Phase I trial of FK973: Description of a delayed vascular leak syndrome

Abstract

FK973 is a novel, substituted dihydrobenzoxazine structurally similar to mitomycin. FK973 lacks cross-resistance with mitomycin, doxorubicin, and vincristine in murine tumor models. A phase I study of FK973 was initiated using a 30-minute infusion repeated every 4 weeks. Of 17 patients enrolled on the study, a minimum of three patients were entered at each dose level: 7, 14, 21, 30, and 45 mg/m2. The dose-limiting toxicity was a vascular leak syndrome (VLS) characterized by pericardial and pleural effusions, ascites, and subcutaneous edema. These conditions were observed in two patients treated with a dose of 30 mg/m2 and in four who received 45 mg/m2. VLS was observed 2 weeks after the third dose of 30 mg/m2 and one week after the second dose of 45 mg/m2. Of nine patients treated with a cumulative dose greater than 60 mg/m2, five experienced this toxic reaction. Reversible drug-related pneumonitis was noted in one patient after the third course of 30 mg/m2. Moderate nausea and vomiting were initially observed at a dose of 14 mg/m2 and alopecia at 30 mg/m2. Grade 3-4 granulocytopenia was observed in two patients treated with 45 mg/m2. Extensive myocardial degeneration was observed at autopsy in a patient who had received three courses of 30 mg/m2. One patient with metastatic colon carcinoma and another with metastatic pancreatic carcinoma experienced partial clinical responses. Although the drug's clinical activity appears promising, additional investigation is needed into the mechanism of toxicity prior to further clinical development.

FK317, a Novel Substituted Dihydrobenzoxazine, Exhibits Potent Antitumor Activity against Human Tumor Xenografts in Nude Mice

“…5,6) Various FK973 derivatives were synthesized in an attempt to isolate the antitumor activity of FK973 from the VLS side effect, and FK317, 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1, 11-diazatetracyclo-[7.4.1.0 2, 7 .0 10, 12 ]tetradeca-2,4,6-trien-9-yl acetate, was selected for further examination. FK317 showed similar antitumor activity to FK973, but did not induce pleural effusion in rats.…”

“…4) FK973 showed good efficacy in clinical studies, but its development was terminated because of a vascular leak syndrome (VLS) side effect which was characterized by pericardial and pleural effusion, ascites and subcutaneous edema. 5,6) Various FK973 derivatives were synthesized in an attempt to isolate the antitumor activity of FK973 from the VLS side effect, and FK317, 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1, 11-diazatetracyclo-[7.4.1.0 2,7 .0 10,12 ]tetradeca-2,4,6-trien-9-yl acetate, was selected for further examination. FK317 showed similar antitumor activity to FK973, but did not induce pleural effusion in rats.…”

Anti‐cachectic Effect of FK317, a Novel Anti‐cancer Agent, in Colon26 and LX‐1 Models in Mice

“…5,6) We sought a new compound having the same potent anti-tumor activity as FK973, but without the undesirable side effect, and selected FK317 (11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.0 2, 7 .0 10, 2 ]-tetradeca-2,4,6-trien-9-yl acetate) as a candidate from among various derivatives of FK973. FK317 is a deacetylated derivative of FK973.…”

“…[2][3][4] However, during phase I clinical trials of FK973, vascular leak syndrome was observed in patients following FK973 treatment and it was thus withdrawn from development; nevertheless it showed therapeutic anti-tumor activity in some of the cancer patients enrolled in the clinical trial. 5,6) We sought a new compound having the same potent anti-tumor activity as FK973, but without the undesirable side effect, and selected FK317 (11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.0 2,7 .0 10,2 ]-tetradeca-2,4,6-trien-9-yl acetate) as a candidate from among various derivatives of FK973. FK317 is a deacetylated derivative of FK973.…”

Cytotoxic Mechanisms of FK317, a New Class of Bioreductive Agent with Potent Antitumor Activity

“…However we were unable to develop this compound because it induces vascular leak syndrome (VLS) as a major side effect. 2,3) In attempts to synthesize new FK973 derivatives which retain the antitumor activity, without the VLS side effect, FK317, 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo[7.4.1.0 2,7 .0 10,12 ]tetradeca-2,4,6,-trien-9-yl acetate, was identified. This agent has a unique bicyclic hydroxylamine hemiketal ring system, and its antitumor activity is more potent than, or equivalent to, that of mitomycin C (MMC), adriamycin (ADR), cisplatin (CDDP), taxol or irinotecan hydrochloride against murine tumors and human xenografts in mice.…”