Dose Individualization of Pemetrexed - IMPROVE-III (IMPROVE-III)

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

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

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

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