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Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity (DARWIN1)

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: NCT02183883
Recruitment Status : Recruiting
First Posted : July 8, 2014
Last Update Posted : November 7, 2018
Boehringer Ingelheim
Information provided by (Responsible Party):
University College, London

Brief Summary:

To assess if targeting activating EGFR and HER2 mutations in Non-Small Cell Lung Cancer (NSCLC) is more effective when these mutations are truncal dominant mutations (≥50%), as opposed to non-dominant (≥5 to <50%) or low frequency mutations (<5%).

This trial will only be available to patients registered to the TRACERx study (NCT01888601).

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Drug: Afatinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity
Actual Study Start Date : December 16, 2016
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Afatinib
Afatinib, tablet, 40mg, 30mg, 20mg, OD, taken until progression, unacceptable toxicity, intercurrent illness, patient/clinician decision
Drug: Afatinib

40mg, 30mg, 20mg, OD, taken until progression, unacceptable toxicity, intercurrent illness, patient/clinician decision.

EGFR positive mutation patients only: dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate a 40 mg/day dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE Grade > 1) in the first 3 weeks. The dose should not be escalated in any patients with a prior dose reduction. The maximum daily dose for EGFR mutation positive patients is 50 mg.

Other Name: Giotrif

Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Up to 60 months ]
    From date of registration until the date of the last documented progression or date of death from any cause, whichever comes first, assessed up to 60 months.

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Up to 60 months ]
    From date of registration until the date of death from any cause assessed up to 60 months.

  2. Time-to-progression [ Time Frame: Up to 60 months ]
    From date of registration until the date of the last documented progression assessed up to 60 month.

  3. Tumour Response [ Time Frame: Up to 60 months ]
    From date of registration until the date of the last documented response assessed up to 60 months.

  4. Toxicity [ Time Frame: Up to 60 months ]
    Adverse events, including any dose reductions, interruptions and modifications from date of registration up until 60 months.

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:

This therapeutic trial is only relevant for patients involved in the TRACERx observational study.

  • Subjects must be willing to have a biopsy of relapsed disease. Consent will be obtained through the TRACERx study. Procurement of the biopsy sample is not necessary at the time of trial registration. However, patients must undergo a biopsy prior to commencement of afatinib.
  • Patients must have tumours harbouring a sensitising EGFR mutation or HER2 mutation in at least one biopsy at recurrence, or region of the primary sample.
  • Written Informed consent for DARWIN1.
  • ECOG performance status 0-3
  • No previous exposure to an EGFR TKI (other than afatinib) or HER2 targeted therapy
  • Measurable disease by RECIST v1.1.
  • At least 18 years of age.
  • Anticipated life expectancy of at least three months.
  • Adequate organ function as defined by the following baseline values:

    • Absolute neutrophil count (ANC) ≥1.5x109/L
    • Platelets ≥100x109/L
    • Serum bilirubin ≤1.5 x upper limit of normal (ULN). In patients with known Gilbert's syndrome, total bilirubin ≤3xULN with direct bilirubin ≤1.5xULN
    • Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤3xULN or ≤5x ULN if liver metastases are present
    • Creatinine clearance must be ≥30mL/min
  • Women with child-bearing potential, or men who are able to father a child, must be willing to practice acceptable methods of birth control during the trial and for 1 month after the end of treatment.
  • Women of childbearing potential must have a negative pregnancy test within 14 days before the first dose of trial medication.

Exclusion Criteria:

  • • Suitable for radical radiotherapy.
  • Palliative radiotherapy within 2 weeks prior to registration.
  • Palliative radiotherapy to a solitary target lesion.
  • Requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption or any medical comorbidity affecting gastrointestinal absorption.
  • Patients with current or pre-existing interstitial lung disease.
  • Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g. Crohn's disease, malabsorption, or CTCAE v4.03 Grade ≥3 diarrhoea of any etiology at baseline.
  • Known hypersensitivity to afatinib or to any of the excipients.
  • Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
  • Anti-cancer therapy including chemotherapy, radiation therapy, immunotherapy, biologic therapy, or major surgery within 14 days prior to start of trial therapy.
  • Known human immunodeficiency virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or syphilis infection. Subjects with evidence of hepatitis B virus clearance may be enrolled.
  • History of other malignancy; Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal therapy with histologically confirmed tumor lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligible.
  • The following cardiac abnormalities:

    • Corrected QT (QTc) interval ≥480 msecs
    • History of acute coronary syndromes (including unstable angina) within the past 24 weeks
    • Coronary angioplasty, or stenting within the past 24 weeks
    • Class III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
    • History of known arrhythmias (except sinus arrhythmia) within the past 24 weeks
    • Myocardial infarction within the last 6 months
  • Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension etc), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to comply with the requirements of the trial, trial protocol or to provide informed consent.
  • Pregnant, lactating or actively breastfeeding females.

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): NCT02183883

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Contact: Harriet Bell

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United Kingdom
Aberdeen Royal Infirmary (NHS Grampian) Recruiting
Aberdeen, United Kingdom
Principal Investigator: Gillian Price         
Heart of England NHS Foundation Trust Recruiting
Birmingham, United Kingdom
Principal Investigator: Shobhit Baijal         
Beatson West of Scotland Cancer Centre (NHS Greater Glasgow & Clyde) Recruiting
Glasgow, United Kingdom
Principal Investigator: Nicola Steele         
Barnet and Chase Farm Hospitals (Royal Free London NHS Foundation Trust) Recruiting
London Borough Of Barnet, United Kingdom
Principal Investigator: Tanya Ahmad         
University College London Hospitals NHS Foundation Trust Recruiting
London, United Kingdom, NW1 2BU
Principal Investigator: Martin Forster         
Cr Uk & Ucl Ctc Active, not recruiting
London, United Kingdom, W1T 4TJ
The Christie NHS Foundation Trust Recruiting
Manchester, United Kingdom
Principal Investigator: Matthew Krebs         
Sponsors and Collaborators
University College, London
Boehringer Ingelheim
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Principal Investigator: Martin Forster UCLH

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Responsible Party: University College, London Identifier: NCT02183883     History of Changes
Other Study ID Numbers: UCL/14/0131
First Posted: July 8, 2014    Key Record Dates
Last Update Posted: November 7, 2018
Last Verified: November 2018

Keywords provided by University College, London:
Non-small cell lung cancer
Intra-tumour heterogeneity
Clonal dominance
Drug resistance
Phase 2

Additional relevant MeSH terms:
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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