Pharmacokinetic Boosting of Osimertinib

Non Small Cell Lung Cancer Clinical Trial

— OSIBOOST  

Official title:

Pharmacokinetic Boosting of Osimertinib in Patients With Non-small Cell Lung Cancer.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03858491
• Other study ID #: 2018-004290-28
• Status: Completed
• Phase: Early Phase 1
• Start date: November 1, 2020
• Est. completion date: December 31, 2021

Study information

• Verified date: September 2022
• Source: Academisch Ziekenhuis Maastricht
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: December 31, 2021
• Est. primary completion date: October 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

Drug:
• Cobicistat
Cobicistat will be added to the treatment with osimertinib. The initial dose will be 150 mg cobicistat, which equals the dose used in the treatment of HIV-infected patients. If this dose is well tolerated and the increase in exposure of osimertinib is not sufficient, the dose of cobicistat will gradually be escalated to 600 mg per day (150 mg cobicistat, four times per day).

Locations

Country	Name	City	State
Netherlands	Antoni van Leeuwenhoek hospital	Amsterdam	Noord-Holland
Netherlands	Maastricht University Medical Centre	Maastricht	Limburg

Sponsors (3)

Lead Sponsor	Collaborator
Academisch Ziekenhuis Maastricht	The Netherlands Cancer Institute, ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

References & Publications (3)

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. — View 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 E — View 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, Ramali — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Osimertinib AUC	Exposure to osimertinib will be measured at the start of the study and after three weeks of treatment with cobicistat. This will be done by measuring the concentration of osimertinib four times during the day (pre-dose and two, four and eight hour post-dose), which will be used to calculate the AUC of osimertinib.	Three weeks
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.	The safety of the combination therapy will be evaluated and scored using NCI CTCAE v4.0. The investigators will evaluate the number of patients that experience treatment-related adverse events. Additionally, the investigators will describe the adverse events which are most common in the lung cancer patients.; Participants will be asked to keep up a patient diary with problems they have experienced during the study.	Three weeks
Secondary	Cmax of osimertinib	The maximum plasma of osimertinib will be determined	Three weeks