Open-label PET Study With [11C]Osimertinib in Patients With EGFRm NSCLC and Brain Metastases

NCT03463525 | Completed Phase 1 Results

• 1 other identifier: D5160C00043
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, single centre, Phase I study to determine the brain exposure of \[11C\]osimertinib in patients with EGFRm NSCLC with brain metastases.

Conditions

Non-small Cell Lung Cancer

Keywords

Carcinoma, Non-Small-Cell Lung

Outcome Measures

Primary Outcomes (4)

• Maximum Concentration of Percent of Injected Dose in the Whole Brain (Cmax, %ID Brain) of [11C]Osimertinib

  During the PET examination time, a series of arterial blood samples were taken to measure Cmax, %ID brain of \[11C\]osimertinib.

  Day 1, Day 2 (or up to Day 8) and Day 25

• Maximum Concentration of Brain Standardized Uptake Value (Cmax, SUV Brain) of [11C]Osimertinib

  During the PET examination time, a series of arterial blood samples were taken to measure Cmax, SUV brain of \[11C\]osimertinib.

  Day 1, Day 2 (or up to Day 8) and Day 25

• Time of Maximum Radioactivity Concentration in the Brain (Tmax, Brain) of [11C]Osimertinib

  The Tmax, brain was determined directly from the observed concentration versus time data.

  Day 1, Day 2 (or up to Day 8) and Day 25

• Brain to Plasma Partition Coefficient (Kp) of [11C]Osimertinib

  The Kp was defined as ratio of radiolabeled drug in brain to that in plasma calculated as area under the brain radioactivity concentration-time curve between 0 and 90 minutes/area under the plasma radioactivity concentration-time curve between 0 and 90 minutes.

  Day 1, Day 2 (or up to Day 8) and Day 25

Secondary Outcomes (5)

• Maximum Concentration at Steady State (Css,Max) of Osimertinib and Metabolite AZ5104

  Pre-dose and 2, 4 and 7.5 hours postdose on Day 25

• Time of Maximum Drug Concentration at Steady State (Tss,Max) of Osimertinib and Metabolite AZ5104

  Pre-dose and 2, 4 and 7.5 hours postdose on Day 25

• Area Under the Concentration-Time Curve at Steady State (AUCss) of Osimertinib and Metabolite AZ5104

  Pre-dose and 2, 4 and 7.5 hours postdose on Day 25

• Metabolite to Parent Ratio of AUCss

  Pre-dose and 2, 4 and 7.5 hours postdose on Day 25

• Metabolite to Parent Ratio of Css,Max

  Pre-dose and 2, 4 and 7.5 hours postdose on Day 25

Study Arms (1)

[11C]osimertinib + oral osimertinib

EXPERIMENTAL

IV microdose administrations of \[11C\]osimertinib co-administered with 80 mg daily oral osimertinib.

Drug: Osimertinib; Drug: [11C]osimertinib

Interventions

Osimertinib DRUG

Osimertinib 80 mg once daily p.o. will be taken continuously by the patient from the day of the second PET exam.

Also known as: Tagrisso, AZD9291

[11C]osimertinib + oral osimertinib

[11C]osimertinib DRUG

Patients will receive 3 single IV microdose administrations of \[11C\]osimertinib and PET exams on: Day 1, Day 2 (or up to Day 8) and Day 29.

Also known as: [11C]AZD9291

[11C]osimertinib + oral osimertinib

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses. Procedures performed for routine clinical practice up to 2 weeks before the provision of written consent are acceptable if not intentionally done for study purposes.
• If a patient declines to participate in any voluntary exploratory research and/or genetic component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study.
• Male or female aged at least 18 years.
• Histological or cytological confirmation of diagnosis of NSCLC.
• Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR-TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or T790M EGFR resistance mutation as assessed by local laboratory/or central laboratory via tissue/cytology or in plasma.
• Mandatory provision (if available) of formalin fixed, paraffin embedded tissue and blood for central confirmation of EGFR mutation status. Please refer to the Laboratory Manual for details.
• In all patients enrolled, confirmed BM as having at least one non-measurable and/or measurable brain lesion at baseline as per CNS RECIST 1.1 via MRI imaging.
• World Health Organisation (WHO) performance status 0 to 2 and a minimum life expectancy of 4 weeks.
• Females should be using adequate contraceptive measures (up to 6 months after the last administration), should not be breastfeeding and must have a negative serum pregnancy test prior to start of dosing if of childbearing potential or must have evidence of non-childbearing potential by fulfilling 1 of the following criteria at screening:
• Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
• Women under 50 years old would be consider postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
• Male subjects should be willing to use barrier contraception
• Have a body mass index (BMI) between 18.0 kg/m2 and 30.0 kg/m2 inclusive and weigh at least 40.0 kg and no more than 100.0 kg, inclusive
• Able and willing to participate in all scheduled evaluations, abide by all study restrictions, and complete all required tests and procedures.

You may not qualify if:

• Participation in another clinical study with an IP during the previous 14 days (or longer, depending on characteristics of agents used).
• Treatment with any of the following: EGFR-TKI (e.g. erlotinib, gefitinib or afatinib) within 10 days or at least 5x the half-life, whichever is the longer; any cytotoxic chemotherapy, investigational agents or other anticancer drugs within 14 days of start of IP; osimertinib in the present or other studies; major surgery (excluding placement of vascular access) within 4 weeks of start of IP; radiotherapy (including brain) with a limited field of radiation within 1 week of start of IP, except in patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation which must be completed within 4 weeks of the first administration of the IP; current receipt (or inability to stop at least 3 weeks before study start) medications or herbal supplements known to be potent inducers of CYP3A4.
• Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting the IP with the exception of alopecia and grade 2, prior platinum therapy-related neuropathy.
• History of brain surgery or major brain trauma in the last year (if the surgery is in the same hemisphere as the brain metastasis).
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses or active infection including hepatitis B, hepatitis C and HIV.
• Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) \>470 msec obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value.
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block, second degree heart block).
• Patient with any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as electrolyte abnormalities including:
• Serum/plasma potassium \<lower limit of normal (LLN)
• Serum/plasma magnesium \<lower limit normal (LLN)
• Serum/plasma calcium \<lower limit normal (LLN)
• Heart failure, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes.
• Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
• Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Stockholm, SE 11 282, Sweden

Location

Related Links

• Related Info
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MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

osimertinib

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

The COVID-19 pandemic resulted in recruitment being put on hold due to the PET center closing. The Global Study Team endorsed the decision to have fewer participants than anticipated. Participants enrolled in the study continued as planned.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

+1 877-240-9479

Study Officials

• Simon Ekman, MD

  Karolinska University Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2018
• First Posted: March 13, 2018
• Study Start: October 24, 2018
• Primary Completion: March 19, 2020
• Study Completion: October 5, 2020
• Last Updated: January 27, 2023
• Results First Posted: January 27, 2023

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

SE (1)