Dose Individualization of Pemetrexed - IMPROVE-II (IMPROVE-II)
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|ClinicalTrials.gov Identifier: NCT03655821|
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : April 30, 2019
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:
- In patients with renal dysfunction, BSA-based dosing may lead to haematological toxicity
- Patients have to discontinue treatment due to declining renal function, and are withheld effective treatment
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Non Small Cell Lung Cancer Mesothelioma||Drug: Pemetrexed||Phase 4|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||94 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|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|
Active Comparator: Arm A (BSA-based dosing)
Dosing of pemetrexed is based on BSA according drug label
Dosing is either based on BSA or renal function
Experimental: Arm B (renal function based dosing)
Dosing of pemetrexed is based on renal function, calculated to reach the target AUC.
Dosing is either based on BSA or renal function
- Exposure (AUC) [ Time Frame: 24 hours ]mg*h/l
- The fraction (percentage) of patients with attainment of therapeutic exposure with BSA-based dosing versus renal function-based dosing. [ Time Frame: 3 months ]The fraction (percentage) of patients with attainment of therapeutic exposure defined as an AUC of 164 mg*h/l ±25%, with pemetrexed dosing based on renal function versus BSA-based dosing.
- Population Clearance (Cl) [ Time Frame: 3 months ]L/h
- Population Intercompartmental Clearance (Q) [ Time Frame: 3 months ]L/h
- Population Central Volume of Distribution (V1) [ Time Frame: 24 hours ]L
- Population Peripheral Volume of Distribution (V2) [ Time Frame: 3 months ]L
- Performance of different renal function algorithms to predict pemetrexed [ Time Frame: 3 months ]Significant change in objective function value (OFV) (<3.84 with 1 degree of freedom)
- Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability) [ Time Frame: 3 months ]Decrease in clearance variablity (%)
- Hematologic assessment during dosing based on renal function in patients with a creatinine clearance >45ml/min versus dosing based on BSA. [ Time Frame: 5 days ]Complete blood count (no per liter)
- The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4' [ Time Frame: 3 months ]through listing
- The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4 [ Time Frame: 3 months ]through listing
- The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation [ Time Frame: 3 months ]through listing
- Quality of life measured with the EORTC QLQ-C30/L13 questionnaire [ Time Frame: 3 months ]0-100 scale
- In silico evaluation of neutropenic response [ Time Frame: 1 year ]Simulation of risk for neutropenic response
- Neutropenia related costs [ Time Frame: 1 year ]Euros
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03655821
|Contact: Rob ter Heine, PhD||+31 (0)24 361 7744||R.terHeine@radboudumc.nl|
|Contact: Nikki de Rouw, MSc||+31 (0)24 361 7744||Nikki.deRouw@radboudumc.nl|
|Jeroen Bosch Hospital||Not yet recruiting|
|Contact: Bonne Biesma email@example.com|
|Principal Investigator: Bonne Biesma|
|Sub-Investigator: Jeroen Derijks|
|Antoni van Leeuwenhoek||Recruiting|
|Contact: Sjaak Burgers firstname.lastname@example.org|
|Principal Investigator: Sjaak Burgers|
|Sub-Investigator: Alwin Huitema|
|Maastricht University Medical centre||Recruiting|
|Contact: Anne-Marie Dingemans email@example.com|
|Principal Investigator: Anne-Marie Dingemans|
|Radboud university medical centre||Recruiting|
|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|
|Contact: Joachim Aerts firstname.lastname@example.org|
|Principal Investigator: Joachim Aerts|
|Sub-Investigator: Ron Mathijsen|
|Principal Investigator:||Rob ter Heine, PhD||Radboud University|