Clinical trial NCT03655834: Dose Individualization of Pemetrexed - 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Non Small Cell Lung Cancer
Mesothelioma
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2018-08-31
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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


Eligibility 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

Primary outcomes:
measure: The predictive performance of microdosing to predict full dose pharmacokinetics
timeFrame: 3 months
measure: The predictive performance of microdosing to predict full dose pharmacokinetics
timeFrame: 3 months
measure: Exposure (AUC) after microdose
timeFrame: 1 day
Secondary outcomes:
Other outcomes:
Locations:
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Hospital
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek
city: Maastricht
country: Netherlands
facility: Maastricht University Medical centre
city: Nijmegen
country: Netherlands
facility: Radboud university medical centre
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Centre
Study officials:
affiliation: Radboud University Medical Center
name: Rob ter Heine, PhD
role: PRINCIPAL_INVESTIGATOR
References: