Folinic Acid for Prevention of Pemetrexed-induced Toxicity

Study Overview
=================
Brief Summary
-----------------
Objective The main objective is to evaluate the haematological toxicity in patients who use pemetrexed with and without rescue therapy with folinic acid. Primary endpoint Difference between treatment groups in neutrophil count (*109/L) at day 8-10 after administration of pemetrexed (nadir). Secondary endpoints The grade neutropenia (according to the CTCAE version 5, 2017) at day 8-10, the homocysteine plasma levels at baseline (predictor for developing toxicity), the efficacy of chemotherapy treatment based on response CT after cycle 2 and 4 and the incidence of discontinuation, dose delays and dose reductions of pemetrexed. Trial design The FLEX-trial is a multi-centre, open label, double arm, randomized trial to compare neutropenia in patients with and without folinic acid rescue therapy where subjects are participating for 4 treatment cycles. Population In total 50 patients (25 in each arm), >18 years with stage IV non-small cell lung cancer (NSCLC) or mesothelioma treated with pemetrexed (in combination with other chemo- or immunotherapy) are eligible for inclusion. Interventions Follow-up will take place during the first 4 cycles of chemotherapy with pemetrexed. Patients in the intervention-arm will receive oral folinic acid orally 4 times 45mg / day for 3 days, starting 24 hours after the administration of pemetrexed.

Official Title
-----------------
The Effect of Oral Folinic Acid Rescue Therapy on Pemetrexed Induced Neutropenia: A Randomized Open-label Trial

Conditions
-----------------
NSCLC, Mesothelioma, Thymoma

Intervention / Treatment
-----------------
* Drug: Folinic acid


Participation Criteria
=================
Eligibility Criteria
-----------------
In order to be eligible to participate in this study, a subject must meet all of the following criteria: ≥18 years old Eligible for treatment with pemetrexed-based chemotherapy based on indication. ECOG performance score of 0-2. Subject is able and willing to sign the Informed Consent Form A potential subject who meets any of the following criteria will be excluded from participation in this study: Contraindications for treatment with folinic acid in line with the SmPC. Hypersensitivity to the active substance or to any of the excipients. Anaemia caused by vitamin B12 deficiency. The presence of clinically relevant drug-drug interactions, according to the current SmPC of folinic acid.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Folinic acid arm<br>Patients in the intervention-arm will receive oral folinic acid orally 4 times 45mg / day for 3 days, starting 24 hours after the administration of pemetrexed. | Drug: Folinic acid<br>* Follow-up will take place during the first 4 cycles of chemotherapy with pemetrexed. Patients in the intervention-arm will receive oral folinic acid orally 4 times 45mg / day for 3 days, starting 24 hours after the administration of pemetrexed.<br>|
| No Intervention: No folinic acid arm<br>Patients will be treated according to regular care. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in neutrophil count (*109/L) at day 8-10 after pemetrexed administration during 2 cycles of chemotherapy | To evaluate the haematological toxicity (continuous measure) in patients who use pemetrexed with and without rescue therapy with folinic acid. | Between day 8-10 in the first 2 cycles (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade neutropenia (according to the CTCAE version 5, 2017) at day 8-10 after pemetrexed administration during 2 cycles of chemotherapy | To evaluate the difference in haematological toxicity based on the CTCAE criteria for neutrophil count | Between day 8-10 in the first 2 cycles (each cycle is 21 days) | 
| Homocysteine plasma levels at baseline (μmol/L) | To evaluate the influence of baseline homocysteine plasma levels on occurrence of haematological toxicity. | Once, before the start of the first cycle (each cycle is 21 days) | 
| Efficacy based on response CT after cycle 2 and 4 (categorical: response, partial response, progression) | To evaluate the efficacy of the treatment with pemetrexed (based on CT-scan). | After the second and fourth cycle (each cycle is 21 days) | 
| Incidence of discontinuation, dose delays and dose reductions of pemetrexed | To evaluate the incidence of treatment delay or dose reduction of pemetrexed. | 3 months |