Deciphering Afatinib Response and Resistance With INtratumour Heterogeneity

• Status: Recruiting
• Trial end date: 2023-11-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University College, London
• Collaborator: Boehringer Ingelheim
• Treatments: Afatinib

Criteria

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.