Dose Individualization of Pemetrexed – IMPROVE-I

Brief Title

Dose Individualization of Pemetrexed - IMPROVE-I

Official Title

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-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
    

Study Phase

Phase 2

Study Type

Interventional

Primary Outcome

Exposure (AUC)

Secondary Outcome

 Population Clearance (Cl)

Condition

Non Small Cell Lung Cancer

Intervention

Pemetrexed

Study Arms / Comparison Groups

 Impaired renal function

Description:  patients will be treated with pemetrexed, with dosing based on renal function.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

23

Start Date

February 1, 2019

Completion Date

October 1, 2021

Primary Completion Date

October 1, 2021

Eligibility 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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Rob ter Heine, PhD, +31 (0)24 361 7744, [email protected]

Location Countries

Netherlands

Location Countries

Netherlands

NCT ID

NCT03656549

Organization ID

IMPROVE-I

Responsible Party

Sponsor

Study Sponsor

Radboud University

Collaborators

 ZonMw: The Netherlands Organisation for Health Research and Development

Study Sponsor

Rob ter Heine, PhD, Principal Investigator, Radboud University

Verification Date

July 2020