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

Boehringer Ingelheim74 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

BIBW 2992 MA2 40mg/day

Eligibility

Sex: ALLMin age: 20 Years

Medical Language ↔ Plain English

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).

Locations (20)

1200.33.010 Boehringer Ingelheim Investigational Site

Akashi, Hyogo, Japan

1200.33.001 Boehringer Ingelheim Investigational Site

Chuo-ku, Tokyo, Japan

1200.33.007 Boehringer Ingelheim Investigational Site

Fukuoka, Fukuoka, Japan

1200.33.013 Boehringer Ingelheim Investigational Site

Hidaka, Saitama, Japan

1200.33.011 Boehringer Ingelheim Investigational Site

Kanazawa, Ishikawa, Japan

1200.33.003 Boehringer Ingelheim Investigational Site

Kashiwa, Chiba, Japan

1200.33.019 Boehringer Ingelheim Investigational Site

Kobe, Hyogo, Japan

1200.33.008 Boehringer Ingelheim Investigational Site

Koto-ku, Tokyo, Japan

1200.33.020 Boehringer Ingelheim Investigational Site

Matsuyama, Ehime, Japan

1200.33.006 Boehringer Ingelheim Investigational Site

Miyakojima-ku, Osaka, Japan

...and 10 more locations

Outcomes

Primary Outcomes

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

Time frame: start of treatment to end of treatment

Phase II Step: Objective Tumour Response According to Response Evaluation Criteria in Solid Tumours (RECIST)

The objective response (complete response \[CR\] and partial response \[PR\]) was defined as determined by the RECIST according to the best response to study treatment.

Time frame: 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

Phase I Step: AUC0-24, AUCtau,ss of BIBW 2992 After Multiple Oral Administration

area under the concentration-time curve of BIBW 2992 over the time interval 0-24 hours (AUC0-24), Area under the concentration-time curve of Afatinib in plasma at steady state (AUCtau,ss) after multiple oral administration Pharmacokinetic was abbreviated to PK.

Time frame: 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

Phase II Step: Clinical Benefit

Clinical benefit was defined as a RECIST assessment of complete response, partial response, or stable disease according to the best response to study treatment as defined in the previous section. Clinical benefit presented as the disease control.

Phase II Step: Time to Objective Response

Number of participants with first response at week 4, 8 and 12, assessed by investigator and independent review.

Phase II Step: Duration of Objective Response

Duration of objective response was defined as the time at which RECIST was first met for CR or PR (whichever was first recorded) until the first date that recurrent or progressive disease (PD) was objectively documented.

Phase I Step: Summary of Epidermal Growth Factor Receptor (EGFR) Mutation Findings

Time frame: Screening visit

Phase II Step: Duration of Clinical Benefit

Presented as duration of disease control.

Phase II Step: Progression-free Survival (PFS)

PFS was defined as the duration of time from the start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to the RECIST) or death.

Phase II Step: Overall Survival (OS)

OS was defined as the duration of time from the start of treatment to the time of death.

Time frame: from start of treatment until end of follow up, up to 53 months

Phase II Step: Safety of BIBW 2992 as Indicated by Intensity and Incidence of Adverse Events, Graded According to CTCAE

outcome data show the number of patients with Adverse events (AE) by intensity and incidence of adverse events, graded according to CTCAE.

Time frame: Start of treatment to end of treatment (up to 41.3 months) plus 4 week follow-up

Phase II Step: Maximum CTC Grade During the Trial for Laboratory Parameters, Among Patients Who Experienced an Increase in CTC Grade From Baseline

outcome data show the number of patients for the maximum CTC grade during the trial for laboratory parameters, among patients who experienced an increase in CTC Grade

Time frame: Start of treatment to end of treatment (up to 41.3 months) plus 4 week follow-up

Phase II Step: Trough Plasma Concentrations of BIBW2992 After Multiple Oral Administration of BIBW 2992: Treatment course1 Day 15

Outcome data show the geometric mean (gMean) of trough plasma concentrations of BIBW 2992 after multiple oral administration of BIBW. The dose determined from the result of the Phase I step (50 mg) will be used. Reduction of dose in accordance to the criteria specified by adverse events to 40 mg or 30 mg was possible.

Time frame: Course 1 Day 15

Phase II Step: Trough Plasma Concentrations of BIBW2992 After Multiple Oral Administration of BIBW 2992: Treatment course2 Day 1

Outcome data show the gMean of trough plasma concentrations of BIBW 2992 after multiple oral administration of BIBW

Time frame: Course 2 Day 1

Phase II Step: Trough Plasma Concentrations of BIBW2992 After Multiple Oral Administration of BIBW 2992: Treatment course2 Day 15

Outcome data show the gMean of trough plasma concentrations of BIBW 2992 after multiple oral administration of BIBW

Time frame: Course 2 Day 15

Phase II Step: Summary of EGFR Mutation Findings

Time frame: Screening visit

Phase I Step: Cmax,Cmax,ss of BIBW 2992 After Multiple Oral Administration

Time frame: Just before start of the treatment to Course 4 Visit 4R2