Abstract
The topoisomerase I inhibitor topotecan has shown activity in acute myeloid leukemia (AML) and myelodysplastic syndromes. The present study was designed to assess whether topotecan with cytosine arabinoside (ara-C) or with etoposide (VP-16) should be studied in phase II trials in patients with refractory or relapsed AML.
Patients with refractory or relapsed AML were assigned to one of 3 strata defined by expected CR rates of 7%, 20% and 40%, then randomly assigned to receive topotecan (d1-5) and ara-C (1 g/m2 over 2 hours; d1-5), topotecan (d1-5) followed by VP-16 (250 mg/m2 twice daily, d6-7), or VP-16 (250 mg/m2 twice daily d1-2) followed by topotecan (d3–d7). A dose-finding phase was conducted in the poorest stratum of each arm (topotecan starting dose: 1.0 mg/m2/day × 5). A Bayesian pre-phase II selection design was used to assess whether the CR rate with a given arm was sufficient to merit investigation in phase II.
Thirty-seven patients, median age 58 years, were treated. Their median first CR duration was 28 weeks and 24% were primary refractory. Grade 3–4 mucositis occurred in the initial patients in the topotecan → VP-16, but not in the topotecan + ara-C or VP-16 → topotecan arms. Consequently, in subsequent patients, the topotecan dose was lower in the topotecan → VP-16 than in the other 2 arms (1.0 vs 1.25 mg/m2 daily × 5) and the VP-16 dose was lower in the topotecan → VP-16 arm (200 vs 250 mg/m2 twice daily × 2). One CR occurred (topotecan → VP-16 arm), and the treatment arms were terminated after 10, 15, and 12 patients were treated on the topotecan + ara-C, topotecan → VP-16, and VP-16 → topotecan arms, respectively. The principal cause of failure was insufficient anti-leukemia effect rather than death on study, and toxicity was minimal at the final doses used.
We concluded that none of the combinations studied here warrants phase II evaluation in very poor prognosis AML salvage patients.
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References
Hertzberg RP, Casanta MJ, Hecht SM: On the mechanism of topoisomerase I inhibition by camptothecin: Evidence for binding to an enzyme-DNA complex. Biochem 28: 4629–4638, 1989
Pommier Y, Kohlhagen G, Kohn K et al.: Interaction of an alkylating camptothecin derivative with a DNA base at topoisomerase I-DNA cleavage sites. Proc Natl Acad Sci 92: 8861–8865, 1995
Hsiang Y-H, Lihou MG, Liu LF: Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49: 5077–5082, 1989
Holm C, Covey JM, Kerrigan D, Pommier Y: Differential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells. Cancer Res 49: 6365–6368, 1989
Rowinsky EK, Adjei A, Donehower RC et al.: Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia. J Clin Oncol 12(10): 2193–2203, 1994
Kantarjian HM, Beran M, Ellis A et al.: Phase I study of topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia. Blood 81: 1146–1151, 1993
Beran M, Kantarjian H, O'Brien S et al.: Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelogenous leukemia. Blood 88(7): 2473–2479, 1996
Kaufman SH: Antagonism between camptothecin and topoisomerase II-directed chemotherapy agents in a human leukemia cell line. Cancer Res 51: 1129–1136, 1991
Chou TC, Notzer RJ, Tong Y: Computerized quantitation of synergism and antagonism of taxol, topotecan and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst 6: 269, 1994
Kano Y, Suzuki K, Akutsu M et al.: Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 50: 604–610, 1992
Bertrand P, O'Conner PM, Kerrigan D et al.: Sequential administration of camptothecin and etoposide circumvents the antagonistic cytotoxicity of simultaneous drug administration in slowly growing human colon carcinoma HT-29 cells. Eur J Cancer 28A(4-5): 743–748, 1992
Whitacre CM, Zborowska E, Gordon NH et al.: Topotecan increases topoisomerase II levels and sensitivity to treatment with etoposide in schedule-dependent process. Cancer Res 57: 1425–1428, 1997
Kim R, Hirabayashi N, Nishiyama M, Jinushi K, Toge T, Okada K: Experimental studies on biochemical modulation targeting topoisomerase I and II in human tumor xenografts in nude mice. Int J Cancer 50: 760–766, 1992
Thall PF, Estey EH: A Bayesian strategy for screening cancer treatments prior to phase II clinical evaluation. Stat Med 12: 1197–1211, 1993
Estey E: Treatment of refractory AML. Leukemia 10: 932–936, 1996
National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988
Beran M, Kantarjian HM, Estey EH: Topotecan and high-dose cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia. Blood 92(10): 2934, 1998
Estey E, Kantarjian H, Giles F, Beran M: Treatment of newlydiagnosed AML and MDS with cyclophosphamide, ara-C, topotecan. Blood 92(10): 951, 1998
Beran M, Pisa P, Kantarjian H et al.: Growth of sensitive and drug-resistant human myeloid leukemia cells in SCID mice. Hematol Pathol 8: 135, 1994
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Vey, N., Kantarjian, H., Beran, M. et al. Combination of topotecan with cytarabine or etoposide in patients with refractory or relapsed acute myeloid leukemia: Results of a randomized phase I/II study. Invest New Drugs 17, 89–95 (1999). https://doi.org/10.1023/A:1006271618635
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DOI: https://doi.org/10.1023/A:1006271618635