Pharmacokinetic Boosting of Osimertinib

NCT03858491 | Completed Early Phase 1

• 1 other identifier: 2018-004290-28
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

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.

Conditions

Non Small Cell Lung Cancer

Keywords

Osimertinib; Cobicistat; Pharmacokinetic boosting

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

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

  Three weeks

• Cmax of osimertinib

  Three weeks

Study Arms (1)

Cobicistat

EXPERIMENTAL

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).

Drug: Cobicistat

Interventions

Cobicistat DRUG

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).

Also known as: Tybost

Cobicistat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Academisch Ziekenhuis Maastricht: lead
• The Netherlands Cancer Institute: collaborator
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (2)

Maastricht University Medical Centre

Maastricht, Limburg, 6225EC, Netherlands

Location

Antoni van Leeuwenhoek hospital

Amsterdam, North Holland, 1066CX, Netherlands

Location

Related Publications (5)

• 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.

  PMID: 29151359 RESULT

• 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.

  PMID: 27959700 RESULT

• 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.

  PMID: 28388255 RESULT

• Westra N, Kruithof PD, Croes S, van Geel RMJM, Hendriks LEL, Touw DJ, Oude Munnink TH, Mian P. Systematic Evaluation of Osimertinib Population Pharmacokinetic Models in a Cohort of Dutch Adults with Non-Small Cell Lung Cancer. Eur J Drug Metab Pharmacokinet. 2024 Jul;49(4):517-526. doi: 10.1007/s13318-024-00904-5. Epub 2024 Jun 15.

  PMID: 38878145 DERIVED

• 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.

  PMID: 35933915 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Cobicistat

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Sander Croes, MSc, PhD

  Maastricht University Medical Centre+ (MUMC+)

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Researcher

Model Details: 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).

Study Record Dates

• First Submitted: February 26, 2019
• First Posted: February 28, 2019
• Study Start: November 1, 2020
• Primary Completion: October 31, 2021
• Study Completion: December 31, 2021
• Last Updated: September 26, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (2)