Single-arm Trial of BIBW 2992 (Afatinib) in Demographically and Genotypically Selected NSCLC Patients

Study Description

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Brief Summary:

The primary objective of this open-label, single arm Phase II trial is to explore the efficacy of BIBW 2992 defined by the objective response rate (CR, PR) as determined by the RECIST criteria, in patients with advanced NSCLC Stage IIIB or IV whose tumours harbour activating mutations within exon 18 to exon 21 of the EGFR receptor, in patients with mutations in the HER2/neu receptor and in patients with EGFR FISH positive tumours with no EGFR mutations.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: BIBW2992; Drug: BIBW2992 + paclitaxel	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	41 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase II Single-arm Trial of BIBW 2992 in Demographically and Genotypically Selected NSCLC
Study Start Date :	June 2008
Actual Primary Completion Date :	January 2012

Arms and Interventions

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Arm	Intervention/treatment
Experimental: BIBW 2992; patient to receive tablets of BIBW 2992 once a day, starting at high dose until progression of the disease	Drug: BIBW2992; tablet BIBW high dose
Experimental: BIBW 2992 + paclitaxel; patient whose disease progressed on treatment with BIBW 2992 monotherapy to receive tablet of BIBW 2992 once a day in combination with i.v. paclitaxel 3 weekly	Drug: BIBW2992 + paclitaxel; tablet BIBW 2992 in combination with i.v. paclitaxel 3 weekly

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Participants With Best Objective Response [ Time Frame: Tumour assessments were performed at baseline (tumour assessment obtained within 4 weeks prior to beginning of treatment), week 8, and every 8 weeks thereafter. ]
   Percentage of participants with best objective response: confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.0.

Secondary Outcome Measures :

1. Percentage of Participants With Disease Control (DC) [ Time Frame: Tumour assessments were performed at baseline (tumour assessment obtained within 4 weeks prior to beginning of treatment), week 8, and every 8 weeks thereafter. ]
   Percentage of participants with OR or stable disease (SD) as determined by RECIST version 1.0.
2. Progression Free Survival (PFS) Time [ Time Frame: Tumour assessments were performed at baseline (tumour assessment obtained within 4 weeks prior to beginning of treatment), week 8, and every 8 weeks thereafter. ]
   PFS time defined as time from the start of treatment to the earliest of progression (RECIST), clinical progression (investigator), start of new anti-cancer treatment or death.
3. Summary of Pre-dose Concentrations of Afatnib in Plasma [ Time Frame: Day 15, 29 and 57 ]
   Pre-dose Concentrations of Afatinib in Plasma at Steady State on Days 15, 29 and 57 (Cpre,ss,15, Cpre,ss,29 and Cpre,ss,57)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

1. patients with pathologically confirmed diagnosis of NSCLC stage IIIB/IV adeno- or bronchoalveolar carcinoma (BAC)
2. non smokers patients or patients having smoked less than 15 pack years and who stopped smoking for at least one year before diagnosis (except for patients with her2-neu mutation)
3. presence of activating mutation(s) in exon 18 to exon 21 of the EGFR or HER2-neu-receptor confirmed by direct DNA sequencing of NSCLC tumor tissue or increased copy number of the EGFR gene as determined by FISH analysis
4. prior treatment up to 3 lines of chemotherapy except for HER2-neu patients (no restrictions) no prior EGFR TKI therapy for EGFR mutation negative and FISCH positive patients
5. patients with at least one tumor lesion that can accurately be measured by CTscan or MRI in at least one dimension with long diameter to be recorded as > or equal to 20 mm using conventional techniques or > or equal to 10 mm with spiral CT scan
6. male or female patient aged above or equal to 18 years
7. life expectancy of at least 3 months
8. written informed consents that is consistent with ICH-GCP guidelines
9. ECOG performance score 0, 1 or 2

Exclusion criteria:

1. more than 3 prior cytotoxic chemotherapy treatment regimen for relapsed or metastatic NSCLC, except for patients with HER2-neu mutations who may have received any prior therapy
2. Any chemo-, hormone- or immunotherapy within the past 4 weeks or within less than 4 half-lives of the previous drug prior to treatment with the trial drug and/or persistence of toxicities of prior anticancer therapies which are deemed to be clinically relevant
3. brain metastases which are symptomatic; patients with treated asymptomatic brain metastases are eligible with stable brain disease for at least 4 weeks without requirement for steroids or anti-epileptic therapy
4. significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g. Crohn's disease, malabsorption or CTCAE Grade > 2 diarrhea of any etiology at baseline
5. patients who have any other life-threatening illness or organ system dysfunction, which in the opinion of the investigator, would either compromise patient safety or interfere with the evaluation of the safety of the test drug
6. other malignancies diagnosed within the past 5 years (other than non melanomatous skin cancer and in situ cervical cancer)
7. radiotherapy within the past 2 weeks prior to treatment with the trial drug
8. patients with any serious active infection (i.e., requiring an IV antibiotic, antifungal, or antiviral agents)
9. patients with known HIV, active hepatitis B or active hepatitis C
10. known or suspected active drug or alcohol abuse
11. 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
12. pregnancy or breast feeding
13. patient unable to comply with the protocol
14. history of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, including New York Heart Association (NYHA) functional classification of 3
15. Cardiac left ventricular function with resting ejection fraction of less than 50% measured by multigated blood pool imaging of the heart (MUGA scan) or Echocardiogram.
16. Absolute neutrophil count (ANC) less than 1500/mm³.
17. Platelet count less than 100 000 / mm³.
18. Bilirubin greater than 1.5 mg / dl (>26 µmol / L, SI unit equivalent).
19. Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than three times the upper limit of normal (if related to liver metastases greater than five times the upper limit of normal).
20. Serum creatinine greater than 1.5 times of the upper normal limit

Contacts and Locations

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Locations

Belgium
1200.41.32003 Boehringer Ingelheim Investigational Site
Antwerpen, Belgium
1200.41.32007 Boehringer Ingelheim Investigational Site
Charleroi, Belgium
1200.41.32001 Boehringer Ingelheim Investigational Site
Jette, Belgium
1200.41.32011 Boehringer Ingelheim Investigational Site
Leuven, Belgium
1200.41.32008 Boehringer Ingelheim Investigational Site
Liège, Belgium
1200.41.32006 Boehringer Ingelheim Investigational Site
Namur, Belgium
Spain
1200.41.34001 Boehringer Ingelheim Investigational Site
Badalona (Barcelona), Spain

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

Study Chair:	Boehringer Ingelheim	Boehringer Ingelheim

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

De Grève J, Teugels E, Geers C, Decoster L, Galdermans D, De Mey J, Everaert H, Umelo I, In't Veld P, Schallier D. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. 2012 Apr;76(1):123-7. doi: 10.1016/j.lungcan.2012.01.008. Epub 2012 Feb 10.

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT00730925 History of Changes
Other Study ID Numbers:	1200.41; 2008-001546-67 ( EudraCT Number: EudraCT )
First Posted:	August 8, 2008
Results First Posted:	October 23, 2013
Last Update Posted:	March 26, 2014
Last Verified:	February 2014

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases	Respiratory Tract Diseases; Paclitaxel; Albumin-Bound Paclitaxel; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action