Clinical trial NCT00711594: LUX-Lung 4: BIBW 2992 (Afatinib) Phase I Trial in Advanced Non Small Cell Lung Cancer Patients & Phase II Trial in Non Small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib
Official title: Phase I/II Open Label Trial of Continuous Once Daily Oral Treatment With BIBW 2992 - Phase I Trial in Advanced Non Small Cell Lung Cancer Patients & Phase II Trial in Non Small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2008-07-09
Enrollment: 74
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The objective of the Phase I step is to estimate the MTD at a dose level up to 50 mg/day (i.e., overseas recommended Phase II dose) in patients with advanced NSCLC and to determine the recommended dose for the Phase II step.

The objective of the Phase II step is to estimate the efficacy of BIBW 2992 monotherapy in patients with first generation EGFR-TKI-resistant advanced NSCLC at the recommended dose determined in the Phase I step.


Eligibility criteria: Inclusion criteria:

Phase II step;

1. Patients with pathologic confirmation of NSCLC with tissue diagnosis or cytologic diagnosis, whose NSCLCs are locally advanced or metastatic Stage III-B / IV adenocarcinoma, and are inoperable and incurable with radiotherapy.
2. Patients who have received the following pretreatments for the treatment of relapsed or metastatic NSCLC.

   * Patients who have received at least one but not more than two lines of chemotherapy. ("Chemotherapy" means only the first line (doublet chemotherapies including a platinum) and/or the second line (single chemotherapy except for a platinum) of cytotoxic chemotherapy according to the standard chemotherapies, and erlotinib (Tarceva®) and gefitinib (Iressa®) should be excluded. One of the chemotherapy regimens must have been platinum-based. In addition, only one prior cytotoxic chemotherapy treatment regimen is allowed after adjuvant chemotherapy containing a platinum. More than two prior cytotoxic chemotherapy treatment regimens are not allowed.)
   * After the above chemotherapies, patients who once got clinical benefits (i.e. complete response, partial response or stable disease) but progressed following at least 12 weeks of treatment with erlotinib (Tarceva®) or gefitinib (Iressa®) as the most recent treatment. ("Clinical benefit" and "progression" should be confirmed by computed tomography (CT) or magnetic resonance imaging (MRI). In addition, "at least 12 weeks of treatment" should be 9 weeks or more as the actual "treatment period except for treatment pause due to adverse events and other reasons.) As long as the treatment is erlotinib or gefitinib monotherapy, patients can receive multiple regimens of either or both treatments, but one of the regimens should be for at least 12 weeks
3. Male or female patients age \>=20 years at the enrolment.
4. Life expectancy of at least three (3) months after the start of administration of the investigational drug.
5. Eastern Cooperative Oncology Group (ECOG) performance Score 0 or 1.
6. Patients with at least one tumor lesion that can accurately be measured by CT or MRI in at least one dimension with longest diameter to be recorded as no less than double the slice thickness and \>=10 mm.
7. Written informed consent that is consistent with ICH-GCP guidelines.

Exclusion criteria:

Phase II step;

1. Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within two weeks before starting the study medication.
2. Patients who have received definitive thoracic radiotherapy with curative intent. Patients who have received radiotherapy or other investigational drugs (non-oncological) within four weeks before enrolment.
3. Significant gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE Grade \>2 diarrhea of any etiology at the enrolment.
4. Patients with distinct / suspected pulmonary fibrosis or interstitial lung disease by the chest radiographic findings, or patients with a previous history of.
5. Brain tumor, and / or brain metastases, which are symptomatic or requiring treatment at the enrolment.
6. Other malignancies diagnosed within the past five years (other than carcinoma in situ of gastric cancer, colon cancer and cervical cancer, and non melanomatous skin cancer).
7. History of uncontrolled cardiac disease such as angina or myocardial infarction within the past 6 months at the enrolment, congestive heart failure including New York Heart Association (NYHA) functional classification of 3, or arrhythmia requiring treatment.
8. Coelomic fluid retention (such as pleural effusion, ascites or pericardial effusion) requiring treatment.
9. Uncontrolled concomitant diseases (e.g. diabetes mellitus, hypertension etc).
10. History of serious drug hypersensitivity.
11. Patients who do not have sufficient baseline organ function and whose laboratory data do not meet the following criteria at the enrolment.11

    * Haemoglobin count \>=9.0 g/dL
    * Absolute neutrophil count (ANC) \>=1500 / mm3
    * Platelet count \>=100 000 / mm3
    * Serum creatinine \<=1.5 mg/dL
    * Total bilirubin \<=1.5 mg/dL
    * Aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) \<=2.5x upper limit of normal range (if related to liver metastases \<=2.5x upper limit of normal also)
    * PaO2 \>=60torr or SpO2 \>=92%
    * LVEF as measured by echocardiography or multigated blood pool imaging of the heart (MUGA scan) \>=50%
    * QTc interval \<0.47 second
12. Patients who disagree with using a medically acceptable method of contraception during the administration of the investigational drug and for at least 6 months after the end of administration.
13. Pregnant or breast-feeding women, or women suspected of being pregnant.
14. Known positive HBs antigen, HCV antibody, or HIV antibody test.
15. Known or suspected active drug or alcohol abuse.
16. Other patients judged ineligible for enrolment in the study by the investigator (sub-investigator).

Primary outcomes:
measure: Phase I Step: Safety of BIBW 2992 Assessed Based on Incidence of Dose Limiting Toxicity (DLT) and Incidence & Intensity of Adverse Events According to CTCAE
timeFrame: start of treatment to end of treatment
measure: Phase II Step: Objective Tumour Response According to Response Evaluation Criteria in Solid Tumours (RECIST)
timeFrame: Tumour Assessment were performed at screening 14 days (prior to enrollment), in week 4, week 8, week 12 and in 8-week intervals thereafter, and at the end of trial visit (patients discontinuation), up to 41.3 months
Secondary outcomes:
measure: Phase I Step: AUC0-24, AUCtau,ss of BIBW 2992 After Multiple Oral Administration
timeFrame: AUC0-24: just before drug administration, 0:30,1:00, 2:00, 3:00, 4:00, 5:00, 7:00, 9:00, 24:00 on Day 1-2 in Course 1; AUCtau,ss: just before drug administration, 0:30,1:00, 2:00, 3:00, 4:00, 5:00, 7:00, 9:00, 24:00, 48:00, 72:00 on Day 28-31 in Course 1
measure: Phase II Step: Clinical Benefit
timeFrame: Tumour Assessment were performed at screening 14 days (prior to enrollment), in week 4, week 8, week 12 and in 8-week intervals thereafter, and at the end of trial visit (patients discontinuation) up to 41.3 months
measure: Phase II Step: Time to Objective Response
timeFrame: Tumour Assessment were performed at screening 14 days (prior to enrollment), in week 4, week 8, week 12 and in 8-week intervals thereafter, and at the end of trial visit (patients discontinuation) up to 41.3 months
measure: Phase II Step: Duration of Objective Response
timeFrame: Tumour Assessment were performed at screening 14 days (prior to enrollment), in week 4, week 8, week 12 and in 8-week intervals thereafter, and at the end of trial visit (patients discontinuation) up to 41.3 months
measure: Phase I Step: Summary of Epidermal Growth Factor Receptor (EGFR) Mutation Findings
timeFrame: Screening visit
measure: Phase II Step: Duration of Clinical Benefit
timeFrame: Tumour Assessment were performed at screening 14 days (prior to enrollment), in week 4, week 8, week 12 and in 8-week intervals thereafter, and at the end of trial visit (patients discontinuation) up to 41.3 months
measure: Phase II Step: Progression-free Survival (PFS)
timeFrame: Tumour Assessment were performed at screening 14 days (prior to enrollment), in week 4, week 8, week 12 and in 8-week intervals thereafter, and at the end of trial visit (patients discontinuation) up to 41.3 months
measure: Phase II Step: Overall Survival (OS)
timeFrame: from start of treatment until end of follow up, up to 53 months
measure: Phase II Step: Safety of BIBW 2992 as Indicated by Intensity and Incidence of Adverse Events, Graded According to CTCAE
timeFrame: Start of treatment to end of treatment (up to 41.3 months) plus 4 week follow-up
measure: Phase II Step: Maximum CTC Grade During the Trial for Laboratory Parameters, Among Patients Who Experienced an Increase in CTC Grade From Baseline
timeFrame: Start of treatment to end of treatment (up to 41.3 months) plus 4 week follow-up
measure: Phase II Step: Trough Plasma Concentrations of BIBW2992 After Multiple Oral Administration of BIBW 2992: Treatment course1 Day 15
timeFrame: Course 1 Day 15
measure: Phase II Step: Trough Plasma Concentrations of BIBW2992 After Multiple Oral Administration of BIBW 2992: Treatment course2 Day 1
timeFrame: Course 2 Day 1
measure: Phase II Step: Trough Plasma Concentrations of BIBW2992 After Multiple Oral Administration of BIBW 2992: Treatment course2 Day 15
timeFrame: Course 2 Day 15
measure: Phase II Step: Summary of EGFR Mutation Findings
timeFrame: Screening visit
measure: Phase I Step: Cmax,Cmax,ss of BIBW 2992 After Multiple Oral Administration
timeFrame: Just before start of the treatment to Course 4 Visit 4R2
Other outcomes:
Locations:
city: Akashi, Hyogo
country: Japan
facility: 1200.33.010 Boehringer Ingelheim Investigational Site
city: Chuo-ku, Tokyo
country: Japan
facility: 1200.33.001 Boehringer Ingelheim Investigational Site
city: Fukuoka, Fukuoka
country: Japan
facility: 1200.33.007 Boehringer Ingelheim Investigational Site
city: Hidaka, Saitama
country: Japan
facility: 1200.33.013 Boehringer Ingelheim Investigational Site
city: Kanazawa, Ishikawa
country: Japan
facility: 1200.33.011 Boehringer Ingelheim Investigational Site
city: Kashiwa, Chiba
country: Japan
facility: 1200.33.003 Boehringer Ingelheim Investigational Site
city: Kobe, Hyogo
country: Japan
facility: 1200.33.019 Boehringer Ingelheim Investigational Site
city: Koto-ku, Tokyo
country: Japan
facility: 1200.33.008 Boehringer Ingelheim Investigational Site
city: Matsuyama, Ehime
country: Japan
facility: 1200.33.020 Boehringer Ingelheim Investigational Site
city: Miyakojima-ku, Osaka
country: Japan
facility: 1200.33.006 Boehringer Ingelheim Investigational Site
city: Nagoya, Aichi
country: Japan
facility: 1200.33.004 Boehringer Ingelheim Investigational Site
city: Nagoya, Aichi
country: Japan
facility: 1200.33.017 Boehringer Ingelheim Investigational Site
city: Niigata, Niigata
country: Japan
facility: 1200.33.016 Boehringer Ingelheim Investigational Site
city: Okayama, Okayama
country: Japan
facility: 1200.33.009 Boehringer Ingelheim Investigational Site
city: Osaka-Sayama, Osaka
country: Japan
facility: 1200.33.005 Boehringer Ingelheim Investigational Site
city: Sakai, Osaka
country: Japan
facility: 1200.33.018 Boehringer Ingelheim Investigational Site
city: Sapporo, Hokkaido
country: Japan
facility: 1200.33.015 Boehringer Ingelheim Investigational Site
city: Sendai, Miyagi
country: Japan
facility: 1200.33.012 Boehringer Ingelheim Investigational Site
city: Sunto-gun, Shizuoka
country: Japan
facility: 1200.33.002 Boehringer Ingelheim Investigational Site
city: Yufu, Oita
country: Japan
facility: 1200.33.014 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. doi: 10.1200/JCO.2012.45.0981. Epub 2013 Jul 1.
citation: Murakami H, Tamura T, Takahashi T, Nokihara H, Naito T, Nakamura Y, Nishio K, Seki Y, Sarashina A, Shahidi M, Yamamoto N. Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4). Cancer Chemother Pharmacol. 2012 Apr;69(4):891-9. doi: 10.1007/s00280-011-1738-1. Epub 2011 Nov 10.