Clinical trial NCT03655821: Dose Individualization of Pemetrexed - IMPROVE-II
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: TERMINATED
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: 81
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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-II is an open label, double arm, randomized study to compare renal function-based dosing of pemetrexed versus BSA-based dosing on attainment of therapeutic exposure.

Study population: IMPROVE-II includes 94 patients with NSCLC or mesothelioma that are eligible for pemetrexed treatment.

Intervention: patients will be randomized in a 1:1 ratio to Arm A (BSA-based dosing according drug label) or to Arm B (renal function based dosing). The renal function-based dose will be calculated to reach the target AUC. Pharmacokinetic assessment after administration will be performed after the first pemetrexed dose in both arms.

Main study endpoints: The fraction (percentage) of patients with attainment of therapeutic exposure with BSA-based dosing versus renal function-based dosing.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

The investigators consider the extra burden from participating in the planned studies limited. The extra interventions compared to routine care, consist of sampling extra blood. The pharmacokinetic assessments require placement of one additional intravenous catheter. To ensure minimal impact of study participation on daily life, a limited sampling strategy will be used. Patients may benefit from participating in IMPROVE I and -II, as they will be treated with a potentially safe and effective drug that is dosed individually, which prevents toxic exposure.


Eligibility criteria: Inclusion Criteria:

1. ≥18 years old
2. Eligible for treatment with pemetrexed-based chemotherapy
3. Creatinine clearance \>45ml/min
4. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
5. 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: Exposure (AUC)
timeFrame: 24 hours
measure: The fraction (percentage) of patients with attainment of therapeutic exposure with BSA-based dosing versus renal function-based dosing.
timeFrame: 3 months
Secondary outcomes:
measure: Population Clearance (Cl)
timeFrame: 3 months
measure: Population Intercompartmental Clearance (Q)
timeFrame: 3 months
measure: Population Central Volume of Distribution (V1)
timeFrame: 24 hours
measure: Population Peripheral Volume of Distribution (V2)
timeFrame: 3 months
measure: Performance of different renal function algorithms to predict pemetrexed
timeFrame: 3 months
measure: Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability)
timeFrame: 3 months
measure: Hematologic assessment during dosing based on renal function in patients with a creatinine clearance >45ml/min versus dosing based on BSA.
timeFrame: 5 days
measure: The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4'
timeFrame: 3 months
measure: The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4
timeFrame: 3 months
measure: The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation
timeFrame: 3 months
measure: Quality of life measured with the EORTC QLQ-C30/L13 questionnaire
timeFrame: 3 months
measure: In silico evaluation of neutropenic response
timeFrame: 1 year
measure: Neutropenia related costs
timeFrame: 1 year
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:
citation: de Rouw N, de Boer M, Boosman RJ, van den Heuvel MM, Burger DM, Lieverse JE, Derijks HJ, Frederix GWJ, Ter Heine R. The Pharmacoeconomic Benefits of Pemetrexed Dose Individualization in Patients With Lung Cancer. Clin Pharmacol Ther. 2022 May;111(5):1103-1110. doi: 10.1002/cpt.2529. Epub 2022 Feb 21.