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Study of AZD9291 in NSCLC Patients Harboring T790M Mutation Who Failed EGFR TKI and With Brain and/or LMS

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03257124
Recruitment Status : Unknown
Verified September 2017 by Myung-Ju Ahn, Samsung Medical Center.
Recruitment status was:  Recruiting
First Posted : August 22, 2017
Last Update Posted : September 7, 2017
Information provided by (Responsible Party):
Myung-Ju Ahn, Samsung Medical Center

Brief Summary:

AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and T790M resistance mutation but sparing wild-type EGFR. Preclinical studies indicate that AZD9291 has significant exposure in the brain and activity against EGFR mutant brain metastasis. In addition, anti-tumor activities of AZD9291 in patients with advanced stage EGFR mutant NSCLC including patients with brain metastasis have been reported in an ongoing Phase I study. More recently, AZD9291 at a dose of 160mg also showed promising efficacy in heavily pre-treated patients with leptomeningeal disease from EGFR mutant NSCLC. Among 11 evaluable for response, 6 patients had LM imaging improvement and 3 out of 7 patients with abnormal neurological exam at baseline had symptomatic improvement. Compared to AZD9291, other 3rd generation EGFR TKIs, rociletinib or HM61713 has not been reported to be effective in most of CNS disease of NSCLC. Further, previous studies with AZD9291 showed anecdotal case series or undetermined for T790M mutation status, indicating more systematic study is warranted.

Based on these data, the investigators are going to conduct phase II study of AZD9291 in NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal metastasis.

Condition or disease Intervention/treatment Phase
Non-Small Cell Lung Cancer With EGFR T790M Mutation With Brain and/or Leptomeningeal Metastasis Failed Tyrosine Kinase Inhibitors Drug: AZD9291 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
  1. Brain Metastasis cohort (BM cohort)
  2. Leptomeningeal Metastasis cohort (LM cohort)
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label, Multicenter, Phase II Study of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients Harboring T790M Mutation Who Failed EGFR TKIs and With Brain and/or Leptomeningeal Metastasis
Actual Study Start Date : May 8, 2017
Estimated Primary Completion Date : December 31, 2018
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: AZD9291 in BM or LM cohort in T790M positive
  1. Brain metastasis cohort (BM cohort)
  2. Leptomeningeal metastasis cohort (LM cohort)
Drug: AZD9291
AZD9291 160mg per oral daily (1 cycle of 28 days)

Primary Outcome Measures :
  1. Overall response rate (ORR) in CNS -brain metastasis cohort [ Time Frame: December, 2019 (one-year follow-up from last patient -in) ]
    At least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria

  2. Overall survival - Leptomeningeal with or without brain metastasis cohort [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months ]
    From the date of study start to the date of all cause death

Secondary Outcome Measures :
  1. Whole body disease control rate (DCR) [ Time Frame: December, 2019 (one-year follow-up from last patient -in) ]
    At least one visit response of CR (complete response), PR (partial response) or SD (stable disease) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria.

  2. Time to brain progression [ Time Frame: December, 2019 (one-year follow-up from last patient -in) ]
    Time to brain progression is measured from the date of start of study to the date of progression of BM or LM.

  3. Progression free survival (PFS) in BM cohort [ Time Frame: December, 2019 (one-year follow-up from last patient -in) ]
    measured from the date of start of study to the date of disease progression or death from any cause.

  4. Overall survival (OS) [ Time Frame: December, 2019 (one-year follow-up from last patient -in) ]
    OS is measured from the date of start of study to the date of death from any cause

  5. Adverse events (AEs) [ Time Frame: December, 2019 (one-year follow-up from last patient -in) ]
    Adverse events will be measured by the CTCAE scale, version 4.

  6. Exploratory analysis of EGFR mutation/T790M [ Time Frame: December, 2019 (one-year follow-up from last patient -in) ]
    Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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

Inclusion Criteria:

  • EGFR activating mutant NSCLC patients who failed EGFR TKIs (gefitinib, erlotinib, or afatinib) and develop CNS disease (BM and/or LM) with T790M mutation either tissue or plasma. For patients with intracranial progression, prior radiation therapy is not mandatory. Extracranial progression is allowed.
  • Patients who failed to 3rd generation EGFR TKIs (AZD9291 (80mg), Rociletinib, HM61713) and develop CNS progression but stable extracranial disease
  • Age ≥18 years
  • ECOG performance status of 0 to 2
  • For BM, at least one measurable intracranial lesion as ≥ 10mm in the longest diameter by magnetic resonance imaging (MRI)
  • For LM, at least one site of CNS leptomeningeal disease that can be assessed by MRI
  • Adequate organ function as evidenced by the following;

    • Absolute neutrophil count > 1.5 x 109/L;
    • platelets > 100 x 109/L;
    • total bilirubin ≤1.5 UNL;
    • AST and/or ALT < 5 UNL;
    • CCr ≥ 50mL/min.
  • Female subjects must either be of non-reproductive potential
  • Subject is willing and able to comply with the protocol
  • Signed written informed consent

Exclusion Criteria:

  • Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week
  • Any unresolved toxicities from prior therapy, greater than CTCAE grade 1
  • Mean QT interval corrected for heart rate (QTc) ≥ 470 ms
  • Uncontrolled systemic illness including uncontrolled hypertension, active bleeding, or active infection.
  • Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment
  • History of hypersensitivity to AZD9291
  • Known intracranial haemorrahge which is unrelated to tumor Refractory nausea and vomiting

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 identifier (NCT number): NCT03257124

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Contact: Myung-Ju Ahn, Professor 82-2-3410-3438

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Korea, Republic of
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine Recruiting
Seoul, Korea, Republic of, 135-710
Contact: Myung-Ju Ahn, M.D.    +82-2-3410-3438   
Sponsors and Collaborators
Samsung Medical Center

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Myung-Ju Ahn, Professor, Samsung Medical Center Identifier: NCT03257124    
Other Study ID Numbers: 2016-09-058
First Posted: August 22, 2017    Key Record Dates
Last Update Posted: September 7, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasm Metastasis
Meningeal Carcinomatosis
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplastic Processes
Pathologic Processes
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action