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Treatment With BIBW 2992, Irreversible Inhibitor of EGFR and HER-2 in Non Small Cell Lung Cancer (NSCLC)

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ClinicalTrials.gov Identifier: NCT01542437
Recruitment Status : Unknown
Verified March 2017 by Oscar Gerardo Arrieta Rodríguez MD, Instituto Nacional de Cancerologia de Mexico.
Recruitment status was:  Active, not recruiting
First Posted : March 2, 2012
Last Update Posted : March 3, 2017
Sponsor:
Information provided by (Responsible Party):
Oscar Gerardo Arrieta Rodríguez MD, Instituto Nacional de Cancerologia de Mexico

Tracking Information
First Submitted Date  ICMJE February 24, 2012
First Posted Date  ICMJE March 2, 2012
Last Update Posted Date March 3, 2017
Study Start Date  ICMJE January 2012
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2015)
  • Overall response [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    Is assigned to each subject the best objective response according to the investigator's decision (according to RECIST criteria). This is defined as the best response recorded from the start of treatment until progression / recurrence of disease. For patients with response status partial (PR) or complete response (CR), changes in tumor measurements must be confirmed by repeated assessments to be made not less than 4 weeks after it first reached the response criteria The CT will be made every two months to assess response to treatment. The objective response will be summarized descriptively.
  • Progression Free Survival [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    Is defined as the time from start of treatment until the date of the first documented evidence of progression (RECIST criteria) or the date of death for any reason in the absence of disease progression (EP). For patients who have died or progressed at the time of final analysis, use the date of last contact.
  • Overall survival [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    Overall survival will be determined from the date of commencement of treatment to date of death, regardless of the cause of death. In patients who did not die at the time of final analysis will use the date of last contact.
Original Primary Outcome Measures  ICMJE
 (submitted: February 24, 2012)
  • Response Rate or objective response [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    Is assigned to each subject the best objective response according to the investigator's decision (according to RECIST criteria). This is defined as the best response recorded from the start of treatment until progression / recurrence of disease. For patients with response status partial (PR) or complete response (CR), changes in tumor measurements must be confirmed by repeated assessments to be made not less than 4 weeks after it first reached the response criteria The CT will be made every two months to assess response to treatment. The objective response will be summarized descriptively.
  • Global control or target [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    Is defined by the sum of partial responses, complete responses and stable disease, excluding only the rate of progression. These are measured by RECIST criteria.
  • Progression Free Survival [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    Is defined as the time from start of treatment until the date of the first documented evidence of progression (RECIST criteria) or the date of death for any reason in the absence of disease progression (EP). For patients who have died or progressed at the time of final analysis, use the date of last contact.
  • Global survival [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    Overall survival will be determined from the date of commencement of treatment to date of death, regardless of the cause of death. In patients who did not die at the time of final analysis will use the date of last contact.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2015)
  • Evaluation of the HER-2 gene copy number and amplification [ Time Frame: Baseline ]
    Assessing the number of copies of the HER-2 gene by FISH
  • DNA Extraction and Mutational Analysis of EGFR and HER-2 [ Time Frame: Baseline ]
    Tumor samples were fixed in formalin and embedded in paraffin, used for histologic diagnosis of patients will be obtained from the Departments of Pathology participating institutes.
  • Toxicity evaluation [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    adverse effect from CTCAE
  • Determination of plasma HGF pre and post-treatment concentration [ Time Frame: Baseline and after 2 months of treatment. ]
    Plasma samples were collected before the start of treatment with afatinib and after 2 months of treatment. HGF plasma levels were determined using ELISA, which was per-formed according to Quantikine human HGF immunoassay (DHG00; R&D System, Minneapolis, MN, USA). All assays were performed in duplicate. Color intensity was measured at 450 nm with a spectrophotometric plate reader. HGF concentrations were determined by comparison with standard curves.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2012)
  • quantification HER-2 [ Time Frame: Baseline ]
    Assessing the number of copies of the HER-2 gene by FISH
  • Identification of mutations in EGFR and KRAS [ Time Frame: Baseline ]
    Tumor samples were fixed in formalin and embedded in paraffin, used for histologic diagnosis of patients will be obtained from the Departments of Pathology participating institutes.
  • descriptive analysis of safety. [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ]
    adverse effect from CTCAE
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment With BIBW 2992, Irreversible Inhibitor of EGFR and HER-2 in Non Small Cell Lung Cancer
Official Title  ICMJE Treatment With BIBW 2992, Irreversible Inhibitor of EGFR and HER-2 in Non Small Cell Lung Cancer in Advanced Stage, Which Have Progressed to Chemotherapy. Analysis of Mutations in EGFR and Number of Copies of HER-2
Brief Summary Patients with stage IIIB and IV lung adenocarcinoma and progression to first-line chemotherapy were enrolled to receive afatinib 40 mg/day. Mutational EGFR and HER-2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Plasma HGF levels were measured by ELISA before and 2 months (mo) after the start of treatment. We assessed changes in serum HGF levels and their association with objective response rate (ORR), PFS and overall survival (OS).
Detailed Description

Lung cancer is the main cause of cancer-related mortality worldwide, accounting for 1.6 million deaths in 2012. Non-small-cell lung cancer (NSCLC) histology comprises ap-proximately 85% of cases. At the time of diagnosis, 75% of the patients have locally advanced or metastatic disease, with a 5-year survival rate of less than 5%. Although treatment options for these patients remain limited, drugs targeting the epidermal growth factor receptor (EGFR) have proved to be a highly effective therapy in NSCLC patients harboring sensitizing EGFR mutations.

Afatinib, a second-generation irreversible TKI, confers a theoretical advantage over re-versible TKIs in patients with acquired resistance. Through covalent binding to the kinase domain of EGFR, afatinib down regulates signaling from all homodimers and heter-odimers formed by ERBB receptor family members including EGFR, HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). HER2 mutations in NSCLC are rare, being found in approximately 1-4% of lung adenocarcinomas.

In contrast with reversible TKIs, the mechanisms of resistance to irreversible TKIs have not been fully elucidated, and identification of biomarkers that predict response to these drugs, particularly in patients progressing after first line therapy, is needed. In this study we assess the usefulness of plasma HGF concentrations as a predictor of response to afatinib in patients with advanced-stage lung adenocarcinoma.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Non-Small Cell Lung Cancer
  • EGFR
  • HER-2
Intervention  ICMJE Drug: BIBW 2992

All patients will receive: BIBW 2992 40mg every 24 hours orally, where a cycle corresponds to complete this treatment for 28 days; option 30mg/day dose reductions, according to established criteria.

Not to be compared with any other drug.

Other Name: Afatinib
Study Arms  ICMJE Experimental: BIBW 2992
Patients received a daily oral 40mg dose of afatinib. Treatment was continued until docu-mented disease progression, unacceptable toxicity or withdrawal of consent. The Common Terminology Criteria for Adverse Events (CTCAE) v4.0 was used to evaluate toxicity. In patients with severe toxicity (grade ≥3) afatinib was temporary discontinued until the patient recovery to at least grade 1 toxicity and continued with a dose reduction to 30 mg/day. Dose reduction below 30mg/day was not allowed. Patients experiencing more than one grade ≥3 event, those with grade ≥2 toxicity after dose reduction, and/or those showing no recovery within 14 days discontinued treatment.
Intervention: Drug: BIBW 2992
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: July 8, 2015)
66
Original Estimated Enrollment  ICMJE
 (submitted: February 24, 2012)
150
Estimated Study Completion Date  ICMJE June 2017
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of lung cancer non-small cell (stage IIIB or IV) inoperable, locally advanced, recurrent or metastatic, histologically or cytologically documented.
  • The patient must present evidence of measurable disease.
  • 18 years of age or older.
  • ECOG performance status of 0-2
  • Life expectancy at least 12 weeks.
  • lung cancer patients with advanced non-small cell, stage IIIB / IV who have received at least one cycle of systemic chemotherapy standard platinum-based first-or second-line fault has been documented that treatment.
  • are admissible 3 or more prior chemotherapy regimens. Patients must have recovered from any toxic effects and should have passed at least 2 weeks after the last dose prior to registration (14 days for vinorelbine and other vinca alkaloids or gemcitabine). Patients in the opinion of the investigator are fully recovered from surgery for 4 weeks at least, can also be considered for the study. Patients must have recovered from any severe toxicity (CTC ≤ 1) caused by any previous therapy.
  • granulocyte count ≥ 1.5x 109 / L and platelet count> 100 × 109 / L.
  • serum bilirubin should be ≤ 1.5 X ULN
  • AST and / or ALT ≤ 2 ULN (or ≤ 5 x ULN when clearly attributable to the presence of liver metastases).
  • Serum creatinine ≤ 1.5 (ULN) or creatinine clearance ≥ 60ml/min
  • Ability to comply with study procedures and monitoring.
  • Of all women of childbearing potential should be obtained a negative pregnancy test within 72 hours before the start of therapy.
  • Patients with reproductive potential must use effective contraception.
  • Written informed consent (signed) to participate in the study.

Exclusion Criteria:

  • Any unstable systemic disease (including active infection, grade 4 hypertension, unstable angina, congestive heart failure, liver disease, renal or metabolic).
  • Pre-treatment with systemic anti-tumor therapy with EGFR inhibitors (tyrosine kinase inhibitors).
  • Any other malignancy within the previous 5 years (except for carcinoma in situ of the cervix or skin cancer adequately treated basal cell type).
  • Excluded patients with brain metastases or spinal cord compression of newly diagnosed and / or have not been definitively treated with surgery and / or radiation, supporting both patients with CNS metastases or spinal cord compression previously diagnosed and treated with evidence of stable disease (clinically stable on imaging studies) for a minimum of 2 months.
  • Any significant ophthalmologic abnormality, especially severe syndrome of dry eye, keratoconjunctivitis sicca, Sjogren's syndrome, severe keratitis exposure and any other condition that may increase the risk of corneal epithelial damage. We do not recommend the use of contact lenses during the study. The decision to continue with the use of contact lenses should be discussed with the treating oncologist and the patient's ophthalmologist.
  • Patients unable to take oral medication, requiring intravenous nutrition, which have undergone prior surgical procedures affecting absorption, or who have active peptic ulceration.
  • lactating women.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Mexico
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01542437
Other Study ID Numbers  ICMJE BIBW2992
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Oscar Gerardo Arrieta Rodríguez MD, Instituto Nacional de Cancerologia de Mexico
Study Sponsor  ICMJE Instituto Nacional de Cancerologia de Mexico
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Oscar Arrieta, MD M Sc Mexico. National Cancer Institute
PRS Account Instituto Nacional de Cancerologia de Mexico
Verification Date March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP