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Everolimus TDM to Predict Long Term Toxicity (Foresight)

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ClinicalTrials.gov Identifier: NCT03033186
Recruitment Status : Unknown
Verified May 2017 by Maastricht University Medical Center.
Recruitment status was:  Recruiting
First Posted : January 26, 2017
Last Update Posted : May 31, 2017
Sponsor:
Information provided by (Responsible Party):
Maastricht University Medical Center

Brief Summary:

Metastatic (HR-positive, HER2-negative) breast cancer (BC), advanced or unresectable neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin and metastatic renal cell carcinoma (mRCC) are diseases with poor outcome. Everolimus increases patients' median progression-free survival (PFS) with 4.6 months in metastatic BC (mBC), 7 months in (p)NET and 3 months in mRCC. However, serious adverse events (AEs) occur frequently. This reduces effectiveness of everolimus, because AEs are managed with dose reductions, treatment interruptions or even complete discontinuation of everolimus.

Therapeutic-drug-monitoring (TDM) is used to adjust the prescribed daily dose, to maintain effective everolimus whole blood concentrations, with the lowest possible risk of AEs. While everolimus TDM has been common in transplantation medicine, it has not been implemented in oncology.

The importance of TDM in oncology is supported by previous research which showed that a 2-fold increased everolimus whole blood trough concentration was associated with a short-term risk of grade ≥ 3 pneumonitis, stomatitis and metabolic events. Moreover, an exposure-toxicity relationship of everolimus in patients with thyroid cancer was observed, since initial everolimus concentrations could be associated with early toxicity (< 12 weeks, e.g. stomatitis). However, the association between initial everolimus measurements and long-term AEs (≥12 weeks, e.g. pneumonitis, anorexia and anemia) of any grade and the need for everolimus dose reductions could not be made. Since levels ±>18 µg/L were associated with toxicity, the investigators assume that the upper therapeutic window of everolimus in the oncologic setting will be ±18 µg/L. Similarly, a tendency to improved PFS and overall survival was observed when Cmin in steady state was above 14.1 μg/L. This seems to be the lower limit of the therapeutic window.

Before consensus about the feasibility of everolimus TDM in the oncologic setting can be achieved, a number of questions (the knowledge gaps) need to be answered: 1. It is unknown whether everolimus whole blood trough levels (over time) predict long-term AEs. 2. The optimal concentration range for everolimus, with the treatment of mBC, mRCC, or (p)NET is unknown, especially the upper limit associated with toxicity. 3. It is unknown what everolimus concentration level is associated with the need for everolimus dose reductions.


Condition or disease
Breast Cancer Renal Cell Carcinoma Pancreatic Neuroendocrine Tumour Gastrointestinal Neuroendocrine Tumour Neuroendocrine Neoplasm of Lung

  Show Detailed Description

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Study Type : Observational
Estimated Enrollment : 40 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Foreseeing the Moments of Occurrence of Everolimus Long-term Side Effects by Follow up of Trough Blood Concentrations
Actual Study Start Date : May 16, 2017
Estimated Primary Completion Date : September 1, 2018
Estimated Study Completion Date : December 31, 2018


Group/Cohort
Everolimus (afinitor)
Patients using everolimus as therapy for cancer: Advanced (Hormone-Receptor [HR]-positive, HER2-negative) breast cancer (BC), advanced or unresectable neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin and metastatic renal cell carcinoma (mRCC)



Primary Outcome Measures :
  1. Everolimus TDM to predict long-term toxicity [ Time Frame: Up to 2 year ]
    The difference in percentage of patients with a high everolimus trough level (i.e. > 18 ng/mL) experiencing NCI-CTCAE v4.0 grade 2, 3 or 4 late AEs (i.e. toxicity reported from ≥ 12 weeks onward, e.g. pneumonitis, anorexia, anemia) compared to participants with lower trough concentrations.


Secondary Outcome Measures :
  1. Everolimus TDM to predict short-term toxicity [ Time Frame: Up to 2 year ]
    The difference in percentage of patients with a high everolimus trough level (i.e. > 18 ng/mL) experiencing NCI-CTCAE v4.0 grade 2, 3 or 4 early AEs (i.e. toxicity reported from < 12 weeks, e.g. stomatitis) compared to participants with lower trough concentrations.

  2. Correlation everolimus concentration DBS from fingerprick with whole blood from venipuncture [ Time Frame: Up to 2 year ]
    To define the correlation between everolimus concentration measured in whole blood after a venipuncture as compared to the everolimus concentration measured from dried capillary blood extracted from the Whatman filterpaper of the DBS.

  3. Correlation everolimus concentration DBS from fingerprick with DBS spiked with whole blood from venipuncture [ Time Frame: Up to 2 year ]
    To define the correlation between everolimus concentration collected with DBS from a finger prick and DBS paper spiked with a drop of everolimus from venipunctured whole blood extracted from the Whatman filterpaper of the DBS.

  4. Everolimus TDM to predict dose reductions [ Time Frame: Up to 2 year ]
    To define the correlation between the everolimus trough levels (over time) between patients using full dose everolimus (e.g. 10 mg once daily) and patients using everolimus in a reduced dose (e.g. 2,5 or 5 mg once daily) at each moment of blood sampling in time.


Biospecimen Retention:   Samples Without DNA
Whole blood and drop of blood


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients currently treated with everolimus for any type of cancer, such as the EMA registered indications i.e. advanced (Hormone-Receptor [HR]-positive, HER2-negative) breast cancer, metastatic renal cell carcinoma (mRCC) or neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin.
Criteria

Inclusion Criteria:

  • Patients currently treated with everolimus for any type of cancer, such as the EMA registered indications i.e. advanced (Hormone-Receptor [HR]-positive, HER2-negative) breast cancer, metastatic renal cell carcinoma (mRCC) or neuroendocrine tumour (NET) of pancreatic, gastrointestinal or lung origin.
  • Aged 18 or above
  • Able and willing to sign the informed consent

Exclusion Criteria:

  • No informed consent
  • Alactasia

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): NCT03033186


Contacts
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Contact: S. Croes, PharmD PhD (+31)43 3871431 s.croes@mumc.nl
Contact: L. Knapen, PharmD (+31)43 3871881 lotte.knapen@mumc.nl

Locations
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Netherlands
Maastricht University Medical Centre Recruiting
Maastricht, Limburg, Netherlands, 6202 AZ
Contact: S. Croes, PharmD, PhD    (+31)43 3871431    s.croes@mumc.nl   
Contact: L.M. Knapen, MSc    (+31)43 3871881    lotte.knapen@mumc.nl   
Principal Investigator: S. Croes, PharmD PhD         
Principal Investigator: L.M. Knapen, MSc         
Sub-Investigator: A. Bast, MD PhD Prof         
Sub-Investigator: V.C.G. Tjan-Heijnen, MD PhD Prof         
Sub-Investigator: N.P. van Erp, PharmD PhD         
Sub-Investigator: M. de Boer, MD PhD         
Sub-Investigator: I.J.H. Vriens, MD         
Sub-Investigator: M.J.B. Aarts, MD PhD         
Sponsors and Collaborators
Maastricht University Medical Center
Investigators
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Principal Investigator: S. Croes, PharmD, PhD Maastricht University Medical Centre+

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Responsible Party: Maastricht University Medical Center
ClinicalTrials.gov Identifier: NCT03033186     History of Changes
Other Study ID Numbers: NL58486.068.16
First Posted: January 26, 2017    Key Record Dates
Last Update Posted: May 31, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Maastricht University Medical Center:
Everolimus
Long term site effects
Dried Blood Spot
Therapeutic Drug Monitoring

Additional relevant MeSH terms:
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Carcinoma, Renal Cell
Neuroendocrine Tumors
Adenoma, Islet Cell
Lung Neoplasms
Intestinal Neoplasms
Pancreatic Neoplasms
Stomach Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Adenoma
Digestive System Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases