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Department of Experimental Therapeutics

Toshihiko Doi, Kiyotaka Yoh, Yoichi Naito, Takahiro Kogawa, Hideaki Takahashi, Tomoko Yamazaki, Yasutoshi Kuboki

Introduction

The Exploratory Oncology Research & Clinical Trial Center (NCC-EPOC) Phase I Group has been organized to promote early drug development especially the first in human (FIH) trial in 2012. The phase I group consists of two sub-units (NCCE-Kashiwa and NCC-Tsukiji), which are organized by each hospital. The goal of both/each unit is to perform initial clinical evaluations of promising new anti-cancer compounds emerging from laboratories. Our phase I unit is the largest program in both Japan and Asia, and we contribute to the development of new cancer drugs through early phase trials.

In April 2013, the Department of Experimental Therapeutics was launched to strongly promote the EPOC missions as previously described. The members of the Department of Experimental Therapeutics consist of specialists in their oncology fields. Also, we have conducted/contributed to IIT using yet-to-be-approved new drug and academia seeds.

Routine activities

This Department plays an important role in new anti-cancer drug development in our center as well as in Japan. The top priority is to conduct the FIH trials, while we also perform the phase I trials for solid tumors (that is, all comers). Recently, we joined a global phase I trial to accelerate new drug development in Japan. Web- and teleconferences are held with EU and US sites, and we are discussing patient enrollment as well as further developmental strategy. Routine webconferences are also held between Kashiwa and Tsukiji campuses every Friday morning, and we are sharing information about adverse events, patient enrollments and are referring candidates to each other to accelerate enrollment. Several IIT-FIH using new class seeds are conducted by each unit and also yet-to-be-approved company agents

Research activities

The elucidation of the proof of concept is essential in new anti-cancer drug development especially in the early phase; we conduct several translational research projects in collaboration with the adjoining research institute. In the Kashiwa campus, comprehensive genomic analyses, which is known as the ABC-study, is ongoing to facilitate patient enrollment for new molecular targeted drugs under investigation. Also, a new immunemonitoring system for immune agents has been established in the hospital; the system is controlled by Professor Nishikawa.

Clinical trials

In 2015, 38 phase I trials were conducted. (Table 1).


Table 1. Phase 1 Trials in 2015

List of papers published in 2015

Journal

  1. Watanabe N, Umemura S, Niho S, Kirita K, Matsumoto S, Yoh K, Ohmatsu H, Goto K. Docetaxel for platinum-refractory advanced thymic carcinoma. Jpn J Clin Oncol, 45:665-669, 2015
  2. Fouad TM, Kogawa T, Liu DD, Shen Y, Masuda H, El-Zein R, Woodward WA, Chavez-MacGregor M, Alvarez RH, Arun B, Lucci A, Krishnamurthy S, Babiera G, Buchholz TA, Valero V, Ueno NT. Overall survival differences between patients with inflammatory and noninflammatory breast cancer presenting with distant metastasis at diagnosis. Breast Cancer Res Treat, 152:407-416, 2015
  3. Fujii T, Le Du F, Xiao L, Kogawa T, Barcenas CH, Alvarez RH, Valero V, Shen Y, Ueno NT. Effectiveness of an Adjuvant Chemotherapy Regimen for Early-Stage Breast Cancer: A Systematic Review and Network Meta-analysis. JAMA Oncol, 1:1311-1318, 2015
  4. Kai M, Kogawa T, Liu DD, Fouad TM, Kai K, Niikura N, Hsu L, Willey JS, Theriault RL, Valero V, Ueno NT. Clinical characteristics and outcome of bone-only metastasis in inflammatory and noninflammatory breast cancers. Clin Breast Cancer, 15:37-42, 2015
  5. Hayashi N, Niikura N, Masuda N, Takashima S, Nakamura R, Watanabe K, Kanbayashi C, Ishida M, Hozumi Y, Tsuneizumi M, Kondo N, Naito Y, Honda Y, Matsui A, Fujisawa T, Oshitanai R, Yasojima H, Yamauchi H, Saji S, Iwata H. Prognostic factors of HER2-positive breast cancer patients who develop brain metastasis: a multicenter retrospective analysis. Breast Cancer Res Treat, 149:277-284, 2015
  6. Mukai H, Saeki T, Shimada K, Naito Y, Matsubara N, Nakanishi T, Obaishi H, Namiki M, Sasaki Y. Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer. Invest New Drugs,33:119-127, 2015
  7. Yoshida T, Yoh K, Niho S, Umemura S, Matsumoto S, Ohmatsu H, Ohe Y, Goto K. RECIST progression patterns during EGFR tyrosine kinase inhibitor treatment of advanced non-small cell lung cancer patients harboring an EGFR mutation. Lung Cancer, 90:477-483, 2015
  8. Daga H, Takeda K, Okada H, Miyazaki M, Ueda S, Kaneda H, Okamoto I, Yoh K, Goto K, Konishi K, Sarashina A, Tanaka T, Kaiser R, Nakagawa K. Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol, 76:1225-1233, 2015
  9. 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
  10. Yoshida T, Ishii G, Goto K, Neri S, Hashimoto H, Yoh K, Niho S, Umemura S, Matsumoto S, Ohmatsu H, Iida S, Niimi A, Nagai K, Ohe Y, Ochiai A. Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation. Clin Cancer Res, 21:642-651, 2015
  11. 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
  12. Miura T, Mitsunaga S, Ikeda M, Shimizu S, Ohno I, Takahashi H, Furuse J, Inagaki M, Higashi S, Kato H, Terao K, Ochiai A. Characterization of patients with advanced pancreatic cancer and high serum interleukin-6 levels. Pancreas, 44:756-763, 2015
  13. Fujii S, Fujihara A, Natori K, Abe A, Kuboki Y, Higuchi Y, Aizawa M, Kuwata T, Kinoshita T, Yasui W, Ochiai A. TEM1 expression in cancer-associated fibroblasts is correlated with a poor prognosis in patients with gastric cancer. Cancer Med, 4:1667-1678, 2015
  14. Komatsu Y, Doi T, Sawaki A, Kanda T, Yamada Y, Kuss I, Demetri GD, Nishida T. Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial. Int J Clin Oncol, 20:905-912, 2015
  15. Sugiyama E, Umemura S, Nomura S, Kirita K, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Tsuboi M, Ohe Y, Goto K. Impact of single nucleotide polymorphisms on severe hepatotoxicity induced by EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring EGFR mutations. Lung Cancer, 90:307-313, 2015
  16. Hishida T, Tsuboi M, Shukuya T, Takamochi K, Sakurai H, Yoh K, Ohashi Y, Kunitoh H. Multicenter observational cohort study of post-operative treatment for completely resected non-smallcell lung cancer of pathological stage I (T1 >2 cm and T2 in TNM classification version 6). Jpn J Clin Oncol, 45:499-501, 2015
  17. Udagawa H, Ishii G, Morise M, Umemura S, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Tsuboi M, Goto K, Ochiai A, Ohe Y. Comparison of the expression levels of molecular markers among the peripheral area and central area of primary tumor and metastatic lymph node tumor in patients with squamous cell carcinoma of the lung. J Cancer Res Clin Oncol, 141:1417-1425, 2015
  18. Koriyama H, Ishii G, Yoh K, Neri S, Morise M, Umemura S, Matsumoto S, Niho S, Ohmatsu H, Tsuboi M, Goto K, Ochiai A. Presence of podoplanin-positive cancer-associated fibroblasts in surgically resected primary lung adenocarcinoma predicts a shorter progression-free survival period in patients with recurrences who received platinum-based chemotherapy. J Cancer Res Clin Oncol, 141:1163-1170, 2015
  19. Doi T, Tamura K, Tanabe Y, Yonemori K, Yoshino T, Fuse N, Kodaira M, Bando H, Noguchi K, Shimamoto T, Ohtsu A. Phase 1 pharmacokinetic study of the oral pan-AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol, 76:409-416, 2015
  20. 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
  21. Doi T, Yoshino T, Shitara K, Matsubara N, Fuse N, Naito Y, Uenaka K, Nakamura T, Hynes SM, Lin AB. Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors. Anticancer Drugs, 26:1043-1053, 2015
  22. Kawazoe A, Shitara K, Fukuoka S, Kuboki Y, Bando H, Okamoto W, Kojima T, Fuse N, Yamanaka T, Doi T, Ohtsu A, Yoshino T. A retrospective observational study of clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations in Japanese patients with metastatic colorectal cancer. BMC Cancer, 15:258, 2015
  23. Kawazoe A, Shitara K, Fukuoka S, Noguchi M, Kuboki Y, Bando H, Okamoto W, Kojima T, Fuse N, Yoshino T, Ohtsu A, Doi T. Clinical outcomes in 66 patients with advanced gastric cancer treated in phase I trials: the NCCHE experience. Invest New Drugs, 33:664-670, 2015
  24. Oh DY, Doi T, Shirao K, Lee KW, Park SR, Chen Y, Yang L, Valota O, Bang YJ. Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer. Cancer Res Treat, 47:687-696, 2015
  25. 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
  26. Takahashi H, Kaniwa N, Saito Y, Sai K, Hamaguchi T, Shirao K, Shimada Y, Matsumura Y, Ohtsu A, Yoshino T, Doi T, Takahashi A, Odaka Y, Okuyama M, Sawada J, Sakamoto H, Yoshida T. Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method. BMC Cancer, 15:718, 2015
  27. Ueda S, Satoh T, Gotoh M, Gao L, Doi T. A phase ib study of safety and pharmacokinetics of ramucirumab in combination with paclitaxel in patients with advanced gastric adenocarcinomas. Oncologist, 20:493-494, 2015
  28. Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R, Nakayama E. Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. Clin Cancer Res, 21:4327-4336, 2015
  29. 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
  30. 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
  31. 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
  32. Kohno T, Nakaoku T, Tsuta K, Tsuchihara K, Matsumoto S, Yoh K, Goto K. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res, 4:156-164, 2015
  33. Nagatsuma AK, Aizawa M, Kuwata T, Doi T, Ohtsu A, Fujii H, Ochiai A. Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer, 18:227-238, 2015
  34. Shinohara A, Ikeda M, Okuyama H, Kobayashi M, Funazaki H, Mitsunaga S, Shimizu S, Ohno I, Takahashi H, Ichida Y, Takahashi K, Okusaka T, Saitoh S. Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in patients with advanced pancreatic cancer: a retrospective study. Am J Clin Dermatol, 16:221-229, 2015
  35. Sasaki T, Fuse N, Kuwata T, Nomura S, Kaneko K, Doi T, Yoshino T, Asano H, Ochiai A, Komatsu Y, Sakamoto N, Ohtsu A. Serum HER2 levels and HER2 status in tumor cells in advanced gastric cancer patients. Jpn J Clin Oncol, 45:43-48, 2015
  36. 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
  37. 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
  38. Doi T, Yoshino T, Fuse N, Boku N, Yamazaki K, Koizumi W, Shimada K, Takinishi Y, Ohtsu A. Phase I study of TAS-102 and irinotecan combination therapy in Japanese patients with advanced colorectal cancer. Invest New Drugs, 33:1068-1077, 2015
  39. Kogawa T, Fouad TM, Wei C, Masuda H, Kai K, Fujii T, El-Zein R, Chavez-MacGregor M, Litton JK, Brewster A, Alvarez RH, Hortobagyi GN, Valero V, Theriault R, Ueno NT. Association of Body Mass Index Changes during Neoadjuvant Chemotherapy with Pathologic Complete Response and Clinical Outcomes in Patients with Locally Advanced Breast Cancer. J Cancer, 6:310-318, 2015
  40. Enomoto Y, Kenmotsu H, Watanabe N, Baba T, Murakami H, Yoh K, Ogura T, Takahashi T, Goto K, Kato T. Efficacy and Safety of Combined Carboplatin, Paclitaxel, and Bevacizumab for Patients with Advanced Non-squamous Non-small Cell Lung Cancer with Pre-existing Interstitial Lung Disease: A Retrospective Multi-institutional Study. Anticancer Res, 35:4259-4263, 2015
  41. Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Lee DH, Liu Y, Yoh K, Zhou JY, Shi X, Webster A, Jiang H, Mok TS. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol, 16:990-998, 2015
  42. Takahashi A, Ishii G, Neri S, Yoshida T, Hashimoto H, Suzuki S, Umemura S, Matsumoto S, Yoh K, Niho S, Goto K, Ohmatsu H, Nagai K, Gemma A, Ohe Y, Ochiai A. Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth. Oncotarget, 6:9531-9541, 2015
  43. Watanabe N, Niho S, Kirita K, Umemura S, Matsumoto S, Yoh K, Ohmatsu H, Goto K. Second-line docetaxel for patients with platinum-refractory advanced non-small cell lung cancer and interstitial pneumonia. Cancer Chemother Pharmacol, 76:69-74, 2015
  44. Watanabe N, Niho S, Kirita K, Umemura S, Matsumoto S, Yoh K, Ohmatsu H, Goto K. Vinorelbine and cisplatin in patients with advanced non-small cell lung cancer with interstitial pneumonia. Anticancer Res, 35:1697-1701, 2015