Dose Individualization of Pemetrexed - IMPROVE-III

Non Small Cell Lung Cancer Clinical Trial

— IMPROVE-III  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03655834
• Other study ID #: IMPROVE-III
• Status: Completed
• Phase: Phase 4
• Start date: February 1, 2019
• Est. completion date: August 1, 2021

Study information

• Verified date: May 2022
• Source: Radboud University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: August 1, 2021
• Est. primary completion date: September 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Mesothelioma
• Mesothelioma, Malignant
• Non Small Cell Lung Cancer

Intervention

Drug:
• Pemetrexed
patients will be administered a microdose with subsequent pharmacokinetic assessment.

Locations

Country	Name	City	State
Netherlands	Jeroen Bosch Hospital	's-Hertogenbosch
Netherlands	Antoni van Leeuwenhoek	Amsterdam
Netherlands	Maastricht University Medical centre	Maastricht
Netherlands	Radboud university medical centre	Nijmegen
Netherlands	Erasmus University Medical Centre	Rotterdam

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University Medical Center	ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The predictive performance of microdosing to predict full dose pharmacokinetics	Mean relative prediction error (MPE)	3 months
Primary	The predictive performance of microdosing to predict full dose pharmacokinetics	Root mean squared relative prediction error (RMSE)	3 months
Primary	Exposure (AUC) after microdose	mg*h/l	1 day