Boosting Osimertinib Blood Brain Barrier Penetration

NCT07485452 | Not Yet Recruiting Phase 2

• 2 other identifiers: OSIBBBOOST2025-523033-26-00
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 3

Brief Summary

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)?

Conditions

Non-Small Cell Lung Cancer

Outcome Measures

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.

  22-25 days after start of combination osimertinib + febuxostat

Secondary Outcomes (5)

• Effect on intracerebral osimertinib concentrations after combination with febuxostat

  22-25 days after start of concurrent treatment

• Effect on osimertinib plasma concentrations

  22-25 days after start of combined treatment

• Plasma concentrations of AZ5104 and AZ7550

  22-25 days after start of combined treatment

• CSF concentrations of AZ5104 and AZ7550

  22-25 days after start of combined treatment

• Tolerability of osimertinib in combination with febuxostat

  22-25 days after start of combined treatment

Other Outcomes (2)

• Effect ABCB1 and ABCG2 genotypes on osimertinib CNS exposure

  22-25 days after start combined therapy

• Correlation between safety and osimertinib, AZ5104 and AZ7550 concentrations in blood and CSF

  22-25 days after start combination treatment

Study Arms (1)

Combining osimertinib with febuxostat on cerebrospinal fluid concentration of osimertinib

EXPERIMENTAL

Determining the effect of combining osimertinib with ABCG2 inhibitor febuxostat on cerebrospinal fluid to unbound plasma osimertinib concentration ratio, in patients with EGFR mutated NSCLC without CNS metastases and without the ABCG2 34G\>A SNP

Drug: Osimertinib & febuxostat

Interventions

Osimertinib & febuxostat DRUG

Combining osimertinib with the ABCG2 inhibitor febuxostat to evaluate the effect on CSF concentrations of osimertinib

Combining osimertinib with febuxostat on cerebrospinal fluid concentration of osimertinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, a subject must meet all of the following criteria:
• 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.
• The patient is able and willing to undergo additional blood sampling for e.g. therapeutic drug monitoring.
• The patient is able and willing to undergo lumbar punctions to obtain CSF.
• The patient must meet the criteria stated in the approved regulatory indication(s) for osimertinib where the clinical study will be performed and agree to the restrictions, monitoring, and dose-adjustment criteria stipulated in the associated product label.
• The patient does not harbour the ABCG2 34G\>A single nucleotide polymorphism.
• The patient does not have any central nervous system (CNS) metastases.
• Demonstrated absence of HCV co-infection or history of HCV co-infection
• Demonstrated absence of HIV infection
• Participants with active HBV infection are eligible if they are:
• Receiving anti-viral treatment for at least 6 weeks prior to study treatment, HBV DNA is suppressed to \<100 IU/mL and transaminase levels are below ULN.
• Participants with a resolved or chronic HBV infection are eligible if they are:

You may not qualify if:

• A potential subject who meets any of the following criteria will be excluded from participation in this study:
• 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)
• The patient has received prior treatment with intrathecal chemotherapy
• The patient has moderate or severe hepatic dysfunction (Child Pugh B or C)
• The patient has a significantly increased rate of uric acid production (such as in Lesch-Nyhan syndrome)
• The patient is pregnant or lactating
• The patient has been diagnosed with severe cardiovascular conditions (including history of myocardial infarction, stroke or instable angina pectoris, or congestive heart failure)
• Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) \> 470 msec, obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value.
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block.
• Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities including: Hypokalaemia\* ≥ CTCAE Grade 2 (\*correction of electrolyte abnormalities should be documented prior to first dose), heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
• Creatinine \>1.5 times ULN concurrent with creatinine clearance \<50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is \>1.5 times ULN

Sponsors & Collaborators

• Maastricht University Medical Center: lead
• AstraZeneca: collaborator
• The Netherlands Cancer Institute: collaborator
• Erasmus Medical Center: collaborator

Study Sites (3)

The Netherlands Cancer Institute

Amsterdam, Netherlands

Location

Maastricht UMC+

Maastricht, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Related Publications (2)

• Planchard D, Janne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, Sugawara S, Yu Y, Fan Y, Geater SL, Laktionov K, Lee CK, Valdiviezo N, Ahmed S, Maurel JM, Andrasina I, Goldman J, Ghiorghiu D, Rukazenkov Y, Todd A, Kobayashi K; FLAURA2 Investigators. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935-1948. doi: 10.1056/NEJMoa2306434. Epub 2023 Nov 8.

  PMID: 37937763 BACKGROUND

• Veerman GDM, Boosman RJ, Jebbink M, Oomen-de Hoop E, van der Wekken AJ, Bahce I, Hendriks LEL, Croes S, Steendam CMJ, de Jonge E, Koolen SLW, Steeghs N, van Schaik RHN, Smit EF, Dingemans AC, Huitema ADR, Mathijssen RHJ. Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer. EClinicalMedicine. 2023 Apr 13;59:101955. doi: 10.1016/j.eclinm.2023.101955. eCollection 2023 May.

  PMID: 37125403 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

osimertinib; Febuxostat

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 15, 2026
• First Posted: March 20, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028
• Last Updated: March 20, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (3)