Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity

NCT02183883 | Completed Phase 2 DMC

• 1 other identifier: UCL/14/0131
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 7

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 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.

Conditions

Non-small Cell Lung Cancer

Keywords

Non-small cell lung cancer; NSCLC; Afatinib; Intra-tumour heterogeneity; Clonal dominance; Drug resistance; EGFR; HER2; Phase 2

Outcome Measures

Primary Outcomes (1)

• 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.

  Up to 60 months

Secondary Outcomes (4)

• Overall survival

  Up to 60 months

• Time-to-progression

  Up to 60 months

• Tumour Response

  Up to 60 months

• Toxicity/Adverse events

  Up to 60 months

Study Arms (1)

Afatinib

EXPERIMENTAL

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

Drug: Afatinib

Interventions

Afatinib DRUG

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.

Also known as: Giotrif

Afatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University College, London: lead
• Boehringer Ingelheim: collaborator

Study Sites (7)

Aberdeen Royal Infirmary (NHS Grampian)

Aberdeen, United Kingdom

Location

Barnet and Chase Farm Hospitals (Royal Free London NHS Foundation Trust)

Barnet, United Kingdom

Location

Heart of England NHS Foundation Trust

Birmingham, United Kingdom

Location

Beatson West of Scotland Cancer Centre (NHS Greater Glasgow & Clyde)

Glasgow, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, NW1 2BU, United Kingdom

Location

Cr Uk & Ucl Ctc

London, W1T 4TJ, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33662447 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Afatinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Amides; Organic Chemicals; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Martin Forster

  UCLH

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 27, 2014
• First Posted: July 8, 2014
• Study Start: December 16, 2016
• Primary Completion: March 22, 2023
• Study Completion: March 22, 2023
• Last Updated: November 29, 2023

Record last verified: 2023-11

Locations

GB (7)