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Phase I trial of FK973: description of a delayed vascular leak syndrome
R Pazdur1, D H Ho, K Daugherty
1Division of Medicine, University of Texas M.D. Anderson Cancer Center, Houston 77030.
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.
Insights
FK973, a novel chemotherapy agent, showed promising activity in early trials but was limited by vascular leak syndrome (VLS). Further research is needed to understand and manage FK973 toxicity before wider clinical use.
Area of Science:
- Pharmacology
- Oncology
- Clinical Trials
Background:
- FK973 is a novel dihydrobenzoxazine derivative with structural similarities to mitomycin.
- Preclinical studies indicated FK973 lacks cross-resistance with established chemotherapeutics like mitomycin, doxorubicin, and vincristine in murine tumor models.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary efficacy of FK973 in a Phase I clinical trial.
- To determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of FK973 when administered via 30-minute infusion every 4 weeks.
Main Methods:
- A Phase I dose-escalation study enrolled 17 patients with advanced malignancies.
- Patients received FK973 at escalating doses (7, 14, 21, 30, 45 mg/m2) administered as a 30-minute infusion every 4 weeks.
- Adverse events, clinical responses, and pharmacokinetic data were monitored throughout the study.
Main Results:
- Vascular leak syndrome (VLS), characterized by effusions and edema, was identified as the dose-limiting toxicity, occurring at doses of 30 and 45 mg/m2.
- Reversible pneumonitis, nausea, vomiting, and alopecia were also observed at specific dose levels.
- Two patients with metastatic colon and pancreatic carcinoma achieved partial clinical responses, suggesting potential anti-tumor activity.
Conclusions:
- FK973 exhibits promising preliminary clinical activity in patients with advanced cancers.
- Vascular leak syndrome is a significant toxicity that requires further investigation into its mechanism.
- Additional research is warranted to optimize FK973 dosing and management strategies to mitigate toxicity before further clinical development.
