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

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ClinicalTrials.gov Identifier: NCT03655834
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : March 1, 2019
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Radboud University

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
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
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : September 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Mesothelioma

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




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



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03655834


Contacts
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Contact: Rob ter Heine, PhD +31 (0)24 361 7744 R.terHeine@radboudumc.nl
Contact: Nikki de Rouw, MSc +31 (0)24 361 7744 R.terHeine@radboudmc.nl

Locations
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Netherlands
Jeroen Bosch Hospital Not yet recruiting
's-Hertogenbosch, Netherlands
Contact: Bonne Biesma       b.biesma@jbz.nl   
Principal Investigator: Bonne Biesma         
Sub-Investigator: Jeroen Derijks         
Antoni van Leeuwenhoek Recruiting
Amsterdam, Netherlands
Contact: Sjaak Burgers       s.burgers@nki.nl   
Principal Investigator: Sjaak Burgers         
Sub-Investigator: Alwin Huitema         
Maastricht University Medical centre Not yet recruiting
Maastricht, Netherlands
Contact: Anne-Marie Dingemans       a.dingemans@mumc.nl   
Principal Investigator: Anne-Marie Dingemans         
Radboud university medical centre Not yet recruiting
Nijmegen, Netherlands
Contact: Rob ter Heine       R.terHeine@radboudumc.nl   
Principal Investigator: Rob ter Heine         
Sub-Investigator: Nikki de Rouw         
Sub-Investigator: Michel van den Heuvel         
Erasmus University Medical Centre Not yet recruiting
Rotterdam, Netherlands
Contact: Joachim Aerts       j.aerts@erasmusmc.nl   
Principal Investigator: Joachim Aerts         
Sub-Investigator: Ron Mathijsen         
Sponsors and Collaborators
Radboud University
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
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Principal Investigator: Rob ter Heine, PhD Radboud University

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03655834     History of Changes
Other Study ID Numbers: IMPROVE-III
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: March 1, 2019
Last Verified: January 2019

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

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Mesothelioma
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
Pemetrexed
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors