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Phase II Trial of BIBW 2992 in Suspected Mutant EGFR Lung Cancer Patients Unfit for Chemotherapy

Phase 2
18 Years
Open (Enrolling)
Carcinoma, Non-Small-Cell Lung

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Trial Information

Phase II Trial of BIBW 2992 in Suspected Mutant EGFR Lung Cancer Patients Unfit for Chemotherapy

Lung cancer is most common cause of death from cancer, of which non-small cell lung cancer
(NSCLC) accounts for ~80% of all cases with most patients presenting with advanced disease.
Patients medically unfit to receive radical or platinum-doublet palliative systemic therapy,
because of poor performance status or comorbidity, account for at least 45% of newly
diagnosed cases and have poor survival. Many oncologists have interpreted single-agent
chemotherapy data as not clinically meaningful when balanced against toxicities,
non-significant improvements in quality of life and comorbidity. Hence, in the UK, this
group of patients are predominantly treated by best-supportive care (BSC).

This study aims to examine the efficacy and safety of using an irreversible EGFR inhibitor
drug BIBW 2992 to treat patients with non-small cell lung cancer and suspected Epidermal
Growth Factor Receptor (EGFR) mutation who are considered unfit for chemotherapy. This drug
is currently unlicensed.

There has been only one small prospective study of medically unfit patients with EGFR
mutation, but it demonstrated good efficacy with a TKI17. This phase II study of East Asian
patients (n=30) with performance status 2-4 and treated with gefitinib demonstrated a rapid
improvement in performance status at 1 month, an overall response rate of 66% and median
survival of 17.8 months. Whilst gefitinib is licensed for EGFR mutant NSCLC, no prospective
studies have yet been performed on medically unfit patients from Western countries. Despite
dramatic initial responses, EGFR mutant NSCLC patients treated with gefitinib/erlotinib
ultimately relapse. In ~50% of cases this is due to the gefitinib/erlotinib-resistant T790M
genotype acquired through either secondary somatic mutation or clonal expansion. There is
therefore a need to improve the outcomes of medically unfit patients with suspected EGFR
mutation, who would otherwise be treated with best supportive care, and in proven EGFR
mutation cases by using an effective EGFR-directed therapy that inhibits EGFRT790M.

Prospective data on medically unfit Western NSCLC patients with EGFR mutation are required
to assess the efficacy of EGFR-TKIs. Additionally, given that 50% of such patients will
become TKI-resistant through EGFRT790M, new therapies are required to overcome this
resistance mechanism.

We aim to recruit patients with clinical characteristics likely to harbour EGFR mutation but
with EGFR genotype unknown either due to no tissue suitable for genotyping, failed genotype;
these will be patients with adenocarcinoma who are never- or ex-light smokers.

Inclusion Criteria:

- Any stage not suitable for radical treatment

- No tissue suitable for EGFR genotyping, failed genotype, or EGFR genotyping

- NSCLC Adenocarcinoma sub-type (including any WHO variant)

- Eligible smoking history:Never smoker (<100 cigarettes in lifetime), or former smoker
(stopped >1year ago and ≤10 pack-years)

- WHO PS 0-3 and predicted life expectancy > 8 weeks

- Unsuitable for or patient declining chemotherapy due to significant co-morbidity.

- Measurable disease according to RECIST version 1.1

- Adequate haematopoietic, hepatic and renal function defined as follows: Absolute
neutrophil count (ANC) ≤1.5 x 109/L and platelet count ≤100 x 109/L

- Bilirubin ≤1.5 x ULN, ALT (SGPT) ≤3 x ULN (or ≤ 5 x ULN in cases of liver metastases)

- Serum creatinine clearance ≥45 ml/min as calculated according to Cockcroft- - Gault

- Palliative radiotherapy allowed unless to a solitary target lesion

- Age 18 or over (no upper age limit)

- Written informed consent that is consistent with ICH-GCP guidelines

Exclusion Criteria:

- Previous treatment with BIBW 2992, or any EGFR-directed inhibitor.

- Any concurrent anticancer systemic therapy.

- Prior chemotherapy for relapsed and/or metastatic NSCLC. Neoadjuvant/adjuvant
chemotherapy is permitted if at least 12 months has elapsed between the end of
chemotherapy and registration.

- Suitable for radical radiotherapy.

- Palliative radiotherapy within 2 weeks prior to registration.

- Palliative radiotherapy to a solitary target lesion.

- Surgery (other than biopsy) within 4 weeks prior to registration.

- Inability to take oral medication, requirement for intravenous feeding, active peptic
ulcer, prior surgical procedures affecting absorption, any medical co-morbidity
affecting gastrointestinal absorption.

- Patients with current or pre-existing interstitial lung disease.

- Active or uncontrolled infections or serious illnesses or medical conditions that
could interfere with the patient's participation in the trial.

- Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major
symptom e.g., Crohn's disease, mal-absorption, or CTCAE version 4.0 Grade ≥3
diarrhoea of any etiology at baseline.

- Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or
requiring treatment with anticonvulsants and/or leptomeningeal disease). Steroids
will be allowed if administered as a stable (same) dose for at least one month before
trial entry.

- Any other current malignancy or malignancy diagnosed within the past five years
(other than non-melanomatous skin cancer and in situ cervical cancer).

- History or presence of clinically relevant cardiovascular abnormalities such as
uncontrolled hypertension, congestive heart failure NYHA classification of 3 or more,
unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6
months prior to registration.

- Symptomatic left ventricular failure with NYHA classification of 3 or more.

- Active viral hepatitis and/or known HIV positive

- Known or suspected active drug or alcohol abuse

- Use of any investigational drug within 8 weeks of registration.

- Known allergy to BIBW 2992 or other ingredients.

- Patients on steroids must have been on the same dose for at least 4 weeks.

- Inability to understand or to comply with the requirements of the trial, trial
protocol or to provide informed consent.

- Women of childbearing potential, or men who are able to father a child, unwilling to
use a medically acceptable method of contraception during the trial.

- Women who are pregnant or breast feeding.

- Requirement for treatment with any of the prohibited concomitant medications listed
in protocol.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival

Outcome Description:

Progression free survival will be determined by measurement of tumour size using RECIST version 1.1 at progression or date of patient death.

Outcome Time Frame:

At 6 months

Safety Issue:


Principal Investigator

Sanjay Popat, BSc MBBS MRCP PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Royal Marsden Hospital London


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

December 2012

Completion Date:

December 2015

Related Keywords:

  • Carcinoma, Non-Small-Cell Lung
  • BIBW2992
  • EGFR Mutation
  • Non Small Cell Lung Cancer
  • Poor performance status
  • Elderly
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms