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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

Tracking Information
First Submitted Date  ICMJE May 14, 2018
First Posted Date  ICMJE August 31, 2018
Last Update Posted Date September 11, 2020
Actual Study Start Date  ICMJE February 1, 2019
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 30, 2018)
  • Exposure (AUC) [ Time Frame: 24 hours ]
    mg*h/l
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 30, 2018)
  • Population Clearance (Cl) [ Time Frame: 3 months ]
    L/h
  • Population Intercompartmental Clearance (Q) [ Time Frame: 3 months ]
    L/h
  • Population Central Volume of Distribution (V1) [ Time Frame: 24 hours ]
    L
  • Population Peripheral Volume of Distribution (V2) [ Time Frame: 3 months ]
    L
  • 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)
  • Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability) [ Time Frame: 3 months ]
    Decrease in clearance variablity (%)
  • 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)
  • The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4' [ Time Frame: 3 months ]
    through listing
  • The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4 [ Time Frame: 3 months ]
    through listing
  • The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation [ Time Frame: 3 months ]
    through listing
  • Quality of life measured with the EORTC QLQ-C30/L13 questionnaire [ Time Frame: 3 months ]
    0-100 scale
  • In silico evaluation of neutropenic response [ Time Frame: 1 year ]
    Simulation of risk for neutropenic response
  • Neutropenia related costs [ Time Frame: 1 year ]
    Euros
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Individualization of Pemetrexed - IMPROVE-II
Official Title  ICMJE Individualized Pemetrexed Dosing in Patients With Non-small Cell Lung Cancer or Mesothelioma Based on Renal Function to Improve Treatment Response
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Non Small Cell Lung Cancer
  • Mesothelioma
Intervention  ICMJE Drug: Pemetrexed
Dosing is either based on BSA or renal function
Study Arms  ICMJE
  • Active Comparator: Arm A (BSA-based dosing)
    Dosing of pemetrexed is based on BSA according drug label
    Intervention: Drug: Pemetrexed
  • Experimental: Arm B (renal function based dosing)
    Dosing of pemetrexed is based on renal function, calculated to reach the target AUC.
    Intervention: Drug: Pemetrexed
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 30, 2018)
94
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2021
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03655821
Other Study ID Numbers  ICMJE IMPROVE-II
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Radboud University
Study Sponsor  ICMJE Radboud University
Collaborators  ICMJE ZonMw: The Netherlands Organisation for Health Research and Development
Investigators  ICMJE
Principal Investigator: Rob ter Heine, PhD Radboud University
PRS Account Radboud University
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP