Boosting Osimertinib Blood Brain Barrier Penetration (OSIBBBOOST)

Boosting Osimertinib Blood Brain Barrier Penetration in Patients With Epidermal Growth Factor Receptor Mutated Non-small Cell Lung Cancer

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)?

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Osimertinib & febuxostat

Detailed Description

One of the preferred first line treatment for metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is osimertinib, a tyrosine kinase inhibitor (TKI). Despite the good intracranial efficacy of osimertinib compared with older-generation EGFR-TKIs, 10-20% of patients develop new or progressing central nervous system (CNS) metastases, the reason for which is unknown. Although the CNS penetration of osimertinib should be sufficient to reach therapeutic concentrations, drug efflux pumps in the blood brain barrier (BBB) could play a role in preventing therapeutic concentrations, especially in patients without baseline CNS metastases. In these patients the BBB is not compromised in contrast to patients with baseline CNS metastases, in whom a leaky BBB allows better penetration of osimertinib. As a result, microscopic CNS metastases then have the opportunity to grow.

Osimertinib is a substrate of drug transporters P-glycoprotein (P-gp; gene: ABCB1) and Breast Cancer Resistance Protein (BCRP) (ABCG2; gene: ABCG2), present in the BBB. Germline variations in these transporters influence intracerebral osimertinib efficacy. Patients without CNS metastases and with the ABCG2 34G>A single nucleotide polymorphism (SNP) have a 72% reduced risk of developing CNS metastases compared to other genotypes, potentially due to diminished osimertinib BBB-efflux, resulting in higher cerebrospinal fluid (CSF) penetration. This finding offers rationale to combine osimertinib with febuxostat, a strong selective ABCG2 transporter inhibitor, in order to enhance the intracerebral osimertinib concentration in patients without the ABCG2 34G>A SNP (~85% of patients).

The main trial endpoint is the change in the CSF to unbound plasma concentration ratio of osimertinib before and after co-administration with febuxostat.

• Study Type: Interventional
• Enrollment (Estimated): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • The Netherlands Cancer Institute
  • Maastricht, Netherlands
    • Maastricht UMC+
    • Contact: R van Geel, PharmD, PhD; Phone Number: +31 (0)43 38 71881
  • Rotterdam, Netherlands
    • Erasmus MC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

1. 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.
2. The patient has an European Cooperative Oncology Group (ECOG) performance status (PS) of 0-2.
3. The patient is 18 years of age or older.
4. The patient is able and willing to sign informed consent prior to any tests or procedures.
5. The patient is able and willing to undergo additional blood sampling for e.g. therapeutic drug monitoring.
6. The patient is able and willing to undergo lumbar punctions to obtain CSF.
7. 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.
8. The patient does not harbour the ABCG2 34G>A single nucleotide polymorphism.
9. The patient does not have any central nervous system (CNS) metastases.

10. Patients with HBV are only eligible for inclusion if they meet all the following criteria:

    • 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:

      • Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG or total anti-HBc Ab]. In addition, patients should be referred to a local hepatologist and treated as per local guidelines. or
      • Positive for HBsAg, but for > 6 months have had transaminases levels below ULN and HBV DNA levels below <100 IU/mL or below the detectable limit of locally available test kit (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment.

11. Patients with HIV are only eligible for inclusion if they meet all the following criteria:

    • Demonstrated absence of HBV/ HCV co-infection
    • Undetectable viral RNA load for 6 months
    • CD4+ count of >350 cells/µL
    • No history of AIDS-defining opportunistic infection within the past 12 months
    • Stable for at least 4 weeks on the same anti-HIV medications

12. Patients must be willing to use protocol specified method of contraception during treatment with osimertinib and 6 weeks tafter the lost dose of osimertinib.

    • Females who are not abstinent (in line with the preferred and usual lifestyle choice of the patient) and intend to be sexually active with a male partner must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of child-bearing potential, or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:

      • Post-menopausal defined as aged 50 years or more and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
      • Women under 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution
      • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
    • Male participants must be willing to use barrier contraception

Exclusion criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

1. The patient has an acute gout attack, and medical history of gout or xanthinuria
2. The patient uses urate-lowering agents, azathioprine, 6-mercaptopurine, tioguanine
3. The patient uses potent inducers of UDP-glucuronosyltransferase (UGT) enzymes, such as rifampicin and carbamazepine
4. The patient uses prohibited co-medication: drugs that moderately or strongly inhibits or induces CYP3A4 or P-glycoprotein (P-gp)
5. The patient has received prior treatment with intrathecal chemotherapy
6. The patient has moderate or severe hepatic dysfunction (Child Pugh B or C)
7. The patient has a significantly increased rate of uric acid production (such as in Lesch-Nyhan syndrome)
8. The patient is pregnant or lactating
9. The patient has been diagnosed with severe cardiovascular conditions (including history of myocardial infarction, stroke or instable angina pectoris, or congestive heart failure)

10. 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.
11. 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
12. Known galactose-intolerance, Lapp lactasedeficiency or glucose-galactose malabsorption
13. Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site)
14. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia and grade 2 prior platinum-therapy related neuropathy.

15. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection (e.g. patients receiving treatment for infection) including hepatitis C and human immunodeficiency virus (HIV), or active uncontrolled HBV infection.

    o Screening for chronic conditions is not required.

16. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
17. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.

18. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

    • Bone marrow reserve (the use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted):

      • Absolute neutrophil count <1.5 x 109/L
      • Platelet count <100 x 109/L
      • Haemoglobin <90 g/L

    • Hepatic function

      • Alanine aminotransferase >2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
      • Aspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
      • Total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases
19. History of hypersensitivity to active or inactive excipients of osimertinib or febuxostat, or drugs with a similar chemical structure or class to osimertinib or febuxostat.
20. Osimertinib dosage of less than 80 mg once daily.
21. Any concurrent and/or other active malignancy that has required systemic treatment within 2 years of first dose of osimertinib.
22. Major surgery within 4 weeks of the first dose of IP. Procedures such as placement of vascular access, biopsy via mediastinoscopy or biopsy via video assisted thoracoscopic surgery (VATS) are permitted.
23. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP.
24. Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
25. Participation in another clinical study with an investigational product during the 4 weeks prior to Day 1. Patients in the follow-up period of an interventional study are permitted.
26. If a patient uses anticoagulants and the treating physician deems it unsafe or not feasible to temporarily interrupt this medication or to bridge oral anticoagulants with parenteral anticoagulation (i.e. LMWH) at the time of the lumbar puncture procedure, the patient will be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combining osimertinib with febuxostat on cerebrospinal fluid concentration of osimertinib; 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; Combining osimertinib with the ABCG2 inhibitor febuxostat to evaluate the effect on CSF concentrations of osimertinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	22-25 days after start of concurrent treatment
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	22-25 days after start of combined treatment
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.	22-25 days after start of combined treatment
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.	22-25 days after start of combined treatment
Tolerability of osimertinib in combination with febuxostat	Determining tolerability of osimertinib combined with febuxostat, by assessing adverse events according to CTCAE v5.0 criteria	22-25 days after start of combined treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	22-25 days after start combined therapy
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	22-25 days after start combination treatment

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: AstraZeneca; Erasmus Medical Center; The Netherlands Cancer Institute

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: January 15, 2026
• First Submitted That Met QC Criteria: March 16, 2026
• First Posted (Actual): March 20, 2026

Study Record Updates

• Last Update Posted (Actual): March 20, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Febuxostat; osimertinib
• Other Study ID Numbers: OSIBBBOOST; 2025-523033-26-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No