Improving Osimertinib Exposure and Cost-effectiveness Using Pharmacokinetic Boosting With Cobicistat (OSIBOOST 2)

Improving Osimertinib Exposure and Cost-effectiveness Using Pharmacokinetic Boosting With Cobicistat (OSIBOOST 2)

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.

Study Overview

• Status: Recruiting
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Cobicistat

Detailed Description

In 2016 Osimertinib was registered for the treatment of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) with an activating Epidermal Growth Factor Receptor (EGFR) mutation, initially only for patients with the T790M resistance mutation, but since 2018 also in the first line treatment. Use of osimertinib in the first line provides improved overall survival and progression-free survival, more potent efficacy against brain metastases, and better tolerability compared to older generation EGFR tyrosine kinase inhibitors (EGFR-TKIs). The downside of osimertinib is that -like many new anticancer agents- it is highly expensive (over €70 000 per patient per year in the Netherlands). In a period of five years, healthcare costs associated with expensive medication have risen from €1.71 billion to €2.46 billion per year in the Netherlands. The Dutch Cancer Society has warned that this astronomical cost increase will start to suffocate the national health care budget. In order to safeguard sustained affordability and accessibility of oncological healthcare, improving cost-effectiveness of available drugs is of paramount importance. In a previous study, we have demonstrated that osimertinib exposure may be boosted, through concomitant use of cobicistat, as a result of CYP3A4 inhibition. We now aim to apply pharmacokinetic (PK) boosting in order to improve osimertinib exposure and cost-effectiveness, without impacting treatment efficacy and safety.

This trial is designed to study whether pharmacokinetic boosting may alleviate these issues. In the first cohort, we will assess whether PK-boosting is able to reduce the amount of osimertinib which a patient needs to take. In order to assess this, the patient will receive cobicistat (the booster drug) and we will measure the amount of osimertinib and its metabolite in blood. Afterwards, the researchers and physicians may calculate how much osimertinib a patient actually needs. Ideally this will both reduce the amount of osimertinib that a patient needs to take, as well as reduce the price-tag of the overall treatment. In the second cohort, we will assess whether PK-boosting is a viable alternative to dose-doubling osimertinib. Some patients with NSCLC develop progressive CNS metastases despite osimertinib therapy. There is an indication that increasing the osimertinib dosage to double the standard therapy might provide longer/better treatment efficacy in these patients. Because of the tremendous cost associated with double-dosing osimertinib, most health care insurance providers in the Netherlands do not cover this therapy. In cohort 2 we look to find out whether PK-boosting might provide a similar effect to increasing the dosage, for a far more affordable price-tag.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Paul Kruithof, PharmD, MSc; Phone Number: +31433871881; Email: paul.kruithof@mumc.nl
• Study Contact Backup: Name: Sander Croes, PharmD, PhD; Phone Number: +31433871881; Email: s.croes@mumc.nl

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229HX
      • Recruiting
      • MaastrichtUMC
      • Contact: Paul Kruithof, PharmD, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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).

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Adjusting osimertinib treatment plans with concomitant pk-boosting; 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; Feasibility of pharmacokinetic boosting using cobicistat for personalized treatment strategies for osimertinib.; Other Names: Tybost
Experimental: Cohort 2: Improving osimertinib CNS penetration in patients with neurometastases; 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; Feasibility of pharmacokinetic boosting using cobicistat for personalized treatment strategies for osimertinib.; Other Names: Tybost

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 1 secondary end-point: plasma concentrations of osimertinib and AZ5104	In order to assess the extent of pharmacokinetic boosting in plasma, the plasma concentrations of osimertinib and AZ5104 (metabolite) will be determined.	2-18 months after intervention initiation
Cohort 1 secondary end-point: safety set	Number of (serious) adverse events as graded by CTCAE	2-18 months after intervention initiation
Cohort 1 secondary end-point: Cost-effectiveness analysis	If in cohort 1 the overall treatment is considered "feasible". An assessment of overall average treatment cost per patient per day will be made for the experimental treatment plan. This will be compared to the current standard treatment cost using a Health-Technology Assessment (HTA). If efficacy endpoints cannot be determined, but the trial treatment is considered "feasible", then the trial treatment will be assessed as "non-inferior" (as the TDM-strategy looks to maintain similar drug exposure).	2-18 months after intervention initiation
Cohort 1 secondary end-point: CYP3A predictiveness for osimertinib exposure	Assessing predictiveness of CYP3A-polymorphism for osimertinib exposure. This will be done by statistically comparing osimertinib exposure for patient groups with different genotypes.	2-18 months after intervention initiation
Cohort 2 secondary end-point: plasma concentrations of osimertinib and AZ5104	In order to assess the extent of pharmacokinetic boosting in plasma, the plasma concentrations of osimertinib and AZ5104 (metabolite) will be determined.	12 weeks after intervention initiation
Cohort 2 secondary end-point: safety set	Number of (serious) adverse events as graded by CTCAE	12 weeks after intervention initiation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 1 exploratory end-point: Comparison of progression-free survival to historical data	The efficacy of palliative cancer treatment is mostly assessed through progression-free survival. Because of its explorative nature, this trial will not be equipped to provide a statistical analysis of both treatments. Therefore average progression-free survival will be compared numerically to historical data, in order to provide an indication of treatment efficacy.	2-18 months after intervention initiation
Cohort 2 exploratory end-point: Comparison of Progression-free Survival to historical data	The efficacy of palliative cancer treatment is mostly assessed through progression-free survival. Because of its explorative nature, this trial will not be equipped to provide a statistical analysis of both treatments. Therefore average progression-free survival will be compared numerically to historical data, in order to provide an indication of treatment efficacy.	12 weeks after intervention initiation
Cohort 2 exploratory end-point: Extracranial disease control	Disease control rate for extracranial disease, as assessed by thoracic imaging	12 weeks after intervention initiation
Cohort 2 exploratory end-point: Osimertinib and AZ5104 concentrations in cerebrospinal fluid.	On a voluntary basis, patients may opt to undergo lumbar punctures, to allow for determination of osimertinib and AZ5104 (metabolite) exposure in the brain liquor (cerebrospinal fluid). This will be a purely descriptive analysis. This technique might help to shed light on how well osimertinib and its metabolite is able to reach CNS metastases. Because of the invasive nature of the analysis, lumbar punctures will be considered optional, and not required for trial participation.	12 weeks after intervention initiation
Cohort 2 exploratory end-point: Liquid biopsy measurements of resistance mutations in cerebrospinal fluid	On a voluntary basis, patients may opt to undergo lumbar punctures, to allow for determination of tumor-cell genotype and the presence of resistance mutations through liquid biopsy analysis. This will be a purely descriptive analysis. This technique might help to shed light on how resistance develops in CNS metastases. Because of the invasive nature of the analysis, lumbar punctures will be considered optional, and not required for trial participation.	12 weeks after intervention initiation

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: Lizza Hendriks, MD, PhD, Maastricht University Medical Centre+

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: February 2, 2023
• First Submitted That Met QC Criteria: February 17, 2023
• First Posted (Actual): February 28, 2023

Study Record Updates

• Last Update Posted (Actual): August 9, 2024
• Last Update Submitted That Met QC Criteria: August 7, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Osimertinib; Non-small Cell Lung Cancer; Cobicistat; CNS metastases; Boosting
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cobicistat
• Other Study ID Numbers: OSIBOOST 2; 2023-505700-35-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes