CANCER CHEMOTHERAPY PROGRAM AREA REPORT
September 1977 to October 1978

Program Coordinators: Dr. Yoshio Sakurai
Dr. Stephen K. Carter


Administrative Report
Progress begun in earlier years in this program area continued during this fifth year of the U.S.-Japan Cooperative Cancer Research Pro-gram. The chemotherapy aspect has worked on three fronts: (1) the exchange of information, (2) the exchange of drugs, and (3) collaborative studies.

MEETINGS, SEMINARS, AND CONFERENCES
Information exchange took place on a variety of levels and symposia continue to play an important role. In November 1977, the Princess Takamatsu Symposium was held on the subject of cancer chemotherapy. Dr. Stephen K. Carter and Dr. Abraham Goldin were the foreign co-organizers of the Symposium. American participants included Dr. Franco Muggia, Dr. Phillip Schein, Dr. Robert Livingston, Dr. Joseph Bertino, Dr. Emil Freireich, Dr. Michael Friedman and Dr. Norman Jaffe. This meeting, while not an official part of the U.S.-Japan Cooperative Cancer Research Program, was another important opportunity for U.S. and Japanese investigators to meet and discuss their many areas of mutual interest. During the same period, small meetings were held concerning PEP-bleomycin, bestatin, and the U.S.-Japan Gastric Cancer Study.
In June 1978, the program review symposium was held on the methodology of Phase I and Phase II studies with emphasis on analogues. Drug classes of emphasis were the anthracycline antitumor antibiotics, bleomycins, nitrosoureas, and fluorinated pyrimidines. The agenda and a list of the participants at this symposium follow this Program Area Report. The papers from this meeting will be published in the new journal, Cancer Chemotherapy and Pharmacology.
The previous year's Symposium on Antitumor Antibiotics, which was held in San Francisco on May 25 and 26, 1977, has now been published as Volume 63 of Recent Results in Cancer Research, published by Springer-Verlag, 1978, Berlin, Heidelberg and New York.

EXCHANGE OF MATERIALS
Several Japanese drugs continued in clinical study in the United States. Neocarzinostatin is now in Phase 11 trials in a range of U.S. institutions. At the Sidney Farber Cancer Institute activity has been observed in hepatomas which has led to several trials in this tumor. Drugs under preclinical study at the NCI include aclacinomycin-A, PEP-bleomycin, and bestatin. Aclacinomycin-A has also been studied preclinically by the Multidisciplinary Drug Research Group of the Northern California Cancer Program, and the Northern California Oncology Group (NCOG) is awaiting a decision by the NC[ concerning filing an IND for the drug with the Food and Drug Administration (FDA). The NCOG is interested in performing Phase I study on the drug.

COLLABORATIVE STUDIES
In the past year a joint collaborative chemotherapy study of advanced gastric cancer was begun between the NCOG and selected Japanese investigators. This study involved a common arm between the U.S. and Japanese investigators which is adriamycin plus 5-FU. This is compared in the NCOG to an American arm of BCNU, adriamycin, and ftorafur and in Japan to an arm of mitomycin-C, adriamycin, and ftorafur. Randomization is performed through the NCOG statistical office which will also be doing the statistical analysis of the data. The study has nearly 50 cases entered and is a logistical success. The fact sheet and schema of the protocol are presented below.

UNITED STATES-JAPAN JOINT PROTOCOL
FOR ADVANCED GASTRIC CANCER
PROTOCOL NUMBER 3S62
NORTHERN CALIFORNIA ONCOLOGY GROUP
1801 page Mill Road
Building B, Suite 200
Palo Alto, California 94304
Telephone: (415) 497-7512

SITE: stomach
HISTOLOGY: adenocarcinoma
STAGE: disseminated
VARIABLE: common arm: Adriamycin + 5-FU
U.S. arm: BCNU + Adriamycin + Ftorafur
Japan Arm: Mitomycin C + Adriamycin + Ftorafur
MODALITIES: chemotherapy

TITLE: A Phase 111 Study Comparing Adrlarnycin + 5-FU versus BCNU + Adriamycin + Ftorafur versus Mitomycin C + Adriamycin + Ftorafur for Patients with Disseminated Gastric Cancer


UNITED STATES
JAPAN
COORDINATOR: Stephen K Carter,M.D
N. California Oncology Group
1801 Page Mill Road Building 3, Suite 200Palo Alto. California 94304
(415) 497-7512
Yoshio Sakurai, M.D., Director
Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
Kami-Ikebukuro 1-37- 1 Toshima-ku. Tokyo
STUDY CHAIRMAN: Michael Friedman, M.D.
Cancer Research Institute
University of California
1276 Moffitt Hospital
San Francisco, California 94143
(415) 666-3278
Kiyoji Kimura, M.D., Vice Director
National Cancer Center Hospital
Tsukiji 5-1-1
Chuo-ku, Tokyo 104
CO-STUDY CHAIRMAN: Karen Fu, M.D.
University of California
Yoshiyuki Koyama, M.D.
National Medical Center Hospital
Theodore Schrock, M.D.
University of California 		Yoshio Sakurai, M.D.
Japanese Foundation for Cancer Research
STUDY SECRETARY: Michael Friedman, M.D.
University of California 		Makoto Ogawa, M.D.
Aichi Cancer Center Hospital
DISEASE COMMITTEE CHAIRMAN: MichaelFriedman,
University of California		 Kiyoji Kimura, M.D.
National Cancer Center Hospital
PARTICIPANTS: Entire Group
DATE ACTIVATED: 5 December 1977


Five-Year Summary Report
The past five years have brought great benefits to both countries. The interaction between U.S. and Japanese scientists interested in cancer chemotherapy has moved through the stages of communication, cooperation, and collaboration. The communication has involved exchange of in-formation concerning methodology of anticancer drug development, methodology of clinical evaluation of new drugs, and new drugs under clinical investigation. This has been accomplished through joint symposia, exchange of scientists, and an extensive exchange of written material. As a result of these communications, improvements in drug development techniques have occurred in both countries. Model systems from both countries have become part of the screening and analogue delineation approaches in both countries. The Japanese Institute for Cancer Research's Cancer Chemotherapy Center has set up a screening pro-gram for new drugs which utilizes the screening protocols of the National Cancer Institute (NCI) and which feeds data into their system. A leading source of new fermentation structures for the NCI natural product program has come from the Japanese Institute for Microbial Research under the brilliant leadership of Professor Hamao Umezawa. The close working relationship that has developed between Professor Umezawa and his institute and the NCI drug development program has been one of the major benefits of the U.S.-Japan Cooperative Cancer Research Program to the United States. Among the new drugs which have entered into the NCI drug development program from Professor Umezawa are the following: macromomycin, diketocariolan, bestatin, PEP-bleomycin, and aclacinomycin-A.
Japanese drugs which have undergone clinical trial in the U.S. in the last five years include: chromomycin A3, cyclocytidine, yoshi-864, and neocarzinostatin.
One of the most important areas of cooperation and collaboration between the two countries has been in the area of analogue drug development. The thrust of analogue development is to take an active structure and attempt to improve its therapeutic index by increasing the efficacy and/or diminishing the toxicity. This has been one of the strongest areas of interaction in the U.S.-Japan Agreement. Four areas have been highlighted for work and these exemplify the truly international flavor of the agreement: (1) the nitrosoureas-compounds developed in the United States by the NCI drug development program: (2) bleomycins-antitumor antibiotics discovered by Umezawa in Japan; (3) anthracyclines-originally developed in Italy with major clinical evaluation in the U.S.; and (4) ftorafur and the fluoridated pyrimidines-an approach originally developed in the U.S.S.R. with major clinical testing and secondary development in Japan.
Work in the nitrosoureas has centered around diminishing the marrow toxicity of this class of drugs by the inclusion of a sugar moiety in the structure. Two closely related compounds have been independently synthesized in the two countries. They are chlorozotocin in the United States and GANU in Japan. As part of the exchange, these two drugs have been compared in the laboratories of both countries. Testing has concentrated on the relative alkylating and carbamoylating activities of both drugs in an attempt to understand the mechanisms of antitumor effect and toxicity with hope of being able to separate them. While the two drugs are very closely related structurally, they have different ratios of the two effects. The two drugs are either in the clinic or will be quite soon. When the clinical results are correlated with the laboratory data the stage should be set for a new understanding which could lead to more rational continued analogue development. This scientific cooperation and collaboration has greatly enriched the programs in both countries.
Bleomycin is one of the most important anti-cancer drugs of the 1970s. The drug has activity against a range of squamous cell cancers as well as lymphomas and testicular cancer. It Is remarkable for its lack of bone marrow toxicity and for its propensity to cause pulmonary fibrosis. Originally developed in Japan it has been extensively tested in the United States. Throughout the five years of the Agreement, several symposia have involved an ex-change of the clinical results from both countries. These exchanges have enriched the clinical value of this drug in the U.S. and Japan. Bleomycin is now an integral part of curative treatments for testicular cancer and the malignant hymphomas. Dr. Umezawa and his co-workers have synthesized more than 200 analogues of bleomycin in hopes of improving the therapeutic index. The strategy for the experimental testing of these analogues has been a major point of discussion in past meetings.
Adriamycin is an anthracycline antitumor antibiotic developed in Italy by the Farmitalia company. Its major clinical testing was performed in the United States. It has the broadest spectrum of any cancer drug that has ever been developed. Its use is limited by a propensity to cause cardiomyopathy. Analogue development to diminish the cardiac toxicity has been extensive. New compounds have come from Japan (aclacinomycin-A), the U.S. (AD-32), the U.S.S.R. (carminomycin), and France (rubidazone). The structure for clinical and experimental testing has been an important aspect of several symposia sponsored by the U.S.-Japan Agreement. It is expected that clinical testing of aclacinomycin will soon begin in the United States.
Ftorafur is a fluorinated pyrimidine analogue of 5-fluorouracil originally synthesized in the U.S.S.R. Extensive clinical testing took place in Japan where the drug is commercially available. Investigational clinical study has also taken place in the U.S. and still continues. Several new analogues have been synthesized in Japan (FD-1, HCFU) and have been discussed at recent symposia.
Another important area of communication and collaboration under the Agreement has been the treatment of stomach cancer. Gastric cancer is the leading cause of cancer death in Japan and, while diminishing in incidence, is still the seventh leading cause of cancer death in the United States. In the past years there has been both exchange of scientists and symposia emphasizing this area. A group of speakers from the U.S. Gastrointestinal Tumor Study Group visited Japan and participated in a symposium on the treatment of gastric cancer. On several occasions, Japanese scientists have come to the U.S. and participated in the meetings of the Gastrointestinal Tumor Study Group. Until recently clinical research into gastric cancer in the U.S. had been a neglected area. The important upsurge of interest in this important tumor in the U.S. has been helped by the extensive knowledge about this tumor area developed in Japan. This has all culminated in a collaborative protocol being initiated by the Northern California Oncology Group of the Northern California Cancer Program and several Japanese centers under the coordination of the Japanese Institute for Cancer Research. Only the years of meeting together, with the resultant development of mutual scientific respect and personal friendship, could lead to the acceptance of a mutual protocol, forms, and statistical analysis. This protocol is currently accessioning patients successfully and will, hopefully, be the cornerstone for a wide range of collaborative clinical studies under the U.S.-Japan Cooperative Cancer Research Pro-gram in the second five years.

Future Directions
In the future, all of the treatment aspects formerly scattered among other aspects of the Pro-gram will be brought together. In the next five years, progress will continue both along modality-oriented lines and along disease-oriented lines, with the two blending together where appropriate. The modality thrusts will involve chemo-therapy, radiation therapy, and immunotherapy. In chemotherapy, the vigorous exchange of drugs for both preclinical and clinical testing will continue. Emphasis will remain on new antitumor antibiotics and other natural products and on the four analogue areas of bleomycins, anthracyclines, nitrosoureas, and fluoropyrimidines. In radiation, the exchange of information on the High Linear Energy Transfer technique in both countries will continue. In addition, a dialogue will begin on other new developments in radiation oncology such as radiation sensitizers, hyperthermia, the interaction of drugs and radiation, and new fractionation schedules. In immunotherapy, there will be continued exchange of information on new immune modulations approaches. Disease-oriented approaches will focus initially on four tumors in which some exchange has already taken place. These are gastric cancer, breast cancer, lung cancer, and bladder cancer. In each of these diseases there will be an attempt to integrate the modality-oriented developments.
Gastric cancer will be a continuing focus. As new drugs are developed in each country, gastric cancer will be an important disease for Phase II testing. This will be particularly true in Japan where this tumor is such a major killer. Any new active drugs uncovered will then be integrated into combination regimens with other active drugs such as mitomycin-C, adriamycin, 5-FU, and methyl CCNU. The impetus begun with the current U.S.-Japan protocol for advanced disease will continue with new mutually developed protocols based on the current status of the clinical research. Discussions will also be held about a joint surgical adjuvant trial in which drugs will be given after curative resection for those patients at high risk for recurrence.
Breast cancer is a disease in which many exciting developments in treatment are taking place. In the area of local and regional control, there are the developments of effective treatments which have better cosmetic results than classical radical mastectomy. These include the approaches for excisional biopsy and radiation. Adjuvant chemotherapy continues to be an area of high clinical research interest. Future developments will involve integration of the hormone receptor assay and hormonal therapy into the use of effective drug treatments. This will be an area where both chemotherapy and radiation therapy can be brought together with breast surgery to explore the possibility of joint trial between the two countries.
In the area of lung cancer, the combined modality treatment of small cell anaplastic (oat-cell) lesions-is resulting in high-response ratios and significant prolongation of survival. Radiation is used to help control the primary lesion and to prophylactically attack any relapse. Drug combinations are used to aid local control and to achieve metastatic cell kill. The interaction of drugs and radiation is a crucial area of study and a high priority area for a joint U.S.-Japan symposium. Again, it is hoped that collaborative studies would ultimately result.
In non-oat cell lesions, surgical resection has some curative potential and this is a prime area for the testing of adjuvant immunotherapy. The drug treatment is currently poor, and emphasis needs to be placed on finding new effective drugs. Both countries will be undertaking Phase II studies and the sharing of results will lead to rapid movement into further clinical study of any new drug found to be active.



U.S. -JAPAN JOINT SYMPOSIUM ON PHASE I AND II IN CANCER CHEMOTHERAPY (*Sponsored by the National Cancer Institute (U.S.A.) and the Japan Society for the Promotion of Science; organized by Drs. Stephen K. Carter, Yoshio Sakurai, and Franco M. Muggia.)
June 5-6, 1978
Keidanren Kaikan, Tokyo

AGENDA
Monday, June 5
9:00 a.m. Welcome Dr. Yoshio Sakurai
9:10 a.m. l. THE METHODOLOGY Chairman: Dr. Michael Friedman
1. Phase I Trials with a New Drug
U.S.A. - The Design of Phase I Clinical Trials Dr. Marcel Rozencweig
Japan - The Methodology of Phase I Trials Dr. Makoto Ogawa
9:50 a.m. 2. Phase II Trials with a New Drug
U.S.A. - Methodology of Phase II Trials Dr. Franco M. Muggia
Japan - Phase II Study: Including Signal Tumors and Evaluation Criteria Dr. Hisashi Majima
10:30 a.m. Discussion
10:40 a.m. COFFEE
10:55 a.m. II. THE CLINICAL EVALUATION OF ANALOGUES Chairman: Dr. Franco M. Muggia
U.S.A. - Dr. Stephen K. Carter
Japan Clinical Evaluation of Ara-C Analogues Dr. Kazumasa Yamada
12: 10 p.m. LUNCH
2:00 p.m. III. CLINICAL EVALUATION STRATEGY IN SPECIFIC DISEASE TYPES Chairman: Dr. John Macdonald
1. Lung
U.S.A.- Dr. Robert Comis
Japan - Present Status of Chemotherapy of Lung Cancer in Japan Dr. Kazuo Ota
2:50 p.m. 2. Breast
U.S.A. - Dr. Robert Benjamin
Japan - Present Situation of Chemotherapy for Breast Cancer in Japan Dr. Hiroki Koyama
3:55 p.m. 3. Gastrointestinal Chairman: Dr. Stephen K. Carter
U.S.A. - Clinical Evaluation Strategy in Gastro-intestinal Cancer Dr. John Macdonald
Japan Clinical Study on Chemotherapy of Gastrointestinal Cancer (in one institute of Japan) Dr. Tatuo Saito
4:45 p.m. 4. Genitourinary
U.S.A. - Clinical Evaluation Strategy in Genitourinary Cancer Dr. Michael Friedman
Japan - Recent Results in the Treatment of a Metastatic Cervical Cancer with a Sequential Combination of Bleomycin and Mitomycin C Dr. Tadaoki Miyamoto
5:35 p.m. Discussion
6:00 p.m. Adjourn

Tuesday, June 6
9:00 a.m. IV. NEW DRUGS Chairman: Dr. Yoshio Sakurai
1. The New NCI Screen and Its Implication for Clinical Evaluation Dr. Abraham Goldin
Discussion
9:30 a.m. 2. Natural Products under Development Chairman: Dr. Abraham Goldin
U.S.A. - Dr. John D. Douros
Japan - Dr. Hamao Umezawa
Discussion
10:20 a.m. COFFEE
10:35 a.m. 3. New Drugs in Clinical Trials Chairman: Dr. Hamao Umezawa
U.S.A. - New Drugs in U.S.A. Dr. Franco M. Muggia
Japan - Effect and Mode of Action of N4-Acyl Cyiosine Arabinoside Dr. Yoshio Sakurai
Discussion
11:25 a.m. V. FOUR SPECIFIC SESSIONS ON DRUG CLASSES OF INTEREST
1. Nitrosoureas		 Chairman: Dr. John D. Douros
U.S.A.- Nitrosoureas of Clinical Interest in Gastrointestinal Cancer Dr. John Macdonald
Japan - Further Phase 11 Study on ACNU Dr. Tatuo Saito
Experimental Studies on Nitrosourea Derivatives in Japan Dr. Shigeru Tsukagoshi
Discussion
12:25 p.m. LUNCH
2:00 p.m. 2. Bleomycins Chairman: Dr. Marcel Rozencweig
U.S.A. - Dr. Robert Comis
Japan - Phase II Study of Pepleomycin: New Synthetic Bleomycin Dr. Tsuyoshi Miura
Discussion
2:50 p.m. 3. Anthracyclines Chairman: Dr. Robert Comis
U.S.A. - Dr. Robert Benjamin
Japan Clinical Experiences on Aclacinomycin:
Phase I and II including Toxicity and Irradiation-drug Effects		 Dr. Hisashi Majima
Discusslon
3:40 p.m. COFFEE
3:55 p.m. 4. Fluorinated Pyrimidines Chairman: Dr. Robert Benjamin
U.S.A. - New Strategy in Fluorinated Pyrimidines Dr. Michael Friedman
Japan - Phase I and Early Phase II Study on FD-1 and HCFU Dr. Tetsuo Taguchi
Discussion
4:55 p.m. VI. THE U.S.-JAPAN JOINT GASTRIC CANCER PROTOCOL Chairman: Dr. Stephen K. Carter
Japan - Dr. Makoto Ogawa
U.S.A. - Dr. Michacl Friedman
5:35 p.m. SUMMARY AND CLOSING REMARKS Dr. Stephen K. Carter
6:00 p.m. Adjourn

Wednesday, June 7 (Palace Hotel)
9:30-11:30 a.m. BUSINESS MEETING: Chemotherapy

PARTICIPANTS

UNITED STATES

Dr. Stephen K. Carter
(U.S. Coordinator)
Director Northern California Cancer Program
1801 Page Mill Road
Building B, Suite 200
Palo Alto, California, U.S.A.

Dr. Robert Benjamin
Assistant Professor
University of Texas System Cancer Center
M.D. Anderson Hospital and Tumor Institute
6723 Bertner Avenue
Houston, Texas, U.S.A.

Dr. Robert L. Comis
Assistant Professor of Medicine
Chief, Solid Tumor Oncology
State University Hospital of the Upstate Medical Center
750 East Adams Street
Syracuse, New York, U.S.A.

Dr. John D. Douros
Chief, Natural Products Branch
Developmental Therapeutics Program
Division of Cancer Treatment
National Cancer Institute
Blair Building, Room 314
8300 Colesville Road
Silver Spring, Maryland, U.S.A.

Dr. Michael A. Friedman
Assistant Professor of Medicine
Cancer Research Institute
1276 Moffitt Hospital
University of California
San Francisco, California, U.S.A.

Dr. Abraham Goldin
Assistant Director for International Treatment Research
Division of Cancer Treatment
National Cancer Institute
Building 31, Room 10A22, NIH
Bethesda, Maryland, U.S.A.

Dr. John Macdonald
Division of Medical Oncology
Georgetown University School of Medicine
3800 Reservoir Road, N.W.
Washington, D.C., U.S.A.

Dr. Franco M. Muggia
(U.S. Co-Coordinator)
Associate Director
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Building 37, Room 6A17, NIH
Bethesda, Maryland, U.S.A.

Dr. Marcel Rozencweig
Special Assistant to the Director
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Building 37, Room 6A17, NIH
Bethesda, Maryland, U.S.A.

JAPAN

Dr. Yoshio Sakurai
(Japan Coordinator)
Director, Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
Kami-Ikebukuro 1-37-1
Toshima-ku, Tokyo 170, Japan

Dr. Hiroki Koyama
Chief, Department of Surgery
Center for Adult Diseases, Osaka
Nakamichi 1-3-3
Higashinari-ku, Osaka 537, Japan

Dr. Hisashi Majima
Head, Department of Internal Medicine
Chiba Cancer Center
Nitona-cho 666-2
Chiba 280, Japan

Dr. Tsuyoshi Miura
Department of Surgery
University of Tokyo,
Faculty of Medicine
Hongo 7-3-1
Bunkyo-ku, Tokyo 113, Japan

Dr. Tadaoki Miyamoto
Department of Internal Medicine
National Institute of Radiological Science
Anagawa 4-9-1
Chiba 280, Japan

Dr. Makoto Ogawa
Chief, Div. of Clinical Chemotherapy
Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
Kami-Ikebukuro 1-37-1
Toshima-ku, Tokyo 170, Japan

Dr. Kazuo Ota
Head, Department of Cancer Chemotherapy
Aichi Cancer Center
Tashiro-cho Kanokoden
Chikusa-ku, Nagoya 464, Japan

Dr. Tatuo Saito
Head, Department of Internal Medicine, and Department of Clinical Oncology
Cancer Institute Hospital
Japanese Foundation for Cancer Research
Kami-Ikebukuro 1-37-1
Toshima-ku, Tokyo 170, Japan

Dr. Tetsuo Taguchi
Professor, Department of Oncologic Surgery
Research Institute for Microbial Diseases
Osaka University
Yamada-kami
Suita, Osaka 565, Japan

Dr. Shigeru Tsukagoshi
Chief, Div. of Experimental Chemotherapy
Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
Kami-Ikebukuro 1-37-1
Toshima-ku, Tokyo 170, Japan

Dr. Hamao Umezawa
Director Institute of Microbial Chemistry
Kami-Osaki 3- 14-23
Shinagawa-ku, Tokyo 141, Japan

Dr. Kazumasa Yamada
Associate Professor
Department of Internal Medicine I
Nagoya University School of Medicine
Tsurumai-cho 65
Showa-ku, Nagoya 466, Japan

ADDITIONAL PARTICIPANTS

Dr. Ikuro Kimura
Professor
Department of Internal Medicine II
Okayama University School of Medicine
Shikada-cho 2-5-1
Okayama 700, Japan

Dr. Tateshi Kataoka
Division of Experimental Chemotherapy
Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
Kami-Ikebukuro 1-37-1
Toshima-ku, Tokyo 170, Japan