Dose Individualization of Pemetrexed - IMPROVE-III (IMPROVE-III)

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

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

Study Overview

• Status: Completed
• Conditions: Non Small Cell Lung Cancer; Mesothelioma
• Intervention / Treatment: Drug: Pemetrexed

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Jeroen Bosch Hospital
  • Amsterdam, Netherlands
    • Antoni van Leeuwenhoek
  • Maastricht, Netherlands
    • Maastricht University Medical Centre
  • Nijmegen, Netherlands
    • Radboud university medical centre
  • Rotterdam, Netherlands
    • Erasmus University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Microdosing; 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	Drug: Pemetrexed; patients will be administered a microdose with subsequent pharmacokinetic assessment.; Other Names: Microdosing

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Rob ter Heine, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2019
• Primary Completion (Actual): September 20, 2020
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: May 14, 2018
• First Submitted That Met QC Criteria: August 30, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Actual): May 10, 2022
• Last Update Submitted That Met QC Criteria: May 9, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Mesothelioma; Mesothelioma, Malignant; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Pemetrexed
• Other Study ID Numbers: IMPROVE-III

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No