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国立がん研究センター 中央病院

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Department of Experimental Therapeutics

Noboru Yamamoto, Kenji Tamura, Yutaka Fujiwara, Shunsuke Kondo, Satoru Iwasa, Shigehisa Kitano


In April 2015, the affiliation of the Department of Experimental Therapeutics was changed from the National Cancer Center (NCC) - the Exploratory Oncology Research & Clinical Trial Center (EPOC) to the NCC-Hospital. The goal of our Department is to perform initial clinical evaluation of promising new anti-cancer compounds emerging from the laboratory in phase I trials. The staff of this Department consists of specialists from various oncology fields (that is, thoracic oncology, breast & medical oncology, gastro-intestinal oncology, hepato-biliary & pancreatic oncology, and immune-oncology).

Routine activities

This Department plays an important role in new anti-cancer drug development in Japan as well as in Asia. The top priority is to conduct First-In-Human (FIH) trials, and we also perform phase I trials for solid tumors (that is, all comers). Recently, we have joined the global phase I trial to accelerate new drug development in Japan. Web- or tele-conferences are held with the EU and US sites, and we discuss patient enrollment as well as further developmental strategy. Routine web-conferences are also held between NCC-Hospital (Tokyo) and NCC-East Hospital (Chiba) every Friday morning, and we share information about adverse events, patient enrollment and refer candidates to each other to accelerate enrollment.

Research activities

The elucidation of the proof of concept is essential in new anti-cancer drug development especially in early phases, so we conduct several translational research (TR) projects in collaboration with the adjoining research institute. Comprehensive genomic analyses, named TOP-GEAR-studies, are ongoing to facilitate patient enrollment for new molecular targeted drugs under investigation. Also, we conduct the TR with the pharmaceutical industry to discover new targets for anti-immune therapy using human tissue (tumor and normal tissue) samples.

Clinical trials

In 2015, 20 phase I trials including 8 FIH trials were conducted (Table 1).

Number of patients

List of papers published in 2015


  1. Ono M, Tsuda H, Yunokawa M, Yonemori K, Shimizu C, Tamura K, Kinoshita T, Fujiwara Y. Prognostic impact of Ki-67 labeling indices with 3 different cutoff values, histological grade, and nuclear grade in hormone-receptor-positive, HER2-negative, node-negative invasive breast cancers. Breast Cancer, 22:141-152, 2015
  2. Yamamoto H, Ando M, Aogi K, Iwata H, Tamura K, Yonemori K, Shimizu C, Hara F, Takabatake D, Hattori M, Asakawa T, Fujiwara Y. Phase I and pharmacokinetic study of trastuzumab emtansine in Japanese patients with HER2-positive metastatic breast cancer. Jpn J Clin Oncol, 45:12-18, 2015
  3. Yagishita S, Horinouchi H, Katsui Taniyama T, Nakamichi S, Kitazono S, Mizugaki H, Kanda S, Fujiwara Y, Nokihara H, Yamamoto N, Sumi M, Shiraishi K, Kohno T, Furuta K, Tsuta K, Tamura T. Epidermal growth factor receptor mutation is associated with longer local control after definitive chemoradiotherapy in patients with stage III nonsquamous non-small-cell lung cancer. Int J Radiat Oncol Biol Phys, 91:140-148, 2015
  4. Utsumi H, Honma Y, Nagashima K, Iwasa S, Takashima A, Kato K, Hamaguchi T, Yamada Y, Shimada Y, Kishi Y, Nara S, Esaki M, Shimada K. Bevacizumab and postoperative wound complications in patients with liver metastases of colorectal cancer. Anticancer Res, 35:2255-2261, 2015
  5. Nakamichi S, Nokihara H, Yamamoto N, Yamada Y, Fujiwara Y, Tamura Y, Wakui H, Honda K, Mizugaki H, Kitazono S, Tanabe Y, Asahina H, Yamazaki N, Suzuki S, Matsuoka M, Ogita Y, Tamura T. Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors. Invest New Drugs, 33:641-651, 2015
  6. Abe S, Oda I, Nakajima T, Suzuki H, Nonaka S, Yoshinaga S, Sekine S, Taniguchi H, Kushima R, Iwasa S, Saito Y, Katai H. A case of local recurrence and distant metastasis following curative endoscopic submucosal dissection of early gastric cancer. Gastric Cancer, 18:188-192, 2015
  7. Asao T, Nokihara H, Yoh K, Niho S, Goto K, Ohmatsu H, Kubota K, Yamamoto N, Sekine I, Kunitoh H, Fujiwara Y, Ohe Y. Phase II study of amrubicin at a dose of 45 mg/m2 in patients with previously treated small-cell lung cancer. Jpn J Clin Oncol, 45:941-946, 2015
  8. Chua C, Tan IB, Yamada Y, Rha SY, Yong WP, Ong WS, Tham CK, Ng M, Tai DW, Iwasa S, Lim HY, Choo SP. Phase II study of trastuzumab in combination with S-1 and cisplatin in the first-line treatment of human epidermal growth factor receptor HER2-positive advanced gastric cancer. Cancer Chemother Pharmacol, 76:397-408, 2015
  9. Davies BR, Guan N, Logie A, Crafter C, Hanson L, Jacobs V, James N, Dudley P, Jacques K, Ladd B, D'Cruz CM, Zinda M, Lindemann J, Kodaira M, Tamura K, Jenkins EL. Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors. Mol Cancer Ther, 14:2441-2451, 2015
  10. Fujiwara Y, Kobayashi S, Nagano H, Kanai M, Hatano E, Toyoda M, Ajiki T, Takashima Y, Yoshimura K, Hamada A, Minami H, Ioka T. Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101). PLoS One, 10:e0143072, 2015
  11. Fujiwara Y, Nokihara H, Yamada Y, Yamamoto N, Sunami K, Utsumi H, Asou H, TakahashI O, Ogasawara K, Gueorguieva I, Tamura T. Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 76:1143-1152, 2015
  12. Guidance Development Review Committee, Working Group for Clinical Studies of Cancer Immunotherapy, Working Group for Effector Cell Therapy, Working Group for CMC/Non-clinical Studies, Working Group for Cancer Vaccines and Adjuvants, Working Group for Anti-immune Checkpoint Therapy and Comprehensive Cancer Immunotherapy, Biostatistics Subcommittee. 2015 Guidance on cancer immunotherapy development in early-phase clinical studies. Cancer Sci, 106:1761-1771, 2015
  13. Hashimoto H, Kitano S, Ueda R, Ito A, Tada K, Fuji S, Kim SW, Yamashita T, Tomura D, Nukaya I, Mineno J, Fukuda T, Mori S, Takaue Y, Heike Y. Erratum to: Infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene for recurrent hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Int J Hematol, 102:506, 2015
  14. Hashimoto H, Kitano S, Ueda R, Ito A, Tada K, Fuji S, Yamashita T, Tomura D, Nukaya I, Mineno J, Fukuda T, Mori S, Takaue Y, Heike Y. Infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene for recurrent hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Int J Hematol, 102:101-110, 2015
  15. Hashimoto H, Kitano S, Yamagata S, Miyagi Maeshima A, Ueda R, Ito A, Tada K, Fuji S, Yamashita T, Tomura D, Nukaya I, Mineno J, Fukuda T, Mori S, Takaue Y, Heike Y. Donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene: detailed immunological function following add-back after haplo-identical transplantation. Cytotherapy, 17:1820-1830, 2015
  16. Hojo T, Masuda N, Mizutani T, Shibata T, Kinoshita T, Tamura K, Hara F, Fujisawa T, Inoue K, Saji S, Nakamura K, Fukuda H, Iwata H. Intensive vs. Standard Post-Operative Surveillance in High-Risk Breast Cancer Patients (INSPIRE): Japan Clinical Oncology Group Study JCOG1204. Jpn J Clin Oncol, 45:983-986, 2015
  17. Horinouchi H, Yamamoto N, Fujiwara Y, Sekine I, Nokihara H, Kubota K, Kanda S, Yagishita S, Wakui H, Kitazono S, Mizugaki H, Tokudome T, Tamura T. Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer. Invest New Drugs, 33:881-889, 2015
  18. Ikeda M, Okuyama H, Takahashi H, Ohno I, Shimizu S, Mitsunaga S, Kondo S, Morizane C, Ueno H, Okusaka T. Chemotherapy for advanced poorly differentiated pancreatic neuroendocrine carcinoma. J Hepatobiliary Pancreat Sci, 22:623-627, 2015
  19. Ito A, Kondo S, Tada K, Kitano S. Clinical Development of Immune Checkpoint Inhibitors. Biomed Res Int, 2015:605478, 2015
  20. Iwasa S, Nagashima K, Yamaguchi T, Matsumoto H, Ichikawa Y, Goto A, Yasui H, Kato K, Okita NT, Shimada Y, Yamada Y. S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: a pooled analysis of four phase II studies. Cancer Chemother Pharmacol, 76:605-614, 2015
  21. Iwasa S, Souda H, Yamazaki K, Takahari D, Miyamoto Y, Takii Y, Ikeda S, Hamaguchi T, Kanemitsu Y, Shimada Y. Safety and efficacy of adjuvant therapy with oxaliplatin, leucovorin and 5-fluorouracil after mesorectal excision with lateral pelvic lymph node dissection for stage iii lower rectal cancer. Anticancer Res, 35:1815-1819, 2015
  22. Kanai M, Hatano E, Kobayashi S, Fujiwara Y, Marubashi S, Miyamoto A, Shiomi H, Kubo S, Ikuta S, Yanagimoto H, Terajima H, Ikoma H, Sakai D, Kodama Y, Seo S, Morita S, Ajiki T, Nagano H, Ioka T. A multi-institution phase II study of gemcitabine/ cisplatin/S-1 (GCS) combination chemotherapy for patients with advanced biliary tract cancer (KHBO 1002). Cancer Chemother Pharmacol, 75:293-300, 2015
  23. Kanda S, Horinouchi H, Fujiwara Y, Nokihara H, Yamamoto N, Sekine I, Kunitoh H, Kubota K, Tamura T, Ohe Y. Cytotoxic chemotherapy may overcome the development of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Lung Cancer, 89:287-293, 2015
  24. Katsuya Y, Fujiwara Y, Sunami K, Utsumi H, Goto Y, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Takashima Y, Osawa S, Ohe Y, Tamura T, Hamada A. Comparison of the pharmacokinetics of erlotinib administered in complete fasting and 2 h after a meal in patients with lung cancer. Cancer Chemother Pharmacol, 76:125-132, 2015
  25. Kitazono S, Fujiwara Y, Nakamichi S, Mizugaki H, Nokihara H, Yamamoto N, Yamada Y, Inukai E, Nakamura O, Tamura T. A phase I study of resminostat in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 75:1155-1161, 2015
  26. Kitazono S, Fujiwara Y, Tsuta K, Utsumi H, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Sasada S, Watanabe S, Asamura H, Tamura T, Ohe Y. Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of Programmed Death-Ligand 1 Expression in Non--Small-Cell Lung Cancer. Clin Lung Cancer, 16:385-390, 2015
  27. Kondo S, Shiba S, Udagawa R, Ryushima Y, Yano M, Uehara T, Asanabe M, Tamura K, Hashimoto J. Assessment of adverse events via a telephone consultation service for cancer patients receiving ambulatory chemotherapy. BMC Res Notes, 8:315, 2015
  28. Kurihara H, Hamada A, Yoshida M, Shimma S, Hashimoto J, Yonemori K, Tani H, Miyakita Y, Kanayama Y, Wada Y, Kodaira M, Yunokawa M, Yamamoto H, Shimizu C, Takahashi K, Watanabe Y, Fujiwara Y, Tamura K. 64Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients. EJNMMI Res, 5:8, 2015
  29. Hattori Y, Yoshida A, Sasaki N, Shibuki Y, Tamura K, Tsuta K. Desmoplastic small round cell tumor with sphere-like clusters mimicking adenocarcinoma. Diagn Cytopathol, 43:214-217, 2015
  30. Mizugaki H, Yamamoto N, Fujiwara Y, Nokihara H, Yamada Y, Tamura T. Current Status of Single-Agent Phase I Trials in Japan: Toward Globalization. J Clin Oncol, 33:2051-2061, 2015
  31. Mizugaki H, Yamamoto N, Nokihara H, Fujiwara Y, Horinouchi H, Kanda S, Kitazono S, Yagishita S, Xiong H, Qian J, Hashiba H, Shepherd SP, Giranda V, Tamura T. A phase 1 study evaluating the pharmacokinetics and preliminary efficacy of veliparib (ABT-888) in combination with carboplatin/paclitaxel in Japanese subjects with non-small cell lung cancer (NSCLC). Cancer Chemother Pharmacol, 76:1063-1072, 2015
  32. Motonaga M, Yamamoto N, Makino Y, Ando-Makihara R, Ohe Y, Takano M, Hayashi Y. Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug-drug interaction. Cancer Chemother Pharmacol, 76:713-721, 2015
  33. Nagashima K, Iwasa S, Yanai T, Hashimoto H, Suzuki K, Ohyanagi F, Shimada Y, Yamamoto N. A double-blind randomized Phase II study of olanzapine 10 mg versus 5 mg for emesis induced by highly emetogenic chemotherapy. Jpn J Clin Oncol, 45:229-231, 2015
  34. Nakamichi S, Nokihara H, Yamamoto N, Yamada Y, Honda K, Tamura Y, Wakui H, Sasaki T, Yusa W, Fujino K, Tamura T. A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 76:1153-1161, 2015
  35. Nishio M, Horiike A, Murakami H, Yamamoto N, Kaneda H, Nakagawa K, Horinouchi H, Nagashima M, Sekiguchi M, Tamura T. Phase I study of the HER3-targeted antibody patritumab (U3-1287) combined with erlotinib in Japanese patients with non-small cell lung cancer. Lung Cancer, 88:275-281, 2015
  36. Nishio M, Horiike A, Nokihara H, Horinouchi H, Nakamichi S, Wakui H, Ohyanagi F, Kudo K, Yanagitani N, Takahashi S, Kuboki Y, Yamamoto N, Yamada Y, Abe M, Tahata T, Tamura T. Phase I study of the anti-MET antibody onartuzumab in patients with solid tumors and MET-positive lung cancer. Invest New Drugs, 33:632-640, 2015
  37. Okusaka T, Ueno H, Morizane C, Kondo S, Sakamoto Y, Takahashi H, Ohno I, Shimizu S, Mitsunaga S, Ikeda M. Cytotoxic chemotherapy for pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci, 22:628-633, 2015
  38. Shiba S, Morizane C, Hiraoka N, Sasaki M, Koga F, Sakamoto Y, Kondo S, Ueno H, Ikeda M, Yamada T, Shimada K, Kosuge T, Okusaka T. Pancreatic neuroendocrine tumors: A single-center 20-year experience with 100 patients. Pancreatology, 16:99-105, 2015
  39. Shoji H, Yamada Y, Okita N, Takashima A, Honma Y, Iwasa S, Kato K, Hamaguchi T, Shimada Y. Amplification of FGFR2 Gene in Patients with Advanced Gastric Cancer Receiving Chemotherapy: Prevalence and Prognostic Significance. Anti-cancer Res, 35:5055-5061, 2015
  40. Takahashi H, Ikeda M, Kumada T, Osaki Y, Kondo S, Kusumoto S, Ohkawa K, Nadano S, Furuse J, Kudo M, Ito K, Yokoyama M, Okusaka T, Shimoyama M, Mizokami M. Multicenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents. Hepatol Res, 45:1220-1227, 2015
  41. Takahashi N, Yamada Y, Furuta K, Nagashima K, Kubo A, Sasaki Y, Shoji H, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Hamaguchi T, Shimada Y. Association between serum ligands and the skin toxicity of anti-epidermal growth factor receptor antibody in metastatic colorectal cancer. Cancer Sci, 106:604-610, 2015
  42. Eba J, Shimokawa T, Nakamura K, Shibata T, Misumi Y, Okamoto H, Yamamoto N, Ohe Y, Lung Cancer Study Group of the Japan Clinical Oncology Group. A Phase II/III study comparing carboplatin and irinotecan with carboplatin and etoposide for the treatment of elderly patients with extensive-disease small-cell lung cancer (JCOG1201). Jpn J Clin Oncol, 45:115-118, 2015
  43. Tamura Y, Fujiwara Y, Yamamoto N, Nokihara H, Horinouchi H, Kanda S, Goto Y, Kubo E, Kitahara S, Tsuruoka K, Tsuta K, Ohe Y. Retrospective analysis of the efficacy of chemotherapy and molecular targeted therapy for advanced pulmonary pleomorphic carcinoma. BMC Res Notes, 8:800, 2015
  44. Tanaka Y, Aoyagi K, Minashi K, Komatsuzaki R, Komatsu M, Chiwaki F, Tamaoki M, Nishimura T, Takahashi N, Oda I, Tachimori Y, Arao T, Nishio K, Kitano S, Narumi K, Aoki K, Fujii S, Ochiai A, Yoshida T, Muto M, Yamada Y, Sasaki H. Discovery of a Good Responder Subtype of Esophageal Squamous Cell Carcinoma with Cytotoxic T-Lymphocyte Signatures Activated by Chemoradiotherapy. PLoS One, 10:e0143804, 2015
  45. Yagishita S, Horinouchi H, Sunami KS, Kanda S, Fujiwara Y, Nokihara H, Yamamoto N, Sumi M, Shiraishi K, Kohno T, Furuta K, Tsuta K, Tamura T, Ohe Y. Impact of KRAS mutation on response and outcome of patients with stage III non-squamous non-small cell lung cancer. Cancer Sci, 106:1402-1407, 2015
  46. Yunokawa M, Tsuta K, Tanaka T, Nara E, Koizumi F, Ito J, Sekine S, Fujiwara Y, Tamura K. Back with a vengeance: micro-vascular tumor embolism. Am J Med, 128:834-836, 2015
  47. Takahashi RU, Miyazaki H, Takeshita F, Yamamoto Y, Minoura K, Ono M, Kodaira M, Tamura K, Mori M, Ochiya T. Loss of microRNA-27b contributes to breast cancer stem cell generation by activating ENPP1. Nat Commun, 6:7318, 2015
  48. Ono M, Tsuda H, Kobayashi T, Takeshita F, Takahashi RU, Tamura K, Akashi-Tanaka S, Moriya T, Yamasaki T, Kinoshita T, Yamamoto J, Fujiwara Y, Ochiya T. The expression and clinical significance of ribophorin II (RPN2) in human breast cancer. Pathol Int, 65:301-308, 2015
  49. Okita K, Izumi N, Ikeda K, Osaki Y, Numata K, Ikeda M, Kokudo N, Imanaka K, Nishiguchi S, Kondo S, Nishigaki Y, Shiomi S, Ueshima K, Isoda N, Karino Y, Kudo M, Tanaka K, Kaneko S, Moriwaki H, Makuuchi M, Okusaka T, Hayashi N, Ohashi Y, Kumada H, Peretinoin Study Group. Survey of survival among patients with hepatitis C virus-related hepatocellular carcinoma treated with peretinoin, an acyclic retinoid, after the completion of a randomized, placebo-controlled trial. J Gastroenterol, 50:667-674, 2015
  50. Okuyama H, Ikeda M, Kuwahara A, Takahashi H, Ohno I, Shimizu S, Mitsunaga S, Senda S, Okusaka T. Prognostic factors in patients with hepatocellular carcinoma refractory or intolerant to sorafenib. Oncology, 88:241-246, 2015