Summary
Eleven patients with solid tumors for whom effective therapy was not available entered a phase I study of mitonafide given as a short intravenous (i.v.) infusion daily for 3 consecutive days. The initial dose level was selected according to the experience from another phase I study using a 5-day administration schedule. Six patients entered the first dose level (180 mg/m2/day × 3 days) and 4 of them had grade 3–4 leukopenia. This level was considered to be the maximum tolerated dose (MTD) and no further dose escalations were attempted. The following 5 patients received a dose approximately 10% inferior to the previous one (160 mg/ m2/day × 3 days). Three of them had grade 3–4 neutropenia. Three partial responses were observed in total.
After inclusion of 11 patients, an unexpected toxicity, central nervous system (CNS) toxicity, consisting of severe loss of memory, temporospatial disorientation and high integrative function impairment was observed in 5 patients (46%). A median patients' follow-up of 3 months after treatment discontinuation showed that these alterations were progressive and not reversible. This disabling toxicity prompted us to an early study interruption.
In conclusion, mitonafide, when administered as a short 3-day i.v. infusion, can induce severe and irreversible CNS toxicity. Nevertheless, since antitumor activity has been observed, further development of the drug is recommended with different schedules of administration that have shown not to produce neurotoxicity,i.e., 5-day continuous infusion.
Similar content being viewed by others
References
Braña MF, Castellano JM, Roldán CM: Synthesis and mode(s) of action of a new series of imide derivatives of 3-nitro-1,8-naphthalic acid. Cancer Chemother Pharmacol 4:61–66, 1980
Waring MJ, González A, Jiménez A, Vázquez D: Intercalative binding to DNA of antitumor drugs derived from 3-nitro-1,8-naphthalic acid. Nucleic Acid Res 7:217–230, 1979
Sinhna BK, Strong J: Mechanism of DNA strand breaks by mitonafide, an imide derivative of 3-nitro-1,8-naphthalic acid. Biochem Pharmacol 34:3845–3852, 1985
Hsiang Y, Jiang JB, Liu LF: Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs. Molecular Pharmacol 36:371–376, 1989
Fernández Braña M, Martínez Sanz A, Castellano JM, Martínez Roldán C, Roldán C: Synthesis and cytostatic activity of benz(de)isoquinolin-1,3-diones. Structure-activity relationships. Eur J Med Chem 16:207–212, 1981
Llombart M, Poveda A, Forner E, Fernández-Martos C, Gaspar C, Muñoz M, Olmos T, Ruiz A, Soriano V, Benavides A, Martín M, Schlick E, Guillem V: Phase I study of mitonafide in solid tumors. Invest New Drugs 10:177–181, 1992
Miller AB, Hoogstraten B, Staquet M: Reporting results of cancer treatment. Cancer 47:207–214, 1981
Castellanos AM, Fields WS: Grading of neurotoxicity in cancer patients. J Clin Oncol 4:1277–1278, 1986
Rosell R, Carles J, Abad A, Ribelles N, Barnadas A, Benavides A, Martín M: Phase I study of mitonafide in 120 h continuous infusion in non-small cell lung cancer. Invest New Drugs 10:171–175, 1992
Folstein MF, Folstein SE, McHugh PR: “Mini-Mental State”. A practical method for grading the cognitive state of patients for the clinician. J Psychiat Res 12:189–198, 1975
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Díaz-Rubio, E., Martín, M., López-Vega, J.M. et al. Phase I study of mitonafide with a 3-day administration schedule: Early interruption due to severe central nervous system toxicity. Invest New Drugs 12, 277–281 (1994). https://doi.org/10.1007/BF00873041
Issue Date:
DOI: https://doi.org/10.1007/BF00873041