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Dose Individualization of Pemetrexed - IMPROVE-III

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:

1. In patients with renal dysfunction, BSA-based dosing may lead to haematological toxicity

2. Patients have to discontinue treatment due to declining renal function, and are withheld effective treatment

3. 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

Tracking Information
First Received DateMay 14, 2018
Last Changed DateFebruary 27, 2019
Start DateFebruary 1, 2019
Anticipated Primary Completion DateSeptember 1, 2021
Primary Outcome Measures

The predictive performance of microdosing to predict full dose pharmacokinetics [Time Frame: 3 months]

The predictive performance of microdosing to predict full dose pharmacokinetics [Time Frame: 3 months]

Exposure (AUC) after microdose [Time Frame: 1 day]

Descriptive Information
PhasePhase 4
Study TypeInterventional
Condition
  • Non Small Cell Lung Cancer
  • Mesothelioma
Intervention
  • Drug: Pemetrexed
Study Arms / Comparison Groups1 / 0
Recruitment Information
Recruitment StatusRecruiting
Anticipated Enrollment10
GenderAll
Ages18 Years - N/A
Accepts Healthy VolunteersNo
Contact Rob ter Heine, PhD
Email: R.terHeine@radboudumc.nl
Phone: +31 (0)24 361 7744
Eligibility Criteria

Inclusion Criteria:

1. ≥18 years old

2. Planned for treatment with pemetrexed-based chemotherapy in IMPROVE-I or -II.

3. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2

4. Subject is able and willing to sign the Informed Consent Form

Exclusion Criteria:

1. Conditions that affect haemostasis in a way that blood drawing is complicated (to be assessed by physician)

2. Contraindications for treatment with pemetrexed in line with the summary of product characteristics (SmPC) (except for creatinine clearance <45 ml/min in IMPROVE-I)

1. Hypersensitivity to the active substance or to any of the excipients

2. Pregnancy or lactation

3. Concomitant yellow fever vaccine

3. The presence of clinically relevant pharmacokinetic interactions, according to the current SmPC

Administrative Information
NCTIDNCT03655834
Responsible PartySponsor
SponsorRadboud University
Verification DateJanuary 2019
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