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

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ClinicalTrials.gov Identifier: NCT03656549
Recruitment Status : Recruiting
First Posted : September 4, 2018
Last Update Posted : July 13, 2020
Sponsor:
Collaborator:
ZonMw: The Netherlands Organisation for Health Research and Development
Information provided by (Responsible Party):
Radboud University

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-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


Condition or disease Intervention/treatment Phase
Non Small Cell Lung Cancer Mesothelioma Drug: Pemetrexed Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group 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 : October 1, 2021
Estimated Study Completion Date : October 1, 2021


Arm Intervention/treatment
Experimental: Impaired renal function
patients will be treated with pemetrexed, with dosing based on renal function.
Drug: Pemetrexed
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.




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

  2. The fraction of patients with attainment of therapeutic exposure. [ Time Frame: 3 months ]
    The fraction (percentage) of patients with attainment of therapeutic exposure, after the second dose, defined as an AUC of 164 mg*h/l ±25%.


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: 3 months ]
    L

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

  5. Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (model fit) [ 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 pemetrexed dosing in patients with a creatinine clearance <45ml/min. [ 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 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

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): NCT03656549


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 Not yet 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 Not yet 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
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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03656549    
Other Study ID Numbers: IMPROVE-I
First Posted: September 4, 2018    Key Record Dates
Last Update Posted: July 13, 2020
Last Verified: July 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