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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2015

01-10-2015 | Original Article

Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer

Authors: Hirofumi Mukai, Norikazu Masuda, Hiroshi Ishiguro, Ayako Mitsuma, Takashi Shibata, Jun Yamamura, Masakazu Toi, Aiko Watabe, Akiko Sarashina, Martina Uttenreuther-Fischer, Yuichi Ando

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2015

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Abstract

Purpose

This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment.

Methods

Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m2 weekly.

Results

Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m2) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m2 and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m2 allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug–drug interactions.

Conclusions

Afatinib 40 mg QD plus vinorelbine 25 mg/m2 weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients.
Appendix
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Literature
1.
Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, Greene MI (2007) ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest 117:2051–2058PubMedCentralCrossRefPubMed
2.
Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12:553–563CrossRefPubMed
3.
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 27:4702–4711PubMedCentralCrossRefPubMed
4.
Solca F, Dahl G, 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 343:342–350CrossRefPubMed
5.
Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334CrossRefPubMed
6.
Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL (2014) Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15:213–222CrossRefPubMed
7.
Yang JC-H, Sequist LV, Schuler MH, Mok T, Yamamoto N, O’Byrne KJ, Hirsh V, Geater SL, Zhou C, Massey D, Zazulina V, Wu Y-L (2014) Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): pooled analysis of two large open-label phase III studies [LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6)] comparing afatinib with chemotherapy (CT). J Clin Oncol 32:[abstract 8004]
8.
9.
10.
Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM, Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G, Jr., de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Cohen EE, LUX-H&N 1 investigators (2015) Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 16(5):583–594CrossRefPubMed
11.
Goss GD, Felip E, Cobo M, Lu S, Syrigos KN, Lee KH, Göker, E., Georgoulias V, Li W, Isla D, Morabito A, Guclu SZ, Min YJ, Ardizzoni A, Gadgeel S, Love J, Chand V, Soria J (2014) A randomized, open-label, phase III trial of afatinib (A) vs erlotinib (E) as second-line treatment of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following first-line platinum-based chemotherapy: LUX-Lung 8 (LL8). Ann Oncol 25:[abstract iv426]
12.
Lin NU, Winer EP, Wheatley D, Carey LA, Houston S, Mendelson D, Munster P, Frakes L, Kelly S, Garcia AA, Cleator S, Uttenreuther-Fischer M, Jones H, Wind S, Vinisko R, Hickish T (2012) A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. Breast Cancer Res Treat 133:1057–1065PubMedCentralCrossRefPubMed
13.
Bahleda R, Soria J, Berge Y, Massard C, Wind S, Uttenreuther-Fischer MM, Fleischer F, De-Montserrat H, Solca F, Tschoepe I, Delord J (2011) Phase I trial assessing safety and pharmacokinetics of afatinib (BIBW 2992) with intravenous weekly vinorelbine in advanced solid tumors. J Clin Oncol 29:[abstract 2585]
14.
15.
16.
17.
18.
Hollebecque A, Bahleda A, Bergé Y, Massard C, Uttenreuther-Fischer M, de Mont-Serrat H, Tschoepe I, Schnell D, Soria J-S, Delord J-P (2013) A phase I trial assessing the safety and pharmacokinetics of afatinib and weekly vinorelbine in patients with advanced solid tumours. Eur J Cancer 49:[abstract 892]
19.
Harbeck N, Huang C-S, Hurvitz SA, Yeh D-C, Shao Z, Im SA, Jung KH, Shen K, Ro J, Jassem J, Zhang Q, Im YH, Wojtukiewicz M, Sun Q, Chen S, Goeldner RG, Lahogue A, Uttenreuther-Fischer M, Xu B, Piccart-Gebhart M (2014) Randomized Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1. Presented at San Antonio Breast Cancer Symposium, 9–13 Dec 2014. Abstract P5-19-01
20.
21.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMed
22.
23.
Hotta K, Kiura K, Takigawa N, Yoshioka H, Harita S, Kuyama S, Yonei T, Fujiwara K, Maeda T, Aoe K, Ueoka H, Kamei H, Umemura S, Moritaka T, Segawa Y, Kawai H, Bessho A, Kato K, Tabata M, Tanimoto M (2010) Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese Patients with non-small cell lung cancer: the Okayama Lung Cancer Study Group experience. J Thorac Oncol 5:179–184CrossRefPubMed
24.
Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N (2013) LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 31:3335–3341CrossRefPubMed
Metadata
Title
Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer
Authors
Hirofumi Mukai
Norikazu Masuda
Hiroshi Ishiguro
Ayako Mitsuma
Takashi Shibata
Jun Yamamura
Masakazu Toi
Aiko Watabe
Akiko Sarashina
Martina Uttenreuther-Fischer
Yuichi Ando
Publication date
01-10-2015
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2015
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-015-2826-4

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