Dose Individualization of Pemetrexed - IMPROVE-II (IMPROVE-II)

Individualized Pemetrexed Dosing in Patients With Non-small Cell Lung Cancer or Mesothelioma Based on Renal Function to Improve Treatment Response

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.

Study Overview

• Status: Terminated
• Conditions: Non Small Cell Lung Cancer; Mesothelioma
• Intervention / Treatment: Drug: Pemetrexed

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Jeroen Bosch Hospital
  • Amsterdam, Netherlands
    • Antoni van Leeuwenhoek
  • Maastricht, Netherlands
    • Maastricht University Medical Centre
  • Nijmegen, Netherlands
    • Radboud university medical centre
  • Rotterdam, Netherlands
    • Erasmus University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A (BSA-based dosing); Dosing of pemetrexed is based on BSA according drug label	Drug: Pemetrexed; Dosing is either based on BSA or renal function
Experimental: Arm B (renal function based dosing); Dosing of pemetrexed is based on renal function, calculated to reach the target AUC.	Drug: Pemetrexed; Dosing is either based on BSA or renal function

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exposure (AUC)	mg*h/l	24 hours
The fraction (percentage) of patients with attainment of therapeutic exposure with BSA-based dosing versus renal function-based dosing.	The fraction (percentage) of patients with attainment of therapeutic exposure defined as an AUC of 164 mg*h/l ±25%, with pemetrexed dosing based on renal function versus BSA-based dosing.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Population Intercompartmental Clearance (Q)	L/h	3 months
Population Peripheral Volume of Distribution (V2)	L	3 months
Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability)	Decrease in clearance variablity (%)	3 months
The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4'	through listing	3 months
The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4	through listing	3 months
The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation	through listing	3 months
Quality of life measured with the EORTC QLQ-C30/L13 questionnaire	0-100 scale	3 months
Population Clearance (Cl)	L/h	3 months
Population Central Volume of Distribution (V1)	L	24 hours
Performance of different renal function algorithms to predict pemetrexed	Significant change in objective function value (OFV) (<3.84 with 1 degree of freedom)	3 months
Hematologic assessment during dosing based on renal function in patients with a creatinine clearance >45ml/min versus dosing based on BSA.	Complete blood count (no per liter)	5 days
In silico evaluation of neutropenic response	Simulation of risk for neutropenic response	1 year
Neutropenia related costs	Euros	1 year

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Rob ter Heine, PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• de Rouw N, de Boer M, Boosman RJ, van den Heuvel MM, Burger DM, Lieverse JE, Derijks HJ, Frederix GWJ, Ter Heine R. The Pharmacoeconomic Benefits of Pemetrexed Dose Individualization in Patients With Lung Cancer. Clin Pharmacol Ther. 2022 May;111(5):1103-1110. doi: 10.1002/cpt.2529. Epub 2022 Feb 21.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2019
• Primary Completion (Actual): May 11, 2021
• Study Completion (Actual): May 11, 2021

Study Registration Dates

• First Submitted: May 14, 2018
• First Submitted That Met QC Criteria: August 30, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Actual): May 13, 2022
• Last Update Submitted That Met QC Criteria: May 9, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Mesothelioma; Mesothelioma, Malignant; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Pemetrexed
• Other Study ID Numbers: IMPROVE-II

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No