Clinical trial NCT03858491: Pharmacokinetic Boosting of Osimertinib
Official title: Pharmacokinetic Boosting of Osimertinib in Patients With Non-small Cell Lung Cancer.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Non Small Cell Lung Cancer
Keywords: Osimertinib
Cobicistat
Pharmacokinetic boosting
Lead sponsor: Academisch Ziekenhuis Maastricht
Sponsor class: OTHER
Collaborators: name: The Netherlands Cancer Institute
name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2019-02-28
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: In this study a group of patients will receive cobicistat as add-on on their regular treatment with osimertinib. All patients experience low osimertinib trough concentration levels when treated with the regular osimertinib dose (80 mg per day).
Primary purpose: TREATMENT

Brief summary: The main objective of this study is to evaluate if systemic exposure of osimertinib (i.e. AUC) is increased when osimertinib is co-administered with cobicistat in patients with relatively low plasma trough concentration while receiving the standard osimertinib dose.

Detailed description: Osimertinib is a new targeted agent registered for the treatment of patients with EGFR-mutated NSCLC. However, the costs of those new treatments are extremely high. Osimertinib is mainly metabolized by CYP3A4, and partially by CYP3A5. Combination of osimertinib with a strong CYP3A4-inhibitor may result in a smaller first-pass effect and a decreased clearance of osimertinib, thereby increasing the exposure to osimertinib.

Cobicistat is a strong CYP3A4-inhibitor, this mechanism may be used to boost osimertinib, as is done for other drugs, mainly drugs used to treat HIV-infected patients.

Using this personalized treatment approach and combining the concepts of therapeutic drug monitoring (TDM) and pharmacokinetic boosting, osimertinib therapy could become much more cost-effective. By reducing the necessary dose of osimertinib, this strategy may ultimately result in a significant reduction in drug costs, as the additional expenditure for the CYP3A4 inhibitor and blood sample analysis are negligible compared to the price of osimertinib.

Eligibility criteria: Inclusion Criteria:

* Patients with EGFR-mutated NSCLC receiving standard treatment with osimertinib for at least 2 months (steady state), without any signs of disease progression, or during treatment beyond progression, if treatment continuation is expected for multiple months. After anticipated EMA approval of osimertinib adjuvant therapy, patients on adjuvant osimertinib treatment may also participate on the following conditions; If they are receiving standard treatment with osimertinib for at least 2 months (steady state), and if treatment will be continued for a longer period than necessary for participation in the OSIBOOST trial.
* Age ≥ 18 years
* WHO performance status ≤ 2.
* Able and willing to give written informed consent.
* Able and willing to undergo blood sampling for pharmacokinetic analysis.
* Patients with osimertinib plasma trough concentration below 195 ng/mL. Plasma trough concentration of osimertinib will be determined in another study (METC MUMC: 2018-0800).

Exclusion Criteria:

* Any concurrent medication that is known to strongly inhibit or induce CYP3A4.
* Any concurrent medication that is primarily metabolized by CYP3A4 with a narrow therapeutic window.
* Impairment of gastrointestinal function that may alter the absorption of osimertinib or cobicistat (e.g. ulcerative disease, uncontrolled nausea or vomiting, malabsorption syndrome, small bowel resection).
* Refusing to refrain from consuming CYP3A4 influencing products, e.g. grapefruit(juice), St. John's wort.
* Pregnancy or breast feeding
* Child-Pugh score class C, chronic liver disease.

Primary outcomes:
measure: Osimertinib AUC
timeFrame: Three weeks
Secondary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.
timeFrame: Three weeks
measure: Cmax of osimertinib
timeFrame: Three weeks
Other outcomes:
Locations:
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Centre
state: Limburg
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek hospital
state: Noord-Holland
Study officials:
affiliation: Maastricht University Medical Centre+ (MUMC+)
name: Sander Croes, MSc, PhD
role: STUDY_DIRECTOR
References:
citation: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18.
citation: Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. doi: 10.1056/NEJMoa1612674. Epub 2016 Dec 6.
citation: Lubberman FJE, van Erp NP, Ter Heine R, van Herpen CML. Boosting axitinib exposure with a CYP3A4 inhibitor, making axitinib treatment personal. Acta Oncol. 2017 Sep;56(9):1238-1240. doi: 10.1080/0284186X.2017.1311024. Epub 2017 Apr 7. No abstract available.
citation: van Veelen A, Gulikers J, Hendriks LEL, Dursun S, Ippel J, Smit EF, Dingemans AC, van Geel R, Croes S. Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial. Lung Cancer. 2022 Sep;171:97-102. doi: 10.1016/j.lungcan.2022.07.012. Epub 2022 Jul 25.