Dose Individualization of Pemetrexed - IMPROVE-III
Study Details
Study Description
Brief Summary
Rationale:
Pemetrexed is a multi-targeted folate antagonist, which is primarily indicated for the treatment of advanced non-small cell lung cancer (NSCLC) and mesothelioma. Dosing of cytotoxic agents like pemetrexed requires balancing the dual risk of sub-therapy and toxicity. Administration of pemetrexed to patients with a creatinine clearance <45 ml/min is currently not advised. Pemetrexed is dosed based on body surface area (BSA), while renal function and dose are the sole determinants for systemic exposure. This causes 3 major issues:
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In patients with renal dysfunction, BSA-based dosing may lead to haematological toxicity
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Patients have to discontinue treatment due to declining renal function, and are withheld effective treatment
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Even in patients with adequate renal function (GFR >45 ml/min) treatment may be improved by individualized dosing based on renal function, resulting in less toxicity. Also, BSA-based dosing may lead to ineffective therapy in patients with above average renal function.
The investigators aim to address these problems.
Objective: The overall main objective is to develop a safe and effective individualized dosing regimen for pemetrexed.
Study design: IMPROVE-III is an explorative microdosing study to assess the extrapolability of microdose-pharmacokinetics to the pharmacokinetics of a therapeutic dose.
Study population: IMPROVE-III includes 10 patients of IMPROVE-I and/or IMPROVE-II.
Intervention: patients will be administered a microdose with subsequent pharmacokinetic assessment.
Main study endpoints: The predictive performance of microdosing to predict full dose pharmacokinetics
Condition or Disease | Intervention/Treatment | Phase |
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Phase 4 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Microdosing Patients will be administered a microdose of pemetrexed with subsequent pharmacokinetic assessment. Afterwards the patients will continue in either IMPROVE-I or -II for second pharmacokinetic assessment |
Drug: Pemetrexed
patients will be administered a microdose with subsequent pharmacokinetic assessment.
Other Names:
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Outcome Measures
Primary Outcome Measures
- The predictive performance of microdosing to predict full dose pharmacokinetics [3 months]
Mean relative prediction error (MPE)
- The predictive performance of microdosing to predict full dose pharmacokinetics [3 months]
Root mean squared relative prediction error (RMSE)
- Exposure (AUC) after microdose [1 day]
mg*h/l
Eligibility Criteria
Criteria
Inclusion Criteria:
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≥18 years old
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Planned for treatment with pemetrexed-based chemotherapy in IMPROVE-I or -II.
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Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
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Subject is able and willing to sign the Informed Consent Form
Exclusion Criteria:
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Conditions that affect haemostasis in a way that blood drawing is complicated (to be assessed by physician)
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Contraindications for treatment with pemetrexed in line with the summary of product characteristics (SmPC) (except for creatinine clearance <45 ml/min in IMPROVE-I)
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Hypersensitivity to the active substance or to any of the excipients
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Pregnancy or lactation
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Concomitant yellow fever vaccine
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The presence of clinically relevant pharmacokinetic interactions, according to the current SmPC
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Jeroen Bosch Hospital | 's-Hertogenbosch | Netherlands | ||
2 | Antoni van Leeuwenhoek | Amsterdam | Netherlands | ||
3 | Maastricht University Medical centre | Maastricht | Netherlands | ||
4 | Radboud university medical centre | Nijmegen | Netherlands | ||
5 | Erasmus University Medical Centre | Rotterdam | Netherlands |
Sponsors and Collaborators
- Radboud University Medical Center
- ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
- Principal Investigator: Rob ter Heine, PhD, Radboud University Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IMPROVE-III