Clinical trial NCT00525148: LUX Lung 2 Phase II Single Arm BIBW 2992 "Afatinib" in NSCLC With EGFR Activating Mutations
Official title: LUX Lung 2 A Phase II Single-arm Trial of BIBW 2992 in Non-small Cell Lung Cancer Patients With EGFR Activating Mutations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2007-09-05
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 RECIST criteria in patients with advanced NSCLC Stage IIIB or IV whose tumors harbor activating mutations within exon 18 to exon 21 of the EGFR receptor. Patients progressing or relapsing after one prior cytotoxic chemotherapy regimen as well as chemotherapy naïve patients (only in stage 2) will be allowed to enter into the trial.


Eligibility criteria: Inclusion criteria:

1. Patients with pathologically confirmed diagnosis of NSCLC Stage IIIB (with pleural effusion) adenocarcinoma or Stage IV adenocarcinoma.
2. Presence of activating mutation(s) in exon 18 to exon 21 of the EGFR-receptor confirmed by direct DNA sequencing of NSCLC tumor tissue.
3. Progressive disease following a first line cytotoxic chemotherapy regimen or have recurrent disease after prior neoadjuvant or adjuvant chemotherapy. Patients who have not received first-line cytotoxic chemotherapy can be enrolled in stage 2 of the trial, if the criteria for entering stage 2 are met.
4. Patients with at least one tumor lesion that can accurately be measured by computed tomography (CT) or magnetic resonance imaging (MRI) in at least one dimension with longest diameter to be recorded as 20 mm using conventional techniques or 10 mm with spiral CT scan.
5. Male or female patient aged 18 years.
6. Life expectancy of at least three (3) months.
7. Written informed consents that is consistent with ICH-GCP guidelines.
8. Eastern Cooperative Oncology Group (ECOG) performance score 0, 1 or 2.

Exclusion criteria:

1. More than one (1) prior cytotoxic chemotherapy treatment regimen for relapsed or metastatic NSCLC.
2. Chemo-, hormone- (other than Megace®) or immunotherapy within the past 4 weeks or within less than four 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. Previous treatment with erlotinib (Tarceva®), gefitinib (Iressa®) or any other EGFR inhibiting small molecule or antibody.
4. Brain metastases, which are symptomatic; patients with treated, asymptomatic brain metastases are eligible with stable brain disease for at least four (4) weeks without the requirement for steroids or anti-epileptic therapy.
5. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohns disease, malabsorption, or CTCAE Grade \>2 diarrhea of any etiology at baseline.
6. 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.
7. Other malignancies diagnosed within the past five (5) years (other than non-melanomatous skin cancer and in situ cervical cancer).
8. Radiotherapy within the past 2 weeks prior to treatment with the trial drug.
9. Patients with any serious active infection (i.e., requiring an IV antibiotic, antifungal, or antiviral agents).
10. Patients with known HIV, active hepatitis B or active hepatitis C.
11. Known or suspected active drug or alcohol abuse.
12. Women of child-bearing potential or men who are able to father a child unwilling to use a medically acceptable method of contraception during the trial.
13. Pregnancy or breast feeding.
14. Patient unable to comply with the protocol.
15. 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.
16. 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.
17. QTc interval greater than 0.47 second.
18. Prior treatment with anthracyclines with a cumulative dose of doxorubicin (or equivalent) greater than 400 mg/m2.
19. Absolute neutrophil count (ANC) less than 1500/mm3.
20. Platelet count less than 100 000 /mm3.
21. Bilirubin greater than 1.5 mg / dl (greater than 26 micromol / L, SI unit equivalent).
22. 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).
23. Serum creatinine greater than 1.5 times of the upper normal limit or calculated/measured creatinine clearance equal or less than 45 ml / min.
24. Patients with known pre-existing interstitial lung disease

Primary outcomes:
measure: Objective Response (OR) as Determined by RECIST 1.0
timeFrame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
Secondary outcomes:
measure: Clinical Benefit as Determined by RECIST 1.0
timeFrame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
measure: Duration of Clinical Benefit
timeFrame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
measure: Duration of Objective Response
timeFrame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
measure: Time to Objective Response
timeFrame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
measure: Progression-free Survival
timeFrame: Response assessment is done at end of Week 4 (after Course 1), Week 8 (after Course 2), Week 12 (after Course 3) and at 8-week intervals thereafter, up to 93 months.
measure: Overall Survival Time
timeFrame: Start of treatment to time to all death, up to 93 months
measure: Cpre,ss,29
timeFrame: -0:05h (pre-dose) on Day 29
measure: Safety of BIBW 2992 as Indicated by Incidence of Specified Adverse Events.
timeFrame: First administration of trial medication until 28 days after last administration of trial medication, up to 93 months.
measure: Safety of BIBW 2992 as Indicated by Intensity and Incidence of Worst Adverse Events Graded According to NCI CTCAE Version 3.0
timeFrame: First administration of trial medication until 28 days after last administration of trial medication, up to 93 months.
Other outcomes:
Locations:
city: Bakersfield
country: United States
facility: 1200.22.28 Boehringer Ingelheim Investigational Site
state: California
city: Beverly Hills
country: United States
facility: 1200.22.32 Boehringer Ingelheim Investigational Site
state: California
city: Mission Hills
country: United States
facility: 1200.22.4 Boehringer Ingelheim Investigational Site
state: California
city: Orange
country: United States
facility: 1200.22.16 Boehringer Ingelheim Investigational Site
state: California
city: Fort Lauderdale
country: United States
facility: 1200.22.19 Boehringer Ingelheim Investigational Site
state: Florida
city: North Miami Beach
country: United States
facility: 1200.22.29 Boehringer Ingelheim Investigational Site
state: Florida
city: Atlanta
country: United States
facility: 1200.22.10 Boehringer Ingelheim Investigational Site
state: Georgia
city: Chicago
country: United States
facility: 1200.22.18 Boehringer Ingelheim Investigational Site
state: Illinois
city: Bethesda
country: United States
facility: 1200.22.3 Boehringer Ingelheim Investigational Site
state: Maryland
city: Boston
country: United States
facility: 1200.22.14 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: Flint
country: United States
facility: 1200.22.24 Boehringer Ingelheim Investigational Site
state: Michigan
city: Minneapolis
country: United States
facility: 1200.22.5 Boehringer Ingelheim Investigational Site
state: Minnesota
city: New York
country: United States
facility: 1200.22.15 Boehringer Ingelheim Investigational Site
state: New York
city: New York
country: United States
facility: 1200.22.26 Boehringer Ingelheim Investigational Site
state: New York
city: Rochester
country: United States
facility: 1200.22.1 Boehringer Ingelheim Investigational Site
state: New York
city: Syracuse
country: United States
facility: 1200.22.27 Boehringer Ingelheim Investigational Site
state: New York
city: Valhalla
country: United States
facility: 1200.22.25 Boehringer Ingelheim Investigational Site
state: New York
city: Canton
country: United States
facility: 1200.22.6 Boehringer Ingelheim Investigational Site
state: Ohio
city: Wynnewood
country: United States
facility: 1200.22.7 Boehringer Ingelheim Investigational Site
state: Pennsylvania
city: Mt. Pleasant
country: United States
facility: 1200.22.22 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Fairfax
country: United States
facility: 1200.22.31 Boehringer Ingelheim Investigational Site
state: Virginia
city: Renton
country: United States
facility: 1200.22.40 Boehringer Ingelheim Investigational Site
state: Washington
city: Seattle
country: United States
facility: 1200.22.33 Boehringer Ingelheim Investigational Site
state: Washington
city: Taichung
country: Taiwan
facility: 1200.22.88604 Taichung Veterans General Hospital
city: Taichung
country: Taiwan
facility: 1200.22.88605 China Medical University Hospital
city: Tainan
country: Taiwan
facility: 1200.22.88606 Boehringer Ingelheim Investigational Site
city: Taipei City
country: Taiwan
facility: 1200.22.88607 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1200.22.88601 National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: 1200.22.88602 Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: 1200.22.88603 Chang Gung Memorial Hosp-Linkou
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. doi: 10.1016/S1470-2045(15)00026-1. Epub 2015 Jun 4.
citation: Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, Miller VA. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012 May;13(5):539-48. doi: 10.1016/S1470-2045(12)70086-4. Epub 2012 Mar 26.