Non-small Cell Lung CancerPhase 2DARWIN1NCT02183883
Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity
A Phase 2 study testing Afatinib in people with Non-small Cell Lung Cancer, run by University College, London at 7 sites in United Kingdom.
Trial 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%). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-small Cell Lung Cancer
- What is being tested?
- Afatinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 7 sitesUnited Kingdom
- Study dates
- 16 Dec 2016to 22 Mar 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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
Show all 19Show fewer
- 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.
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
United Kingdom7 sites
Aberdeen Royal Infirmary (NHS Grampian)
Aberdeen
Barnet and Chase Farm Hospitals (Royal Free London NHS Foundation Trust)
Barnet
Heart of England NHS Foundation Trust
Birmingham
Beatson West of Scotland Cancer Centre (NHS Greater Glasgow & Clyde)
Glasgow
University College London Hospitals NHS Foundation Trust
London, NW1 2BU
Cr Uk & Ucl Ctc
London, W1T 4TJ
The Christie NHS Foundation Trust
Manchester
About this study
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.
Read the 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.
- Conditions
- Non-small Cell Lung Cancer
- Being tested
- Afatinib
- Keywords
- Non-small cell lung cancer, NSCLC, Afatinib, Intra-tumour heterogeneity, Clonal dominance, Drug resistance, EGFR, HER2, Phase 2
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AfatinibDrug
Also called Giotrif
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.
| Study group | Role | What they receive |
|---|---|---|
| Afatinib | Experimental | Afatinib, tablet, 40mg, 30mg, 20mg, OD, taken until progression, unacceptable toxicity, intercurrent illness, patient/clinician decision Receives: Drug: Afatinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival (PFS)
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.
Measured: Up to 60 months
Secondary outcomes (4)
Overall survival
From date of registration until the date of death from any cause assessed up to 60 months.
Measured: Up to 60 months
Time-to-progression
From date of registration until the date of the last documented progression assessed up to 60 month.
Measured: Up to 60 months
Tumour Response
From date of registration until the date of the last documented response assessed up to 60 months.
Measured: Up to 60 months
Toxicity/Adverse events
Adverse events, including any dose reductions, interruptions and modifications from date of registration up until 60 months.
Measured: Up to 60 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jul 2014 (estimated)
- Study start16 Dec 2016
- Primary completion22 Mar 2023
- Study completion22 Mar 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Non-small Cell Lung CancerStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Collaborators
- Boehringer Ingelheim
- Responsible party
- Sponsor
- Investigators
- Martin Forster, Principal investigator, University College London Hospitals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02183883
- Sponsor's protocol ID
- UCL/14/0131
- Acronym
- DARWIN1
- Status last verified
- Nov 2023
- First submitted
- 27 Jun 2014
- Last updated
- 29 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Danilenko M, Clifford SC, Schwalbe EC. Inter and intra-tumoral heterogeneity as a platform for personalized therapies in medulloblastoma. Pharmacol Ther. 2021 Dec;228:107828. doi: 10.1016/j.pharmthera.2021.107828. Epub 2021 Mar 1.
PubMed 33662447
Study at a glance
From the registry record, last updated by the sponsor on 29 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity
- ClinicalTrials.gov ID
- NCT02183883
- Acronym / sponsor ID
- DARWIN1 / UCL/14/0131
- Conditions
- Non-small Cell Lung Cancer
- Keywords
- Non-small cell lung cancer, NSCLC, Afatinib, Intra-tumour heterogeneity, Clonal dominance, Drug resistance, EGFR, HER2
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University College, LondonUniversity, hospital or other
- Collaborators
- Boehringer Ingelheim
- Study start
- 16 Dec 2016 (actual)
- Primary completion
- 22 Mar 2023 (actual)
- Study completion
- 22 Mar 2023 (actual)
- First posted
- 8 Jul 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Afatinib | Experimental | Drug: AfatinibAfatinib, tablet, 40mg, 30mg, 20mg, OD, taken until progression, unacceptable toxicity, intercurrent illness, patient/clinician decision |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- 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
Key exclusion criteria (19 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AfatinibAlso: Giotrif40mg, 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. | Drug | Afatinib |
Primary outcome
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.
4 secondary outcomes
Overall survival
Time frame: Up to 60 months
Time-to-progression
Time frame: Up to 60 months
Tumour Response
Time frame: Up to 60 months
Toxicity/Adverse events
Time frame: Up to 60 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Nov 2023.
- Derived from this study: PubMed 33662447Danilenko M, Clifford SC, Schwalbe EC. Inter and intra-tumoral heterogeneity as a platform for personalized therapies in medulloblastoma. Pharmacol Ther. 2021 Dec;228:107828. doi: 10.1016/j.pharmthera.2021.107828. Epub 2021 Mar 1.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martin Forster principal investigator
University College London Hospitals
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Afatinib in people with Non-small Cell Lung Cancer, run by University College, London at 7 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression Free Survival (PFS) (time frame: Up to 60 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02183883, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2023.