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

• ClinicalTrials.gov Identifier: NCT03655834
• Recruitment Status: Completed
• First Posted: August 31, 2018
• Last Update Posted: May 10, 2022
• Sponsor: Radboud University Medical Center
• Collaborator: ZonMw: The Netherlands Organisation for Health Research and Development
• Information provided by (Responsible Party): Radboud University Medical Center

Study Description

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

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer; Mesothelioma	Drug: Pemetrexed	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Individualized Pemetrexed Dosing in Patients With Non-small Cell Lung Cancer or Mesothelioma Based on Renal Function to Improve Treatment Response
• Actual Study Start Date: February 1, 2019
• Actual Primary Completion Date: September 20, 2020
• Actual Study Completion Date: August 1, 2021

Arms and Interventions

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 Name: Microdosing

Outcome Measures

Primary Outcome Measures :

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

Eligibility Criteria

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

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

Contacts and Locations

Locations

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, Netherlands

Sponsors and Collaborators

Radboud University Medical Center

ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

• Principal Investigator: Rob ter Heine, PhD; Radboud University Medical Center

More Information

• Responsible Party: Radboud University Medical Center
• ClinicalTrials.gov Identifier: NCT03655834
• Other Study ID Numbers: IMPROVE-III
• First Posted: August 31, 2018
• Last Update Posted: May 10, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Mesothelioma; Mesothelioma, Malignant; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial; Pleural Neoplasms; Pemetrexed; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors