REPORTS ON SEMINARS


(1) Seminar on "Progress of Treatment of Hematologic Tumors: Strategy to Cure"
The first meeting of the US-Japan Cooperative Cancer Research Treatment Program Area for FY 1989 was held on November 11-12, 1988, in Tokyo, Japan. Dr. D. Kufe discussed aspects of cellular pharmacology of Ara-C. The mechanisms of cytotoxicity discussed were DNA polymerase, DNA repair inhibition and incorporation into DNA and RNA. Ara-C is primarily incorporated into DNA and its effects are dose-time (CXT) dependent. With higher concentration, chain termination appears to be a crucial component of cytotoxicity. Inhibition of DNA polymerase (alpha and beta) is not however the principal mechanism of cytotoxicity. Based on these observations, Ara-C effects in vivo can be studied in ANLL blasts. Attaining 10 -5 molar Ara-C is crucial - higher doses are unnecessary and continuous infusions are often utilized. Preliminary correlation suggest a higher incorporation rate is associated with better response. Currently he is utilizing 6gm/m2/d q o d with little GI or CNS toxicity (mostly marrow).
Dr. Nakamura then described the studies of Ara-C and analogues in Japan. Behenoyl Ara-C is popular in Japan (BHAC); studies of BHAC and Ara-C in human leukocytes have been performed. BHAC seems to be a long acting form of Ara-C. Another analogue used in Japan is Palmitoyl-Ara C, which has been similarly studied. Dr. C. Schiffer described a number of lab-clinical correlations in ANLL patients. There has generally been no major improvement in survival for the past ten years (approximately 25 percent of CR patients are long-term survivors). ANLL is extremely heterogenous (both withi and between patients’ blasts). Mo leukemia (undifferentiated) is relatively resistant, as is Auer + Tdt +.
Examining gene rearrangements, some 10-20 percent of patients have lg markers, and these represent resistant disease. These cells are called myeloid ANLL, Tdt + ANLL, T cell ANLL, minimally differentiated ANLL-hybrid, promiscuous diseases with lineage infidelity. Cytogenetics is also a crucial prognostic factor - 8;21 = M2, 15;17 = M3, 16g; 22 = M4 EOS. Balanced translocations do extremely well (little drug resistance); as opposed to abnormal 5 or 7 or tisomy 8 who do poorly. Patients over 60 years of age have less durable remissions. Moreover, pharmacokinetic considerations are important DNR clearance and Ara-C variability is great between patients.
Dr. Ohno presented an overview of ANLL studies in Japan. At Nagoya University all studies utilized BHAC and combinations with DNR (25mg/m2/dx2) BHAC (170mg/m2 daily) with 6MP and prednisone. Approximately 15-20 percent overall survival was noted in 50 patients. The subsequent protocol increased the dosage of DNR and BHAC, but had severe toxicity and no apparent increased efficacy. The most successful study is perhaps B-DOMP at Hiroshima Red Cross Hospital. This is a very complicated regimen resulting in 43 percent, 7 year survival. More recently a Japan Leukemia Society group was organized. A total of 17 institutions joined together studying the value of VCR, duration of maintenance, etc. The accrual is about 150 patients yearly.
Dr. Masaoka presented the results of allogeneic bone marrow transplantation in patients in first remission and a 60 percent survival rate was demonstrated. Also Grade I GVHD (acute and chronic) was associated with better responses. Acyclovir is given prophylactically. Additionally, HU-GCSF is administered with allogeneic BMT to speed recovery, but febrile days and documented infections were not changed. However, engraftment is superior. In Japan, the 5,000 new leukemias/year (CML = 850 and acute leukemia 4,000/year). There are 500 CML and 2,500 AL. About 2,600 cases are BMT appropriate and 650 with HLA matches.
Dr. Coleman discussed combined modality therapy of acute lymphoblastic lymphomas in adults in the U.S. This high-grade lymphoma is a rare disease. The natural history of this disease with poor-initial regimens at Stanford University for adult patients revealed a high CR rate but too frequent CNS relapses. A modified CHOP and ALL regimen was employed. A second generation protocol integrated CNS prophylaxis earlier. Responses were excellent (95 percent CR) in 30 patients. Freedom from CNS relapse did not correlate with improved survival. The most significant prognostic features were LDH Ievel and Ann Arbor Stage (III or IV). Low risk disease requires no new therapies, but high risk patients require either the introduction of new agents (such as VM 26 and Ara-C) or BMT. Both approaches have considerable promise.
Dr. Morishima focused on the use of BMT in ALL. High risk patients were evaluated and 51 received allogeneic BMT, 11 ABMT. For the allogeneic patients 22/51 were in first CR and they had relatively good survival. Interstitial pneumonitis and GVHD were principal causes of death. The preparatory regimen now contains Ara-C + DNR. Allogeneic transplants in first CR survive free of disease, but for accelerated-blast crisis patients, the survival is much lower.
Dr. Mihich discussed differentiation as a potential approach in therapeutics. New sites for therapeutic intervention include gene function, cell regulation, growth factors, and differentiation. Approaches include: sensitization by DNA specific cytotoxins to natural DF, stimulation of endogenous DF, exogenous DF, interference with GF, and the induction of maturation with DF analogues. A variety of DNA reactive drugs can effect differentiation of ML1 cells in vitro.
Dr. Kufe presented an elegant description of CSF-1 (MCSF) and its relation to myeloid hematopoiesis. Using the models of TNF---->Monocyte differentiation and CSF-1(MCSF)---->C-fms gene product. C-fms is a tryosine kinase (similar to PDG F, ILGF, etc.). HL 60 cells treated with TPA have downregulation of C-myc and appearance of C-fms transcripts. Inducers of monocytes included phorbol esters, D3, IFN Alpha, TNF--tyrosine kinase growth factor receptors. Examining leukemic myeloblasts in 17 patients, 10 had CSF-1 and 7 FMS (5 both and 5 had neither). Autocrine and paracrine models exists (pregnant rat uterus makes CSF-1 and C-fms receptor in placenta).
Dr. Motoyoshi has also studied MCSF and he presented data on clinical studies. Phase II studies were performed by giving chemotherapy without and with CSF-1. Forty-four patients with urogenital cancer were entered (14 testis, 14 bladder, etc.). Thrombocytopenia was ameliorated but leukopenia less so. The average WBC nadir was 1,500 vs. 2,100 (P<.O1) and 11.2 vs. 7.7 days to waC recovery (Pv.05). Some patients with MDS received CSF-1 with benefits. The duration of benefits on neutrophils and myeloblasts was longer than GMCSF in RAEB.
Dr. Ogawa discussed phase I studies of GCSF in Japan. In 17 normal patients, either placebo or GCSF was administered. Dose related leukocytosis was observed (lymphocyte numbers were stable). Pharmacology was performed and no toxicity observed. In cancer patients, GCSF was given 72 hours after the first cycle (for 14 days) of chemotherapy but not with the second. Doses of 50 to 800 micro g/m2 were given in this ongoing phase I study. Both nadir and duration of leucopenia were affected by GCSF. Toxicities included: skin rash in one and bone pain in two. The optimal dose was considered to 100 micro g/m2/day.
Finally, Dr. Takaku described three areas of use for GCSF-neutropenia after CT or BMT and in resistant leukemia. A total of 43 BMT patients were evaluated (32 allo BMT, 11 ABMT). Speedier engraftment, Iess infection, and fewer ill effects were noted. For patients with AML, GCSF can speed recovery from leucopenia and can be used with antileukemic drugs (in resistant patients). In nine patients with MDS and AML, increases in neutrophils were observed in blasts and mature WBC. GCSF can increase number and improve function of leukocytes (super oxide generation, chemotaxis, and phagocytosis). Six patients with Ara C were treated with GCSF with benefits. Also a patient with SBE responded well to combined antibiotics + GCSF.
Overall, this meeting was exceedingly successful with important new information exchanged. The activities in Japan and the U.S. are complimentary and thus this information is extremely valuable.

(2) Seminar on 'New Drugs Under Development'
Molokai, Hawaii February 21-22, 1989
Dr. Tsuruo began the discussion with a presentation on MX-2 and other drugs especially effective against P388 both IV and PO, and is useful in CNS Walker 256. MX-2 has less cardiotoxicity than DXR and is also active in ADR/NCR resistant lines. A second compound is ME 2303 (an ADR analogue), with colon 26 and P388 activity. It also is more effective in resistant cell lines than the parent compound. ME 2303 is beginning phase I testing. MX-2 has completed phase I studies. Dr. John Kuhn then described a series of studies with BW 770 and 773, arylmethyl amino-propanediols (AMAPS). All are more active on chronic schedule of administration. Thought to be intercalators, 770 is more lipid soluble. The DLT for 770 is neurologic and resolves rapidly (associated with peak plasma concentration). For the 773 compound, the DLT was hemolysis. Phlebitis, nausea, and vomiting were not substantial. For compound 502, the major toxicity was prolonged EKG-QT, and PR intervals. This compound looks similar to Acodazol and has similar toxicity.
The next compound discussed was Taxol. Major clinical toxicities are leucopenia, paraesthesia, and myalgias. Responses have been seen in lung, melanoma, and especially ovary cancer patients. Premedication to prevent anaphylaxis is not routinely needed in those with 10-hour infusion. The 6-hour infusion every 3 weeks is the best schedule.
Dr. Tamura described Japanese studies of Deoxyspergualin (DSG). This agent is active against L1210 and P388 and is highly schedule dependent. The major metabolic pathway is renal excretion. Three hour infusions for 5 consecutive days was the schedule employed. Beginning in April 1987 and ending September 1988, NKT-O1 was studied in a phase I trial. Toxicities observed included numbness and hypotension. MTD = 500mg/m2/d x 5 days.
DSG in the U.S. studies was reviewed by Dr. Von Hoff. In vitro studies are complicated by the need to be activated by MAO. The schedule is 120 hour continuous infusion. Doses have ranged from 80 to 2800mg/m2 resulted in hypotension as the DLT. This toxicity will be addressed with saline loading. The neurologic toxicity may be related to MAO inhibition.
Dr. P. Schein presented information on WR2721--used as a radiation-alkylator protector. The ability to exhibit dose modifying factor (DMF) effect varies from 2.4 (RT), to 4.6 (HN2), to 3.2 (CDDP), to 2.7 (5FU). It may protect against mutagenesis as well. There is evidence of possible enhanced activity with CDDP in breast, melanoma, H&N, and esophagus cancer patients. Current studies:

CP + WR 2721 Ovarian (Pa)
MitoC + WR 2721 Colon (Ky)
ThioTEPA + WR 2721 Breast (Pa)
ThioTEPA + ABMT + WR 2721 (WSU)
TBI + WR 2721 (Fox Chase)

A newer compound, WR 151327 is orally active in preclinical studies and looks promising.
Dr. Tsukagoshi described studies with Diarylsulfonylurea (LY 186641) which is active in MX-1, Colon 26, but not B16. Pre-phase I studies revealed no evidence of ADR cross resistance. It is also capable of inhibiting pulmonary metastases. Apparently while the mechanism of action is not known, DNA is not affected by this agent.
Dr. John Kuhn also presented U.S. data on LY 186641. No hypoglycemia, but methemoglobinemia was seen preclinically. The initial phase I schedule was po (single) q 21 days. Both hemolysis and methemoglobinemia were mild and not requiring therapy (methylene blue or vitamin c). Large doses may saturate absorption (hence possible need for divided doses). The single dose study resulted in 2 patients requiring transfusions.
The second day of the conference began with a discussion of developing analogs of active agents. Dr. Ogawa reviewed the new Japanese anthracyclines-po Menogaril and FAD (104) and SM5887 and KRN. The SM compound was active in P388 but only 1/10 cardiotoxicity of ADM. Both compounds have undergone phase I and initial phase II studies.
Dr. Ariyoshi described a series of platinum compounds including 254S, DWA 2114R, and NK121. The DLT for NK121 and 254S included myelotoxicity. Similar preclinical murine tumor profiles were obtained. Overall there is little difference between toxicities of these three and CBDCA There is the same suggestion of activity in a spectrum of malignancies expected for CDDP.
Dr. Tamura presented data on DWA 2114R in patients with leukemias and lymphomas. Doses of 800-1600mg/m2/day were used for 24 -hour infusions (up to 5 days). Some antileukemic effects were seen, but only ICR noted (AML).
Dr. Taguchi described studies with CPT-11, another analogue of Camptothecin. Phase I studies were started in 1986 and phase II data are now available. The metabolite SN-38 is active also. The DLT was leukopenia, and GI toxicity. The standard dose was 200mg/m2 and activity has been noted in stomach, lung, breast, gynecologic, and skin cancer. Also studied were patients with hematologic malignancies.
Dr. Mitchell presented an overview of BRM and chemotherapy. He pointed out that ADR, BLM, Mithranycin, Myleran, and DTIC have little immunosuppressive action. Immunoaugmentive therapies are low dose cytoxan, CDDP, BLM, ADR, and prostaglandin antagonists. These drugs increase susceptibility to cell membrane immune lysis--ACTD, ADR, MMC, DTIC, BCNU, and MTX. These change the membrane cholesterol: phospholipid ratio. Using a program of 350mg/m2 cytoxan prior to IL2 therapy resulted in 2CR and 8PR in 39 melanoma patients. The opportunity for MoAb plus LAK cells is of real interest, and such interactions are real.
Dr. Takaku discussed the use of GCSF in Japan for leukopenia after CT or BMT, MDS, Infection, AIDS, and to sensitize AML cells. The study design included a crossover (placebo vs. rhGCSF). Currently 200-400mg/m2/d is employed. In 7/9 AML cases, GCSF increased tumor cell number in vitro. Receptors for GCSF or AML cells could be quantified, and were in excess of that found in normal granulocytes. No differentiation occurred in vivo, although with established cell lines this could be seen. He also described the use of MCSF in clinical trials. This molecule activates and increases monocytes, modulates both antibody dependent and independent tumor killing, and affects pregnancy and cholesterol metabolism.

(3) Seminar on 'Innovative Therapy for Poor Prognosis Breast and Gastrointestinal Cancers,'
Los Angeles, CA March 30-31, 1989
The program offered several new perspectives on the difficult and unfortunately common problems of breast and gastrointestinal cancer. Prognostic factors in early and advanced breast cancer are being refined and quantitated to guide future clinical approaches. The Her-2/neu oncogene work both in the U.S. and in Japan may yield clues on the biological behavior of breast cancer, ovarian cancer, and other adenocarcinomas perhaps in relation to autocrine versus endocrine growth. Adjuvant chemotherapy questions refined in National Cancer Institute-supported studies and consensus conference, were complemented by Japanese inquiries into alkylating drug-antiestrogen sequences. All this information is an essential background for the aggressive approaches in bone marrow transplantation of poor prognosis breast cancer. The results from one center each in the U.S. and Japan encourage the soundness of this approach in carefully selected patients and in the context of careful study.
In GI cancer, the focus on the U.S. side was on colorectal adjuvant studies leading to the tentative conclusion that as yet adjuvant chemotherapy's contribution is still open to question for high risk colon cancer (Dukes C, and high risk Dukes B2), whereas in rectal cancer combined radiation and chemotherapy have had demonstrable effects on survival still uncertain from either modality alone. Several new studies are ongoing based partly on the biochemical modulation of fluoropyrimidines that were highlighted on the second day of the meeting. Japanese studies in gastric cancer have recently been subjected to greater selfscrutiny in terms of large percentages of exclusion. Nevertheless, effects of intraperitoneal and perioperative mitomycin continue to be apparent. U.S. investigators have generally dealt with patients differing in staging features which in part explains controversial and discouraging results. The issues of aggressive local approaches followed by surgery in a patient with carcinoma of the gastroesophageal junction. Perhaps advances in chemotherapy and other local strategies will enable the wider application of curative approaches, now utilized only in the minority of afflicted patients.
Biochemical knowledge of fluoropyrimidines have yielded tangible improvements in efficacy by pointing to their combined use with leucovorin. Randomized clinical trials in the U.S. and Canada have shown improved responses in 6 of 7, and improved survival in 2 of 7 studies. Patients in earlier stages may have more clearly benefited. Additional experience in breast cancer appears favorable, and further efforts at modulation with cisplatin and dipyridamole were described. Pharmacodynamics of thymidylate synthase inhibition are complex and currently fueling controversy as to optimal dosing schedules and types of fluoropyrimidines or folate cofactors to be used, and of other modulators of folate metabolism including other cytotoxic drugs, amino acids, and nucleosides. Nevertheless such controversies should not obscure the clear facts of leucovorin enhancing the cell kill of fluoropyrimidines in relationship to the buildup of 5, 10 methylene tetrahydrofolate, and to the very evanescent effect of FdUMP binding in the absence of excess reduced folates. A new prodrug of FdUMP is being tested in Japan and seeks to exploit the importance of this pathway of fluoropyrimidine action. Determinants of susceptibility to platinums are of interest and studies on characteristics of resistance applicable to clinical circumstances were thoroughly studied. Biochemical changes that occur and may explain platinum anti-metabolite synergy seen initially through perturbation of folate metabolism, and later development of cross-resistance with antimetabolites have been thoroughly explored by the polymerase chain reaction. Finally, techniques of IP therapy in the U.S. and two route chemotherapy in Japan were of interest for the application of these techniques with varying focus. In the U.S., studies of local pharmacologic advantage coupled with intact action via "capillary flow" was sought. In Japan studies sought to totally neutralize systemic effect, by use of sodium thiosulfate I.V. and further protect normal target tissues by brief treatment with angiotensin II. Chemoembolization and percutaneous hepatic artery infusion studies from the U.S. and Japan, respectively, further represent variable use of technique to optimize therapy to liver metastases. Dilemmas in demonstrating effects and technical problems were finally discussed. Many of these issues are vital to the clinical programs of our Cancer Center, thus constituting further reason for being grateful for this opportunity of hosting the meeting.



SEMINAR AGENDA AND PARTICIPANTS

(1) PROGRESS OF TREATMENT OF HEMATOLGOC TUMORS: STRATEGY TO CURE


AGENDA
November 11 (Friday)
8:55a.m. Welcome Remarks Dr. M. Ogawa & Dr. M. Friedman
Session 1: Acute Non-Lymphocytic Leukemia (ANLL)
Chairperson: Dr. M. Friedman
9:00-9:15 Selected updates on Ara-C clinical and cellular pharmacology Dr. D.W. Kufe
9:15-9:30 Comparative analysis of mechanism of Ara-C and its analogs developed in Japan Dr. T. Nakamura
9:35-10:00 Discussion
Chairperson: Dr. D. W. Kufe
10:00-10:30 Selected laboratory and clinical issues in the treatment of ANLL Dr. L.W. Schiffer
10:30-11:00 Current overview of ANLL study in Japan Dr. R. Ohno
11:00-11:30 Allogeneic bone marrow transplantation on ANLL Dr. T. Masaoka
11:30-12:00 Discussion
12:00-1:00 Lunch
Session 2: Acute Lymphoblastic Leukemia (ALL) and Lymphomas
Chairperson: Dr. T. Masaoka
1:00-1:30 Treatment of Lymphoblastic lymphoma in adults Dr. C.N. Colman
1:30-2:00 Bone marrow transplantation in ALL Dr. Y. Morishima
2:00-2:30 Discussion
Session 3 Selected Topics on Hematologic Tumors
Chairperson: Dr. L.W. Schiffer
2:30-3:00 New developments in the therapy of patients with CLL and HCL Dr. M. Friedman
3:00-3:30 Clinical characteristics of Japanese HCL Dr. T. Machii
3:30-4:00 Discussion
4:00-4:30 Ways to reduce ph + cells and promote regrowth of diploid cells in CML Dr. A. Deisseroth
4:30-5:00 Current results of interferons and allogeneic BMT on CML Dr. H. Shibata
5:00-5:30 Discussion
Session 4 Special Lecture
Chairperson: Dr. M. Ogawa
5:30-6:00 Differentiation as a Potential Approach in Therapeutics Dr. E. Mihich
6:10-8:00 Reception (Buffet style) Sky Room

November 12 (Saturday)
Session 5: Colony Stimulating Factor (CSF)
Chairperson: Dr. C.N. Coleman
9:00-9:30 CSF-1 and its relation to myeloid hematopoiesis Dr. D.W. Kufe
9:30-10:00 M-CSF study Dr. K Motoyoshi
10:00-10:20 Phase I trial of G-CSF Dr. M. Ogawa
10:20-10:50 Phase II trial of G-CSF Dr. F. Takaku
10:50-11:30 Discussion
11:30 Closing Remarks Dr. M. Ogawa & Dr. M. Friedman
11:40 Adjourn


PARTICIPANTS

UNITED STATES

C.Norman Coleman, M.D.
Director
Department of Radiation Therapy
Joint Center for Radiation Therapy
Binney Street,
Boston, MA 02115

Albert B. Deisseroth, M.D.
M.D. Anderson Cancer Center
1515 Holcombe Boulevard
Box 24, Houston, Texas 77030

Donal W. Kufe, M.D.
Associate Professor of Medicine
Dana-Farber Cancer Institute
44 Binney Street,
Boston, Massachusetts 02115

Enrico Mihich, M.D.
Roswell Park Memorial Institute
Elm & Carlton Streets,
Buffalo, New York 14263

Charles A. Schiffer, M.D.
University of Maryland Cancer Center
22 South Green Street,
Baltimore, Maryland 21201

Michael A. Friedman, M.D.
Associate Director
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 742
Bethesda, Maryland 20892

JAPAN

Tohru Masaoka, M.D.
The Center for Adult Disease, Osaka
Nakamichi 1-2-3, Higashinari-ku, Osaka 537

Fumimaro Takaku, M.D.
University of Tokyo
Hongo 7-31, Bunkyo-ku, Tokyo

Hirotoshi Shibata, M.D.
The Center for Adult Disease
Nakamichi 1-2-3, Higashinari-ku, Osaka 537

Ryuzo Ohno, M.D.
Nagoya University School of Medicine
Tsurumai-cho, 65 Showa-ku, Nagoya 461

Yasuo Morishima, M.D.
Nagoya University School of Medicine
Tsurumai-cho, 65 Showa-ku, Nagoya 461

Toru Nakamura, M.D.
Fukui Medical School
Shimoaizuki 23-28, Matsuoka-cho,
Yoshida-gun Fukui 910-11

Takashi Machii, M.D.
Research Institute for Microbial Diseases
Osaka University
Yamadaoka 3-1 Suita, Osaka 565

Kazuo Motoyoshi, M.D.
Jichi Medical School, School of Medicine
Yakushiji 3311-1, Minami-Kawachi, Kawachi-gun
Tochigi 329-04

Makoto Ogawa, M.D.
Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
Kami-ikebukuro, Toshima-ku, Tokyo 170


OBSERVERS
Toshiteru Ohshima, M.D. Nihon University School of Medicine
Akira Horikoshi, M.D. Nihon University, School of Medicine
Hitoshi Takeuchi, M.D. Saitama Medical School
Yoshinori Itoh, M.D. Nagoya University School of Medicine
Hideaki Mizoguchi, M.D. Tokyo Women's Medical College
Toshiko Motoji, M.D. Tokyo Women's Medical College
Teruo Kitani, M.D. Osaka University
Kazumi Sampi, M.D. Saitama Cancer Center
Yasunobu Kuraishi, M.D. The Jikei University School of Medicine
Tadashi Kobayashi, M.D. The Jikei University School of Medicine
Nobuko Takasaki, M.D. The Jikei University School of Medicine
Kuniyuki Imai, M.D. Tokyo Metropolitan Komagome Hospital
Yasusuke Onozawa, M.D. Tokyo Metropolitan Komagome Hospital
Shigeru Takamoto, M.D. Tokyo Metropolitan Komagome Hospital
Takanori Ueda, M.D. Fukui Medical School
Akihisa Kanamaru, M.D. Hyogo College of Medicine
Kazuo Tamura, M.D. Miyazaki Prefectural Hospital
Taiichi Kyo, M.D. Hiroshima University, School of Medicine
Koichiro Yamaguchi, M.D. Sankyo Co., Ltd.
Akihiro Shimosaka, M.D. Kirin Brewery Co., Ltd.
Yoshikazu Tizuka, M.D. Nihon University, School of Medicine
Mineo Kanemaru, M.D. Nihon University, School of Medicine
Fumiaki Sano, M.D. St. Marianna University
Mitsuru Koike, M.D. St. Marianna University
Keisuke Toyama, M.D. Tokyo Medical College
Noboru Horikoshi, M.D. Cancer Chemotherapy Center
Katsuhiro Inoue, M.D. Cancer Chemotherapy Center
Taketo Mukaiyama, M.D. Cancer Chemotherapy Center



(2) SEMINAR ON NEW DRUGS UNDER DEVELOPMENT
Molokai, Hawaii, February 21-22, 1989

AGENDA
Tuesday, February 21, 1989
8:55 a.m. Opening Remarks Dr. M. Friedman
Dr. M. Ogawa
Session 1 New Compounds Under Preclinical Investigation
Chairperson: Dr. D. Von Hoff
9:00-9:30 Japanese new compounds Dr. T. Tsuruo
9:30-10:00 New antiemetic compounds Dr. J. Kuhn
10:00-10:30 Discussion
Session 2 New Compounds Under Clinical Investigation
Chairperson: Dr. M. Ogawa
10:30-11:30 Taxol Dr. R. Donehower
Dr. D. Von Hoff
11:30-12:00 Discussion
12:00-1:00 Lunch
1:00-2:00 Deoxyspergualin Dr. K. Tamura
Dr. D. Von Hof
2:00-2:30 Discussion
Chairperson: Dr. T. Tsuruo
2:30-3:00 WR2721 Dr. P. Schein
3:00-3:15 Discussion
3:15-4:15 LY186641 Dr. S. Tsukagoshi
Dr. J. Kuhn
4:15-4:45 Discussion Discussion Leader: Dr. M. Friedman
4:45-5:45 Other agents
Group Discussion
6:00 Adjourn

Wednesday, February 22, 1989
Session 3 New Directions in Analog Development
Chairperson: Dr. P. Schein
9:00-9:30 Anthracyclines Dr. M. Ogawa
9:30-10:00 Cisplatins Dr. Y. Arioshi
10:00-10:30 CPT-11 Dr. T. Taguchi
10:30-12:00 Discussion (Including other agents)
12:00-1:00 Lunch
Session 4 New Directions in Cytokines
Chairperson: Dr. T. Tsukagoshi
1:00-1:30 Interferons plus cytotoxic agents Dr. M. Mitchell
1:30-2:30 Ganulocyte colony stimulating factor Dr. F. Takaku
Dr. M.Friedman
2:30-3:00 Discussion
3:00 Closing Remarks Dr. M. Friedman
Dr. M. Ogawa

PARTICIPANTS

JAPAN
Makoto Ogawa, M.D.
Chief, Div. of Clinical Chemotherapy
Cancer Chemotherapy Center
Toshima-ku, Tokyo 170

Shigeru Tsukagoshi, Ph.D.
Vice Director,
Cancer Chemotherapy Center
Toshima-ku, Tokyo 170

Fumimaro Takaku, M.D.
Prof.
Faculty of Medicine
University of Tokyo
Bunkyo-ku, Tokyo 113

Yutaka Ariyoshi, M.D.
Chief,
Aichi Cancer Center
Chikusa-ku, Nagoya, 464

Tetsuo Taguchi, M.D.
Professor,
Dept. of Oncologic Surgery
Research Institute for Microbial Disease
Osaka University,
Suita, Osaka 563

Kazuo Tamura, M.D.
Chief,
Miyazaki Prefectural Hospital
5-30 Kitatakamatsu-cho, Miyazaki, 880

UNITED STATES

Michael A Friedman, M.D.
Associate Director
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 742
Bethesda, MD 20892

John G. Kuhn, Pharm. D.
University of Texas
Health Science Center at San Antonio
Department of Pharmacology
Division of Clinical Pharmacy
7703 Floyd Curl Drive
San Antonio, TX 78284-7765

Ross C. Donehower, M.D.
Johns Hopkins Oncology Center
Johns Hopkins University
School of Medicine
Baltimore, MD 21205

Malcolm Mitchell, M.D.
University of Southern California Cancer Center
2025 Zonal Avenue
Los Angeles, CA 90033

Philip S. Schein, M.D.
President, U.S. Bioscience
920-B Harvest Drive, P.O. Box 220
Blue Bell, PA 19422

Daniel D. Von Hoff, M.D.
University of Texas
Health Science Center at San Antonio
Department of Medicine
Division of Oncology,
7703 Floyd Curl Drive
San Antonio, Texas 78284-7884


(3) SEMINAR ON NEO ADJUVANT AND ADJUVANT CHEMOTHERAPY INNOVATIVE THERAPY FOR POOR PROGNOSIS BREAST AND GASTROINTESTINAL CANCERS
Pasadena Hilton, Los Angeles, March 30-31, 1989

AGENDA
March 30, 1989
8:25a.m. Opening Remarks Dr. M. Friedman
Dr. F. Muggia
Session I: Breast Cancer
Chairman: Dr. Makoto Ogawa
Prognostic Factors
8:30 a.m. Dr. Marilyn Owens
9:00 a.m. Dr. Makoto Ogawa
9:30 a.m. Discussion
Oncogenes
10:00 a.m. Dr. Dennis Slamon
10:30 a.m. Dr. Shigeo Mori
11:00 a.m. Discussion
11:30-1:00 p.m. LUNCH
Adjuvant Chemotherapy
1:00 p.m. Dr. Michael
1:30 p.m. Dr. Tetsuro Kubota
2:00 p.m. Discussion
Bone Marrow Transplantation
2:30 p.m. Dr. James Shogan
3:00 p.m. Dr. Tomoo Tajima
3:30 p.m. Travel to Norris, Tour Facilities (Bone Marrow Unit, Clinical Investigations Support Office) before and after Tumor Board
4:00 p.m. Tumor Board
Introduction: Dr. Franco Muggia
Moderator: Dr. Lawrence Leichman
7:00 p.m. DINNER (U.S. and Japan participants) Parkway Grill

Session II: GI Cancer
Chairman: Dr. Michael Friedman
March 31, 1989
Adjuvant Chemotherapy
8:00 a.m. Dr. Michael O'Connell
8:30 a.m. Dr. Toshifusa Nakajima
9:00 a.m. Discussion

Session III: New Therapies and Modalities
Chairman: Dr. Franco Muggia
Biochemical Modulation
9:30 a.m. Dr. Michael O'Connell
9:50 a.m. Dr. James Doroshow
10:10 a.m. Dr. Paul Spears
10:30 a.m. Discussion
New Antimetabolites
11:00 a.m. Dr. Richard Moran - Cellular
11:30 a.m. Dr. Tetsuro Kubota - FdUMP analogs
12:00 p.m. Discussion
12:20 p.m.-1:30 p.m. LUNCH
Platinums
1:30 p.m. Dr. Paul Andrews - Review of Platinum Resistance
2:00 p.m. Dr. Kevin Scanlon - Platinum Antimetabolites Interaction
2:30 Discussion
IP Therapy/2 Route Therapy
2:45 p.m. Dr. Edward McClay - IP Therapy
3:15 p.m. Dr. Tsuyoshi Akiyoshi - 2 Route Chemotherapy
3:45 p.m. Discussion
Chemoembolization
4:15 p.m. Dr. John Daniels
Hepatic Artery Chemotherapy
4:45 p.m. Dr. Yoshiaki Arai
5:15 p.m. Discussion
5:45 p.m. Closing Remarks Dr. M. Friedman
Dr. M. Ogawa


PARTICIPANTS

UNITED STATES

Paul Andrews, Ph.D.
Univ. of Calif., San Diego Cancer Center, T-012 La Jolla, CA 92093 (619) 543-5530

John Daniels, M.D.
Norris Cancer Hospital 1441 Eastlake Ave. Los Angeles, CA 90033 (213) 224-6675

James Doroshow, M.D.
Medical Oncology City of Hope Medical Center 1500 E. Duarte Rd. Duarte, CA 91010 (818) 359-8111

Lawrence Leichman, M.D.
Norris Cancer Hospital 1441 Eastlake Ave. Los Angeles, CA 90033 (213) 226-4009

Ed McClay, M.D.
Director, Chemotherapy Program Univ. of Calif., San Diego Cancer Center - T-012 La Jolla, CA 92093 (619) 543-6178

Dr. Kevin Scanlon
Medical Oncology City of Hope Medical Center 1500 E. Duarte Rd. Duarte, CA 91010 (818) 301-8477

James Shogan, M.D.
Duke Univ. Medical Center Box 3961 Durham, NC 27710 (919) 684-8111

Dennis Slamon, M.D.
UCLA School of Medicine 650 Circle Dr., South Factor Bldg., Rm. 11-259A Los Angeles, CA 90024 (213) 825-9440

C. Paul Spears
Norris Cancer Hospital 1441 Eastlake Ave. Los Angeles, CA 90033 (213) 224-7780

Michael Friedman, M.D.
Associate Director Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute Executive Plaza North, Rm. 742 Bethesda, MD 20892 (301) 496-6138

Richard Moran, Ph.D.
USC Cancer Research Lab 1403 N. Mission Rd., Rm. 206 Los Angeles, CA 90033 (213) 224-7780

Michael O'Connell, M.D.
812 Paxton Rd., S.W. Mayo Clinic, Dept. of Oncology Rochester, MN 55902 (507) 284-3903

Franco Muggia, M.D.
Norris Cancer Center 1441 Eastlake Ave. Los Angeles, CA 90033

Marilyn Owens, Ph.D.
Nichols Inst. of Endocrinology 329 Calleperfecto San Juan Capistrano, CA 92675 (I-800-6424657)

JAPAN

Tsuyoshi Akiyoshi, M.D.
Professor, Dept. of Clinical Oncology Medical Inst. of Bioregulation Kyushu University Beppu City, Kyushu, 874

Yoshiaki Arai, M.D.
Section Chief, Dept. of Radiotherapy Aichi Cancer Center, Chikusa-ku Nagoya, 464

Tetsuro Kubota, M.D.
Dept. of Surgery, School of Medicine Keio University, Shinjuku-ku Tokyo, 160

Shigeo Mori, M.D.
Professor, Dept. of Pathology The Inst. of Medical Science The University of Tokyo Minato-ku Tokyo 108

Toshifusa Nakajima, M.D.
Dept. of Surgery of Gastroenterology Cancer Inst. Hospital Toshima-ku, Tokyo 170

Dr. Makoto Ogawa
Department of Chemotherapy Cancer Institute Hospital Toshima-ku, Tokyo, 107