Investigational Drug Development for Solid Tumors

Introduction
Investigational drug development for solid tumors is a representative research activity in the Division of Oncology/Hematology. In daily medical practice, patients with various cancers, including cancer of the breast, head and neck and malignant lymphoma, are treated with chemotherapy. These cancers are major and specific targets of the Division, and most patients with these malignancies have been treated by standard chemotherapy and/or in clinical trials. Primary unknown malignancy is another major target. Other various solid tumors, including gastrointestinal cancer, lung cancer, and soft tissue sarcoma, have been treated mainly in early clinical trials of anticancer agents.
Our clinical and research activities are mainly focused on the following six fields:
1. Developmental therapeutics using new anticancer agents in phase I trials that are conducted by pharmaceutical companies.
2. Clinical pharmacology studies for adequate dose modification.
3. Development of combination chemotherapy involving a newly developed drug or new combination chemotherapy using already availably drugs.
4. Disease-oriented clinical trials especially for breast, head and neck cancer, malignant lymphoma and hematological malignancies.
5. High dose chemotherapy with peripheral blood stem cell support in experimental or standard treatment.
6. Standard treatment with chemotherapy as medical practice.
7. Palliative care research for terminal stage patients.

Practice Activities 
A variety of malignant diseases were treated in the past year. The major and specific target diseases of the Division were breast cancer, head and neck cancer, and malignant lymphoma, and in 2002, 91, 82 and 82 patients, respectively, were admitted to the hospital for treatment. These patients accounted for three fourths of all patients admitted in 2002. Eligible patients were asked to enroll in large phase II or III studies. Primary unknown cancers and leukemia were other major targets of the Division. Gastrointestinal cance,r including esophageal and colorectal cancer, lung cancer, pancreatic cancer, soft tissue sarcoma, and gynecological cancer, including uterine and ovarian cancer were also treated in the Division. For patients with diseases for which established standard chemotherapy is available but no phase II or III clinical trial projects are ongoing, standard chemotherapy was administered as routine medical practice. Patients who did not respond to standard chemotherapy or patients with cancer for which standard chemotherapy was not available were treated with an experimental therapy that is a part of our research activities.

Research Activities / Investigational Drug Development
1) Phase I study of a novel drug
Flavopiridol is a molecular targeting agent that inhibits cycline-dependent kinases and modulates the cell cycle. We completed a phase I study of Flavopiridol infused over 24 hours every week and started a new phase I study of the drug using a different infusion schedule, a weekly 1-hour infusion.
Other new agents with molecular targets that we evaluated in phase I studies included ZD6474 (an inhibitor of VEGF receptor-2 tyrosine kinase), BAY-43-9006 (an inhibitor of raf kinase), and GW572016 (a new quinazolin derivative with an inhibitory activity on EGFR and ErbB2). Although the number of phase I studies of molecular targeting drugs is increasing, a phase I study of a cytotoxic drug such as CHC12103 was also begun.
In contrast to these phase I studies that are at a very early stage of clinical development and that enroll patients with various cancers, phase I studies with a specific disease target are also underway. A recommended dose of fludarabine was determined in a phase I study in patients with low grade lymphoma, and a phase II study will be activated in the immediate future. ⁹⁰Y-ibritumomab tiuxetan is under phase I evaluation with the same target. For breast cancer, a phase I study of combination chemotherapy with capecitabine and docetaxel is now underway.
2) Phase I study of new combination chemotherapy
A phase I study of combination chemotherapy with weekly docetaxel and irinotecan is performed as an in-house study to determine recommended combination doses and an optimal administration sequence of the drugs. In addition, the pharmaco- kinetic drug-drug interaction and predictability of docetaxel clearance by hydrocortisone will be evaluated in this study.
3) Phase II/III study
Against breast cancer we are conducting two phase II studies using S-1 and furtulon. The study of furtulon is an investigator-driven study and pharmacokinetic evaluation has been implemented to elucidate the difference in pharmacokinetics between furtulon and a related drug, capecitabine. In a randomized study we are evaluating the clinical relevance of the inhibitory activity of MS-209 on p-glycoprotein in patients with breast cancer treated with CAF chemotherapy. In this study, the influence of MS-209 on pharmacokinetics of doxorubicin, which is a concern as a p-glycoprotein inhibitor, is also being evaluated. We participated in a large international phase II/III study comparing exemestane and tamoxifen in patients with breast cancer. Other large phase III studies we are participating in are JCOG studies for patients with breast cancer and malignant lymphoma and JALSG studies for patients with leukemia.
4) Pharmacological studies
The investigational drugs that we are developing include not only anticancer agents but also supportive agents. We are conducting a pharmacological study of S-8116 (oxycodone) and a phase II study of epoetin beta (recombinant erythropoietin).
To develop better strategies for administration of anticancer agents, we are conducting population pharmacokinetic studies of anticancer agents that are commercially available in medical practice. Doxorubicin and docetaxel are currently evaluated in population pharmacokinetic studies. Another approach to improve cancer chemotherapy is a pharmacogenomics study. We pursue such an approach in cyclophosphamide as an in-house study as well as in irinotecan, taxanes and S-1 as millennium projects.

H. MINAMI

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