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

Study Overview
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Brief Summary
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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.

Detailed Description
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A Single-centre, Open-label, PET imaging and Pharmacokinetic Study of IV Administered [11C]osimertinib in EGFRm Non-small cell lung cancer patients with brain metastases. The study will consist of 2 phases, an imaging phase and a continuous access phase.

Official Title
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An Open-label PET Study to Determine Brain Exposure of Osimertinib After IV Microdose Administration of [11C]Osimertinib and Therapeutic Oral Doses of Osimertinib to Patients With EGFR Mutated NSCLC With Brain Metastases

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib
* Drug: [11C]osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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. Exclusion Criteria 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: ANC <1.5 × 109/L; Platelets <100 × 109/L; Haemoglobin <90 g/L; Alanine aminotransferase (ALT) >2.5x ULN or >5x ULN in the presence of liver metastases; Aspartate aminotransferase (AST) >2.5x ULN or >5x ULN in the presence of liver metastases; Total bilirubin >1.5x ULN or >3x ULN in the presence of liver metastases or Gilbert's Syndrome; Creatinine >1.5xl ULN concurrent with creatinine clearance <50 mL/min (using Cockcroft-Gault formula). Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the tablet or previous significant bowel resection that would preclude adequate absorption of osimertinib. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib. In addition, the following is considered a criterion for exclusion from the exploratory genetic research: Previous allogenic bone marrow transplant Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection Patients on anticoagulant treatment. Absence of collateral flow between ulnar and radial artery as assessed by the Allen´s test. Suffering from claustrophobia and/or having implanted metal devices or implants such as pacemaker, vascular or heart valves or metal deposits such as bullets, shells, metal grains in the eyes. Previous participation in a research PET or PET/CT study. The following are exclusion criteria for contrast enhanced MRIs: Glomerular filtration rate <30 ml/min History of renal insufficiency Pregnancy Women who are breast-feeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: [11C]osimertinib + oral osimertinib<br>IV microdose administrations of [11C]osimertinib co-administered with 80 mg daily oral osimertinib. | Drug: Osimertinib<br>* Osimertinib 80 mg once daily p.o. will be taken continuously by the patient from the day of the second PET exam.<br>* Other names: AZD9291;Drug: [11C]osimertinib<br>* 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.<br>* Other names: [11C]AZD9291;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration at Steady State (Css,Max) of Osimertinib and Metabolite AZ5104 | Venous blood samples were collected to determine 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 | Venous blood samples were collected to determine 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 | Venous blood samples were collected to determine 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 | Venous blood samples were collected to determine AUCss of osimertinib and metabolite AZ5104. | Pre-dose and 2, 4 and 7.5 hours postdose on Day 25 | 
| Metabolite to Parent Ratio of Css,Max | Venous blood samples were collected to determine Css,max of osimertinib and metabolite AZ5104. | Pre-dose and 2, 4 and 7.5 hours postdose on Day 25 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, Non-Small-Cell Lung