Boosting Osimertinib Blood Brain Barrier Penetration
ConditionNon-Small Cell Lung Cancer
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorMaastricht University Medical Center
About this trial
The goal of this proof-of-concept clinical study is to determine the effect of combining osimertinib with febuxostat on cerebrospinal fluid concentrations of osimertinib in patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). The main question it aims to answer is: what is the effect of combining osimertinib with the ABCG2 inhibitor febuxostat on cerebrospinal fluid to unbound plasma osimertinib concentration ratio in patients with EGFR mutated NSCLC without central nervous system (CNS) metastases and without the ABCG2 34G\>A single nucleotide polymorphism (SNP)?
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
The patient has metastatic EGFR-mutated NSCLC and is treated with osimertinib as part of regular care with CT-confirmed stable disease or better. Patients with (signs of) disease progression, are also eligible if their treating physician deems the treatment to be appropriate beyond progression and the expected osimertinib treatment duration is at least 1 month.
The patient has an European Cooperative Oncology Group (ECOG) performance status (PS) of 0-2.
The patient is 18 years of age or older.
The patient is able and willing to sign informed consent prior to any tests or procedures.
Disqualifiers
The patient has an acute gout attack, and medical history of gout or xanthinuria
The patient uses urate-lowering agents, azathioprine, 6-mercaptopurine, tioguanine
The patient uses potent inducers of UDP-glucuronosyltransferase (UGT) enzymes, such as rifampicin and carbamazepine
The patient uses prohibited co-medication: drugs that moderately or strongly inhibits or induces CYP3A4 or P-glycoprotein (P-gp)
Trial design
Design model
Single group
Treatments tested in this trial
Osimertinib & febuxostat
DrugCombining osimertinib with the ABCG2 inhibitor febuxostat to evaluate the effect on CSF concentrations of osimertinib
Treatment groups
7 Participants
are divided into 1 treatment groupGroup A: Combining osimertinib with febuxostat on cerebrospinal fluid concentration of osimertinibExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Effect of combining osimertinib with febuxostat on osimertinib CSF:plasma ratio in patients with EGFR NSCLC without CNS metastases
Determining the effect of combining osimertinib with the ABCG2 inhibitor febuxostat on osimertinib cerebrospinal fluid to plasma (CSF:plasma) concentration ratio, in patients with EGFR mutated NSCLC without central nervous system (CNS) metastases on brain MRI. Both CSF and plasma concentrations will be measured before and after combination of osimertinib with febuxostat.
Time frame
22-25 days after start of combination osimertinib + febuxostatSecondary outcomes
1
Effect on intracerebral osimertinib concentrations after combination with febuxostat
Evaluating the extent by which febuxostat increases intracerebral osimertinib concentrations, by measuring osimertinib concentration in CSF before and after combination with febuxostat
Time frame
22-25 days after start of concurrent treatment2
Effect on osimertinib plasma concentrations
Assessing the effect of febuxostat on osimertinib plasma trough concentration in steady-state, by comparing concentrations before and after combination with febuxostat
Time frame
22-25 days after start of combined treatment3
Plasma concentrations of AZ5104 and AZ7550
Assessing the effect of febuxostat on AZ5104 and AZ7550 (i.e. active metabolites of osimertinib) steady-state trough concentrations, by comparing concentrations before and after combined use.
Time frame
22-25 days after start of combined treatment4
CSF concentrations of AZ5104 and AZ7550
Assessing the effect of febuxostat on AZ5104 and AZ7550 (i.e. active metabolites of osimertinib) concentrations in CSF, by comparing concentrations before and after combined use.
Time frame
22-25 days after start of combined treatmentOther outcomes
1
Effect ABCB1 and ABCG2 genotypes on osimertinib CNS exposure
Exploring potential effects of different ABCB1 and ABCG2 genotypes on CNS exposure of osimertinib and active metabolites AZ5104 and AZ7550 before and during combination with febuxostat. Therefore, it will be assessed whether variations in osimertinib concentrations (and concentrations of active metabolites) before and during combination with febuxostat may be explained by different ABCB1 and ABCG2 genotypes.
Time frame
22-25 days after start combined therapy2
Correlation between safety and osimertinib, AZ5104 and AZ7550 concentrations in blood and CSF
Exploring potential correlations between safety (AEs according to CTCAE v5.0) and osimertinib, AZ5104 and AZ7550 concentrations in blood and CSF
Time frame
22-25 days after start combination treatmentSponsors and contacts
Click on the lead sponsor to view all of their trials.
Maastricht University Medical Center
Lead sponsor
AstraZeneca
Collaborator
The Netherlands Cancer Institute
Collaborator
Source ClinicalTrials.gov