Phase I study of mitonafide in solid tumors

Abstract

Mitonafide was the first synthetized compound of a new series of 3-nitronaphthalimides with intercalative properties. A phase I study with a conventional escalation scheme was developed. The schedule of drug administration was a daily x 5 days by short (1 h) intravenous (i.v.) infusion, every 21 days. Thirty evaluable patients were treated at doses from 15.4 mg/m2/d x 5 days to 138.6 mg/m2/d x 5 days. The study was interrupted due to appearance of central nervous system toxicity in 5 patients treated at doses above 118 mg/m2 x 5 days. This toxicity consisted firstly of loss of memory in all patients. It was irreversible and progressed in 3 patients to disorientation and confusion, leading to dementia in one of them. This was considered to be dose-limiting toxicity, and since it appeared to be related to the administration schedule, no further studies with short i.v. infusions of mitonafide are recommended. A phase I study utilizing a more desirable administration schedule over longer periods of time is ongoing in other centers.

Antitumor efficacy and apoptotic activity of substituted chloroalkyl 1H-benz[de]isoquinoline-1,3-diones: a new class of potential antineoplastic agents

“…It has been shown earlier that substituted naphthalimides containing N-(2,2-dimethylaminoethyl) chain best represented by Mitonafide [5-nitro group in the aromatic ring] and Amonafide [5-amino group in the aromatic ring] possess significant anti-tumor activities. These have undergone Phase I-II clinical trials with limited results [1,2]. Other types of naphthalimides were also prepared and assessed [3][4][5][6].…”

Naphthalimides as Anticancer Agents: Synthesis and Biological Activity

“…Mitonafide was studied in Phase I and II trials, using a short administration schedule (1-h infusion every day x 3-5 d), and it showed activity against solid tumors [19]. However, this dosing schedule was associated with central neurotoxicity.…”

“…Phase I clinical trials are currently in progress in Europe and the USA. The absence of a nitro group in the chromophore of elinafide may be advantageous, since the nitro substitution on the monomeric compounds appears to be responsible for the central nervous system toxicity observed in mitonafide clinical trials [19].…”

Naphthalimides and Azonafides as Promising Anti-Cancer Agents

“…Chau et al [40] reported that amonafide (xanafide, 14) is neither a substrate nor inhibitor of Pgp. Zhu et al [41] examined the cytotoxicity of amonafide and its derivative R16 (80) in comparison with reference compounds (adriamycin, vincristine and VP16) in three MDRexpressing sublines: K562/A02, MCF-7/ADR and KB/VCR. For each of these cell lines, they calculated the RF as the [42] reported both non-resistant KB3-1 and resistant KB8-5 tumor xenografts in nude mice were highly and equally sensitive to i.v.…”

“…When administered according to a fast infusion schedule: 1h every day for 3 days at 160-180 mg/m 2 /day [79] or every day for 5 days at 15.4-138.6 mg/m 2 /day [80], mitonafide displayed activity against solid tumors but this was accompanied by leukopenia, neutropenia and central neurotoxicity (consisting of severe loss of memory, temporospatial disorientation and high integrative function impairment), while a slow infusion schedule (continuous infusion for 5 days at 107-200mg/m 2 x120h) was safe but devoid of significant activity [81].…”