| Autor: |
M. Boyer, Masahiro Tsuboi, M. Laniado, T. Nukiwa, Kazuhiko Nakagawa, Hirohisa Yoshizawa, S. Kobayashi, Filip Janku, M. Takeda, Manfred B. Klevesath, Jun Sakakibara-Konishi, W. Uhl, K. Arakawa, Akihiko Gemma, N. Omachi, T. Tsuji, A. Tamiya, T. Yoshino, Yoshiki Ishii, N. Yamamoto, G. Falchook, T. Kawaguchi, Satoshi Oizumi, Luis Paz-Ares, Gerald S. Falchook, Andreas Johne, Y-L. Wu, J-C. Soria, Isamu Okamoto, P. Rougier, S. Atagi, A. Campbell, H. Lannert, Razelle Kurzrock, T. Shiroyama, Siquing Fu, K. Asami, H. Isobe, A. Ohtsu, V. Antic, S.-Y. Lee, K. Park, H. Crane, C.-M. Tsai, Sojiro Morita, Ralph Zinner, Jennifer J. Wheler, M. Wirth, Stephen P. Letrent, Sarina Anne Piha-Paul, Pasi A. Jänne, N. Yoshizuka, M. Tamiya, Tony Mok, K. Takeda, Motoki Yoshida, M. D. Rutstein, J.J. Wheler, H. Suzuki, Thierry Gil, H. Tada, S. Ballal, A. Grothey, S. Zastrow, N. Okamoto, Akira Inoue, Y. Ichinose, K. Sugio, S. Minomo, Aung Naing, Ian Taylor, S. Nakamura, Yoichi Nakanishi, Joe O'Connell, Y. Saijyo, J. T.abernero, Jane Q. Liang, F. Nasroulah, Suresh S. Ramalingam, K. O'Byrne, T. Mitsudomi, Axel Heidenreich, N. Morishita, V. Jego, K. Okishio, K. Yamazaki, Jürgen E. Gschwend, T. Hirashima, David S. Hong, M. Zühlsdorf, T. Yamanaka, D.S. Hong, X. Zhang, Apostolia-Maria Tsimberidou, J. Gerloff, A. Miao, Koichi Hagiwara, Kazuhiko Kobayashi, Hesham M. Amin |
| Rok vydání: |
2012 |
| Předmět: |
|
| Zdroj: |
Annals of Oncology. 23:xi21 |
| ISSN: |
0923-7534 |
| Popis: |
Background The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor (HGF), are implicated in tumor cell migration, invasion, survival and proliferation. EMD 1214063 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods This is a phase I, first in human (FIH) clinical trial with escalating doses of EMD 121406(NCT 01014936). The primary objective is to determine the MTD. Secondary objectives include evaluation of safety, pharmacokinetics, anti-tumor effect and pharmacodynamics (Pd). Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3 + 3 dose escalation scheme, successive cohorts of patients were treated with once daily oral EMD 1214063 according to two 21-day-cycle schedules, either days 1-14 followed by a 7-day rest(regimen 1, R1), or continuous three times weekly administration (regimen 2, R2). Pd markers were evaluated in paired tumor biopsies. Results As of 30 March 2011, a total of 41 patients had been enrolled, 21 in R1 and 20 in R2. The dose was escalated from 30 mg/day to 115 mg/day in R2 and to 230 mg/day in R1. One DLT was reported in R1 at 115 mg/day, an asymptomatic, grade 4 lipase and G3 amylase elevation. No other DLTs or treatment-related SAEs were observed. The remaining treatment-related AEs of grade 2 or higher included nausea (n = 1), vomiting (n = 1), anorexia (n = 1), diarrhea (n = 1), and fatigue (n = 1) in R1, and neutropenia (n = 1) in R2. 37 patients (90%) had no drug-related toxicity greater than grade 1. At the dose levels investigated, median Cmax and AUC values increased with dose. Immunohistochemical analysis of a patient with pre- and on-treatment biopsies showed a decrease in phospho-c-Met staining intensity under treatment. Preliminary anti-tumor activity has been observed, including an unconfirmed PR in one patient and stable disease lasting for at least 4 months in 5 patients. One patient with sarcomatoid bladder carcinoma and multiple MET copies due to polysomy of chromosome 7 achieved SD for 16+ months. Conclusions The MTD has not yet been reached and dose escalation of EMD 1214063 continues. Updated results of this FIH study will be presented. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
