Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity (DARWIN1)

November 28, 2023 updated by: University College, London

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 be available to patients registered to the TRACERx study (NCT01888601), or non-TRACERx patients who have two archival tissue/DNA samples who are willing to have a biopsy of their relapsed disease.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Increasing evidence suggests that clonal dominance of the drug target should be considered when stratifying therapeutics in solid tumours. It is likely that intratumour heterogeneity and cancer subclonal diversity may contribute to the high failure rate of oncology drugs relative to other medical specialties where drugs are applied to stable somatic genomes rather than unstable genomes found in cancer populations. In addition, increasing evidence in NSCLC and other solid tumours suggests that the selection of resistant subclones during the disease course is responsible for the acquisition of drug resistance and therapeutic failure. Finally, spatial separation of cancer subclones within the same tumour is likely to contribute to the difficulties associated with cancer biomarker validation.

"Actionable mutations" may not be optimally actionable if they are present at one site of disease or within a minority tumour subclone. Such minority subclones are likely to contribute to intratumour heterogeneity and discordant results when interpreting multiple biopsies from the same tumour. Our work in NSCLC, renal cancers and glioblastomas is demonstrating that such subclones, carrying potentially targetable events, may be spatially separated within the same tumour or between primary and metastatic sites. This has been demonstrated in the context of EGFR somatic mutations that may be heterogeneous in up to 25-30% of patients, present at one site of disease but not another. The impact of such actionable driver heterogeneity on treatment response, drug resistance and outcome is currently unclear and is the subject of investigation within this protocol; DARWIN1 will assess the impact of EGFR activating mutation and HER2 mutation heterogeneity on progression free survival outcomes in advanced NSCLC treated with the EGFR tyrosine kinase inhibitor, afatinib.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
12

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Aberdeen, United Kingdom
        • Aberdeen Royal Infirmary (NHS Grampian)
      • Birmingham, United Kingdom
        • Heart of England NHS Foundation Trust
      • Glasgow, United Kingdom
        • Beatson West of Scotland Cancer Centre (NHS Greater Glasgow & Clyde)
      • London, United Kingdom, NW1 2BU
        • University College London Hospitals NHS Foundation Trust
      • London, United Kingdom, W1T 4TJ
        • Cr Uk & Ucl Ctc
      • London Borough Of Barnet, United Kingdom
        • Barnet and Chase Farm Hospitals (Royal Free London NHS Foundation Trust)
      • Manchester, United Kingdom
        • The Christie NHS Foundation Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Subjects must be willing to have a biopsy of relapsed disease. Consent will be obtained through the TRACERx study or with the 'trial entry tissue collection' consent form(non-TRACERx patients). 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.
  • Non-TRACERx patients must have at least two archival tissue/DNA samples of their disease available.
  • 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. Patients without measurable disease may be eligible following discussion with the CI and UCL CTC but will not count towards the primary PFS endpoint.
  • 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 highly effective methods of contraception 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:

  • Currently suitable for radical radiotherapy.
  • 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
  • Women of childbearing potential, or men who are able to father a child, unwilling to use a highly effective method of contraception during the trial.
  • Anti-cancer therapy including chemotherapy, 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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 Names:
  • Giotrif

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
Up to 60 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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.
Up to 60 months
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.
Up to 60 months
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.
Up to 60 months
Toxicity/Adverse events
Time Frame: Up to 60 months
Adverse events, including any dose reductions, interruptions and modifications from date of registration up until 60 months.
Up to 60 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University College, London

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Boehringer Ingelheim

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Martin Forster, UCLH

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 16, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 22, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 22, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 27, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 2, 2014

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 8, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 29, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 28, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • UCL/14/0131

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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