Investigational Drug Development for Solid Tumors

Introduction
The Investigational Drug Development for Solid Tumors is one of the representative activities of the Oncology/Hematology Division, which manages various kinds of malignancies. Cancers of the breast, head and neck, lung, malignant lymphoma, and primary unknown malignancies are major and specific targets. Most of these malignancies are treated by standard chemotherapy and/or by clinical trial setting.
Our clinical and research activities are mainly focused on the following six fields:
1. Developmental therapeutics of newly synthesized anticancer agent through phase I trails that are conducted by pharmaceutical industries in and outside Japan
2. Disease oriented clinical trials especially for breast cancer, head & neck cancers, malignant lymphomas and hematological malignancies
3. High dose chemotherapy with peripheral blood stem cell support in experimental or standard treatment
4. Standard chemotherapy treatment as clinical practice
5. Palliative care research for terminal stage patients
6. Clinical pharmacology studies for adequate dose modification.

Routine Activities　
We managed many kinds of malignant disease in the past year including breast cancer, non-Hodgkinis lymphoma, Hodgkin disease, acute leukemia, lung cancer, colorectal cancer, pharyngeal and laryngeal cancers, pancreatic cancers, soft tissue sarcomas, uterine cancer, ovarian cancer as well as primary unknown adenocarcinoma. For the diseases with established standard chemotherapy and without phase III clinical trial project, routine chemotherapy was administered as clinical practice. Experimental therapeutics was conducted for patients without standard treatment or who failed standard chemotherapy.

Research Activities
1) Phase I of Flavopyridol
Flavopyridol is one of the promising molecular targeting agents, which inhibits cycline dependent kinases to modulate cell cycle. We started phase I of this compound by 24 hours continuous infusion repeating every week for 4 consecutive weeks. This administration schedule is the first one that is tested in clinical setting. We could observe stabilization of tumor markers in several patients, and tumor regression was not identified. In addition, substantial decrease in glucose uptake by PET scan was also identified without evidence of tumor regression in CAT scan.
2) Phase I of ZD6474
ZD6474 is a novel orally active small molecule inhibitor of vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase that blocks signal transduction pathway that are critical for endothelial cell proliferation and survival of cancer cells. Phase I of ZD6474 is now successfully on-going with clinical evidence of biological activity.
3) Phase I of weekly Docetaxel/Irinotecan combi-nation chemotherapy
This project is in-house combination phase I trial that determine recommended combination doses repeating 3 consecutive weeks. In addition, drug-drug interaction and clinical significance of cortisone as prove drug to predict docetaxel clearance will be analyzed.

New Developments
The followings are clinical trials, which we have investigated in 2001.

Phase I Trials
	Flavopiridol
	ZD6474
	A643
	SHT586
	Docetaxel/Irinotecan
Phase II Trial
	Furturon for 3rd line breast cancer
Phase III Trials
	JCOG (Japan Clinical Oncology Group) breast cancer trials
	JALSG (Japan Acute Leukemia
	Study Group) for leukemia
	JCOG (Japan Clinical Oncology Group) lymphoma study

Y. SASAKI

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