Dose Individualization of Pemetrexed - IMPROVE-I

Phase 4

Completed

• Conditions: Non Small Cell Lung Cancer; Mesothelioma
• Interventions: Drug: Pemetrexed + oral folinic acid rescue

• Registration Number: NCT03656549
• Lead Sponsor: Radboud University Medical Center

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 these 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

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-05-14
• Study First Submitted QC: 2018-08-31
• Study First Posted: 2018-09-04
• Study Start: 2019-02-01
• Status Verified: 2023-12
• Primary Completion: 2023-12-01
• Study Completion: 2023-12-29
• Last Update Submitted: 2024-12-11
• Last Update Posted: 2024-12-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 6

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Impaired renal function	Pemetrexed + oral folinic acid rescue	patients will be treated with pemetrexed, with dosing based on renal function in combination with oral folinic acid rescue

Primary Outcome Measures

Name	Time	Method
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.	3 months

Secondary Outcome Measures

Name	Time	Method
The AUC of pemetrexed for each patient at 100% dose	3 months	mg\*h/L
Complete blood count prior to start of every cycle and on day 7 and 14 after administration	From start of treatment to the last day of the 4th cycle of chemotherapy
The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4'	3 months	through listing
The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4	3 months	through listing
The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation	3 months	through listing

Trial Locations

Locations (6)

Catharina hospital; 🇳🇱 Eindhoven, Netherlands

Jeroen Bosch Hospital; 🇳🇱 's-Hertogenbosch, Netherlands

Antoni van Leeuwenhoek; 🇳🇱 Amsterdam, Netherlands

Maastricht University Medical centre; 🇳🇱 Maastricht, Netherlands

Radboud university medical centre; 🇳🇱 Nijmegen, Netherlands

Erasmus University Medical Centre; 🇳🇱 Rotterdam, Netherlands