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Dose Individualization of Pemetrexed - IMPROVE-II

Brief Summary

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.

Tracking Information
First Received DateMay 14, 2018
Last Changed DateFebruary 27, 2019
Start DateFebruary 1, 2019
Anticipated Primary Completion DateSeptember 1, 2021
Primary Outcome Measures

Exposure (AUC) [Time Frame: 24 hours]

The fraction (percentage) of patients with attainment of therapeutic exposure with BSA-based dosing versus renal function-based dosing. [Time Frame: 3 months]

Secondary Outcome Measures

Population Clearance (Cl) [Time Frame: 3 months]

Population Intercompartmental Clearance (Q) [Time Frame: 3 months]

Population Central Volume of Distribution (V1) [Time Frame: 24 hours]

Population Peripheral Volume of Distribution (V2) [Time Frame: 3 months]

Performance of different renal function algorithms to predict pemetrexed [Time Frame: 3 months]

Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability) [Time Frame: 3 months]

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]

The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4' [Time Frame: 3 months]

The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4 [Time Frame: 3 months]

The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation [Time Frame: 3 months]

Quality of life measured with the EORTC QLQ-C30/L13 questionnaire [Time Frame: 3 months]

In silico evaluation of neutropenic response [Time Frame: 1 year]

Neutropenia related costs [Time Frame: 1 year]

Descriptive Information
PhasePhase 4
Study TypeInterventional
Condition
  • Non Small Cell Lung Cancer
  • Mesothelioma
Intervention
  • Drug: Pemetrexed
Study Arms / Comparison Groups2 / 0
Recruitment Information
Recruitment StatusRecruiting
Anticipated Enrollment94
GenderAll
Ages18 Years - N/A
Accepts Healthy VolunteersNo
Contact Rob ter Heine, PhD
Email: R.terHeine@radboudumc.nl
Phone: +31 (0)24 361 7744
Eligibility Criteria

Inclusion Criteria:

1. ≥18 years old

2. Eligible for treatment with pemetrexed-based chemotherapy

3. 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

Administrative Information
NCTIDNCT03655821
Responsible PartySponsor
SponsorRadboud University
Verification DateJanuary 2019
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