Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity (DARWIN1)
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|ClinicalTrials.gov Identifier: NCT02183883|
Recruitment Status : Active, not recruiting
First Posted : July 8, 2014
Last Update Posted : March 8, 2022
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.
|Condition or disease||Intervention/treatment||Phase|
|Non-small Cell Lung Cancer||Drug: Afatinib||Phase 2|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||48 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
Afatinib, tablet, 40mg, 30mg, 20mg, OD, taken until progression, unacceptable toxicity, intercurrent illness, patient/clinician decision
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
- 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.
- 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.
- 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.
- 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.
- 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.
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 ClinicalTrials.gov identifier (NCT number): NCT02183883
|Aberdeen Royal Infirmary (NHS Grampian)|
|Aberdeen, United Kingdom|
|Heart of England NHS Foundation Trust|
|Birmingham, United Kingdom|
|Beatson West of Scotland Cancer Centre (NHS Greater Glasgow & Clyde)|
|Glasgow, United Kingdom|
|Barnet and Chase Farm Hospitals (Royal Free London NHS Foundation Trust)|
|London Borough Of Barnet, United Kingdom|
|University College London Hospitals NHS Foundation Trust|
|London, United Kingdom, NW1 2BU|
|Cr Uk & Ucl Ctc|
|London, United Kingdom, W1T 4TJ|
|The Christie NHS Foundation Trust|
|Manchester, United Kingdom|
|Principal Investigator:||Martin Forster||UCLH|