Dose Individualization of Pemetrexed - IMPROVE-I

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-I is a single arm phase II pharmacokinetic safety study using a Simon two stage design to assess the feasibility of renal function-based dosing of pemetrexed in renal impaired patients. Study population: IMPROVE-I includes 23 patients with NSCLC or mesothelioma with an estimated creatinine clearance <45ml/min that meet all other requirements for pemetrexed treatment. Intervention:Patients will be treated with pemetrexed, with dosing based on renal function. As a safety measure, the first dose will be calculated to 50% exposure. After administration, safety and pharmacokinetics are assessed. If tolerated well, dose escalation to reach 100% exposure is performed, including assessment of safety and pharmacokinetics. Main study endpoints: The fraction (percentage) of patients with attainment of therapeutic exposure. 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 based on indication Estimated 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Impaired renal function<br>patients will be treated with pemetrexed, with dosing based on renal function. | Drug: Pemetrexed<br>* patients will be treated with pemetrexed, with dosing based on renal function. As a safety measure, the first dose will be calculated to 50% exposure. After administration, safety and pharmacokinetics are assessed. If tolerated well, dose escalation to reach 100% exposure is performed, including assessment of safety and pharmacokinetics.<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 of patients with attainment of therapeutic exposure. | The fraction (percentage) of patients with attainment of therapeutic exposure, after the second dose, defined as an AUC of 164 mg*h/l ±25%. | 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 | 3 months | 
| Population Peripheral Volume of Distribution (V2) | L | 3 months | 
| Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (model fit) | 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 pemetrexed dosing in patients with a creatinine clearance <45ml/min. | 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 |