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Pharmacokinetic Boosting of Osimertinib (OSIBOOST)

Primary Purpose

Non Small Cell Lung Cancer

Status

Completed

Phase

Early Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Cobicistat

About this trial

This is an interventional treatment trial for Non Small Cell Lung Cancer focused on measuring Osimertinib, Cobicistat, Pharmacokinetic boosting

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Maastricht University Medical Centre
Antoni van Leeuwenhoek hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Cobicistat

Arm Description

Cobicistat will serve as experimental drugs, and will be added to the regular treatment with osimertinib. Combination-treatment will be started at 150 milligram cobicistat, and can be increased to a maximum daily dose of 600 milligram cobicistat (four times 150 milligram).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Cmax of osimertinib

The maximum plasma of osimertinib will be determined

Full Information

NCT ID

NCT03858491

First Posted

February 26, 2019

Last Updated

September 23, 2022

Sponsor

Academisch Ziekenhuis Maastricht

Collaborators

The Netherlands Cancer Institute, ZonMw: The Netherlands Organisation for Health Research and Development

1. Study Identification

Unique Protocol Identification Number

NCT03858491

Brief Title

Pharmacokinetic Boosting of Osimertinib

Acronym

OSIBOOST

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Completed

Study Start Date

November 1, 2020 (Actual)

Primary Completion Date

October 31, 2021 (Actual)

Study Completion Date

December 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Academisch Ziekenhuis Maastricht

Collaborators

The Netherlands Cancer Institute, ZonMw: The Netherlands Organisation for Health Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non Small Cell Lung Cancer

Keywords

Osimertinib, Cobicistat, Pharmacokinetic boosting

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

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).

Masking

None (Open Label)

Allocation

N/A

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cobicistat

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Cobicistat

Other Intervention Name(s)

Tybost

Intervention Description

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).

Primary Outcome Measure Information:

Title

Osimertinib AUC

Description

Time Frame

Three weeks

Secondary Outcome Measure Information:

Title

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.

Description

Time Frame

Three weeks

Title

Cmax of osimertinib

Description

The maximum plasma of osimertinib will be determined

Time Frame

Three weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sander Croes, MSc, PhD

Organizational Affiliation

Maastricht University Medical Centre+ (MUMC+)

Official's Role

Study Director

Facility Information:

Facility Name

Maastricht University Medical Centre

City

Maastricht

State/Province

Limburg

ZIP/Postal Code

6225EC

Country

Netherlands

Facility Name

Antoni van Leeuwenhoek hospital

City

Amsterdam

State/Province

Noord-Holland

ZIP/Postal Code

1066CX

Country

Netherlands

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

29151359

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.

Results Reference

result

PubMed Identifier

27959700

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.

Results Reference

result

PubMed Identifier

28388255

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.

Results Reference

result

PubMed Identifier

35933915

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.

Results Reference

derived

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Pharmacokinetic Boosting of Osimertinib

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