A PHASE-I STUDY OF SWAINSONINE IN PATIENTS WITH ADVANCED MALIGNANCIES

Swainsonine, an alpha-mannosidase inhibitor which blocks Golgi oligosa ccharide processing, represents a new class of compounds that inhibit both rate of tumor growth, and metastasis, in murine experimental tumo r models. In this first phase I study, the quantitative and qualitativ e toxicities of swainsonine have been studied in patients given a cont inuous i.v. infusion over 5 days, repeated at 28-day intervals. Dose l evels were escalated in increments of 100 mu g/kg/day from 50-550 mu g /kg/day. Nineteen patients with both solid tumor and hematological mal ignancies were given a total of 31 courses. Hepatotoxicity, particular ly in patients with liver metastases, was the dose-limiting toxicity. The maximum tolerated dose (MTD) and the recommended starting dose (MT D -1 level) were 550 and 450 mu g/kg/day, respectively. Common side ef fects included edema, mild liver dysfunction, a rise in serum amylase, and decreased serum retinol. Acute respiratory distress syndrome poss ibly precipitated by swainsonine resulted in a treatment-related death in a patient with significant pretreatment hepatic dysfunction. One p atient with head and neck cancer showed >50% shrinkage of tumor mass f or 6 weeks after treatment. Two patients with lymphangitis carcinomato sis on chest X-ray noted improvement in cough and shortness of breath during the infusion of swainsonine and for 1 week thereafter. Clearanc e and serum half-life for swainsonine were determined to be approximat ely 2 ml/h/kg, and 0.5 day, respectively. Golgi oligosaccharide proces sing, a putative anticancer target for swainsonine was inhibited in pe ripheral blood lymphocytes as evidenced by a marked decrease in leukoa gglutinin binding after 5 days of treatment. Oligomannosides in patien t urine increased 5-to 10-fold over the 5 days of treatment, indicatin g that tissue lysosomal alpha-mannosidases were also blocked by swains onine. Urine oligomannoside accumulation reached steady state at 3 day s, approximately 1 day after serum drug levels reached steady state. T he fraction of HLA-DR-positive cells in peripheral blood lymphocytes i ncreased following 5 days of swainsonine treatment, an effect similar to that observed for peripheral blood lymphocytes from normal subjects cultured with swainsonine. No significant changes in CD3, CD4, CD8, C D16, and CD25 were observed. Swainsonine produces minimal toxicity whe n administered i.v. to cancer patients at dosages that inhibit both Go lgi a-mannosidase II and lysosomal alpha-mannosidases. Detection of he patic metastases or liver enzyme abnormalities prior to treatment pred ict for more significant toxicity.