Dose Individualization of Pemetrexed - IMPROVE-II

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-II is an open label, double arm, randomized study to compare renal function-based dosing of pemetrexed versus BSA-based dosing on attainment of therapeutic exposure. Study population: IMPROVE-II includes 94 patients with NSCLC or mesothelioma that are eligible for pemetrexed treatment. Intervention: patients will be randomized in a 1:1 ratio to Arm A (BSA-based dosing according drug label) or to Arm B (renal function based dosing). The renal function-based dose will be calculated to reach the target AUC. Pharmacokinetic assessment after administration will be performed after the first pemetrexed dose in both arms. Main study endpoints: The fraction (percentage) of patients with attainment of therapeutic exposure with BSA-based dosing versus renal function-based dosing. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The investigators consider the extra burden from participating in the planned studies limited. The extra interventions compared to routine care, consist of sampling extra blood. The pharmacokinetic assessments require placement of one additional intravenous catheter. To ensure minimal impact of study participation on daily life, a limited sampling strategy will be used. Patients may benefit from participating in IMPROVE I and -II, as they will be treated with a potentially safe and effective drug that is dosed individually, which prevents toxic exposure.

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 Eligible for treatment with pemetrexed-based chemotherapy Creatinine clearance >45ml/min 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (BSA-based dosing)<br>Dosing of pemetrexed is based on BSA according drug label | Drug: Pemetrexed<br>* Dosing is either based on BSA or renal function<br>|
| Experimental: Arm B (renal function based dosing)<br>Dosing of pemetrexed is based on renal function, calculated to reach the target AUC. | Drug: Pemetrexed<br>* Dosing is either based on BSA or renal function<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exposure (AUC) | mg*h/l | 24 hours | 
| The fraction (percentage) of patients with attainment of therapeutic exposure with BSA-based dosing versus renal function-based dosing. | The fraction (percentage) of patients with attainment of therapeutic exposure defined as an AUC of 164 mg*h/l ±25%, with pemetrexed dosing based on renal function versus BSA-based dosing. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Population Clearance (Cl) | L/h | 3 months | 
| Population Intercompartmental Clearance (Q) | L/h | 3 months | 
| Population Central Volume of Distribution (V1) | L | 24 hours | 
| Population Peripheral Volume of Distribution (V2) | L | 3 months | 
| Performance of different renal function algorithms to predict pemetrexed | Significant change in objective function value (OFV) (<3.84 with 1 degree of freedom) | 3 months | 
| Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability) | Decrease in clearance variablity (%) | 3 months | 
| Hematologic assessment during dosing based on renal function in patients with a creatinine clearance >45ml/min versus dosing based on BSA. | Complete blood count (no per liter) | 5 days | 
| The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4' | through listing | 3 months | 
| The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4 | through listing | 3 months | 
| The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation | through listing | 3 months | 
| Quality of life measured with the EORTC QLQ-C30/L13 questionnaire | 0-100 scale | 3 months | 
| In silico evaluation of neutropenic response | Simulation of risk for neutropenic response | 1 year | 
| Neutropenia related costs | Euros | 1 year |