Improving Osimertinib Exposure and Cost-effectiveness Using Pharmacokinetic Boosting With Cobicistat

NCT05748093 | Recruiting Phase 4

• 2 other identifiers: OSIBOOST 22023-505700-35-00
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to assess the feasibility of pharmacokinetically boosting osimertinib using cobicistat in order to improve osimertinib exposure in individual patients with advanced NSCLC (Non-Small Cell Lung Cancer) with mutated EGFR (Epidermal Growth Factor Receptor). The main questions it aims to answer are:

• Cohort 1: Does concurrent use of osimertinib and cobicistat allow for osimertinib weekly intake reductions? If so, how much can the intake be reduced while retaining clinically effective exposure?
• Cohort 2: Does concurrent use of osimertinib and cobicistat allow for improved penetration of osimertinib in the central nervous system, in patients with CNS (central nervous system) oligoprogression? Participants who are taking osimertinib in regular care will receive cobicistat in addition to their other medication. They will undergo blood sampling to measure the amount of osimertinib in blood, and measure the effect of boosting. Additionally, in cohort 1 patients will be dose-reduced if their exposure levels allow.

Conditions

Non-small Cell Lung Cancer

Keywords

Osimertinib; Cobicistat; Pharmacokinetics; Boosting; Non-small Cell Lung Cancer; CNS metastases

Outcome Measures

Primary Outcomes (2)

• Cohort 1 primary end-point: Dose modification feasibility

  This cohort aims to demonstrate feasibility and clinical applicability of PK-boosting in the oncological setting. PK-boosting will increase osimertinib availability in plasma. When the availability is increased, a patient will require less osimertinib to achieve the same effect. Therefore, they can be dose-reduced in order to restore them to their normal exposure. In order for this treatment to be considered feasible, the following conditions need to be met: a patient needs to have a stable osimertinib exposure when using the PK-booster, and the patient needs to be dose-modified as a result. The primary endpoint will describe the amount of patients who have: stable exposure; similar to their respective baseline; while using concomitant pk-boosting therapy and a dose modified osimertinib treatment plan; without experiencing significant toxicity. The aim is for this treatment strategy to be considered feasible for at least 75% of patients.

  2-18 months after intervention initiation

• Cohort 2 primary end-point: Disease Control Rate at 12 weeks

  This cohort aims to provide improved treatment efficacy in patients with intracranial metastases from NSCLC. Osimertinib penetration in the CNS is much better than that of older generation TKIs, but it is still only 1,49%. Many patients with NSCLC end up developing CNS metastases, a condition known for its dismal prognosis. Currently the only way to increase osimertinib CNS penetration is through dose-escalation: a strategy which causes a tremendous increase in treatment-related toxicity. This cohort looks to improve CNS penetration of osimertinib through the use of a PK-booster (cobicistat). In order to assess treatment efficacy, a MRI will be taken at the start of the trial, and after 12 weeks. A neuro-radiology panel will then assess metastatic response rate. This metastatic response rate will be compared to historical data in order to assess the intracranial treatment efficacy.

  12 weeks after intervention initiation

Secondary Outcomes (6)

• Cohort 1 secondary end-point: plasma concentrations of osimertinib and AZ5104

  2-18 months after intervention initiation

• Cohort 1 secondary end-point: safety set

  2-18 months after intervention initiation

• Cohort 1 secondary end-point: Cost-effectiveness analysis

  2-18 months after intervention initiation

• Cohort 1 secondary end-point: CYP3A predictiveness for osimertinib exposure

  2-18 months after intervention initiation

• Cohort 2 secondary end-point: plasma concentrations of osimertinib and AZ5104

  12 weeks after intervention initiation

Other Outcomes (5)

• Cohort 1 exploratory end-point: Comparison of progression-free survival to historical data

  2-18 months after intervention initiation

• Cohort 2 exploratory end-point: Comparison of Progression-free Survival to historical data

  12 weeks after intervention initiation

• Cohort 2 exploratory end-point: Extracranial disease control

  12 weeks after intervention initiation

Study Arms (2)

Cohort 1: Adjusting osimertinib treatment plans with concomitant pk-boosting

EXPERIMENTAL

Feasibility of using pharmacokinetic boosting and TDM to individualize treatment plans and dosage for osimertinib, in patients with advanced NSCLC with mutated EGFR. In this cohort, patients will receive cobicistat for pharmacokinetic boosting of standard osimertinib treatment. Afterwards, they will receive personalised treatment plans, guided by therapeutic drug monitoring.

Drug: Cobicistat

Cohort 2: Improving osimertinib CNS penetration in patients with neurometastases

EXPERIMENTAL

Assessing whether pharmacokinetic boosting can improve CNS penetration of osimertinib, in patients with advanced NSCLC with mutated EGFR with asymptomatic CNS oligoprogression. Patients who experience progressive disease intracranially, are sometimes dose-escalated to try and improve osimertinib intracranial exposure. This study will look to demonstrate the feasibility of using a PK-booster instead, potentially providing patients the benefits of higher intracranial treatment efficacy, without needing to take extra osimertinib.

Drug: Cobicistat

Interventions

Cobicistat DRUG

Feasibility of pharmacokinetic boosting using cobicistat for personalized treatment strategies for osimertinib.

Also known as: Tybost

Cohort 1: Adjusting osimertinib treatment plans with concomitant pk-boosting; Cohort 2: Improving osimertinib CNS penetration in patients with neurometastases

Eligibility Criteria

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

You may qualify if:

• In order to be eligible to participate in this cohort 1, a subject must meet all of the following criteria:
• The patient is set to receive osimertinib 80 mg QD as part of their standard treatment plan
• The patient has a World Health Organization (WHO) Performance Status (PS) of ≤2.
• The patient is 18 years or older
• The patient is able and willing to sign informed consent
• The patient is able and willing to undergo blood sampling
• The patient has non-squamous advanced EGFR-mutated NSCLC with no signs of imminent progression (CT confirmed). If the patient does have signs of progression, they are only eligible if their treating physician deems the treatment to be appropriate beyond progression.
• The patient consents to their blood being analysed for CYP3A-genotype
• In order to be eligible to participate in this cohort 2, a subject must meet all of the following criteria:
• The patient is set to receive osimertinib 80 mg QD as part of their standard treatment plan
• The patient has a World Health Organization (WHO) Performance Status (PS) of ≤2.
• The patient is 18 years or older
• The patient is able and willing to sign informed consent
• The patient is able and willing to undergo blood sampling
• The patient has non-squamous EGFR-mutated NSCLC with radiologically confirmed progressive (RECIST v1.1), but asymptomatic intracranial metastasis, not in an eloquent area (to be discussed with neurologist). Furthermore, the disease is controlled extracranially (no RECIST v1.1 progression).

You may not qualify if:

• A potential participant who meets any of the following criteria will be excluded from participation in this study:
• The patient does not take any other drug which is known to strongly inhibit CYP3A4/CYP3A5 activity
• The patient does not take any other drug which is metabolized by CYP3A4/CYP3A5 and which has a small therapeutic window
• The patient does not take any drug or product which may otherwise affect CYP3A4/CYP3A5 metabolic activity
• The patient does not have impaired gastrointestinal function
• The patient is neither pregnant nor breastfeeding
• The patient does not have any contra-indication for cobicistat prescription, as listed in the summary of product characteristics for cobicistat

Sponsors & Collaborators

• Maastricht University Medical Center: lead

Study Sites (1)

MaastrichtUMC

Maastricht, Limburg, 6229HX, Netherlands

RECRUITING

Related Publications (2)

• 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 BACKGROUND

• 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 BACKGROUND

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

• Lizza Hendriks, MD, PhD

  Maastricht University Medical Centre+

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Paul Kruithof, PharmD, MSc

CONTACT

+31433871881; paul.kruithof@mumc.nl

Sander Croes, PharmD, PhD

CONTACT

+31433871881; s.croes@mumc.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study will involve two cohorts, which will both receive PK-boosting, but for different purposes, and with different primary outcomes. The cohorts will not be compared, and there will be no cross-over between cohorts.

Study Record Dates

• First Submitted: February 2, 2023
• First Posted: February 28, 2023
• Study Start: April 1, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: August 9, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)