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.

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.

Inclusion Criteria

1. 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.

2. Male or female aged at least 18 years.

3. Histological or cytological confirmation of diagnosis of NSCLC.

4. 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.

5. 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.

6. 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.

7. World Health Organisation (WHO) performance status 0 to 2 and a minimum life expectancy of 4 weeks.

8. 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.

9. Male subjects should be willing to use barrier contraception

10. 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

11. Able and willing to participate in all scheduled evaluations, abide by all study restrictions, and complete all required tests and procedures.

Exclusion Criteria

1. Participation in another clinical study with an IP during the previous 14 days (or longer, depending on characteristics of agents used).

2. 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.

3. 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.

4. History of brain surgery or major brain trauma in the last year (if the surgery is in the same hemisphere as the brain metastasis).

5. 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.

6. 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.

7. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.

8. 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).

9. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the tablet or previous significant bowel resection that would preclude adequate absorption of osimertinib.

10. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.

11. 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

12. Patients on anticoagulant treatment.

13. Absence of collateral flow between ulnar and radial artery as assessed by the Allen´s test".

14. 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.

15. Previous participation in a research PET or PET/CT study.

16. The following are exclusion criteria for contrast enhanced MRIs:

    • Glomerular filtration rate <30 ml/min
    • History of renal insufficiency
    • Pregnancy

17. Women who are breast-feeding.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

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.

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.

The safety analysis set included all participants who received at least one administration of [11C]osimertinib and/or osimertinib.

Adverse events were collected from the first dose administration of study drug (Day 1) up to 30 days after last dose administration of study drug, approximately 55 days.

The safety analysis set included all participants who received at least one administration of [11C]osimertinib and/or osimertinib.

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.