Treatment With BIBW 2992, Irreversible Inhibitor of EGFR and HER-2 in Non Small Cell Lung Cancer (NSCLC)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Overall response [ Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died. ] [ Designated as safety issue: Yes ]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. ] [ Designated as safety issue: Yes ]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. ] [ Designated as safety issue: Yes ]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.
- Evaluation of the HER-2 gene copy number and amplification [ Time Frame: Baseline ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: Yes ]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. ] [ Designated as safety issue: Yes ]adverse effect from CTCAE
- Determination of plasma HGF pre and post-treatment concentration [ Time Frame: Baseline and after 2 months of treatment. ] [ Designated as safety issue: Yes ]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.
|Study Start Date:||January 2012|
|Estimated Study Completion Date:||June 2016|
|Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
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.
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
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01542437
|National Cancer Institute of Mexico|
|Mexico city, Distrito Federal, Mexico, 14080|
|Principal Investigator:||Oscar Arrieta, MD M Sc||Mexico. National Cancer Institute|