care
everolimus dose is continued independently of everolimus AUC
Active Comparator: everolimus dose escalation
patients with an AUC below mean will have dose escalation of everolimus based on their AUC
Drug: everolimus dose escalation
patients with an AUC below mean will have dose escalation of everolimus based on their AUC




Primary Outcome Measures :
  1. everolimus AUC [ Time Frame: 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 :
  1. correlation between early metabolic response and PFS [ Time Frame: 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.


  2. correlation between early metabolic response and AUC [ Time Frame: 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.


  3. effect dose escalation on metabolic respons [ Time Frame: 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.


  4. correlation between AUC and frequency of adverse event [ Time Frame: 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01948960


Locations
Netherlands
Maasziekenhuis Pantein
Boxmeer, Netherlands
Spaarne Gasthuis
Hoofddorp, Netherlands
Maastricht University Medical Center
Maastricht, Netherlands
St. Antonius Ziekenhuis
Nieuwegein, Netherlands
Radboud university medical center
Nijmegen, Netherlands
Bernhoven Ziekenhuis
Uden, Netherlands
Isala Klinieken
Zwolle, Netherlands
Sponsors and Collaborators
Radboud University
Novartis
Investigators
Principal Investigator: Carla van Herpen, MD, PhD Radboud university medical center, department of medical oncology
Principal Investigator: Nielka van Erp, PharmD, PhD Radboud university medical center, department of Pharmacy

Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT01948960     History of Changes
Other Study ID Numbers: UMCNONCO201301
First Posted: September 24, 2013    Key Record Dates
Last Update Posted: April 12, 2018
Last Verified: October 2017

Keywords provided by Radboud University:
Breast Neoplasms
everolimus
pharmacokinetics
elderly patients
obese patients

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents