Dose Individualization of Pemetrexed - IMPROVE-III

Phase 4

Completed

• Conditions: Non Small Cell Lung Cancer; Mesothelioma
• Interventions: Drug: Pemetrexed

• Registration Number: NCT03655834
• Lead Sponsor: Radboud University Medical Center

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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-05-14
• Study First Submitted QC: 2018-08-30
• Study First Posted: 2018-08-31
• Study Start: 2019-02-01
• Primary Completion: 2020-09-20
• Study Completion: 2021-08-01
• Status Verified: 2022-05
• Last Update Submitted: 2022-05-09
• Last Update Posted: 2022-05-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Microdosing	Pemetrexed	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

Primary Outcome Measures

Name	Time	Method
Exposure (AUC) after microdose	1 day	mg\*h/l
The predictive performance of microdosing to predict full dose pharmacokinetics	3 months	Root mean squared relative prediction error (RMSE)

Trial Locations

Locations (5)

Antoni van Leeuwenhoek; 🇳🇱 Amsterdam, Netherlands

Maastricht University Medical centre; 🇳🇱 Maastricht, Netherlands

Radboud university medical centre; 🇳🇱 Nijmegen, Netherlands

Jeroen Bosch Hospital; 🇳🇱 's-Hertogenbosch, Netherlands

Erasmus University Medical Centre; 🇳🇱 Rotterdam, Netherlands