- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01542437
Treatment With BIBW 2992, Irreversible Inhibitor of EGFR and HER-2 in Non-small Cell Lung Cancer (NSCLC)
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
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Distrito Federal
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Mexico city, Distrito Federal, Mexico, 14080
- National Cancer Institute of Mexico
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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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.
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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 Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Overall response
Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died.
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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.
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from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died.
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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.
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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.
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from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died.
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Overall survival
Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died.
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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.
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from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Evaluation of the HER-2 gene copy number and amplification
Time Frame: Baseline
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Assessing the number of copies of the HER-2 gene by FISH
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Baseline
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DNA Extraction and Mutational Analysis of EGFR and HER-2
Time Frame: Baseline
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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.
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Baseline
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Toxicity evaluation
Time Frame: from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died.
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adverse effect from CTCAE
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from the start of consumption until at least 6 months after stopping BIBW 2992 or when all patients have died.
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Determination of plasma HGF pre and post-treatment concentration
Time Frame: Baseline and after 2 months of treatment.
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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.
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Baseline and after 2 months of treatment.
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Collaborators and Investigators
Investigators
- Principal Investigator: Oscar Arrieta, MD M Sc, Mexico. National Cancer Institute
Publications and helpful links
General Publications
- Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman J, Tompkins RG, Lynch TJ, Toner M, Haber DA. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008 Jul 24;359(4):366-77. doi: 10.1056/NEJMoa0800668. Epub 2008 Jul 2.
- Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232. doi: 10.1016/1040-8428(94)00144-i. No abstract available.
- Rusch V, Mendelsohn J, Dmitrovsky E. The epidermal growth factor receptor and its ligands as therapeutic targets in human tumors. Cytokine Growth Factor Rev. 1996 Aug;7(2):133-41. doi: 10.1016/1359-6101(96)00016-0.
- Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.
- Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005 Feb 24;352(8):786-92. doi: 10.1056/NEJMoa044238.
- Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007 Mar;7(3):169-81. doi: 10.1038/nrc2088.
- Modjtahedi H, Dean C. The receptor for EGF and its ligands - expression, prognostic value and target for therapy in cancer (review). Int J Oncol. 1994 Feb;4(2):277-96. doi: 10.3892/ijo.4.2.277.
- Davies DE, Chamberlin SG. Targeting the epidermal growth factor receptor for therapy of carcinomas. Biochem Pharmacol. 1996 May 3;51(9):1101-10. doi: 10.1016/0006-2952(95)02232-5.
- Veale D, Ashcroft T, Marsh C, Gibson GJ, Harris AL. Epidermal growth factor receptors in non-small cell lung cancer. Br J Cancer. 1987 May;55(5):513-6. doi: 10.1038/bjc.1987.104.
- Sekine I, Takami S, Guang SG, Yokose T, Kodama T, Nishiwaki Y, Kinoshita M, Matsumoto H, Ogura T, Nagai K. Role of epidermal growth factor receptor overexpression, K-ras point mutation and c-myc amplification in the carcinogenesis of non-small cell lung cancer. Oncol Rep. 1998 Mar-Apr;5(2):351-4.
- Pfeiffer P, Clausen PP, Andersen K, Rose C. Lack of prognostic significance of epidermal growth factor receptor and the oncoprotein p185HER-2 in patients with systemically untreated non-small-cell lung cancer: an immunohistochemical study on cryosections. Br J Cancer. 1996 Jul;74(1):86-91. doi: 10.1038/bjc.1996.320.
- Cerny T, Barnes DM, Hasleton P, Barber PV, Healy K, Gullick W, Thatcher N. Expression of epidermal growth factor receptor (EGF-R) in human lung tumours. Br J Cancer. 1986 Aug;54(2):265-9. doi: 10.1038/bjc.1986.172.
- Reissmann PT, Koga H, Figlin RA, Holmes EC, Slamon DJ. Amplification and overexpression of the cyclin D1 and epidermal growth factor receptor genes in non-small-cell lung cancer. Lung Cancer Study Group. J Cancer Res Clin Oncol. 1999;125(2):61-70. doi: 10.1007/s004320050243.
- Fujino S, Enokibori T, Tezuka N, Asada Y, Inoue S, Kato H, Mori A. A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer. Eur J Cancer. 1996 Nov;32A(12):2070-4. doi: 10.1016/s0959-8049(96)00243-2.
- Fontanini G, Vignati S, Bigini D, Mussi A, Lucchi H, Angeletti CA, Pingitore R, Pepe S, Basolo F, Bevilacqua G. Epidermal growth factor receptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer. 1995;31A(2):178-83. doi: 10.1016/0959-8049(93)00421-m.
- Rusch V, Baselga J, Cordon-Cardo C, Orazem J, Zaman M, Hoda S, McIntosh J, Kurie J, Dmitrovsky E. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res. 1993 May 15;53(10 Suppl):2379-85.
- Ohsaki Y, Tanno S, Fujita Y, Toyoshima E, Fujiuchi S, Nishigaki Y, Ishida S, Nagase A, Miyokawa N, Hirata S, Kikuchi K. Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep. 2000 May-Jun;7(3):603-7. doi: 10.3892/or.7.3.603.
- Lei W, Mayotte JE, Levitt ML. Enhancement of chemosensitivity and programmed cell death by tyrosine kinase inhibitors correlates with EGFR expression in non-small cell lung cancer cells. Anticancer Res. 1999 Jan-Feb;19(1A):221-8.
- Veale D, Kerr N, Gibson GJ, Kelly PJ, Harris AL. The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival. Br J Cancer. 1993 Jul;68(1):162-5. doi: 10.1038/bjc.1993.306.
- Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol. 2001 Jun;144(6):1169-76. doi: 10.1046/j.1365-2133.2001.04226.x.
- Van Doorn R, Kirtschig G, Scheffer E, Stoof TJ, Giaccone G. Follicular and epidermal alterations in patients treated with ZD1839 (Iressa), an inhibitor of the epidermal growth factor receptor. Br J Dermatol. 2002 Sep;147(3):598-601. doi: 10.1046/j.1365-2133.2002.04864.x.
- Herbst RS, LoRusso PM, Purdom M, Ward D. Dermatologic side effects associated with gefitinib therapy: clinical experience and management. Clin Lung Cancer. 2003 May;4(6):366-9. doi: 10.3816/clc.2003.n.016.
- Giovino GA. Epidemiology of tobacco use in the United States. Oncogene. 2002 Oct 21;21(48):7326-40. doi: 10.1038/sj.onc.1205808.
- Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, Padera RF, Shapiro GI, Baum A, Himmelsbach F, Rettig WJ, Meyerson M, Solca F, Greulich H, Wong KK. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene. 2008 Aug 7;27(34):4702-11. doi: 10.1038/onc.2008.109. Epub 2008 Apr 14.
- Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H, van Doorn L, Burger H, Stopfer P, Verweij J, de Vries EG. A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer. 2008 Jan 15;98(1):80-5. doi: 10.1038/sj.bjc.6604108. Epub 2007 Nov 20.
- Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, Ang J, Temple G, Bell S, Shahidi M, Uttenreuther-Fischer M, Stopfer P, Futreal A, Calvert H, de Bono JS, Plummer R. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol. 2010 Sep 1;28(25):3965-72. doi: 10.1200/JCO.2009.26.7278. Epub 2010 Aug 2.
- Spicer JF, Rudman SM. EGFR inhibitors in non-small cell lung cancer (NSCLC): the emerging role of the dual irreversible EGFR/HER2 inhibitor BIBW 2992. Target Oncol. 2010 Dec;5(4):245-55. doi: 10.1007/s11523-010-0140-y. Epub 2010 Jun 24.
- Takezawa K, Okamoto I, Tanizaki J, Kuwata K, Yamaguchi H, Fukuoka M, Nishio K, Nakagawa K. Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor. Mol Cancer Ther. 2010 Jun;9(6):1647-56. doi: 10.1158/1535-7163.MCT-09-1009. Epub 2010 Jun 8.
- Arrieta O, Cruz-Rico G, Soto-Perez-de-Celis E, Ramirez-Tirado LA, Caballe-Perez E, Martinez-Hernandez JN, Martinez-Alvarez I, Soca-Chafre G, Macedo-Perez EO, Astudillo-de la Vega H. Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial. Target Oncol. 2016 Oct;11(5):619-629. doi: 10.1007/s11523-016-0425-x.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Respiratory Tract Diseases
- Neoplasms
- Lung Diseases
- Neoplasms by Site
- Respiratory Tract Neoplasms
- Thoracic Neoplasms
- Carcinoma, Bronchogenic
- Bronchial Neoplasms
- Lung Neoplasms
- Carcinoma, Non-Small-Cell Lung
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Afatinib
Other Study ID Numbers
- BIBW2992
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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