Open-label PET Study With [11C]Osimertinib in Patients With EGFRm NSCLC and Brain Metastases
Condition: Non-small Cell Lung Cancer
MeSH terms: Brain Neoplasms
Intervention: Osimertinib; [11C]osimertinib
Intervention description: Osimertinib 80 mg once daily p.o. will be taken continuously by the patient from the day of the second PET exam.; 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.
Intervention MeSH terms: Osimertinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Carcinoma, Non-Small-Cell Lung

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.
    

Eligibility criteria:

        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.