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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BIBW 2992 MA2 40mg/day
* Drug: BIBW 2992 MA2 50mg/day
* Drug: BIBW 2992 MA2 20mg/day
* Drug: BIBW 2992 QD


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Phase II step; 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. 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 Male or female patients age >=20 years at the enrolment. Life expectancy of at least three (3) months after the start of administration of the investigational drug. Eastern Cooperative Oncology Group (ECOG) performance Score 0 or 1. 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. Written informed consent that is consistent with ICH-GCP guidelines. Exclusion criteria: Phase II step; Use of erlotinib (Tarceva®) or gefitinib (Iressa®) within two weeks before starting the study medication. 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. 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. Patients with distinct / suspected pulmonary fibrosis or interstitial lung disease by the chest radiographic findings, or patients with a previous history of. Brain tumor, and / or brain metastases, which are symptomatic or requiring treatment at the enrolment. 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). 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. Coelomic fluid retention (such as pleural effusion, ascites or pericardial effusion) requiring treatment. Uncontrolled concomitant diseases (e.g. diabetes mellitus, hypertension etc). History of serious drug hypersensitivity. 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 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. Pregnant or breast-feeding women, or women suspected of being pregnant. Known positive HBs antigen, HCV antibody, or HIV antibody test. Known or suspected active drug or alcohol abuse. Other patients judged ineligible for enrolment in the study by the investigator (sub-investigator).

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBW 2992 MA2<br>Phase I step: Find maximum tolerated dose of the non-marketed substance:BIBW 2992 given orally. Escalating doses of BIBW 2992 starting at 20mg daily. | Drug: BIBW 2992 MA2 40mg/day<br>* Phase I step: Increased dose cohorts from low dose to MTD<br>Drug: BIBW 2992 MA2 50mg/day<br>* Phase I step: Increased dose cohorts from low dose to MTD<br>Drug: BIBW 2992 MA2 20mg/day<br>* Phase I step: Increased dose cohorts from low dose to MTD<br>|
| Experimental: BIBW 2992 QD<br>Phase II step: Patients start continuous once daily oral treatment of BIBW 2992 at high dose, until progression or undue Adverse Events (AEs) develop. Patients can be dose-reduced up to two times if needed after temporary discontinuation of treatment due to drug-related AEs. | Drug: BIBW 2992 QD<br>* Phase II step: This is an open label study. Patients are treated with BIBW 2992 until disease progression or undue AEs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | 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. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| Phase I Step: Summary of Epidermal Growth Factor Receptor (EGFR) Mutation Findings |  | Screening visit | 
| Phase II Step: Duration of Clinical Benefit | Presented as duration of disease control. | 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 | 
| 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. | 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 | 
| Phase II Step: Overall Survival (OS) | OS was defined as the duration of time from the start of treatment to the time of death. | 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. | 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 | 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. | 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 | 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 | Course 2 Day 15 | 
| Phase II Step: Summary of EGFR Mutation Findings |  | Screening visit | 
| Phase I Step: Cmax,Cmax,ss of BIBW 2992 After Multiple Oral Administration |  | Just before start of the treatment to Course 4 Visit 4R2 |