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.
Phase:
Phase 4
Details
Lead Sponsor:
Radboud University
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development