<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03033186</url>
  </required_header>
  <id_info>
    <org_study_id>NL58486.068.16</org_study_id>
    <nct_id>NCT03033186</nct_id>
  </id_info>
  <brief_title>Everolimus TDM to Predict Long Term Toxicity</brief_title>
  <acronym>Foresight</acronym>
  <official_title>Foreseeing the Moments of Occurrence of Everolimus Long-term Side Effects by Follow up of Trough Blood Concentrations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Maastricht University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Metastatic (HR-positive, HER2-negative) breast cancer (BC), advanced or unresectable&#xD;
      neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin and metastatic&#xD;
      renal cell carcinoma (mRCC) are diseases with poor outcome. Everolimus increases patients'&#xD;
      median progression-free survival (PFS) with 4.6 months in metastatic BC (mBC), 7 months in&#xD;
      (p)NET and 3 months in mRCC. However, serious adverse events (AEs) occur frequently. This&#xD;
      reduces effectiveness of everolimus, because AEs are managed with dose reductions, treatment&#xD;
      interruptions or even complete discontinuation of everolimus.&#xD;
&#xD;
      Therapeutic-drug-monitoring (TDM) is used to adjust the prescribed daily dose, to maintain&#xD;
      effective everolimus whole blood concentrations, with the lowest possible risk of AEs. While&#xD;
      everolimus TDM has been common in transplantation medicine, it has not been implemented in&#xD;
      oncology.&#xD;
&#xD;
      The importance of TDM in oncology is supported by previous research which showed that a&#xD;
      2-fold increased everolimus whole blood trough concentration was associated with a short-term&#xD;
      risk of grade ≥ 3 pneumonitis, stomatitis and metabolic events. Moreover, an&#xD;
      exposure-toxicity relationship of everolimus in patients with thyroid cancer was observed,&#xD;
      since initial everolimus concentrations could be associated with early toxicity (&lt; 12 weeks,&#xD;
      e.g. stomatitis). However, the association between initial everolimus measurements and&#xD;
      long-term AEs (≥12 weeks, e.g. pneumonitis, anorexia and anemia) of any grade and the need&#xD;
      for everolimus dose reductions could not be made. Since levels ±&gt;18 µg/L were associated with&#xD;
      toxicity, the investigators assume that the upper therapeutic window of everolimus in the&#xD;
      oncologic setting will be ±18 µg/L. Similarly, a tendency to improved PFS and overall&#xD;
      survival was observed when Cmin in steady state was above 14.1 μg/L. This seems to be the&#xD;
      lower limit of the therapeutic window.&#xD;
&#xD;
      Before consensus about the feasibility of everolimus TDM in the oncologic setting can be&#xD;
      achieved, a number of questions (the knowledge gaps) need to be answered: 1. It is unknown&#xD;
      whether everolimus whole blood trough levels (over time) predict long-term AEs. 2. The&#xD;
      optimal concentration range for everolimus, with the treatment of mBC, mRCC, or (p)NET is&#xD;
      unknown, especially the upper limit associated with toxicity. 3. It is unknown what&#xD;
      everolimus concentration level is associated with the need for everolimus dose reductions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR), a key signal&#xD;
      transduction molecule of the phosphatidylinositol 3-kinase/Akt pathway. This pathway, which&#xD;
      regulates cellular growth, proliferation, metabolism, survival and angiogenesis, is&#xD;
      frequently dysregulated in human cancers and thus is a rational target for anticancer&#xD;
      therapy. Everolimus is currently approved by the European Medicines Agency (EMA) and U.S.&#xD;
      Food and Drug administration (FDA) for the treatment of different solid malignancies.&#xD;
&#xD;
      Metastatic (Hormone-Receptor [HR]-positive, HER2-negative) breast cancer (BC), advanced or&#xD;
      unresectable neuroendocrine tumours of pancreatic (pNET), gastrointestinal or lung origin and&#xD;
      metastatic renal cell carcinoma (mRCC) are diseases with poor outcome. Everolimus is part of&#xD;
      palliative treatment and increases patients' median progression-free survival (PFS) with 4.6&#xD;
      months in metastatic BC (mBC), 7 months in pNET and 3 months in mRCC. However, serious&#xD;
      adverse events (AEs) occur frequently; stomatitis up to 67%, non-infectious pneumonitis (NIP)&#xD;
      up to 15%. This reduces effectiveness of everolimus, because AEs are managed with dose&#xD;
      reductions, treatment interruptions or even complete discontinuation of everolimus.&#xD;
&#xD;
      Everolimus shows a large inter-individual pharmacokinetic variation in whole blood&#xD;
      concentrations, due to variability in oral drug availability, patient non-compliance (e.g.&#xD;
      due to drug-related toxicity, forgetting and/or overuse), drug-drug interactions with&#xD;
      co-medication and many other factors. Furthermore, variation in the population&#xD;
      pharmacokinetics of everolimus is caused by everolimus' hematocrit effect. This effect is&#xD;
      present at high everolimus concentrations in combination with low hematocrit values, which is&#xD;
      likely to be the case in the oncologic population. High incidences of anemia in oncologic&#xD;
      patients treated with everolimus have been described, respectively being 32.1%&#xD;
      (CI=17.5-51.3%) for all-grade (grades 1-4) toxicities and 6.9% (95% CI=4.1-11.3%) for&#xD;
      high-grade (grades 3-4) toxicities. Therefore, studies have recommended to correct the&#xD;
      everolimus whole blood concentrations for hematocrit determination.&#xD;
&#xD;
      The very different whole blood concentrations between individuals can result in&#xD;
      supratherapeutic or subtherapeutic exposure levels and consequently in over- or&#xD;
      undertreatment, respectively. Despite the inter-patient variability in systemic exposure,&#xD;
      everolimus is currently prescribed at a fixed dose. Given the narrow therapeutic index and a&#xD;
      positive exposure-efficacy relationship, there is a rationale for pharmacokinetically guided&#xD;
      dosing also known as therapeutic drug monitoring (TDM) of everolimus. Such an approach could&#xD;
      theoretically contribute to a tailor-made everolimus treatment with improved therapeutic&#xD;
      efficacy and decreased risk for toxicity. Since daily everolimus dosing demonstrates dose&#xD;
      proportionality and linear pharmacokinetics, this seems to be easily applicable. Furthermore,&#xD;
      requirements for dose reduction at physicians discretion can be supported when it is known at&#xD;
      what everolimus trough level a dose reduction is recommended.&#xD;
&#xD;
      Therapeutic-drug-monitoring (TDM) (i.e. measurement of everolimus whole blood levels after&#xD;
      venipuncture) is used to adjust the prescribed daily dose, to maintain effective everolimus&#xD;
      whole blood concentrations, with the lowest possible risk of AEs. In addition, TDM is a&#xD;
      useful tool for early detection of non-adherence, and might also be used to monitor the&#xD;
      effects of drug-drug interactions and food effects. While TDM, according to international&#xD;
      consensus, has been common in transplantation medicine for 10 years, it has not been&#xD;
      implemented in oncology. The importance of TDM in oncology is, however, supported by previous&#xD;
      research that showed a 2-fold increased trough concentration (Cmin) of everolimus whole blood&#xD;
      with a short-term risk of grade ≥ 3 pulmonary events (relative risk [RR] 1.9; 95% CI&#xD;
      1.1-3.3], stomatitis events (RR 1.5; 95% CI 1.1-2.1) and metabolic events (RR 1.3 95%&#xD;
      1.0-1.7). Moreover, an exposure-toxicity relationship of everolimus in patients with thyroid&#xD;
      cancer was observed, since initial everolimus concentrations could be associated with early&#xD;
      toxicity (&lt; 12 weeks), i.e. stomatitis. However, the association between initial everolimus&#xD;
      measurements and long-term AEs (≥ 12 weeks, e.g. pneumonitis, anorexia and anemia) of any&#xD;
      grade and the need for everolimus dose reductions could not be made. Since a trough&#xD;
      concentration of approximately 18 µg/L was associated with toxicity, the investigators assume&#xD;
      that the upper therapeutic window of everolimus in the oncologic setting will be ±18 µg/L.&#xD;
      Therefore, an upper threshold of &gt;18 µg/L was considered for this study.Similarly, a tendency&#xD;
      to improved PFS and overall survival (OS) was noted when CminSS was above 14.1 μg/L. This&#xD;
      might be the lower limit of the therapeutic window.&#xD;
&#xD;
      However, the following knowledge gaps exist: 1. It is unknown whether everolimus trough whole&#xD;
      blood levels (over time) predict for long-term AEs (≥12 weeks, e.g. pneumonitis, anorexia and&#xD;
      anemia). 2. The optimal concentration range for everolimus, for the treatment of mBC, mRCC,&#xD;
      or (p)NET is unknown, especially the upper limit associated with toxicity. 3. It is unknown&#xD;
      what everolimus concentration level is associated with the need for everolimus dose&#xD;
      reductions.&#xD;
&#xD;
      In order to quantitate the outcome toxicity, the number of dose reductions can be&#xD;
      investigated as this is the sum of all different toxicities experienced by patients and these&#xD;
      are also the toxicities that lead to clinical action by the treating physician. Furthermore,&#xD;
      especially all NCI-CTCAE v4.0 grade ≥2 are important, and special attention should be focused&#xD;
      on AEs that are highly prevalent, objectively measurable, clinically relevant and/or&#xD;
      untreatable. These AEs will be leading to dose reductions or discontinuation of therapy.&#xD;
&#xD;
      Dose individualization based on the measured drug concentration could theoretically result in&#xD;
      less toxicity and more efficacy. Further studies are required to determine the clinical&#xD;
      utility of TDM for everolimus in oncology settings. Determination of everolimus&#xD;
      concentrations at the onset of severe AEs (dose interruptions or reductions) and disease&#xD;
      progression may enable better understanding of pathophysiology, permitting dose reduction at&#xD;
      the right moment rather than drug withdrawal in patients with high everolimus concentrations.&#xD;
      The clinical impact of this approach can be large, since everolimus treatment optimization is&#xD;
      better than unnecessary switching to the next line of palliative treatment in these oncologic&#xD;
      patients. This is supported by the study by Generali et al., finding the combination of&#xD;
      everolimus plus exemestaan as first- or second-line therapy for mBC patients more efficacious&#xD;
      than several chemotherapy regimens that were reported in the literature. Furthermore, it is&#xD;
      important to realise that the initial concentration (&lt; 12 weeks) does not reflect a change in&#xD;
      steady-state trough concentration over time (≥12 weeks) due to various reasons. Some of them&#xD;
      being drug-drug interactions, high-fat food effects, a change in haematocrit, non-adherence,&#xD;
      dose-reductions and interruptions of the everolimus treatment.&#xD;
&#xD;
      Follow up of the everolimus concentration over time implies frequent pharmacokinetic sampling&#xD;
      (blood draws). Nowadays everolimus exposure is determined by everolimus concentration&#xD;
      measurement in whole blood. Therefore, a venipuncture is always necessary. This is invasive&#xD;
      and requires patients to come to the hospital. It would be convenient for patients to have&#xD;
      their everolimus concentration determined by dried blood spot (DBS) analysis. With DBS only a&#xD;
      single drop of blood from the finger is necessary, which can be done at home and send by&#xD;
      regular mail for analysis. Previous studies have showed the feasibility of the DBS approach&#xD;
      in the oncologic setting. The physician may benefit from the ease of the DBS sampling method&#xD;
      providing results timely before the patient visits the clinic for their (routine) check-up.&#xD;
&#xD;
      Previous methods for the measurement of everolimus by means of DBS have been developed. In&#xD;
      the past, emphasis has been put on the development and analytical validation of the assay&#xD;
      while the clinical validation was of minor importance. Some information has been gathered in&#xD;
      transplantation medicine. However, in patients with cancer, the correlation between&#xD;
      everolimus DBS concentrations and whole blood concentration is unknown. Furthermore,&#xD;
      information regarding the important everolimus hematocrit effect in DBS at high concentration&#xD;
      levels common in the oncology population is lacking. Therefore, the secondary objective is to&#xD;
      determine the everolimus concentration collected with DBS from a finger prick and DBS paper&#xD;
      spiked with a drop of venipunctured whole blood containing everolimus.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 16, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2018</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Everolimus TDM to predict long-term toxicity</measure>
    <time_frame>Up to 2 year</time_frame>
    <description>The difference in percentage of patients with a high everolimus trough level (i.e. &gt; 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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Everolimus TDM to predict short-term toxicity</measure>
    <time_frame>Up to 2 year</time_frame>
    <description>The difference in percentage of patients with a high everolimus trough level (i.e. &gt; 18 ng/mL) experiencing NCI-CTCAE v4.0 grade 2, 3 or 4 early AEs (i.e. toxicity reported from &lt; 12 weeks, e.g. stomatitis) compared to participants with lower trough concentrations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation everolimus concentration DBS from fingerprick with whole blood from venipuncture</measure>
    <time_frame>Up to 2 year</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation everolimus concentration DBS from fingerprick with DBS spiked with whole blood from venipuncture</measure>
    <time_frame>Up to 2 year</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Everolimus TDM to predict dose reductions</measure>
    <time_frame>Up to 2 year</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Renal Cell Carcinoma</condition>
  <condition>Pancreatic Neuroendocrine Tumour</condition>
  <condition>Gastrointestinal Neuroendocrine Tumour</condition>
  <condition>Neuroendocrine Neoplasm of Lung</condition>
  <arm_group>
    <arm_group_label>Everolimus (afinitor)</arm_group_label>
    <description>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)</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood and drop of blood&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients currently treated with everolimus for any type of cancer, such as the EMA&#xD;
        registered indications i.e. advanced (Hormone-Receptor [HR]-positive, HER2-negative) breast&#xD;
        cancer, metastatic renal cell carcinoma (mRCC) or neuroendocrine tumours of pancreatic&#xD;
        (pNET), gastrointestinal or lung origin.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients currently treated with everolimus for any type of cancer, such as the EMA&#xD;
             registered indications i.e. advanced (Hormone-Receptor [HR]-positive, HER2-negative)&#xD;
             breast cancer, metastatic renal cell carcinoma (mRCC) or neuroendocrine tumour (NET)&#xD;
             of pancreatic, gastrointestinal or lung origin.&#xD;
&#xD;
          -  Aged 18 or above&#xD;
&#xD;
          -  Able and willing to sign the informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  No informed consent&#xD;
&#xD;
          -  Alactasia&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>S. Croes, PharmD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Maastricht University Medical Centre+</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>S. Croes, PharmD PhD</last_name>
    <phone>(+31)43 3871431</phone>
    <email>s.croes@mumc.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>L. Knapen, PharmD</last_name>
    <phone>(+31)43 3871881</phone>
    <email>lotte.knapen@mumc.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Maastricht University Medical Centre</name>
      <address>
        <city>Maastricht</city>
        <state>Limburg</state>
        <zip>6202 AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>S. Croes, PharmD, PhD</last_name>
      <phone>(+31)43 3871431</phone>
      <email>s.croes@mumc.nl</email>
    </contact>
    <contact_backup>
      <last_name>L.M. Knapen, MSc</last_name>
      <phone>(+31)43 3871881</phone>
      <email>lotte.knapen@mumc.nl</email>
    </contact_backup>
    <investigator>
      <last_name>S. Croes, PharmD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>L.M. Knapen, MSc</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>A. Bast, MD PhD Prof</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>V.C.G. Tjan-Heijnen, MD PhD Prof</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>N.P. van Erp, PharmD PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>M. de Boer, MD PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>I.J.H. Vriens, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>M.J.B. Aarts, MD PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>January 24, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 26, 2017</study_first_posted>
  <last_update_submitted>May 30, 2017</last_update_submitted>
  <last_update_submitted_qc>May 30, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Everolimus</keyword>
  <keyword>Long term site effects</keyword>
  <keyword>Dried Blood Spot</keyword>
  <keyword>Therapeutic Drug Monitoring</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Renal Cell</mesh_term>
    <mesh_term>Neuroendocrine Tumors</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03033186
org study id: NL58486.068.16
nct id: NCT03033186
lead sponsor: 
has dmc: No
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.
Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR), a key signal
      transduction molecule of the phosphatidylinositol 3-kinase/Akt pathway. This pathway, which
      regulates cellular growth, proliferation, metabolism, survival and angiogenesis, is
      frequently dysregulated in human cancers and thus is a rational target for anticancer
      therapy. Everolimus is currently approved by the European Medicines Agency (EMA) and U.S.
      Food and Drug administration (FDA) for the treatment of different solid malignancies.

      Metastatic (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) are diseases with poor outcome. Everolimus is part of
      palliative treatment and increases patients' median progression-free survival (PFS) with 4.6
      months in metastatic BC (mBC), 7 months in pNET and 3 months in mRCC. However, serious
      adverse events (AEs) occur frequently; stomatitis up to 67%, non-infectious pneumonitis (NIP)
      up to 15%. This reduces effectiveness of everolimus, because AEs are managed with dose
      reductions, treatment interruptions or even complete discontinuation of everolimus.

      Everolimus shows a large inter-individual pharmacokinetic variation in whole blood
      concentrations, due to variability in oral drug availability, patient non-compliance (e.g.
      due to drug-related toxicity, forgetting and/or overuse), drug-drug interactions with
      co-medication and many other factors. Furthermore, variation in the population
      pharmacokinetics of everolimus is caused by everolimus' hematocrit effect. This effect is
      present at high everolimus concentrations in combination with low hematocrit values, which is
      likely to be the case in the oncologic population. High incidences of anemia in oncologic
      patients treated with everolimus have been described, respectively being 32.1%
      (CI=17.5-51.3%) for all-grade (grades 1-4) toxicities and 6.9% (95% CI=4.1-11.3%) for
      high-grade (grades 3-4) toxicities. Therefore, studies have recommended to correct the
      everolimus whole blood concentrations for hematocrit determination.

      The very different whole blood concentrations between individuals can result in
      supratherapeutic or subtherapeutic exposure levels and consequently in over- or
      undertreatment, respectively. Despite the inter-patient variability in systemic exposure,
      everolimus is currently prescribed at a fixed dose. Given the narrow therapeutic index and a
      positive exposure-efficacy relationship, there is a rationale for pharmacokinetically guided
      dosing also known as therapeutic drug monitoring (TDM) of everolimus. Such an approach could
      theoretically contribute to a tailor-made everolimus treatment with improved therapeutic
      efficacy and decreased risk for toxicity. Since daily everolimus dosing demonstrates dose
      proportionality and linear pharmacokinetics, this seems to be easily applicable. Furthermore,
      requirements for dose reduction at physicians discretion can be supported when it is known at
      what everolimus trough level a dose reduction is recommended.

      Therapeutic-drug-monitoring (TDM) (i.e. measurement of everolimus whole blood levels after
      venipuncture) is used to adjust the prescribed daily dose, to maintain effective everolimus
      whole blood concentrations, with the lowest possible risk of AEs. In addition, TDM is a
      useful tool for early detection of non-adherence, and might also be used to monitor the
      effects of drug-drug interactions and food effects. While TDM, according to international
      consensus, has been common in transplantation medicine for 10 years, it has not been
      implemented in oncology. The importance of TDM in oncology is, however, supported by previous
      research that showed a 2-fold increased trough concentration (Cmin) of everolimus whole blood
      with a short-term risk of grade ≥ 3 pulmonary events (relative risk [RR] 1.9; 95% CI
      1.1-3.3], stomatitis events (RR 1.5; 95% CI 1.1-2.1) and metabolic events (RR 1.3 95%
      1.0-1.7). 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), i.e. 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 a trough
      concentration of approximately 18 µg/L was associated with toxicity, the investigators assume
      that the upper therapeutic window of everolimus in the oncologic setting will be ±18 µg/L.
      Therefore, an upper threshold of >18 µg/L was considered for this study.Similarly, a tendency
      to improved PFS and overall survival (OS) was noted when CminSS was above 14.1 μg/L. This
      might be the lower limit of the therapeutic window.

      However, the following knowledge gaps exist: 1. It is unknown whether everolimus trough whole
      blood levels (over time) predict for long-term AEs (≥12 weeks, e.g. pneumonitis, anorexia and
      anemia). 2. The optimal concentration range for everolimus, for 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.

      In order to quantitate the outcome toxicity, the number of dose reductions can be
      investigated as this is the sum of all different toxicities experienced by patients and these
      are also the toxicities that lead to clinical action by the treating physician. Furthermore,
      especially all NCI-CTCAE v4.0 grade ≥2 are important, and special attention should be focused
      on AEs that are highly prevalent, objectively measurable, clinically relevant and/or
      untreatable. These AEs will be leading to dose reductions or discontinuation of therapy.

      Dose individualization based on the measured drug concentration could theoretically result in
      less toxicity and more efficacy. Further studies are required to determine the clinical
      utility of TDM for everolimus in oncology settings. Determination of everolimus
      concentrations at the onset of severe AEs (dose interruptions or reductions) and disease
      progression may enable better understanding of pathophysiology, permitting dose reduction at
      the right moment rather than drug withdrawal in patients with high everolimus concentrations.
      The clinical impact of this approach can be large, since everolimus treatment optimization is
      better than unnecessary switching to the next line of palliative treatment in these oncologic
      patients. This is supported by the study by Generali et al., finding the combination of
      everolimus plus exemestaan as first- or second-line therapy for mBC patients more efficacious
      than several chemotherapy regimens that were reported in the literature. Furthermore, it is
      important to realise that the initial concentration (< 12 weeks) does not reflect a change in
      steady-state trough concentration over time (≥12 weeks) due to various reasons. Some of them
      being drug-drug interactions, high-fat food effects, a change in haematocrit, non-adherence,
      dose-reductions and interruptions of the everolimus treatment.

      Follow up of the everolimus concentration over time implies frequent pharmacokinetic sampling
      (blood draws). Nowadays everolimus exposure is determined by everolimus concentration
      measurement in whole blood. Therefore, a venipuncture is always necessary. This is invasive
      and requires patients to come to the hospital. It would be convenient for patients to have
      their everolimus concentration determined by dried blood spot (DBS) analysis. With DBS only a
      single drop of blood from the finger is necessary, which can be done at home and send by
      regular mail for analysis. Previous studies have showed the feasibility of the DBS approach
      in the oncologic setting. The physician may benefit from the ease of the DBS sampling method
      providing results timely before the patient visits the clinic for their (routine) check-up.

      Previous methods for the measurement of everolimus by means of DBS have been developed. In
      the past, emphasis has been put on the development and analytical validation of the assay
      while the clinical validation was of minor importance. Some information has been gathered in
      transplantation medicine. However, in patients with cancer, the correlation between
      everolimus DBS concentrations and whole blood concentration is unknown. Furthermore,
      information regarding the important everolimus hematocrit effect in DBS at high concentration
      levels common in the oncology population is lacking. Therefore, the secondary objective is to
      determine the everolimus concentration collected with DBS from a finger prick and DBS paper
      spiked with a drop of venipunctured whole blood containing everolimus.
observational model: Cohort
time perspective: Prospective
measure: Everolimus TDM to predict long-term toxicity
time frame: Up to 2 year
description: 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.
measure: Everolimus TDM to predict short-term toxicity
time frame: Up to 2 year
description: 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.
measure: Correlation everolimus concentration DBS from fingerprick with whole blood from venipuncture
time frame: Up to 2 year
description: 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.
measure: Correlation everolimus concentration DBS from fingerprick with DBS spiked with whole blood from venipuncture
time frame: Up to 2 year
description: 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.
measure: Everolimus TDM to predict dose reductions
time frame: Up to 2 year
description: 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.
arm group label: Everolimus (afinitor)
description: 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)
Whole blood and drop of blood
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: S. Croes, PharmD, PhD
role: Principal Investigator
affiliation: Maastricht University Medical Centre+
last name: S. Croes, PharmD PhD
phone: (+31)43 3871431
email: s.croes@mumc.nl
last name: L. Knapen, PharmD
phone: (+31)43 3871881
email: lotte.knapen@mumc.nl
facility: 
status: Recruiting
contact: 
contact backup: 
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country: Netherlands
responsible party type: Sponsor
mesh term: Carcinoma, Renal Cell
mesh term: Neuroendocrine Tumors
mesh term: Lung Neoplasms
sharing ipd: No