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Non Small Cell Lung CancerPhase 4IMPROVE-INCT03656549

Dose Individualization of Pemetrexed - IMPROVE-I

A Phase 4 study testing Pemetrexed + oral folinic acid rescue in people with Non Small Cell Lung Cancer and Mesothelioma, run by Radboud University Medical Center at 6 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

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 + oral folinic acid rescue
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6 participants
Where
6 sitesNetherlands
Study dates
1 Feb 2019to 29 Dec 2023
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 based on indication
  • Estimated 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

6 sites in 1 country.

6 sites in 1 country

Netherlands6 sites

  • Jeroen Bosch Hospital

    's-Hertogenbosch

  • Antoni van Leeuwenhoek

    Amsterdam

  • Catharina hospital

    Eindhoven

  • 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 these 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

Objective:

The main objective is to develop a safe dosing regimen for pemetrexed in patients with renal impairment.

Study design:

IMPROVE-I is a single arm dose finding study to assess the feasibility of renal function-based dosing of pemetrexed in combination with folinic acid or folinic acid and pegfilgrastim in renally impaired patients.

Study population:

IMPROVE-I includes a maximum of twelve evaluable patients with NSCLC or mesothelioma with a renal function <45ml/min that meet all other requirements for pemetrexed treatment.

Intervention:

IMPROVE-I: patients who have an indication for treatment with pemetrexed, but who have an impaired renal function will be treated with pemetrexed in combination with folinic acid rescue therapy. Dosing of pemetrexed will be based on renal function to reach the target AUC. As a safety measure a minimum of 4 intra-patient dose escalations in the first patient will be performed starting from 10% of the target AUC. A standard 3+3 study design is used. If folinic acid is not sufficient to prevent haematotoxicity, prophylactic treatment with pegfilgrastim will be added to the combination therapy.

Main study endpoints:

IMPROVE-I: The fraction of patients safely reaching the target dose.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

We 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, we will use a limited sampling strategy. Patients may benefit from participating in IMPROVE I, as they will be treated with a potentially safe and effective drug that is dosed individually, which prevents toxic exposure.

Being tested
Pemetrexed + oral folinic acid rescue
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.

  • Pemetrexed + oral folinic acid rescueDrug

    3+3 dose escalation study of pemetrexed in patients with impaired renal function in combination with roal folinic acid rescue

Study groups in NCT03656549
Study groupRoleWhat they receive
Impaired renal functionExperimentalpatients will be treated with pemetrexed, with dosing based on renal function in combination with oral folinic acid rescue
Receives: Drug: Pemetrexed + oral folinic acid rescue

What is being measured

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

  1. The fraction of patients safely reaching the target dose in combination with folinic acid or folinic acid and G-CSF, with the target dose being the dose most likely to result in an AUC of 164 mg*h/L.

    Measured: 3 months

Secondary outcomes (5)

  1. The AUC of pemetrexed for each patient at 100% dose

    mg*h/L

    Measured: 3 months

  2. Complete blood count prior to start of every cycle and on day 7 and 14 after administration

    Measured: From start of treatment to the last day of the 4th cycle of chemotherapy

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

    through listing

    Measured: 3 months

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

    through listing

    Measured: 3 months

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

    through listing

    Measured: 3 months

Timeline

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

  1. First posted4 Sep 2018
  2. Study start1 Feb 2019
  3. Primary completion1 Dec 2023
  4. Study completion29 Dec 2023

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
Not applicable
Intervention model
Single group
Model description
Dose escalation study
Masking
None (open label)
Enrolment
6 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03656549
Sponsor's protocol ID
IMPROVE-I
Acronym
IMPROVE-I
Status last verified
Dec 2023
First submitted
14 May 2018
Last updated
17 Dec 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • de Rouw N, Otten LS, Kicken MP, Piet B, Biesma B, van Veggel B, Steendam CMJ, van den Borne B, Hendriks LEL, Croes S, Dingemans AC, Dumoulin DW, Mathijssen RHJ, Burgers JA, Huitema ADR, Derijks HJ, Deenen MJ, van den Heuvel MM, Ter Heine R. Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment. Clin Pharmacol Ther. 2025 Sep;118(3):715-722. doi: 10.1002/cpt.3735. Epub 2025 May 27.

    PubMed 40421804

  • 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

  • Boosman RJ, Dorlo TPC, de Rouw N, Burgers JA, Dingemans AC, van den Heuvel MM, Hendriks LEL, Biesma B, Aerts JGJV, Croes S, Mathijssen RHJ, Huitema ADR, Ter Heine R. Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment. Int J Cancer. 2021 Oct 15;149(8):1576-1584. doi: 10.1002/ijc.33721. Epub 2021 Jul 7.

    PubMed 34181276

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Pemetrexed + oral folinic acid rescue in people with Non Small Cell Lung Cancer and Mesothelioma, run by Radboud University Medical Center at 6 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: finished, as of the sponsor's last update on 17 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

The fraction of patients safely reaching the target dose in combination with folinic acid or folinic acid and G-CSF, with the target dose being the dose most likely to result in an AUC of 164 mg*h/L. (time frame: 3 months). 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 NCT03656549, 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 17 Dec 2024.

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