Summary
This paper reviews the methodology of phase I study in Japan. Most major leading institutions participated in a phase I study when the decision was made to proceed with clinical trials after detailed analysis of experimental results of a new antitumor agent. An initial dose in phase I study used to be calculated according to the dose comparable to the minimum effective dose, 1/100 of LD50 (mg/kg) in rodents, but the dose recently has been estimated based on one-tenth of mouse LD10(mg/m2) or one-third TLD in sensitive large animals. Qualitative prediction through preclinical toxicology indicated better correlation with clinically observed toxicities in gastrointestinal and hematopoietic systems, but renal and hepatic toxicities were being overestimated, and neurologic and skin toxicities were being underestimated. A recent trend in the development of new antitumor agents has been to find a less toxic and more effective compound. This has made phase I study more complicated, because metabolites produced in the midway of metabolic pathway might induce unprediced toxicities. Several approaches to conduct a phase I study more efficiently are discussed.
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References
Arakawa, M., Aoki, T., Nakao, H.: Effect of carbazilquinone on lymphoid leukemia L-1210. Gann 61, 485 (1970)
Carter, S. K.: Study design principles for the clinical evalation of new drugs as developed by the chemotherapy program of the National Cancer Institute. In: The design of clinical trials in cancer therapy. Brussels: Editions Scientifiques Europeenes 1972, p. 242
Carter, S. K.: Clinical trials in cancer chemotherapy. Cancer 40, 544 (1977)
Cooperative Study Group of Phase I Study on ACNU: Phase I study of l-(4-amino-2-methyl-5-pyrimidinyl)-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU). Jpn. J. Clin. Oncol. 6, 55 (1976)
Creaven, D. J., Mihich, E.: The clinical toxicity of anticancer drugs and its prediction. Semin. Oncol. 4, 147 (1977)
El-Merzabani, M. M., Sakurai, Y.: A new alkylating antitumor agent effective on experimental tumors resistant to nitrogen mustard. Gann 56, 589 (1965)
Goldsmith, M. A., Slavik, M., Carter, S. K.: Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Res. 35, 1354 (1975)
Hasegawa, M., Itatzu, Y., Asai, I., Miwa, S., Amaki, I., Ito, M., Osamura, S., Takeuchi, R., Hino, S., Miyata, H., Morita, H.: Effect of a new antileukemic agent, thioinosine (6-mercaptopurine riboside) on acute meylogenous leukemia. Jpn. J. Clin. Hematol. 12, 429 (1971)
Homan, E. R.: Quantitative relationships between toxic doses of antitumor chemotherapeutic agents in animals and man. Cancer Chemother. Rep. [Part 3] 3, 13 (1972)
Hoshi, A., Kanzawa, F., Kuretani, K., Saneyoshi, M., Arai, Y.: 2,2′-0-Cyclocytidine, an antitumor cytidine analog resistant to cytidine deaminase. Gann 62, 145 (1971)
Hoshi, A., Iigo, M., Nakamura, N., Kuretani, K.: Antitumor activity of benzoyl and ben-zensulfonyl derivatives of 5-fluorouracil. Gann 65, 463 (1974)
Ichikawa, T., Matzumoto, K., Umezawa, H.: Clinical study of a new anti-tumor antibiotic, bleomycin (preliminary report). Proc. 5th Int. Congr. Chemother. A IV-4/35, 507 (1967)
Ishida, N., Miyazaki, K., Kumagai, K., Rikimaru, M.: Neocarzinostatin, an antitumor antibiotic of high molecular weight, isolation, physicochemical properties and biological activities. J. Antibiot. (Tokyo) [A] 18, 68 (1965)
Kurita, S., Nishimura, M., Ogawa, M., Kamei, Y., Ariyoshi, Y., Murakami, M., Oyama, A., Sugiura, T., Kato, R., Ota, K.: Clinical studies on carbazilquinone in the treatment of malignant disease. J. Jpn. Soc. Cancer Ther. 8, 119 (1973)
Ohara, T., Tokuyama, H.: Clinical experience with nitromin (HN2-N-oxide). Tokyo, Osaka: Igaku Shoin 1957
Ota, K.: Multiple combination therapy in cancer chemotherapy in Japan. Gann 60, 239 (1969)
Saito, T., Ohira, S., Wakui, A., Yokoyama, M., Himori, T.: Studies on the dosage schedule of new anticancer drugs: Phase I and phase II evaluation of some new drugs. Jpn. J. Cancer Clin. 17, 589 (1971)
Saito, T., Wakui, A., Yokoyama, M., Himori, T., Takahashi, H., Kudo, T., Takahashi, K.: Combination chemotherapy for solid tumors using 5-fluorouracil, chromomycin A3 and prednisolone. Gann 68, 375 (1977)
Sakai, Y., Konda, C., Shimoyama, M., Kitahara, T., Sakano, T., Kimura, K.: Cyclocytidine — a phase I study. Jpn. J. Clin. Oncol. 6, 57 (1972)
Sakai, Y., Sakano, T., Konda, C., Shimoyama, M., Kitahara, T., Minato, K., Ibuka, T., Sasaki, T., Inoue, K., Takenaka, T., Kimura, K.: Clinical experience of cyclocytidine. Igaku-no-Ayumi 91, 114 (1974)
Schein, P. S.: Preclinical toxicology of anticancer agents. Cancer Res. 37, 1934 (1977)
Shiba, S., Taguchi, T.: Mitomycin C — its experimental research and clinical application. Tokyo, Osaka: Igaku Shoin 1967
Takamizawa, A., Matsumoto, S., Iwata, T., Makino, I.: Synthesis, stereochemistry and antitumor activity of 4-hydroperoxyisophosphamide(NSC-227114) and related compounds. Chem. Pharm. Bull. (Tokyo) 25, 1877 (1977)
Umezawa, H., Maeda, K., Takeuchi, T., Okami, Y.: New antibiotics, bleomycin A and B. J. Antibiot. (Tokyo) [A] 19, 200 (1966)
Unemi, N., Takeda, S., Kitasato, K., Kajihara, M., Fujii, S.: Studies on the antitumor activity of 1,3-bis(tetrahydro-2-furanyl)-5-fluoro-2,4-pyrimidinedione (FD-1). A new antitumor agent. I. Chemotherapy 26, 200 (1978)
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© 1980 Springer-Verlag Berlin Heidelberg
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Ogawa, M. (1980). Methodology of Phase I Study in Japan. In: Carter, S.K., Sakurai, Y. (eds) New Anticancer Drugs. Recent Results in Cancer Research, vol 70. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-81392-4_4
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DOI: https://doi.org/10.1007/978-3-642-81392-4_4
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