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出境医 / 临床实验 / Open-label PET Study With [11C]Osimertinib in Patients With EGFRm NSCLC and Brain Metastases (ODIN-BM)

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

Study Description
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.

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Drug: Osimertinib Drug: [11C]osimertinib Phase 1

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: 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
Actual Study Start Date : October 24, 2018
Actual Primary Completion Date : March 19, 2020
Actual Study Completion Date : October 5, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: [11C]osimertinib + oral osimertinib
IV microdose administrations of [11C]osimertinib co-administered with 80 mg daily oral osimertinib.
 Drug: Osimertinib
Osimertinib 80 mg once daily p.o. will be taken continuously by the patient from the day of the second PET exam.
Other Names:
  • Tagrisso
  • AZD9291

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.
Other Name: [11C]AZD9291
Outcome Measures
Primary Outcome Measures :
  1. Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 1 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan at baseline.

  2. Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken at baseline.

  3. Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken at baseline.

  4. Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken at baseline.

  5. Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 2 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan after a single dose of oral osimertinib.

  6. Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 29 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan after at least 21days of continuous oral osimertinib dosing.

  7. Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

  8. Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

  9. Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

  10. Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

  11. Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

  12. Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.


Secondary Outcome Measures :
  1. Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio [ Time Frame: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary). ]
    Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.

  2. Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax) [ Time Frame: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary). ]
    Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

  3. Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve [ Time Frame: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary). ]
    Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.

  4. Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary). ]
    Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.


Other Outcome Measures:
  1. Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with IV [11C]osimertinib administration [ Time Frame: From study Day 1 and until 30 days after the study drug is discontinued. ]
    Collection and assessment of adverse events graded using CTCAE (version 4.03).

  2. Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with continuous oral osimertinib [ Time Frame: From study Day 1 and until 30 days after the study drug is discontinued. ]
    Collection and assessment of adverse events using CTCAE (version 4.03)


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations

Locations
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Sweden
Research Site
Stockholm, Sweden, SE 11 282
Sponsors and Collaborators
AstraZeneca
Investigators
Layout table for investigator information
Principal Investigator: Simon Ekman, MD Karolinska University Hospital
Tracking Information
First Submitted Date  ICMJE February 20, 2018
First Posted Date  ICMJE March 13, 2018
Last Update Posted Date January 14, 2021
Actual Study Start Date  ICMJE October 24, 2018
Actual Primary Completion Date March 19, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 9, 2019)
  • Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 1 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan at baseline.
  • Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken at baseline.
  • Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken at baseline.
  • Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken at baseline.
  • Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 2 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan after a single dose of oral osimertinib.
  • Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 29 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan after at least 21days of continuous oral osimertinib dosing.
  • Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.
Original Primary Outcome Measures  ICMJE
 (submitted: March 12, 2018)
  • Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 1 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan at baseline.
  • Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken at baseline.
  • Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken at baseline.
  • Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken at baseline.
  • Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 2 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan after a single dose of oral osimertinib.
  • Brain Exposure to [11C]osimertinib in Tumour Region of Interest [ Time Frame: PET Scan on Day 29 ]
    Measurement of the brain standard uptake value (SUV) seen on PET scan after at least 21days of continuous oral osimertinib dosing.
  • Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 292, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib [ Time Frame: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.
  • Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC) [ Time Frame: Measurement collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection. ]
    Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2019)
  • Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio [ Time Frame: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary). ]
    Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.
  • Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax) [ Time Frame: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary). ]
    Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve [ Time Frame: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary). ]
    Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.
  • Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary). ]
    Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2018)
  • Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio [ Time Frame: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose. ]
    Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.
  • Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax) [ Time Frame: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose. ]
    Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve [ Time Frame: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose. ]
    Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.
  • Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 2 at pre-administration, 1, 2,4 and 6 hours post dose. ]
    Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio [ Time Frame: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose. ]
    Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.
  • Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax) [ Time Frame: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose. ]
    Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.
  • Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve [ Time Frame: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose. ]
    Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.
  • Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax) [ Time Frame: Blood samples collected on Day 29 at pre-administration, 1,2,4 and 6 hours post dose. ]
    Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.
Current Other Pre-specified Outcome Measures
 (submitted: March 12, 2018)
  • Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with IV [11C]osimertinib administration [ Time Frame: From study Day 1 and until 30 days after the study drug is discontinued. ]
    Collection and assessment of adverse events graded using CTCAE (version 4.03).
  • Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with continuous oral osimertinib [ Time Frame: From study Day 1 and until 30 days after the study drug is discontinued. ]
    Collection and assessment of adverse events using CTCAE (version 4.03)
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Open-label PET Study With [11C]Osimertinib in Patients With EGFRm NSCLC and Brain Metastases
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Non-small Cell Lung Cancer
Intervention  ICMJE
  • Drug: Osimertinib
    Osimertinib 80 mg once daily p.o. will be taken continuously by the patient from the day of the second PET exam.
    Other Names:
    • Tagrisso
    • AZD9291
  • 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.
    Other Name: [11C]AZD9291
Study Arms  ICMJE Experimental: [11C]osimertinib + oral osimertinib
IV microdose administrations of [11C]osimertinib co-administered with 80 mg daily oral osimertinib.
Interventions:
  • Drug: Osimertinib
  • Drug: [11C]osimertinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 22, 2020) 		4
Original Estimated Enrollment  ICMJE
 (submitted: March 12, 2018) 		8
Actual Study Completion Date  ICMJE October 5, 2020
Actual Primary Completion Date March 19, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03463525
Other Study ID Numbers  ICMJE D5160C00043
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: 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.
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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Simon Ekman, MD Karolinska University Hospital
PRS Account AstraZeneca
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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