Top

Published in:

Open Access 01-06-2013 | PHASE I STUDIES

Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors

Authors: A. H. Awada, H. Dumez, A. Hendlisz, P. Wolter, T. Besse-Hammer, M. Uttenreuther-Fischer, P. Stopfer, F. Fleischer, M. Piccart, P. Schöffski

Published in: Investigational New Drugs | Issue 3/2013

Summary

Background A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. Methods Patients with advanced solid malignancies received docetaxel 75 mg/m² intravenously on day 1 and oral afatinib once daily on days 2–4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3–6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. Results Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m² docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2–4) with docetaxel 75 mg/m². The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed. Conclusion Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m² is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile.

Hynes NE, MacDonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21(2):177–184. doi:10.1016/j.ceb.2008.12.010 PubMedCrossRef

Arteaga CL (2002) Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 7(Suppl 4):31–39PubMedCrossRef

Baselga J, Arteaga CL (2005) Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 23(11):2445–2459. doi:10.1200/JCO.2005.11.890 PubMedCrossRef

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 (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34):4702–4711. doi:10.1038/onc.2008.109 PubMedCrossRef

Solca F, Dahl C, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, Himmelsbach F, Haaksma E, Adolf GR (2012) Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. doi:10.1124/jpet.1112.197756

Reid A, Vidal L, Shaw H, de Bono J (2007) Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu). Eur J Cancer 43(3):481–489. doi:10.1016/j.ejca.2006.11.007 PubMedCrossRef

Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H, van Doorn L, Burger H, Stopfer P, Verweij J, de Vries EG (2008) 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 98(1):80–85. doi:10.1038/sj.bjc.6604108

Marshall J, Hwang J, Eskens FALM, Burger , Malik S, Uttenreuther-Fischer M, Stopfer P, Ould Kaci M, Cohen RB, Lewis NL (2012) A Phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors. Investigational New Drugs. (in press)

Agus DB, Terlizzi E, Stopfer P, Amelsberg A, Gordon MS (2006) A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a continuous schedule in patients with advanced solid tumours. J Clin Oncol 24(18S):2074

10.

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 J, Plummer R (2010) Phase I trial of the irrevisible ErbB1 (EGFR) and ErbB2 (HER2) kinase inhibitor BIBW 2992 in patients with advanced solid tumours. J Clin Oncol 28(25):3965–3972PubMedCrossRef

11.

Solca F, Baum A, Himmelsbach F, Amelsberg A, Adolf G (2006) Efficacy of BIBW 2992, an irreversible dual EGFR/HER2 kinase inhibitor in combination with cytotoxic agents. Eur J Cancer Suppl 4(12):172CrossRef

12.

Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 22(5):777–784. doi:10.1200/JCO.2004.08.001 PubMedCrossRef

13.

Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 22(5):785–794PubMedCrossRef

14.

von Pawel J, Kaiser R, Eschbach C, Stefanic M, Love J, Gatzemeier U, Reck M (2007) A double blind phase II study of BIBF 1120 in patients suffering from relapsed advanced non-small cell lung cancer (NSCLC). In: American Society of Clinical Oncology Chicago, IL, USA, 1–5 June

15.

Davies A, Hesketh P, Beckett L, Lau D, Mack P, Lara P, Jernigan J, LaPointe J, Gandara D (2007) Pharmacodynamic separation of erlotinib and docetaxel (DOC) in advanced non-small cell lung cancer (NSCLC): Overcoming hypothesized antagonism. ASCO Meeting Abstracts 25 (18_suppl):7618

16.

Davies A, Lara P, Lau D, Mack P, Gumerlock P, Gandara D (2005) Intermittent erlotinib in combination with docetaxel (DOC): Phase I schedules designed to achieve pharmacodynamic separation. ASCO Meeting Abstracts 23 (16_suppl):7038

17.

Gumerlock P, Pryde B, Kimura T, Galvin I, Scott S, Mack P, Davies A, Gandara D (2003) Enhanced cytotoxicity of docetaxel OSI-774 combination in non-small cell lung carcinoma (NSCLC). Proc Am Soc Clin Oncol 22(662a):abstr 2661

18.

Mahaffey CM, Davies AM, Lara PN Jr, Pryde B, Holland W, Mack PC, Gumerlock PH, Gandara DR (2007) Schedule-dependent apoptosis in K-ras mutant non-small-cell lung cancer cell lines treated with docetaxel and erlotinib: rationale for pharmacodynamic separation. Clin Lung Cancer 8(9):548–553PubMedCrossRef

19.

Solca F, Schweifer N, Baum A, Rudolph D, Amelsberg A, Himmelsbach F, Beug H (2005) BIBW 2992, an irreversible dual EGFR/HER2 kinase inhibitor, shows activity on L858R/T790M EGFR mutants. Clin Cancer Res 11(23):A242

20.

Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, Miller VA (2012) Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncology 13(5):539–548

21.

Marshall J, Shapiro GI, Terlizzi P, Stopfer P, Amelsberg A, Gordon M (2008) A Phase I dose escalation trial of BIBW 2992, an irreversible EGFR/HER2 kinase inhibitor, for 20 and 13 days in combination with docetaxel every 21 days. In: ESMO, Stockholm, Sweden, September 2008, pp viii153–165

22.

Campas C, Bolos J (2008) BIBW-2992. Dual EGFR/HER2 inhibitor oncolytic. Drugs Future 33(8):649–654CrossRef

23.

Pronk LC, Stoter G, Verweij J (1995) Docetaxel (Taxotere): single agent activity, development of combination treatment and reducing side-effects. Cancer Treat Rev 21(5):463–478PubMedCrossRef

24.

Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC (2012) Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncology 13(5):528–538

25.

Riely G, Rizvi N, Kris M, Milton D, Solit DB, Rosen N, Senturk E, Azzoli C, Brahmer J, Sirotnak FM, Seshan V, Fogle M, Ginsberg MS, Miller V, Rudin CM (2009) Randomized phase II study of pulse erlotinib before or after carboplatin and paclitaxel in current or former smokers with advanced non-small-cell lung cancer. J Clin Oncol 27(27):264–270PubMedCrossRef

26.

Fury MG, Solit DB, Su YB, Rosen N, Sirotnak FM, Smith RP, Azzoli CG, Gomez JE, Miller VA, Kris MG, Pizzo BA, Henry R, Pfister DG, Rizvi NA (2007) A phase I trial of intermittent high-dose gefitinib and fixed-dose docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 59(4):467–475. doi:10.1007/s00280-006-0286-6 PubMedCrossRef

27.

Bradshaw-Pierce EL, Eckhardt SG, Gustafson DL (2007) A physiologically based pharmacokinetic model of docetaxel disposition: from mouse to man. Clin Cancer Res 13(9):2768–2776. doi:10.1158/1078-0432.CCR-06-2362 PubMedCrossRef

28.

Clarke SJ, Rivory LP (1999) Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet 36(2):99–114PubMedCrossRef

Title: Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors
Authors: A. H. Awada
H. Dumez
A. Hendlisz
P. Wolter
T. Besse-Hammer
M. Uttenreuther-Fischer
P. Stopfer
F. Fleischer
M. Piccart
P. Schöffski
Publication date: 01-06-2013
Publisher: Springer US
Published in: Investigational New Drugs / Issue 3/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-012-9880-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 3/2013

The novel antiangiogenic VJ115 inhibits the NADH oxidase ENOX1 and cytoskeleton-remodeling proteins

EGFR and HER2 inhibition in pancreatic cancer

Cytotoxicity of withaferin A in glioblastomas involves induction of an oxidative stress-mediated heat shock response while altering Akt/mTOR and MAPK signaling pathways

A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma

Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics

Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system

Keynote webinar | Spotlight on antibody–drug conjugates in cancer