The goal of the solid Tumor Autologous Marrow Program (STAMP) is the application of curative intent treatment to hitherto incurable diseases (e.g., metastatic breast cancer, small cell lung cancer. Poor prognosis testis cancer, ovarian carcinoma, & sarcoma. lt is predicated in parr on principles underlying curative treatment for hematologic malignancies (recognition of the importance of dose, using non-cross-resistant agents in combination, and treatment of patients with reduced tumor burdens.) Alkylating agents in the autologous bone marrow transplant setting provide an ideal approach. Alkylating agents have substantial activity against solid tumors. Because of differing non-myelosuppressive dose- limiting toxicity, combinations at doses approaching those possible with single agents are feasible. Finally, experimentally in vivo & against human tumor cells in vitro alkylating-agent induced resistance is low level; cross-resistance is the exception, and synergism can be demonstrated experimentally. We have constructed phase I/II clinical trials of high-dose combination alkylating agent therapy against alkylating agent sensitive tumors based on experimental data obtained here & elsewhere. Our initial studies (STAMP I) demonstrated substantial antitumor activity (& toxicity) against refractory solid tumors. Second generation studies have modified the disease-oriented regimens in the direction of lesser toxicity and greater therapeutic effects. Our phase I studies initially include single alkylating agent studies & then combinations. Phase II studies define more precisely the therapeutic effects. Major attention is given to avoiding toxicity; e.g. hematopoietins to potentially improve hematopoietic reconstitution and bone marrow harvest. In vitro immunologic and related studies will define the presence of & importance of tumor cell contamination of marrow and the potential for marrow purging. Since we are working at the outer limits of safety, pharmacokinetics data are key. Clinical, laboratory, & experimental factors which affect pharmacokinetics will be assessed quantitatively. Prospective studies may allow some individualization of dosing. Parallel, preclinical studies include the biology and biochemistry of alkylating agent resistance, cross- resistance, & synergism, using human in vitro, as well as high dose in vivo experimental models. Modulation of alkylating agent effectiveness may be possible using topoisomerase inhibitors, fluosol, and glutathione ethyl ester. Finally, major interaction with biostatisticians will assure optimal & critical experimental design, data management, & interpretation of clinical trials and pharmacokinetics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA038493-04
Application #
3093656
Study Section
(SRC)
Project Start
1985-07-01
Project End
1991-07-31
Budget Start
1988-09-30
Budget End
1989-07-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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Teicher, B A; Ikebe, M; Ara, G et al. (1997) Transforming growth factor-beta 1 overexpression produces drug resistance in vivo: reversal by decorin. In Vivo 11:463-72
Gong, J; Chen, L; Chen, D et al. (1997) Induction of antigen-specific antitumor immunity with adenovirus-transduced dendritic cells. Gene Ther 4:1023-8
Wheeler, C; Eickhoff, C; Elias, A et al. (1997) High-dose cyclophosphamide, carmustine, and etoposide with autologous transplantation in Hodgkin's disease: a prognostic model for treatment outcomes. Biol Blood Marrow Transplant 3:98-106
Holden, S A; Emi, Y; Kakeji, Y et al. (1997) Host distribution and response to antitumor alkylating agents of EMT-6 tumor cells from subcutaneous tumor implants. Cancer Chemother Pharmacol 40:87-93

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