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

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ClinicalTrials.gov Identifier: NCT03655821
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : September 11, 2020
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Radboud University

Study Description
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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.


Condition or disease Intervention/treatment Phase
Non Small Cell Lung Cancer Mesothelioma Drug: Pemetrexed Phase 4

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 94 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Individualized Pemetrexed Dosing in Patients With Non-small Cell Lung Cancer or Mesothelioma Based on Renal Function to Improve Treatment Response
Actual Study Start Date : February 1, 2019
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : September 1, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Exposure (AUC) [ Time Frame: 24 hours ]
    mg*h/l

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


Secondary Outcome Measures :
  1. Population Clearance (Cl) [ Time Frame: 3 months ]
    L/h

  2. Population Intercompartmental Clearance (Q) [ Time Frame: 3 months ]
    L/h

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

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

  5. Performance of different renal function algorithms to predict pemetrexed [ Time Frame: 3 months ]
    Significant change in objective function value (OFV) (<3.84 with 1 degree of freedom)

  6. Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability) [ Time Frame: 3 months ]
    Decrease in clearance variablity (%)

  7. 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 ]
    Complete blood count (no per liter)

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

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

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

  11. Quality of life measured with the EORTC QLQ-C30/L13 questionnaire [ Time Frame: 3 months ]
    0-100 scale

  12. In silico evaluation of neutropenic response [ Time Frame: 1 year ]
    Simulation of risk for neutropenic response

  13. Neutropenia related costs [ Time Frame: 1 year ]
    Euros


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03655821


Contacts
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Contact: Rob ter Heine, PhD +31 (0)24 361 7744 R.terHeine@radboudumc.nl
Contact: Nikki de Rouw, MSc +31 (0)24 361 7744 Nikki.deRouw@radboudumc.nl

Locations
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Netherlands
Jeroen Bosch Hospital Recruiting
's-Hertogenbosch, Netherlands
Contact: Bonne Biesma       b.biesma@jbz.nl   
Principal Investigator: Bonne Biesma         
Sub-Investigator: Jeroen Derijks         
Antoni van Leeuwenhoek Recruiting
Amsterdam, Netherlands
Contact: Sjaak Burgers       s.burgers@nki.nl   
Principal Investigator: Sjaak Burgers         
Sub-Investigator: Alwin Huitema         
Maastricht University Medical centre Recruiting
Maastricht, Netherlands
Contact: Anne-Marie Dingemans       a.dingemans@mumc.nl   
Principal Investigator: Anne-Marie Dingemans         
Radboud university medical centre Recruiting
Nijmegen, Netherlands
Contact: Rob ter Heine       R.terHeine@radboudumc.nl   
Principal Investigator: Rob ter Heine         
Sub-Investigator: Nikki de Rouw         
Sub-Investigator: Michel van den Heuvel         
Erasmus University Medical Centre Recruiting
Rotterdam, Netherlands
Contact: Joachim Aerts       j.aerts@erasmusmc.nl   
Principal Investigator: Joachim Aerts         
Sub-Investigator: Ron Mathijsen         
Sponsors and Collaborators
Radboud University
ZonMw: The Netherlands Organisation for Health Research and Development
Investigators
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Principal Investigator: Rob ter Heine, PhD Radboud University
More Information
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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03655821    
Other Study ID Numbers: IMPROVE-II
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: September 11, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Mesothelioma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
 Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Mesothelial
Pemetrexed
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors