Dose Individualization of Pemetrexed - IMPROVE-I

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 these 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

Objective:

The main objective is to develop a safe dosing regimen for pemetrexed in patients with renal impairment.

Study design:

IMPROVE-I is a single arm dose finding study to assess the feasibility of renal function-based dosing of pemetrexed in combination with folinic acid or folinic acid and pegfilgrastim in renally impaired patients.

Study population:

IMPROVE-I includes a maximum of twelve evaluable patients with NSCLC or mesothelioma with a renal function \<45ml/min that meet all other requirements for pemetrexed treatment.

Intervention:

IMPROVE-I: patients who have an indication for treatment with pemetrexed, but who have an impaired renal function will be treated with pemetrexed in combination with folinic acid rescue therapy. Dosing of pemetrexed will be based on renal function to reach the target AUC. As a safety measure a minimum of 4 intra-patient dose escalations in the first patient will be performed starting from 10% of the target AUC. A standard 3+3 study design is used. If folinic acid is not sufficient to prevent haematotoxicity, prophylactic treatment with pegfilgrastim will be added to the combination therapy.

Main study endpoints:

IMPROVE-I: The fraction of patients safely reaching the target dose.

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

We 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, we will use a limited sampling strategy. Patients may benefit from participating in IMPROVE I, 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 based on indication
3. Estimated 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