OSIMERTINIB for Non-small cell lung cancer (EGFR-mutated, metastatic)

Inclusion criteria

• {"criterion_text":"- Pathologically confirmed metastatic EGFR-mutated nonsquamous NSCLC 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. All patients with an EGFR ex19del or ex21 L858R mutation are eligible for inclusion.\n- Patients with HBV are only eligible for inclusion if they meet all the following criteria: o\tDemonstrated absence of HCV co-infection or history of HCV co-infection o\tDemonstrated absence of HIV infection o\tParticipants with active HBV infection are eligible if they are: o\tReceiving 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. o\tParticipants with a resolved or chronic HBV infection are eligible if they are: \tNegative 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 \tPositive 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.\n- Patients with HIV are only eligible for inclusion if they meet all the following criteria: o\tDemonstrated absence of HBV/ HCV co-infection o\tUndetectable viral RNA load for 6 months o\tCD4+ count of >350 cells/µL o\tNo history of AIDS-defining opportunistic infection within the past 12 months o\tStable for at least 4 weeks on the same anti-HIV medications\n- Patients must be willing to use protocol specified method of contraception during treatment with osimertinib and 6 weeks tafter the lost dose of osimertinib. o\tFemales 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: \tPost-menopausal defined as aged 50 years or more and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments \tWomen 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 \tDocumentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. o\tMale subjects must be willing to use barrier contraception.\n- ECOG-PS of 0-1.\n- Male or female, 18 years of age or older.\n- Able and willing to sign informed consent prior to any tests or procedures, which includeds compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Signed and dated, written informed consent form should be provided prior to any mandatory study-specific procedures, sampling, and analyses.\n- Able and willing to undergo additional blood sampling for e.g. therapeutic drug monitoring.\n- Able and willing to undergo two lumbar punctions to obtain CSF\n- Patients 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.\n- Absence of ABCG2 34G>A SNP\n- Absence of CNS metastases"}

Exclusion criteria

• {"criterion_text":"- Acute gout attack, and medical history of gout or xanthinuria\n- Prior intrathecal chemotherapy\n- Moderate or severe hepatic dysfunction (Child Pugh B or C)\n- Significantly increased rate of uric acid production (such as in Lesch-Nyhan syndrome)\n- Pregnancy or breast-feeding\n- Severe cardiovascular conditions (including history of myocardial infarction, stroke or instable angina pectoris, or congestive heart failure)\n- Use of urate-lowering agents, azathioprine, 6-mercaptopurine, tioguanine\n- Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site)\n- 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.\n- 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.\n- 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\tScreening for chronic conditions is not required.\n- 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.\n- 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.\n- 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.\n- Osimertinib dosage of less than 80 mg once daily.\n- Any concurrent and/or other active malignancy that has required systemic treatment within 2 years of first dose of osimertinib.\n- 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.\n- 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.\n- 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.\n- Any of the following cardiac criteria: o\tMean resting corrected QT interval (QTc) > 470 msec, obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value. o\tAny 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. o\tPatient 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.\n- Use of potent inducers of UDP-glucuronosyltransferase (UGT) enzymes, such as rifampicin and carbamazepine\n- Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: o\tBone marrow reserve (the use of granulocyte colony stimulating factor support, platelet transfusion and blood transfusions to meet these criteria is not permitted): \tAbsolute neutrophil count <1.5 x 109/L \tPlatelet count <100 x 109/L \tHaemoglobin <90 g/L o\tHepatic function \tAlanine 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 \tAspartate aminotransferase >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases \tTotal 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\n- 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\n- Use of prohibited co-medication\n- 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.\n- Known galactose-intolerance, Lapp lactasedeficiency or glucose-galactose malabsorption"}

Primary endpoints

• {"endpoint_text":"- Osimertinib concentration in CSF and plasma before and after combination with febuxostat","definition_or_measurement_approach":"Measurement of osimertinib concentrations in cerebrospinal fluid (CSF) and plasma before and after co-administration with febuxostat, with primary objective focused on CSF:plasma (cerebrospinal fluid to unbound plasma) concentration ratio."}

Secondary endpoints

• {"endpoint_text":"- Osimertinib concentration in CSF before and after combination with febuxostat","definition_or_measurement_approach":"CSF osimertinib concentrations measured before and after febuxostat co-administration."}
• {"endpoint_text":"- Osimertinib plasma trough concentration before and after addition of febuxostat","definition_or_measurement_approach":"Steady-state trough (pre-dose) plasma concentrations of osimertinib measured before and after febuxostat."}
• {"endpoint_text":"- AZ5104 and AZ7550 plasma trough concentration before and after combination with febuxostat","definition_or_measurement_approach":"Steady-state trough plasma concentrations of osimertinib active metabolites AZ5104 and AZ7550 before and after febuxostat."}
• {"endpoint_text":"- AZ5104 and AZ7550 CSF concentration before and after combination with febuxostat","definition_or_measurement_approach":"CSF concentrations of AZ5104 and AZ7550 measured before and after febuxostat co-administration."}
• {"endpoint_text":"- Adverse events according to CTCAE v5.0 criteria","definition_or_measurement_approach":"Safety assessed by recording adverse events and grading according to CTCAE v5.0."}
• {"endpoint_text":"- ABCB1 and ABCG2 genotype status, and osimertinib, AZ5104 and AZ7550 CNS concentrations","definition_or_measurement_approach":"Genotyping for ABCB1 and ABCG2 and correlation with CNS (CSF) concentrations of osimertinib and metabolites."}
• {"endpoint_text":"- AEs and osimertinib, AZ5104 and AZ7550 concentrations in blood and CSF","definition_or_measurement_approach":"Exploratory correlations between adverse events and drug concentrations in blood and CSF."}

Netherlands

Earliest CTIS Part Ii Submission Date

06-03-2026

Latest Decision Or Authorization Date

19-03-2026

Processing Time Days

13

Number Of Sites

3

Number Of Participants

14

Primary sponsor

Full Name

Academisch Ziekenhuis Maastricht

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands

Third parties

• {"country":"","full_name":"AstraZeneca","duties_or_roles":"Source of monetary support","organisation_type":""}