Summary
Ninety-eight patients with previously-treated advanced soft tissue sarcoma, bone sarcoma, or mesothelioma were randomly assigned to one of two intravenous single-agent treatment regimens, either 6-diazo-5-oxo-l-norleucine (DON; brief infusions of 50 mg/m2/day for 5 consecutive days every 4 weeks) or aclacinomycinA (ACM-A, as 30-min infusions of 100 mg/m2 or 85 mg/m2, administered every 3 weeks). Of 43 patients who were evaluable for response, survival and toxicity, there were two responses (5%) produced by ACM-A; one in a male with mesothelioma, and one in a female with malignant fibrous histiocytoma. None of the 36 evaluable patients treated with DON developed an objective tumor response. Median survival was 4.8 months in the DON treatment arm, and 6.8 months in the ACM-A treatment arm. No patients on the DON arm experienced lethal or life-threatening toxicities, and severe toxicities resulting from this treatment included nausea and emesis (10%), stomatitis (2%), gastrointestinal toxicity (2%), and anemia (2%). Moderate toxicities included vomiting (24%), hematologic toxicity (24%), neurologic toxicity (7%), diarrhea (7%), mucositis (5%), fever (5%), palpitations (2%), hepatotoxicity (2%), bleeding (2%) and edema (2%). Fifteen percent experienced at least one severe reaction, and 63% experienced at least one moderate or greater toxicity. ACM-A was associated with four cases of life-threatening myelosuppression (7%); severe toxicities included myelosuppression (11%), neurologic toxicity (4%), diarrhea (2%), respiratory toxicity (2%), pain and muscle spasms (2%), edema (2%), and ulceration following extravasation (2%). Moderate toxicities included diarrhea (9%), mucositis (7%), hepatotoxicity (7%), infection (5%), fever (7%), gastrointestinal toxicity (4%), respiratory (2%), dehydration (2%), cardiac (2%), alopecia (2%), ulceration following extravasation (7%), and edema (2%). Thirty-eight percent of patients on the ACM-A arm developed one or more severe or worse toxicity, and 76% had at least one moderate or worse toxicity. Neither regimen produces useful clinical results in patients with advanced sarcomas or mesotheliomas.
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Lawrence Jr W, Donegan WL, Natarajan N, Mettlin C, Beart R, Winchester D: Adult Soft Tissue Sarcomas. Ann Surg 205:349–359, 1987
Vezeridis MP, Moore R, Karakousis CP: Metastatic Patterns in Soft-Tissue Sarcomas. Arch Surg 118:915–918, 1983
Potter DA, Glenn J, Kinsella T, Glatstein E, Lack EE, Restrepo C, White DE, Seipp CA, Wesley R, Rosenberg SA: Patterns of Recurrence in Patients With High-Grade SoftTissue Sarcomas. J Clin Oncol 3:353–366, 1985
Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J: Adjuvant Chemotherapy for Osteosarcoma: A Randomized Prospective Trial. J Clin Oncol 5:21–26, 1987
Rosenberg SA, Tepper J, Glatstein E, Costa J, Young R, Baker A, Brennan MF, Demoss EV, Seipp C, Sindelar WF, Sugarbaker P, Wesley R: Prospective Randomized Evaluation of Adjuvant Chemotherapy in Adults with Soft Tissue Sarcomas of the Extremities. Cancer 52:424–434, 1983
Gherlinzoni F, Bacci G, Picci P, Capanna R, Calderoni R, Lorenzi EG, Bernini M, Emiliani E, Barbieri E, Normand A, Campanacci M: A Randomized Trial for the Treatment of High-Grade Soft-Tissue Sarcomas of the Extremities: Preliminary Observations. J Clin Oncol 4:552–558, 1986
Pinedo HM, Kenis Y: Chemotherapy of advanced softtissue sarcomas in adults. Cancer Treat Rev 4:67–86, 1977
Greenall MJ, Magill GB, DeCosse JJ, Brennan MF: Chemotherapy for Soft Tissue Sarcoma. Surg Gyn Obstet 162:193–198, 1986
Catane R, Von Hoff DD, Glaubiger DL, Muggia FM: Azaserine, DON, and Azotomycin: Three Diazo Analogs of 1-Glutamine with Clinical Antitumor Activity. Cancer Treat Rep 63:1033–1038, 1979
Pittillo RF, Woolley C, Brockman RW, Ho DH: Azotomycin (NSC-56654): biologic fate in mice and man. Cancer Chemother Rep 55:47–52, 1971
Weiss AJ, Ramirez, G, Grage T, Strawitz J, Goldman L, Downing V: Phase II Study of Azotomycin (NSC 56654). Cancer Chemother Rep 52:611–614, 1968
Chang P, Wiernik PH: Phase II Study of Azotomycin in Sarcomas. Cancer Treat Rep 61:1719–1720, 1977
Magill GB, Myers WPL, Reilly HC, Putnam RC, Magill JW, Sykes MP, Escher GC, Karnofsky DA, Burchenal JH:Pharmacological and Initial Therapeutic Observations on 6-diazo-5-oxo-l-norleucine (DON) in Human Neoplastic Disease. Cancer 10:1138–1150, 1957
Sklaroff RB, Casper ES, Magill GB, Young CW: Phase I Study of 6-diazo-5-oxo-l-norleucine (DON). Cancer Treat Rep 64:1247–1251, 1980
Earhart RH, Koeller JM, Davis HL: Phase I Trial of 6-Diazo-5-oxo-l-norleucine (DON) Administered by 5-Day Courses. Cancer Treat Rep 66:1215–1217, 1982
Crooke ST, Duvernay VH, Galvan L, Prestayko AW: Structure-Activity Relationship of Anthracycline Relative to Effects on Macromolecular Synthesis. Mol Pharmacol 14:290–298, 1978
Oki T, Matsuzawa Y, Yoshimoto A, Numata K, Kitamura I, Hori S, Takamatsu A, Umezawa H, Ishizuka M, Naganawa H, Suda H, Hamada M, Takeuchi T: New Antitumor Antibiotics, Aclacinomycin A and B. J Antibiot 28:830–834, 1975
Majima H: Preliminary Clinical Study of Aclacinomycin A. In: Carter SK, et al (eds), Recent Results in Cancer Research, Springer, New York, 1980, pp 75–81
Ogawa J, Inagaki J, Horikoshi N, Inoue K, Chinen T, Ueoka H, Nagura E: Clinical Study of Aclacinomycin A. Cancer Treat Rep 63:931–934, 1979
Zelen M: The randomization and stratification of patients to clinical trials. J Chronic Dis 27:365–375, 1974
Amato DA, Borden EC, Shiraki M, Enterline HT, Rosenbaum C, Davis HL, Paul AR, Stevens CM, Lerner HJ: Evaluation of bleomycin, chlorozotocin, MGBG, and bruceantin in patients with advanced soft tissue sarcoma, bone sarcoma, or mesothelioma. Invest New Drugs 3:397–401, 1985
Bertrand M, Multhauf P, Bartolucci A, Ellison D, Gockerman J: Phase II Study of Aclarubicin in Previously Untreated Patients with Advanced Soft Tissue Sarcomas: A South-western Cancer Study Group Trial. Cancer Treat Rep 69:725–726, 1985
Marsoni S, Hoth D, Simon R, Leyland-Jones B, De Rosa M, Wittes RE: Clinical drug development: An analysis of phase II trials, 1970–1985. Cancer Treat Rep 71:71–80, 1987
Thigpen JT, Vaughn C, Stuckey WJ: Phase II Trial of Anguidine in Patients With Sarcomas Unresponsive to Prior Chemotherapy: A Southwest Oncology Group Study. Cancer Treat Rep 65:881–882, 1981
Bramwell V, Van Oosterom A, Mouridsen HT, Cheix F, Somers R, Thomas D, Rozencweig M: N-(Phosphonacetyl)-1-aspartate (PALA) in Advanced Soft Tissue Sarcoma: a Phase II Trial of the EORTC Soft Tissue Sarcoma Group. Eur J Clin Oncol 18:81–84, 1982
Bramwell VHC, Mouridsen HT, Mulder JH, Somers R, Van Oosterom AT, Santoro A, Thomas D, Sylvester R, Markham D: Carminomycin vs Adriamycin in Advanced Soft Tissue Sarcomas: an EORTC Randomized Phase II Study. Eur J Cancer Clin Oncol 19:1097–1104, 1983
Somers R, Rouesse J, Van Oosterom A, Thomas D: Phase II Study of Elliptinium in Metastatic Soft Tissue Sarcoma. Eur J Cancer Clin Oncol 21:591–593, 1985
Pazdur R, Samson MK, Baker LH: Fludarabine Phosphate: Phase II Evaluation in Advanced Soft-Tissue Sarcomas. Am J Clin Oncol 10:341–343, 1987
Stuart-Harris RC, Harper PG, Parsons CA, Kaye SB, Mooney CA, Gowing NF, Wiltshaw E: High-dose alkylation therapy using ifosfamide infusion with mesna in the treatment of adult advanced soft-tissue sarcoma. Cancer Chemother Pharmacol 11:69–72, 1983
Bramwell VHC, Mouridsen HT, Santoro A, Blackledge G, Somers R, Verwey J, Dombernowsky P, Onsrud M, Thomas D, Sylverter R, Van Oosterom A: Cyclophosphamide versus Ifosfamide: Final Report of a Randomized Phase II Trial in Adult Soft Tissue Sarcomas. Eur J Cancer Clin Oncol 23:311–321, 1987
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Earhart, R.H., Amato, D.J., Yuang-Chi Chang, A. et al. Phase II trial of 6-diazo-5-oxo-L-norleucine versus aclacinomycin-A in advanced sarcomas and mesotheliomas. Invest New Drugs 8, 113–119 (1990). https://doi.org/10.1007/BF00216936
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DOI: https://doi.org/10.1007/BF00216936