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BIBW 2992 (Afatinib) vs Gemcitabine-cisplatin in 1st Line Non-small Cell Lung Cancer (NSCLC)

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ClinicalTrials.gov Identifier: NCT01121393
Recruitment Status : Completed
First Posted : May 12, 2010
Results First Posted : January 26, 2015
Last Update Posted : December 14, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
To investigate the efficacy and safety of BIBW 2992 compared to standard first-line chemotherapy in patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Adenocarcinoma Drug: Gemcitabine+Cisplatin Drug: BIBW 2992 Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 364 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: LUX-Lung 6: A Randomized, Open-label, Phase III Study of BIBW 2992 Versus Chemotherapy as First-line Treatment for Patients With Stage IIIB or IV Adenocarcinoma of the Lung Harbouring an EGFR Activating Mutation
Actual Study Start Date : April 19, 2010
Actual Primary Completion Date : November 23, 2017
Actual Study Completion Date : November 26, 2017


Arm Intervention/treatment
Experimental: Arm A BIBW 2992
Patients receive a tablet of BIBW 2992 daily until progression or unacceptable toxicity
Drug: BIBW 2992
starting dose is 40 mg, in the event of no or minimal drug-related adverse events after one course, the dose will be increased to 50mg. in the event of certain drug related Adverse Event (AE), dose reduction will be increments of 10 mg, with the lowest dose being 20mg.

Active Comparator: Arm B Chemotherapy
Patients receive Gemcitabine and Cisplatin, maximum is 6 courses
Drug: Gemcitabine+Cisplatin
Gemcitabine d1,8, Cisplatin d1, 21 days as a course, up to 6 courses.




Primary Outcome Measures :
  1. Progression-free Survival [ Time Frame: Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 168 ]

    The primary endpoint was progression-free survival (PFS) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Progression-free survival was defined as the time from randomisation to disease progression or death whichever occurs earlier. A pre-defined set of censoring rules were used for patients who did not have a PFS.

    Only data collected up until the analysis cut-off date (27 December 2013) were considered. Median time results from unstratified Kaplan-Meier estimates.



Secondary Outcome Measures :
  1. Objective Response (OR) [ Time Frame: Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374 ]

    OR is defined as a best overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1 and will be presented as the percentage of patients with OR.

    CR is defined as the disappearance of all target lesions and non-target lesions and no new lesions.

    PR is defined as at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD, non-Progressive Disease or non evaluation of all non-target lesions and no new lesions.

    (Exact 95% Confidence interval by Clopper and Pearson.)


  2. Disease Control (DC) [ Time Frame: Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374 ]
    DC is defined as a patient with objective response (OR) or stable disease (SD) assessed by central independent review according to RECIST version 1.1 and will be presented as the percentage of patients with DC.

  3. Overall Survival (OS) [ Time Frame: From randomisation up to 374 weeks ]

    OS is defined as the time from randomisation to death. For patients who had not died until 7 December 2017, the date they were last known to be alive was derived from patient status records, the trial completion record, radiological imaging assessments, the study treatment termination record, and the randomisation date.

    Median time results from unstratified Kaplan-Meier estimates.


  4. Time to Objective Response (OR) [ Time Frame: Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374 ]

    OR is defined as a best of overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1.

    For patients with an objective response, time to objective response was defined as the time from randomisation to the first objective response.

    Outcome data are the percentage of patients with OR by each scheduled tumour assessment.


  5. Duration of Objective Response [ Time Frame: Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374 ]

    OR is defined as a best of overall response of complete response (CR) or partial response (PR) assessed by central independent review according to RECIST version 1.1.

    For patients with an objective response, duration of objective response was defined as the time from the first objective response to disease progression or death whichever occurs earlier. A pre-defined set of censoring rules were used for patients who did not progress/die. The Median values are Kaplan-Meier estimates.


  6. Duration of Disease Control [ Time Frame: Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374 ]
    For patients with disease control, duration of disease control was defined as the time from randomisation to progression or death whichever occurs first. A pre-defined set of censoring rules were used for patients who did not progress/die. The Median values are Kaplan-Meier estimates.

  7. Tumour Shrinkage [ Time Frame: Tumour assessment were performed at screening, week 6, 12, 18, 24, 30, 36, 42, 48 and then every 12 weeks until progression or death whichever occurs first up to week 374 ]

    Tumour shrinkage is calculated as the minimum post-baseline sum of longest diameters of target lesions (longest for non-nodal lesions, short axis for nodal lesions) (SLD), as assessed by central independent review. The mean of these minimum values are presented after adjusting for baseline sum of longest diameters and EGFR mutation category. Only data collected up until the analysis cut-off date (27 Dec 2013) were considered. A negative value means the smallest post-baseline SLD was smaller than baseline (decreased since baseline); a positive value means tumor size increased since baseline.

    The means are adjusted for baseline sum of lesions and EGFR mutation category.


  8. Change From Baseline in Body Weight [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]
    The change from baseline to the lowest and the last body weight recorded or during the the study.

  9. Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]

    The last ECOG performance score category recorded during the study. Outcome data are the percentage of patients with an shift of ECOG performance status from baseline to the last ECOG performance status.

    ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction;

    1. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work;
    2. Ambulatory (>50 percent of waking hours), capable of all selfcare, unable to carry out any work activities;
    3. Capable of only limited self care, confined to bed or chair more then 50 percent of waking hours;
    4. Completely disabled, cannot carry on any selfcare, totally confined to bed or chair;
    5. Dead

  10. Health Related Quality of Life (HRQOL): Time of Deterioration in Coughing [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]

    HRQOL as measured by standardised questionnaires (EuropeanOrganisation for Research and Treatment of Cancer (EORTC)) quality of life questionaires (OLQ-C30) and its lung cancer module (QLQ-LC13). Analysis for cough: QLQ-LC13, question 1.

    Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.


  11. Health Related Quality of Life (HRQOL): Time of Deterioration in Dyspnoea [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]

    HRQOL as measured by OLQ-C30 and its lung cancer module (QLQ-LC13). Analysis for dyspnoea: composite of QLQ-LC13, questions 3 to 5; individual item from QLQ-C30, question 8.

    Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.


  12. Health Related Quality of Life (HRQOL): Time of Deterioration in Pain [ Time Frame: Baseline and throughout the study (every 3 weeks) until progression or death (whichever occurs first) up to 374 weeks. ]

    HRQOL as measured by OLQ-C30 and its lung cancer module QLQ-LC13. Analysis for pain: composite of QLQ-C30, questions 9 and 19; individual items from QLQ-LC13, questions 10, 11 and 12.

    Time to deterioration was defined as the time from randomisation to a score increase (i.e. worsened) of at least 10 points from baseline (0 to 100 point scale). Patients without deterioration (including those with disease progression) were censored at the date of the last available HRQOL assessment; patients without post-baseline assessments were censored at the date of randomisation. Patients were considered as having deteriorated at the time of death. The median is Kaplan-Meier estimates.


  13. Pharmacokinetics of Afatinib at Day 22 [ Time Frame: Day 22 (course 2, visit 1) ]
    Outcome data are the trough plasma concentrations of afatinib at day 22 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the Pharmacokinetics (PK) assessment period).

  14. Pharmacokinetics of Afatinib at Day 29 [ Time Frame: Day 29 (course 2, visit 2) ]
    Outcome data are the trough plasma concentrations of afatinib at day 29 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the PK assessment period).

  15. Pharmacokinetics of Afatinib at Day 43 [ Time Frame: Day 43 (course 3, visit 1) ]
    Outcome data are the trough plasma concentrations of afatinib at day 43 after multiple daily dosing of 40mg afatinib and after dose escalation to 50mg or dose reduction to 30mg afatinib (no patient dose reduced to 20mg during the PK assessment period).

  16. Safety of Afatinib as Indicated by Intensity and Incidence of Adverse Events [ Time Frame: From first administration of study medication up to 28 days after the last administration of study medication up to 374 weeks. ]
    Safety of Afatinib as indicated by intensity and incidence of adverse events graded according to the US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Presented as the percentage of patients with an Adverse Events during the on-treatment period by highest CTCAE grade.

  17. Changes in Safety Laboratory Parameters [ Time Frame: From first administration of study medication up to 28 days after the last administration of study medication up to 374 weeks. ]

    Outcome data presented are the percentage of patients by worst CTCAE grade (only Grades 2 to 4 presented) on treatment for the following laboratory parameters: Potassium, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Creatine and Creatine Kinase.

    For Potassium; only CTCAE grades resulting from hypokalemia (low values) are presented.




Information from the National Library of Medicine

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

Inclusion criteria:

  1. pathologically confirmed diagnosis of stage IIIB or stage IV adenocarcinoma of the Lung
  2. EGFR(Epidermal Growth Factor Receptor) mutation detected by central laboratory analysis of tumor biopsy material
  3. Measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST)1.1
  4. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
  5. Age>=18 years
  6. life expectancy of at least three months
  7. Written informed consent that is consistent with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines.

Exclusion criteria:

  1. Prior chemotherapy for relapsed and/or metastatic NSCLC.
  2. Prior treatment with EGFR targeting small molecules or antibodies.
  3. Radiotherapy or surgery(other than biopsy) within 4 weeks prior to randomization
  4. Active brain metastases
  5. Any other current malignancy or malignancy diagnosed within the past 5 years
  6. Known pre-existing interstitial lung disease
  7. Significant or recent acute gastrointestinal disorders with diarrhoea as a a major symptoms.
  8. History or presence of clinically relevant cardiovascular abnormalities
  9. Cardiac left ventricular function with resting ejection fraction of less than 50%.
  10. Any other concomitant serious 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.
  11. Absolute neutrophil count(ANC)<1500/mm3
  12. Platelet count<100,000/mm3
  13. Creatinine clearance<60ml/min or serum creatinine>1.5 times Upper Limit of Normal (ULN).
  14. Bilirubin>1.5 times ULN
  15. Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) > 3 times ULN
  16. 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
  17. Pregnancy of breast-feeding
  18. Patients unable to comply with the protocol
  19. Active hepatitis B infection, active hepatitis C infection or known HIV(Human Immunodeficiency Virus) carrier.
  20. Known or suspected active drug or alcohol abuse.
  21. requirement for treatment with any of the prohibited concomitant medications listed in section 4.2.2
  22. Any contraindications for therapy with gemcitabine/cisplatin
  23. Known hypersensitivity to BIBW2992 or the excipient of any of the trial drugs
  24. Use of any investigational drug within 4 weeks of randomization.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01121393


Locations
China
Beijing Chao-Yang Hospital
Beijing, China, 100020
307 Hospital of PLA
Beijing, China, 100071
Peking Union Medical College Hospital
Beijing, China, 100730
Beijing Chest Hospital
Beijing, China, 101149
First Hospital of Jilin University
Changchun, China, 130021
Xiangya Hospital, Central South University
Changsha, China, 410008
Hunan Province Tumor Hospital
Changsha, China
West China Hospital
Chengdu, China, 610041
Fujian Provincial Tumor Hospital
Fuzhou, China, 350014
Guangdong General Hospital
Guangzhou, China, 510080
Guangzhou Institute of Respiratory Disease
Guangzhou, China, 510120
NanFang Hosptial
Guangzhou, China, 510515
The Third Affiliated Hospital of Harbin Medical University
Haerbin, China, 150081
Zhejiang Cancer Hospital
Hangzhou, China, 310022
Hubei Cancer Hospital
HongShan, China
Yunnan Provincial Tumor Hospital
Kunming, China, 650118
Lin Yi Tumor Hospital
Linyi, China, 276001
The Affiliated Cancer Hospital, Guangxi Medical University
Nan Ning, China
the 81th Hospital of PLA
Nanjing, China, 210002
Jiangsu Cancer Hospital
Nanjing, China, 210009
The affiliated hospital of medicalcollege qingdao university
Qingdao, China, 266101
Shanghai Changzheng Hospital
Shanghai, China, 200003
Shanghai Chest Hospital
Shanghai, China, 200030
Zhongshan Hospital Fudan University
Shanghai, China, 200032
Shanghai Pulmonary Hospital
Shanghai, China, 200433
Changhai Hospital
Shanghai, China, 200443
The First Hospital of Chinese Medical University
Shenyang, China, 110001
Hebei Provincial Tumor Hospital
Shijiazhuang, China
Tangdu Hospital
Xi'An, China, 710038
Northern Jiangsu People's Hospital
Yangzhou, China, 225001
Korea, Republic of
Kosin University Gospel Hospital
Busan, Korea, Republic of, 602-702
Chungbuk National University Hospital
Cheongju, Korea, Republic of, 361711
Yeungnam University Medical Center
Daegu, Korea, Republic of, 705-717
Konkuk University Medical Center
Seoul, Korea, Republic of, 143-729
Korea University Guro Hospital
Seoul, Korea, Republic of, 152-703
Thailand
Songklanagarind Hospital
Songkla, Thailand, 90110
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:
Study Protocol  [PDF] October 16, 2013
Statistical Analysis Plan  [PDF] December 5, 2012


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

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01121393     History of Changes
Other Study ID Numbers: 1200.34
First Posted: May 12, 2010    Key Record Dates
Results First Posted: January 26, 2015
Last Update Posted: December 14, 2018
Last Verified: December 2018

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma, Non-Small-Cell Lung
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Gemcitabine
Cisplatin
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs