Liquid Biopsy as a Tool to Evaluate Resistance to First and Third (AZD9291) (EGFR) (TKIs) in (EGFR) Mutant NSCLC

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02771314
Recruitment Status : Recruiting
First Posted : May 13, 2016
Last Update Posted : October 4, 2016
Information provided by (Responsible Party):
Hellenic Oncology Research Group

Brief Summary:
Based on the possibilities that both plasma and circulating tumor cells (CTCs) (the "liquid biopsy") may offer, we consider that it could be feasible to longitudinally monitor the genetic evolution and the biologic characteristics of CTCs, by using Circulating tumor DNA (ctDNA) and CTCs as a source of biologic material. This approach could provide information regarding the genetic/molecular changes associated with primary and acquired resistance to AZD9291 and, thus, to facilitate to more appropriately adapt the tailored treatment in this particular group of NSCLC patients. It has been recently reported that the detection of resistant clones, based on the tumor-associated genetic aberrations in the blood, can identify treatment resistance up to 10 months earlier than the radiological methods providing, thus, the potential for an early switch to a non cross-resistant therapy in order to improve patients' outcome.

Condition or disease Intervention/treatment Phase
Non Small Cell Lung Cancer Drug: AZD9291 Phase 2

Detailed Description:

Lung cancer is among the most common tumor types representing 13% of the newly diagnosed cancers worldwide. Both the absolute and relative frequency of lung cancer has risen dramatically. Unfortunately, lung cancer remains by far the leading cause of cancer-related deaths, accounting for 18% of the total number of deaths. Non Small Lung Cancer (NSCLC) accounts for 85% of all cases of lung cancer and is further classified in several subtypes based on various molecular and histological features.

The initial dose of 80 mg AZD9291 administered once daily orally in the fasted state can be reduced to 40 mg AZD9291 once daily under circumstances

Single arm, open-label, phase II, multicenter study. NSCLC patients with activating EGFR mutations, who are under front line treatment with first generation EGFR TKIs according to the physicians' choice and present disease progression, will be treated with single agent AZD9291. The patients will be followed every 3 months for the detection of mutations (T790M), (C797S), (L858R), del 19 EGFR mutations as well as the mutations [(KRAS)/(NRAS), (BRAF), (PI3K)] in the serum/plasma, the determination of the serum levels of Hepatocyte Growth Factor (HGF), the presence of T790M (+) and C797S(+) CTCs as well as the molecular (c-MET) and (HER2 amplification) and phenotypic characterization of CTCs using the filtration platform (ISET). The elimination or the emergence of each of these circulating tumor biomarkers will be correlated with patients' clinical outcome [objective response to treatment (ORR), (PFS) and (OS)].

There is no specific control group in this study. Biomarkers profile at baseline will be used as internal control for each patient to monitor changes throughout treatment.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Official Title: A Longitudinal Study Evaluating Molecular Changes Associated With Resistance to First and Third (AZD9291) Generation EGFR TKIs in Patients With EGFR Mutant NSCLC Using "Liquid Biopsy"
Study Start Date : June 2016
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Biopsy
Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: AZD9291
Drug: AZD9291
AZD9291, 80 mg (tablets) once daily, administered orally in the fasted state
Other Names:
  • Tagrisso
  • Osimertinib

Primary Outcome Measures :
  1. Biomarkers of resistance to first and third (AZD9291) generation EGFR TKIs, explored by studying baseline serial serum or plasma DNA specimens and baseline Circulating Tumor Cells (CTCs) [ Time Frame: Up to 2.5 years ]

Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Up to 2.5 years ]
  2. Overall Survival [ Time Frame: Up to 2.5 years ]
  3. Response rate, assessed using RECIST 1.1 [ Time Frame: Up to 2.5 years ]

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

Inclusion Criteria:

  1. Age >18 years
  2. Both sexes
  3. Histologically or cytologically documented NSCLC
  4. Stage 3b (IIIb) not amenable to radical therapy or stage IV
  5. Presence of EGFR activating mutations (exon 19 deletion or L858R in exon 21)
  6. First or second line treatment with EGFR TKIs
  7. Performance status (ECOG): 0-1
  8. Measurable or evaluable disease
  9. Adequate organ function tests (Hb>=10g/dL, white blood cell (WBC) >=3.0 x 10^9/L, neutrophils count >=1.5 x 10^9/L, platelets≥100 x 10^9/L, Creatinine clearance >=50 mL/min, Total bilirubin=<1.5 X UNL, aspartate aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline phosphatase (ALP) =<2.5 x UNL)
  10. Normal QT interval in ECG
  11. Central nervous system (CNS) metastases are allowed provided that they have been irradiated and the patient is clinically stable
  12. Women of child bearing potential and all men will be required to use adequate contraceptive measures
  13. Life expectancy of at least 3 months
  14. Written informed consent

Exclusion Criteria:

  1. History of serious drug allergy
  2. Refractory nausea, vomiting and chronic gastrointestinal diseases
  3. 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.
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
  4. Severe or uncontrolled systemic liver disease, including those with known hepatitis B, hepatitis C, and Human Immunodeficiency virus (HIV) infection
  5. Interstitial lung disease or pulmonary fibrosis
  6. Pregnancy, lactation or other concomitant serious medical condition
  7. Other concurrent active malignancy

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): NCT02771314

Contact: Vassilis Georgoulias, MD +302106448330
Contact: Efthimios Prinarakis, PhD +302106448330

University Hospital of Heraklion Crete Recruiting
Heraklion, Crete, Greece, 71110
Contact: Ioannis Athanasakis    +302810392783   
Principal Investigator: Athanasios Kotsakis, MD         
251 Air Forces Military Hospital of Athens Recruiting
Athens, Greece
Contact: Nikolaos Kentepozidis, MD   
Principal Investigator: Nikolaos Kentepozidis, MD         
Anticancer Hospital of Athens "Agios Savvas" Not yet recruiting
Athens, Greece
Contact: George Koumakis, MD         
Principal Investigator: George Koumakis, MD         
Athens Hospital "Mitera" Hygia Polis Not yet recruiting
Athens, Greece
Contact: Ilias Athanasiadis, MD         
Principal Investigator: Ilias Athanasiadis, MD         
General Hospital of Athens "Aretaieio" Not yet recruiting
Athens, Greece
Contact: Christos Papadimitriou, MD         
Principal Investigator: Christos Papadimitriou, MD         
General Hospital of Athens "Evangelismos" Not yet recruiting
Athens, Greece
Contact: Theodoros Tegos, MD         
Principal Investigator: Theodoros Tegos, MD         
General Oncology Hospital of Athens "Ag. Anargiroi" Not yet recruiting
Athens, Greece
Contact: Epaminondas Samantas, MD         
Principal Investigator: Epaminondas Samantas, MD         
IASO General Hospital Recruiting
Athens, Greece
Contact: Panagiotis Katsaounis, MD    +302106502639      
Principal Investigator: Panagiotis Katsaounis, MD         
Universtiy Hospital of Athens "Attikon" Not yet recruiting
Athens, Greece
Contact: Anna Koumarianou, MD         
Principal Investigator: Anna Koumarianou, MD         
University Hospital of Patras-Rio Not yet recruiting
Rio-Patra, Greece
Contact: Charalampos Kalofonos, Professor         
Principal Investigator: Charalampos Kalofonos, Professor         
General Hospital of Thesaloniki "G. Papanikolaou" Not yet recruiting
Thesaloniki, Greece
Contact: Konstantinos Zarogoulidis, MD         
Principal Investigator: Konstantinos Zarogoulidis, MD         
Diabalkaniko General Hospital of Thessaloniki Not yet recruiting
Thessaloniki, Greece
Contact: Christos Emmanouilidis, MD         
Principal Investigator: Christos Emmanouilidis, MD         
Thessaloniki Bioclinic Not yet recruiting
Thessaloniki, Greece
Contact: Ioannis Boukovinas, MD         
Principal Investigator: Ioannis Boukovinas, MD         
Sponsors and Collaborators
Hellenic Oncology Research Group
Principal Investigator: Athanasios Kotsakis, PhD Hellenic Oncology Research Group

Responsible Party: Hellenic Oncology Research Group Identifier: NCT02771314     History of Changes
Other Study ID Numbers: D5160C00030
First Posted: May 13, 2016    Key Record Dates
Last Update Posted: October 4, 2016
Last Verified: October 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Hellenic Oncology Research Group:
>= 2nd line
liquid biopsy
EGFR mutant

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action