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Non Small Cell Lung CancerPhase 4IMPROVE-IINCT03655821

Dose Individualization of Pemetrexed - IMPROVE-II

A Phase 4 study testing Pemetrexed in people with Non Small Cell Lung Cancer and Mesothelioma, run by Radboud University Medical Center at 5 sites in Netherlands.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Non Small Cell Lung Cancer, Mesothelioma
What is being tested?
Pemetrexed
Could I receive a placebo?
No, everyone receives an active treatment
How many people
81 participants
Where
5 sitesNetherlands
Study dates
1 Feb 2019to 11 May 2021
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥18 years old
  • Eligible for treatment with pemetrexed-based chemotherapy
  • Creatinine clearance >45ml/min
  • Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
  • Subject is able and willing to sign the Informed Consent Form

Who cannot join

  • Conditions that affect haemostasis in a way that blood drawing is complicated (to be assessed by physician)
  • Contraindications for treatment with pemetrexed in line with the summary of product characteristics (SmPC) (except for creatinine clearance <45 ml/min in IMPROVE-I)
  • Hypersensitivity to the active substance or to any of the excipients
  • Pregnancy or lactation
  • Concomitant yellow fever vaccine
  • The presence of clinically relevant pharmacokinetic interactions, according to the current SmPC

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

Netherlands5 sites

  • Jeroen Bosch Hospital

    's-Hertogenbosch

  • Antoni van Leeuwenhoek

    Amsterdam

  • Maastricht University Medical centre

    Maastricht

  • Radboud university medical centre

    Nijmegen

  • Erasmus University Medical Centre

    Rotterdam

Other trials in Netherlands

About this study

Official title: 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:

Read more
  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.

Being tested
Pemetrexed
Medical subject headings
Carcinoma, Non-Small-Cell Lung, Mesothelioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PemetrexedDrug

    Dosing is either based on BSA or renal function

Study groups in NCT03655821
Study groupRoleWhat they receive
Arm A (BSA-based dosing)Active comparatorDosing of pemetrexed is based on BSA according drug label
Receives: Drug: Pemetrexed
Arm B (renal function based dosing)ExperimentalDosing of pemetrexed is based on renal function, calculated to reach the target AUC.
Receives: Drug: Pemetrexed

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Exposure (AUC)

    mg*h/l

    Measured: 24 hours

  2. 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.

    Measured: 3 months

Secondary outcomes (13)

  1. Population Clearance (Cl)

    L/h

    Measured: 3 months

  2. Population Intercompartmental Clearance (Q)

    L/h

    Measured: 3 months

  3. Population Central Volume of Distribution (V1)

    L

    Measured: 24 hours

  4. Population Peripheral Volume of Distribution (V2)

    L

    Measured: 3 months

  5. Performance of different renal function algorithms to predict pemetrexed

    Significant change in objective function value (OFV) (<3.84 with 1 degree of freedom)

    Measured: 3 months

  6. Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability)

    Decrease in clearance variablity (%)

    Measured: 3 months

  7. 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)

    Measured: 5 days

  8. The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4'

    through listing

    Measured: 3 months

  9. The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4

    through listing

    Measured: 3 months

  10. The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation

    through listing

    Measured: 3 months

  11. Quality of life measured with the EORTC QLQ-C30/L13 questionnaire

    0-100 scale

    Measured: 3 months

  12. In silico evaluation of neutropenic response

    Simulation of risk for neutropenic response

    Measured: 1 year

  13. Neutropenia related costs

    Euros

    Measured: 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Aug 2018
  2. Study start1 Feb 2019
  3. Primary completion11 May 2021
  4. Study completion11 May 2021

Why it stopped: 81 patients included, difficult inclusion and full inclusion would not change the results

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
81 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03655821
Sponsor's protocol ID
IMPROVE-II
Acronym
IMPROVE-II
Status last verified
May 2022
First submitted
14 May 2018
Last updated
13 May 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • de Rouw N, Boosman RJ, Burgers JA, Huitema ADR, Dingemans AC, Derijks HJ, Burger DM, Piet B, Hendriks LEL, Biesma B, Pruis MA, Dumoulin DW, Croes S, Mathijssen RHJ, van den Heuvel MM, Ter Heine R. Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial. Cancer Chemother Pharmacol. 2023 Jan;91(1):33-42. doi: 10.1007/s00280-022-04489-1. Epub 2022 Nov 21.

    PubMed 36413252

  • Boosman RJ, de Rouw N, Huitema ADR, Burgers JA, Ter Heine R. Prediction of the pharmacokinetics of pemetrexed with a low test dose: A proof-of-concept study. Br J Clin Pharmacol. 2023 Feb;89(2):699-704. doi: 10.1111/bcp.15520. Epub 2022 Sep 21.

    PubMed 36053283

  • 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.

    PubMed 35048355

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Pemetrexed in people with Non Small Cell Lung Cancer and Mesothelioma, run by Radboud University Medical Center at 5 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 13 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: 81 patients included, difficult inclusion and full inclusion would not change the results). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Exposure (AUC) (time frame: 24 hours). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03655821, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2022.

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