Dose Individualization of Pemetrexed - IMPROVE-III

Study Overview
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Brief Summary
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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: In patients with renal dysfunction, BSA-based dosing may lead to haematological toxicity Patients have to discontinue treatment due to declining renal function, and are withheld effective treatment 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

Official Title
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Individualized Pemetrexed Dosing in Patients With Non-small Cell Lung Cancer or Mesothelioma Based on Renal Function to Improve Treatment Response

Conditions
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Non Small Cell Lung Cancer, Mesothelioma

Intervention / Treatment
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* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old Planned for treatment with pemetrexed-based chemotherapy in IMPROVE-I or -II. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2 Subject is able and willing to sign the Informed Consent Form Exclusion Criteria: Conditions that affect haemostasis in a way that blood drawing is complicated (to be assessed by physician) Contraindications for treatment with pemetrexed in line with the summary of product characteristics (SmPC) (except for creatinine clearance <45 ml/min in IMPROVE-I) Hypersensitivity to the active substance or to any of the excipients Pregnancy or lactation Concomitant yellow fever vaccine The presence of clinically relevant pharmacokinetic interactions, according to the current SmPC

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Microdosing<br>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<br>* patients will be administered a microdose with subsequent pharmacokinetic assessment.<br>* Other names: Microdosing;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The predictive performance of microdosing to predict full dose pharmacokinetics | Mean relative prediction error (MPE) | 3 months | 
| The predictive performance of microdosing to predict full dose pharmacokinetics | Root mean squared relative prediction error (RMSE) | 3 months | 
| Exposure (AUC) after microdose | mg*h/l | 1 day |