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Open Label, Prospective Study to Investigate Efficacy and Safety of AZD9291 in BM From NSCLC Patients With EGFR T790M

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ClinicalTrials.gov Identifier: NCT02972333
Recruitment Status : Unknown
Verified November 2016 by Jinming Yu, Shandong Cancer Hospital and Institute.
Recruitment status was:  Not yet recruiting
First Posted : November 23, 2016
Last Update Posted : November 23, 2016
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Jinming Yu, Shandong Cancer Hospital and Institute

Brief Summary:
The study aims to investigate the efficacy and safety of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.

Condition or disease Intervention/treatment Phase
EGFR-TKI Resistant Mutation Nonsmall Cell Lung Cancer AZD9291 Brain Metastases Drug: AZD9291 80mg oral each day Radiation: Radiation therapy Phase 3

Detailed Description:
Patients with confirmed EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI and concurrent with brain metastasis will be enrolled into the study. All eligible patients will have access to AZD9291 regimen through the ASTRIS study as long as they continue to show clinical benefit.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open Label, Multi-center, Prospective Study to Investigate the Efficacy and Safety of AZD9291 in Brain Metastases From Patients With EGFR T790M Positive NSCLC Who Have Received Prior Therapy With an EGFR-TKI
Study Start Date : December 2016
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: AZD9291 80mg oral each day±RT
AZD9291(80mg, QD, p.o.) was provided to patients with confirmed EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI and concurrent with brain metastasis. Radiation therapy will be implemented according to investigator's clinical practice(A 7-10 days washout period before radiotherapy and 1 week period after completion of brain radiothearpy before re-starting AZD9291.).
Drug: AZD9291 80mg oral each day
All eligible patients will have access to AZD9291 regimen through the ASTRIS study as long as they continue to show clinical benefit.
Other Name: AZD9291, 80mg, QD, p.o. (2nd line or later)

Radiation: Radiation therapy
Radiation therapy will be implemented according to investigator's clinical practice.Based on the guidelines provided for the interruption of ADZ9291 with brain radiation therapy, a 7-10 days washout period before radiotherapy and 1 week period after completion of brain radiothearpy before re-starting AZD9291.
Other Name: WBRT or SRS




Primary Outcome Measures :
  1. PFSo (overall progression free survival) [ Time Frame: 2 years ]
    To assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI by PFSo


Secondary Outcome Measures :
  1. PFSe (extracranial progression-free survival) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  2. PFSi (intracranial progression-free survival) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  3. ORRo (overall objective response rate) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  4. ORRe (extracranial objective response rate) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  5. ORRi (intracranial objective response rate) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  6. DCRo (overall disease control rate) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  7. DCRe (extracranial disease control rate) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  8. DCRi (intracranial disease control rate) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  9. DoRo (overall duration of response) [ Time Frame: 3 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  10. DoRe (extracranial duration of response) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  11. DoRi (intracranial duration of response) [ Time Frame: 2 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  12. OS(overall survival) [ Time Frame: 3 years ]
    To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

  13. Adverse events/Serious adverse events [ Time Frame: 2 years ]
    To evaluate the safety and tolerability profile of AZD9291 and subgroups such as AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy and etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.

  14. QoL [ Time Frame: 2 years ]
    To assess disease-related symptoms and QoL in overall population as well as in pre-specified subgroups, e.g. AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.

  15. Cognitive function [ Time Frame: 2 years ]
    To assess disease-related symptoms and cognitive function in overall population as well as in pre-specified subgroups, e.g. AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.


Other Outcome Measures:
  1. T790M mutation positive rate [ Time Frame: 2 years ]
    To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.

  2. Concordance of T790M status between CSF and plasma [ Time Frame: 2 years ]
    To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.

  3. Change of imputed ctDNA concentration before and after treatment [ Time Frame: 2 years ]
    To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.

  4. Proportion of each genetic mutation [ Time Frame: 2 years ]
    To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.

  5. Change from baseline in glucose and protein levels [ Time Frame: 2 years ]
    To evaluate the changes from baseline in CSF biochemistry to support the demonstration of the anti-tumour effect of AZD9291 in addition to CSF cytology.

  6. Change from baseline in tumor cell count [ Time Frame: 2 years ]
    To evaluate the changes from baseline in CSF biochemistry to support the demonstration of the anti-tumour effect of AZD9291 in addition to CSF cytology.

  7. AZD9291 concentration level in CSF/plasma [ Time Frame: 2 years ]
    To explore potential relation between relevant efficacy measures, biomarkers or safety variables and plasma or CSF concentration of AZD9291 (or metabolites).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures
  2. Metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation.
  3. For patients with LM: Confirmed diagnosis of LM by positive CSF cytology. Diagnosis by MRI only is not eligible for study entry. At least one site of CNS leptomeningeal disease that can be assessed by magnetic resonance imaging (MRI) and which is suitable for repeat assessments. Measurable CNS or extracranial disease is not required.
  4. For patients with measurable BM but without LM: At least one measurable intracranial lesion that, if previously irradiated, has progressed or not responded to radiation therapy, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter by magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements. Measurable extracranial disease is not required.
  5. Prior therapy with an EGFR-TKI. Patients may have also received additional lines of treatment.
  6. World Health Organization (WHO) performance status 0-2 with no deterioration over the previous 2 weeks and a minimum life expectancy of 3 months.
  7. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, biochemistry in blood and urine at baseline.
  8. ECG recording at baseline showing absence of any cardiac abnormality as per exclusion criterion #10.
  9. Female patients of childbearing potential must be using adequate contraceptive measures (see Restrictions, Section 3.5), must not be breast feeding, and must have a negative pregnancy test prior to start of dosing. Otherwise, they must have evidence of nonchild bearing potential as defined below:

    1. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
    2. Women less than 50 years would be consider post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
    3. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
  10. Male patients must be willing to use barrier contraception, i.e., condoms.

Exclusion Criteria:

Subjects should not enter the study if any of the following exclusion criteria are fulfilled:

  1. Previous (within 6 months) or current treatment with AZD9291
  2. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of AZD9291) any treatment known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4 (Appendix B)
  3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, active infection* including hepatitis B, hepatitis C and human immunodeficiency virus, or significantly impaired bone marrow reserve or organ function, including hepatic and renal impairment, which in the investigator's opinion would significantly alter the risk/benefit balance.

    * active infection will include any patients receiving intravenous treatment for any infection and patients with hepatitis B or C surface antigen (+) - Patients receiving oral antiviral suppressive therapy for hepatitis B or C will be permitted to enrol in the study.

  4. Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids to manage CNS symptoms within the 2 weeks prior to start AZD9291 administration.
  5. Prior whole brain radiation therapy.
  6. Known intracranial hemorrhage which is unrelated to tumor.
  7. For patients with LM and/or BM, CNS complications that require urgent neurosurgical intervention (e.g. resection or shunt placement).
  8. For patients with LM, inability to undergo collection of CSF.
  9. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD
  10. Any of the following cardiac criteria:

    1. Mean resting corrected QT interval (QTcF) > 470 ms using Fredericia's formula :
    2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block)
    3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
  11. Any unresolved toxicity from prior therapy CTCAE > grade 3 at the time of starting treatment
  12. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical structure or class to AZD9291
  13. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:

    • Absolute neutrophil count < 1.5 x 10^9/L
    • Platelet count < 100 x 10^9/L
    • Haemoglobin < 90 g/L
    • Alanine aminotransferase > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases
    • Aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases
    • Total bilirubin > 1.5 times ULN. Total bilirubin >3 times the ULN in patients with documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or in the presence of liver metastases
    • Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 mL/min (measured or calculated by Cockcroft and Gault equation). Confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.
    • If bone metastases are present and liver function is otherwise considered adequate by the investigator then elevated ALP will not exclude the patient.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02972333


Contacts
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Contact: Jinming Yu, MD.PhD. 0086-531-67626919 sdyujinming@163.com
Contact: Ligang Xing, MD.PhD. 0086-531-67626819 xinglg@medmail.com.cn

Sponsors and Collaborators
Shandong Cancer Hospital and Institute
AstraZeneca
Investigators
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Principal Investigator: Jinming Yu, MD.PhD. Shandong Cancer Hospital and Institute
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Jinming Yu, Dean, Shandong Cancer Hospital and Institute
ClinicalTrials.gov Identifier: NCT02972333    
Other Study ID Numbers: APOLLO
First Posted: November 23, 2016    Key Record Dates
Last Update Posted: November 23, 2016
Last Verified: November 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Neoplasm Metastasis
Carcinoma, Non-Small-Cell Lung
Neoplastic Processes
Neoplasms
Pathologic Processes
Neoplasms by Site
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action