Dose Individualization of Pemetrexed - IMPROVE-I (IMPROVE-I)

• ClinicalTrials.gov Identifier: NCT03656549
• Recruitment Status: Recruiting
• First Posted: September 4, 2018
• Last Update Posted: July 13, 2020
• Sponsor: Radboud University
• Collaborator: ZonMw: The Netherlands Organisation for Health Research and Development
• Information provided by (Responsible Party): Radboud University

Study Description

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

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer; Mesothelioma	Drug: Pemetrexed	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Individualized Pemetrexed Dosing in Patients With Non-small Cell Lung Cancer or Mesothelioma Based on Renal Function to Improve Treatment Response
• Actual Study Start Date: February 1, 2019
• Estimated Primary Completion Date: October 1, 2021
• Estimated Study Completion Date: October 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Impaired renal function; patients will be treated with pemetrexed, with dosing based on renal function.	Drug: Pemetrexed; 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.

Outcome Measures

Primary Outcome Measures :

1. Exposure (AUC) [ Time Frame: 24 hours ]
   mg*h/l
2. The fraction of patients with attainment of therapeutic exposure. [ Time Frame: 3 months ]
   The fraction (percentage) of patients with attainment of therapeutic exposure, after the second dose, defined as an AUC of 164 mg*h/l ±25%.

Secondary Outcome Measures :

1. Population Clearance (Cl) [ Time Frame: 3 months ]
   L/h.
2. Population Intercompartmental Clearance (Q) [ Time Frame: 3 months ]
   L/h
3. Population Central Volume of Distribution (V1) [ Time Frame: 3 months ]
   L
4. Population Peripheral Volume of Distribution (V2) [ Time Frame: 3 months ]
   L
5. Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (model fit) [ Time Frame: 3 months ]
   Significant change in objective function value (OFV) (<3.84 with 1 degree of freedom)
6. Performance of different renal function algorithms to predict pemetrexed pharmacokinetics (decrease in variability) [ Time Frame: 3 months ]
   Decrease in clearance variablity (%)
7. Hematologic assessment during pemetrexed dosing in patients with a creatinine clearance <45ml/min. [ Time Frame: 5 days ]
   Complete blood count (no per liter)
8. The incidence of hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4' [ Time Frame: 3 months ]
   through listing
9. The incidence of non-hematologic dose limiting toxicities (DLT) and adverse events, as measured with the CTCAE V4 [ Time Frame: 3 months ]
   through listing
10. The incidence of toxicity-related dose reductions, treatment delays and treatment discontinuation [ Time Frame: 3 months ]
    through listing
11. Quality of life measured with the EORTC QLQ-C30/L13 questionnaire [ Time Frame: 3 months ]
    0-100 scale

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

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

Locations

Netherlands

Jeroen Bosch Hospital; Not yet recruiting

's-Hertogenbosch, Netherlands

Contact: Bonne Biesma b.biesma@jbz.nl

Principal Investigator: Bonne Biesma

Sub-Investigator: Jeroen Derijks

Antoni van Leeuwenhoek; Recruiting

Amsterdam, Netherlands

Contact: Sjaak Burgers s.burgers@nki.nl

Principal Investigator: Sjaak Burgers

Sub-Investigator: Alwin Huitema

Maastricht University Medical centre; Recruiting

Maastricht, Netherlands

Contact: Anne-Marie Dingemans a.dingemans@mumc.nl

Principal Investigator: Anne-Marie Dingemans

Radboud university medical centre; Recruiting

Nijmegen, Netherlands

Contact: Rob ter Heine R.terHeine@radboudumc.nl

Principal Investigator: Rob ter Heine

Sub-Investigator: Nikki de Rouw

Sub-Investigator: Michel van den Heuvel

Erasmus University Medical Centre; Not yet recruiting

Rotterdam, Netherlands

Contact: Joachim Aerts j.aerts@erasmusmc.nl

Principal Investigator: Joachim Aerts

Sub-Investigator: Ron Mathijsen

Sponsors and Collaborators

Radboud University

ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

• Principal Investigator: Rob ter Heine, PhD; Radboud University

More Information

• Responsible Party: Radboud University
• ClinicalTrials.gov Identifier: NCT03656549
• Other Study ID Numbers: IMPROVE-I
• First Posted: September 4, 2018
• Last Update Posted: July 13, 2020
• Last Verified: July 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Mesothelioma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial; Pemetrexed; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors