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-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
Phase:
Phase 2
Details
Lead Sponsor:
Radboud University
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development