Boosting osimertinib Blood Brain Barrier penetration in patients with epidermal growth factor receptor mutated non-small cell lung cancer (OSIBBBOOST)

Prior treatment

• Prior intrathecal chemotherapy
• 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.
• 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.
• 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.
• 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.
• 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.
• Any concurrent and/or other active malignancy that has required systemic treatment within 2 years of first dose of osimertinib.
• 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.
• 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.
• Use of prohibited co-medication

Other illness

• Acute gout attack, and medical history of gout or xanthinuria
• Significantly increased rate of uric acid production (such as in Lesch-Nyhan syndrome)
• Severe cardiovascular conditions (including history of myocardial infarction, stroke or instable angina pectoris, or congestive heart failure)
• 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.
• 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.

Lab values

• Any of the following cardiac criteria: o Mean resting corrected QT interval (QTc) > 470 msec, obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value. o 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. o 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.
• Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: o 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 o 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
• 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
• Known galactose-intolerance, Lapp lactasedeficiency or glucose-galactose malabsorption

Other

• Moderate or severe hepatic dysfunction (Child Pugh B or C)
• Pregnancy or breast-feeding
• Use of urate-lowering agents, azathioprine, 6-mercaptopurine, tioguanine
• Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site)
• Osimertinib dosage of less than 80 mg once daily.
• 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.
• Use of potent inducers of UDP-glucuronosyltransferase (UGT) enzymes, such as rifampicin and carbamazepine

• 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.
• Patients with HBV are only eligible for inclusion if they meet all the following criteria: o Demonstrated absence of HCV co-infection or history of HCV co-infection o Demonstrated absence of HIV infection o Participants with active HBV infection are eligible if they are: o 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. o 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.
• Patients with HIV are only eligible for inclusion if they meet all the following criteria: o Demonstrated absence of HBV/ HCV co-infection o Undetectable viral RNA load for 6 months o CD4+ count of >350 cells/µL o No history of AIDS-defining opportunistic infection within the past 12 months o Stable for at least 4 weeks on the same anti-HIV medications
• 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 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. o Male subjects must be willing to use barrier contraception.
• ECOG-PS of 0-1.
• Male or female, 18 years of age or older.
• 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.
• Able and willing to undergo additional blood sampling for e.g. therapeutic drug monitoring.
• Able and willing to undergo two lumbar punctions to obtain CSF
• 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.
• Absence of ABCG2 34G>A SNP
• Absence of CNS metastases