Ignite Creation Date:
2024-05-06 @ 9:38 AM
Last Modification Date:
2024-10-26 @ 12:17 PM
Study NCT ID:
NCT03033186
Status:
UNKNOWN
Last Update Posted:
2017-05-31
First Post:
2017-01-24
Brief Title:
Everolimus TDM to Predict Long Term Toxicity
Sponsor:
Maastricht University Medical Center
Organization:
Maastricht University Medical Center
Study Overview
Official Title:
Foreseeing the Moments of Occurrence of Everolimus Long-term Side Effects by Follow up of Trough Blood Concentrations
Status:
UNKNOWN
Status Verified Date:
2017-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Foresight
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 46 months in metastatic BC mBC 7 months in pNET 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 eg stomatitis However the association between initial everolimus measurements and long-term AEs 12 weeks eg pneumonitis anorexia and anemia of any grade and the need for everolimus dose reductions could not be made Since levels 18 µgL were associated with toxicity the investigators assume that the upper therapeutic window of everolimus in the oncologic setting will be 18 µgL Similarly a tendency to improved PFS and overall survival was observed when Cmin in steady state was above 141 μgL 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 pNET 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
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 eg stomatitis However the association between initial everolimus measurements and long-term AEs 12 weeks eg pneumonitis anorexia and anemia of any grade and the need for everolimus dose reductions could not be made Since levels 18 µgL were associated with toxicity the investigators assume that the upper therapeutic window of everolimus in the oncologic setting will be 18 µgL Similarly a tendency to improved PFS and overall survival was observed when Cmin in steady state was above 141 μgL 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 pNET 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
Detailed Description:
Everolimus is an oral inhibitor of mammalian target of rapamycin mTOR a key signal transduction molecule of the phosphatidylinositol 3-kinaseAkt 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 US 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 46 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 eg due to drug-related toxicity forgetting andor 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 321 CI175-513 for all-grade grades 1-4 toxicities and 69 95 CI41-113 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 ie 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 19 95 CI 11-33 stomatitis events RR 15 95 CI 11-21 and metabolic events RR 13 95 10-17 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 ie stomatitis However the association between initial everolimus measurements and long-term AEs 12 weeks eg 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 µgL was associated with toxicity the investigators assume that the upper therapeutic window of everolimus in the oncologic setting will be 18 µgL Therefore an upper threshold of 18 µgL was considered for this studySimilarly a tendency to improved PFS and overall survival OS was noted when CminSS was above 141 μgL 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 eg pneumonitis anorexia and anemia 2 The optimal concentration range for everolimus for the treatment of mBC mRCC or pNET 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 v40 grade 2 are important and special attention should be focused on AEs that are highly prevalent objectively measurable clinically relevant andor 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
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 46 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 eg due to drug-related toxicity forgetting andor 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 321 CI175-513 for all-grade grades 1-4 toxicities and 69 95 CI41-113 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 ie 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 19 95 CI 11-33 stomatitis events RR 15 95 CI 11-21 and metabolic events RR 13 95 10-17 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 ie stomatitis However the association between initial everolimus measurements and long-term AEs 12 weeks eg 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 µgL was associated with toxicity the investigators assume that the upper therapeutic window of everolimus in the oncologic setting will be 18 µgL Therefore an upper threshold of 18 µgL was considered for this studySimilarly a tendency to improved PFS and overall survival OS was noted when CminSS was above 141 μgL 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 eg pneumonitis anorexia and anemia 2 The optimal concentration range for everolimus for the treatment of mBC mRCC or pNET 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 v40 grade 2 are important and special attention should be focused on AEs that are highly prevalent objectively measurable clinically relevant andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None