Dose Individualization of Pemetrexed - IMPROVE-III

NCT03655834 | Completed Phase 4

• 1 other identifier: IMPROVE-III
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 5

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. 1.In patients with renal dysfunction, BSA-based dosing may lead to haematological toxicity
2. 2.Patients have to discontinue treatment due to declining renal function, and are withheld effective treatment
3. 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.

Conditions

Non Small Cell Lung Cancer; Mesothelioma

Outcome Measures

Primary Outcomes (3)

• 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

Study Arms (1)

Microdosing

EXPERIMENTAL

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

Interventions

Pemetrexed DRUG

patients will be administered a microdose with subsequent pharmacokinetic assessment.

Also known as: Microdosing

Microdosing

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥18 years old
• Planned for treatment with pemetrexed-based chemotherapy in IMPROVE-I or -II.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
• Subject is able and willing to sign the Informed Consent Form

You may not qualify if:

• Conditions that affect haemostasis in a way that blood drawing is complicated (to be assessed by physician)
• Contraindications for treatment with pemetrexed in line with the summary of product characteristics (SmPC) (except for creatinine clearance \<45 ml/min in IMPROVE-I)
• Hypersensitivity to the active substance or to any of the excipients
• Pregnancy or lactation
• Concomitant yellow fever vaccine
• The presence of clinically relevant pharmacokinetic interactions, according to the current SmPC

Sponsors & Collaborators

• Radboud University Medical Center: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (5)

Jeroen Bosch Hospital

's-Hertogenbosch, Netherlands

Location

Antoni van Leeuwenhoek

Amsterdam, Netherlands

Location

Maastricht University Medical centre

Maastricht, Netherlands

Location

Radboud university medical centre

Nijmegen, Netherlands

Location

Erasmus University Medical Centre

Rotterdam, Netherlands

Location

Related Publications (1)

• Boosman RJ, de Rouw N, Huitema ADR, Burgers JA, Ter Heine R. Prediction of the pharmacokinetics of pemetrexed with a low test dose: A proof-of-concept study. Br J Clin Pharmacol. 2023 Feb;89(2):699-704. doi: 10.1111/bcp.15520. Epub 2022 Sep 21.

  PMID: 36053283 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Mesothelioma

Interventions

Pemetrexed; Clinical Trials, Phase I as Topic

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Clinical Trials as Topic; Clinical Studies as Topic; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Public Health; Environment and Public Health

Study Officials

• Rob ter Heine, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2018
• First Posted: August 31, 2018
• Study Start: February 1, 2019
• Primary Completion: September 20, 2020
• Study Completion: August 1, 2021
• Last Updated: May 10, 2022

Record last verified: 2022-05

Locations

NL (5)