Dose Individualization of Pemetrexed - IMPROVE-I (IMPROVE-I)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03656549|
Recruitment Status : Recruiting
First Posted : September 4, 2018
Last Update Posted : July 13, 2020
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-I is a single arm phase II pharmacokinetic safety study using a Simon two stage design to assess the feasibility of renal function-based dosing of pemetrexed in renal impaired patients.
Study population: IMPROVE-I includes 23 patients with NSCLC or mesothelioma with an estimated creatinine clearance <45ml/min that meet all other requirements for pemetrexed treatment.
Intervention:Patients will be treated with pemetrexed, with dosing based on renal function. As a safety measure, the first dose will be calculated to 50% exposure. After administration, safety and pharmacokinetics are assessed. If tolerated well, dose escalation to reach 100% exposure is performed, including assessment of safety and pharmacokinetics.
Main study endpoints: The fraction (percentage) of patients with attainment of therapeutic exposure.
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 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||23 participants|
|Intervention Model:||Single Group 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 :||October 1, 2021|
|Estimated Study Completion Date :||October 1, 2021|
Experimental: Impaired renal function
patients will be treated with pemetrexed, with dosing based on renal function.
patients will be treated with pemetrexed, with dosing based on renal function. As a safety measure, the first dose will be calculated to 50% exposure. After administration, safety and pharmacokinetics are assessed. If tolerated well, dose escalation to reach 100% exposure is performed, including assessment of safety and pharmacokinetics.
- Exposure (AUC) [ Time Frame: 24 hours ]mg*h/l
- The fraction of patients with attainment of therapeutic exposure. [ Time Frame: 3 months ]The fraction (percentage) of patients with attainment of therapeutic exposure, after the second dose, defined as an AUC of 164 mg*h/l ±25%.
- 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: 3 months ]L
- Population Peripheral Volume of Distribution (V2) [ Time Frame: 3 months ]L
- Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (model fit) [ 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 pemetrexed dosing in patients with a creatinine clearance <45ml/min. [ 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
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): NCT03656549
|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|