Phase 1 pharmacokinetic study of the oral pan-AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors

详细信息    查看全文

• 作者：Toshihiko Doi ; Kenji Tamura ; Yuko Tanabe…
• 关键词：MK ; 2206 ; pan ; AKT inhibitor ; Pharmacokinetics ; Phase I study ; Skin toxicity
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：76
• 期：2
• 页码：409-416
• 全文大小：440 KB
• 参考文献：1.Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550-62. doi:10.-038/?nrc2664 PubMed View Article
  2.Okuzumi T, Fiedler D, Zhang C, Gray DC, Aizenstein B, Hoffman R, Shokat KM (2009) Inhibitor hijacking of Akt activation. Nat Chem Biol 5:484-93. doi:10.-038/?nchembio.-83 PubMed Central PubMed View Article
  3.Yan L (2009) MK-2206: a potent oral allosteric AKT inhibitor [abstract #DDT01-1]. In: Proceedings of the 100th annual meeting of the American association for cancer research, Denver, CO, 18-2 Apr 2009
  4.Lu W, Defeo-Jones D, Davis L et al (2009) In vitro and in vivo antitumor activities of MK-2206, a new allosteric Akt inhibitor [abstract #3714]. In: Proceedings of the 100th annual meeting of the American association for cancer research, Denver, CO, 18-2 Apr 2009
  5.Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, Ueno Y, Hatch H, Majumder PK, Pan BS, Kotani H (2010) MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 9:1956-967. doi:10.-158/-535-7163.?MCT-09-1012 PubMed View Article
  6.Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, Riisnaes R, Pope LL, Heaton SP, Thomas G, Garrett MD, Sullivan DM, de Bono JS, Tolcher AW (2011) First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29:4688-695. doi:10.-200/?JCO.-011.-5.-263 PubMed View Article
  7. Biondo A, Yap TA, Yan L et al (2011) Phase I clinical trial of an allosteric AKT inhibitor, MK-2206, using a once weekly (QW) dose regimen in patients with advanced solid tumors. J Clin Oncol 29:(suppl; abstr 3037)
  8.Yap TA, Yan L, Patnaik A, Tunariu N, Biondo A, Fearen I, Papadopoulos K, Olmos D, Baird RD, Delgado LM, Tetteh E, Beckman RA, Lupinacci L, Riisnaes R, Decordova S, Heaton SP, Swales K, deSouza NM, Leach MO, Garrett MD, Sullivan DM, de Bono JS, Tolcher A (2014) Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers. Clin Cancer Res 15(20):5672-685. doi:10.-158/-078-0432 View Article
  9.Ji Y, Li Y, Bekele BN (2007) Dose-finding in phase I clinical trials based on toxicity probability intervals. Clin Trials 4(3):235-44PubMed View Article
  10.Curry JL, Torres-Cabala CA, Kim KB, Tetzlaff MT, Duvic M, Tsai KY, Hong DS, Prieto VG (2014) Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions. Int J Dermatol 53:376-84. doi:10.-111/?ijd.-2205 PubMed View Article
  11.Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, Demanse D, De Buck SS, Ru QC, Peters M, Goldbrunner M, Baselga J (2012) Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 20;30(3):282-90. doi:10.-200/?JCO.-011.-6.-360 View Article
  12.Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395-02PubMed View Article
  13.Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221-230. doi:10.-158/-008-5472.?CAN-08-1740 PubMed Central PubMed View Article
  14.Brognard J, Clark AS, Ni Y, Dennis PA (2001) Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61:3986-997PubMed
  15.Hu L, Hofmann J, Lu Y, Mills GB, Jaffe RB (2002) Inhibition of phosphatidylinositol 3-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res 62:1087-092PubMed
  16.Molife LR, Yan L, Vitfell-Rasmussen J, Zernhelt AM, Sullivan DM, Cassier PA, Chen E, Biondo A, Tetteh E, Siu LL, Patnaik A, Papadopoulos KP, de Bono JS, Tolcher AW, Minton S (2014) Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J Hematol Oncol 7:1. doi:10.-186/-756-8722-7-1 PubMed Central PubMed View Article
  17.Hudis C, Swanton C, Janjigian YY, Lee R, Sutherland S, Lehman R, Chandarlapaty S, Hamilton N, Gajria D, Knowles J, Shah J, Shannon K, Tetteh E, Sullivan DM, Moreno C, Yan L, Han HS (2013) A phase 1 study evaluating the combination of an alloster
• 作者单位：Toshihiko Doi (1)
  Kenji Tamura (2)
  Yuko Tanabe (2)
  Kan Yonemori (2)
  Takayuki Yoshino (1)
  Nozomu Fuse (1)
  Makoto Kodaira (2)
  Hideaki Bando (1)
  Kazuo Noguchi (4)
  Takashi Shimamoto (4)
  Atsushi Ohtsu (3)
  
  1. National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
  2. National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
  4. MSD K.K., Kitanomaru Square, 1-13-12, Kudan-kita, Chiyoda-ku, Tokyo, 102-8667, Japan
  3. Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Cancer Research
  Pharmacology and Toxicology
  Oncology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0843

文摘

Purpose MK-2206 is an oral, highly selective inhibitor of AKT. The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MK-2206 was evaluated in Japanese patients with advanced solid tumors. Methods Patients received a single oral dose of MK-2206 according to an every other day (QOD) dosing schedule or a once weekly (QW) dosing schedule in repeating 28-day treatment cycles, with a 7-day rest after only the first cycle. The dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Full PK sampling was performed during Cycle 1. Results Twenty-four patients were treated at 45?mg (n?=?3) or 60?mg (n?=?9) QOD or at 135?mg (n?=?3) or 200?mg (n?=?9) QW. One patient experienced a DLT at 60?mg QOD, and three patients experienced DLTs at 200?mg QW. No DLTs were observed at 45?mg QOD or at 135?mg QW. The DLTs included mucosal inflammation, hyponatremia, face edema, erythema multiforme, and hyperglycemia. Common adverse events related to MK-2206 included rash, an elevated insulin c-peptide level, stomatitis, pyrexia, eosinophilia, leukopenia, and hyperglycemia. PK differences in MK-2206 exposure were observed between Japanese patients and non-Japanese patients. The higher exposure in Japanese patients was likely caused by the relatively lower weight of Japanese patients versus non-Japanese patients. No tumor responses were observed, but six patients exhibited stable disease lasting longer than 4?months. Conclusions MK-2206 has an acceptable safety profile in Japanese patients with advanced solid tumors and warrants further investigation.