Non-small Cell Lung Cancer
Conditions
Keywords
Carcinoma, Non-Small-Cell Lung
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.
Detailed description
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.
Interventions
DRUGOsimertinib
Osimertinib 80 mg once daily p.o. will be taken continuously by the patient from the day of the second PET exam.
DRUG[11C]osimertinib
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.
Sponsors
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration of Percent of Injected Dose in the Whole Brain (Cmax, %ID Brain) of [11C]Osimertinib | Day 1, Day 2 (or up to Day 8) and Day 25 | During the PET examination time, a series of arterial blood samples were taken to measure Cmax, %ID brain of \[11C\]osimertinib. |
| Maximum Concentration of Brain Standardized Uptake Value (Cmax, SUV Brain) of [11C]Osimertinib | Day 1, Day 2 (or up to Day 8) and Day 25 | During the PET examination time, a series of arterial blood samples were taken to measure Cmax, SUV brain of \[11C\]osimertinib. |
| Time of Maximum Radioactivity Concentration in the Brain (Tmax, Brain) of [11C]Osimertinib | Day 1, Day 2 (or up to Day 8) and Day 25 | The Tmax, brain was determined directly from the observed concentration versus time data. |
| Brain to Plasma Partition Coefficient (Kp) of [11C]Osimertinib | Day 1, Day 2 (or up to Day 8) and Day 25 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Venous blood samples were collected to determine Css,max of osimertinib and metabolite AZ5104. |
| Metabolite to Parent Ratio of Css,Max | Pre-dose and 2, 4 and 7.5 hours postdose on Day 25 | Venous blood samples were collected to determine Css,max of osimertinib and metabolite AZ5104. |
| 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 | Venous blood samples were collected to determine tss,max of osimertinib and metabolite AZ5104. |
| 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 | Venous blood samples were collected to determine AUCss of osimertinib and metabolite AZ5104. |
| Metabolite to Parent Ratio of AUCss | Pre-dose and 2, 4 and 7.5 hours postdose on Day 25 | Venous blood samples were collected to determine AUCss of osimertinib and metabolite AZ5104. |
Countries
Sweden
Participant flow
Recruitment details
This Phase 1 study was conducted in participants with epidermal growth factor receptor mutation positive non-small cell lung cancer with brain metastases at a single center in Sweden.
Pre-assignment details
The study consisted of 2 phases, an Imaging Phase and a Continued Access Phase. A total of 4 participants were enrolled in this study. All 4 participants received treatment and completed the study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received \[11C\]osimertinib IV microdose (\< 10 μg) with radioactivity of 300 MBq/70 kg of body weight prior to PET examinations on Day 1, Day 2 (or up to Day 8), and Day 25 (±4 days). The minimum injected radioactivity was 200 MBq/70 kg and the maximum was 330 MBq/70 kg of body weight. Additionally, participants received osimertinib 80 mg oral tablets once daily from the day of the second PET examination for at least 21 days till the third PET examination. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 4 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 3 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
Primary
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.
Time frame: Day 1, Day 2 (or up to Day 8) and Day 25
Population: The PET analysis set included all participants who completed at least one PET examination for the evaluation of \[11C\]osimertinib brain distribution.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Brain to Plasma Partition Coefficient (Kp) of [11C]Osimertinib | Day 1: PET1 | 3.753 ratio | Standard Deviation 0.8328 |
| All Participants | Brain to Plasma Partition Coefficient (Kp) of [11C]Osimertinib | Day 2 (or up to Day 8): PET2 | 3.960 ratio | Standard Deviation 0.9413 |
| All Participants | Brain to Plasma Partition Coefficient (Kp) of [11C]Osimertinib | Day 25: PET3 | 4.658 ratio | Standard Deviation 1.5362 |
Primary
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.
Time frame: Day 1, Day 2 (or up to Day 8) and Day 25
Population: The PET analysis set included all participants who completed at least one PET examination for the evaluation of \[11C\]osimertinib brain distribution.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Maximum Concentration of Brain Standardized Uptake Value (Cmax, SUV Brain) of [11C]Osimertinib | Day 1: PET1 | 1.006 SUV | Geometric Coefficient of Variation 27.1 |
| All Participants | Maximum Concentration of Brain Standardized Uptake Value (Cmax, SUV Brain) of [11C]Osimertinib | Day 25: PET3 | 1.054 SUV | Geometric Coefficient of Variation 29.1 |
| All Participants | Maximum Concentration of Brain Standardized Uptake Value (Cmax, SUV Brain) of [11C]Osimertinib | Day 2 (or up to Day 8): PET2 | 1.111 SUV | Geometric Coefficient of Variation 22 |
Primary
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.
Time frame: Day 1, Day 2 (or up to Day 8) and Day 25
Population: The PET analysis set included all participants who completed at least one PET examination for the evaluation of \[11C\]osimertinib brain distribution.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Maximum Concentration of Percent of Injected Dose in the Whole Brain (Cmax, %ID Brain) of [11C]Osimertinib | Day 25: PET3 | 1.492 percent of radioactive drug | Geometric Coefficient of Variation 15.1 |
| All Participants | Maximum Concentration of Percent of Injected Dose in the Whole Brain (Cmax, %ID Brain) of [11C]Osimertinib | Day 1: PET1 | 1.465 percent of radioactive drug | Geometric Coefficient of Variation 9.6 |
| All Participants | Maximum Concentration of Percent of Injected Dose in the Whole Brain (Cmax, %ID Brain) of [11C]Osimertinib | Day 2 (or up to Day 8): PET2 | 1.617 percent of radioactive drug | Geometric Coefficient of Variation 6.6 |
Primary
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.
Time frame: Day 1, Day 2 (or up to Day 8) and Day 25
Population: The PET analysis set included all participants who completed at least one PET examination for the evaluation of \[11C\]osimertinib brain distribution.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Time of Maximum Radioactivity Concentration in the Brain (Tmax, Brain) of [11C]Osimertinib | Day 1: PET1 | 22.160 minutes |
| All Participants | Time of Maximum Radioactivity Concentration in the Brain (Tmax, Brain) of [11C]Osimertinib | Day 2 (or up to Day 8): PET2 | 36.340 minutes |
| All Participants | Time of Maximum Radioactivity Concentration in the Brain (Tmax, Brain) of [11C]Osimertinib | Day 25: PET3 | 37.125 minutes |
Secondary
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.
Time frame: Pre-dose and 2, 4 and 7.5 hours postdose on Day 25
Population: The PK analysis set included all participants who received at least one administration of either \[11C\]osimertinib and/or osimertinib and had postadministration PK assessments of osimertinib and/or its metabolite AZ5104 without any protocol deviations or administration deviations that could have affected the PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Area Under the Concentration-Time Curve at Steady State (AUCss) of Osimertinib and Metabolite AZ5104 | Osimertinib | 13080 h*nmol/L | Geometric Coefficient of Variation 32.7 |
| All Participants | Area Under the Concentration-Time Curve at Steady State (AUCss) of Osimertinib and Metabolite AZ5104 | Metabolite AZ5104 | 1666 h*nmol/L | Geometric Coefficient of Variation 64.12 |
Secondary
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.
Time frame: Pre-dose and 2, 4 and 7.5 hours postdose on Day 25
Population: The Pharmacokinetic (PK) analysis set included all participants who received at least one administration of either \[11C\]osimertinib and/or osimertinib and had postadministration PK assessments of osimertinib and/or its metabolite AZ5104 without any protocol deviations or administration deviations that could have affected the PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Maximum Concentration at Steady State (Css,Max) of Osimertinib and Metabolite AZ5104 | Osimertinib | 648.0 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 29.61 |
| All Participants | Maximum Concentration at Steady State (Css,Max) of Osimertinib and Metabolite AZ5104 | Metabolite AZ5104 | 76.53 nanomole per liter (nmol/L) | Geometric Coefficient of Variation 59.58 |
Secondary
Metabolite to Parent Ratio of AUCss
Venous blood samples were collected to determine AUCss of osimertinib and metabolite AZ5104.
Time frame: Pre-dose and 2, 4 and 7.5 hours postdose on Day 25
Population: The PK analysis set included all participants who received at least one administration of either \[11C\]osimertinib and/or osimertinib and had postadministration PK assessments of osimertinib and/or its metabolite AZ5104 without any protocol deviations or administration deviations that could have affected the PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Metabolite to Parent Ratio of AUCss | 0.1274 ratio | Geometric Coefficient of Variation 27.89 |
Secondary
Metabolite to Parent Ratio of Css,Max
Venous blood samples were collected to determine Css,max of osimertinib and metabolite AZ5104.
Time frame: Pre-dose and 2, 4 and 7.5 hours postdose on Day 25
Population: The PK analysis set included all participants who received at least one administration of either \[11C\]osimertinib and/or osimertinib and had postadministration PK assessments of osimertinib and/or its metabolite AZ5104 without any protocol deviations or administration deviations that could have affected the PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| All Participants | Metabolite to Parent Ratio of Css,Max | 0.1181 ratio | Geometric Coefficient of Variation 28.91 |
Secondary
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.
Time frame: Pre-dose and 2, 4 and 7.5 hours postdose on Day 25
Population: The PK analysis set included all participants who received at least one administration of either \[11C\]osimertinib and/or osimertinib and had postadministration PK assessments of osimertinib and/or its metabolite AZ5104 without any protocol deviations or administration deviations that could have affected the PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Time of Maximum Drug Concentration at Steady State (Tss,Max) of Osimertinib and Metabolite AZ5104 | Osimertinib | 4.0 hours (h) |
| All Participants | Time of Maximum Drug Concentration at Steady State (Tss,Max) of Osimertinib and Metabolite AZ5104 | Metabolite AZ5104 | 4.0 hours (h) |