Phase IB clinical trial of the oligosaccharide processing inhibitor swainsonine in patients with advanced malignancies.
The indolizidine alkaloid swainsonine, a potent inhibitor of Golgi alpha-mannosidase II, has been shown to reduce tumor cell metastasis, enhance cellular immune responses, and reduce solid tumor growth in mice. In our previous Phase I study, swainsonine administered by 5-day continuous infusion inhibited L-phytohemagglutinin-reactive N-linked oligosaccharide expression on peripheral blood lymphocytes. Significant toxicities included edema and elevated serum aspartate aminotransferase (AST). One patient with head and neck cancer had objective (>50%) tumor remission. Two patients showed symptomatic improvement. The objectives of this Phase IB trial were to examine the pharmacokinetics, toxicities, and biochemical effects of bi-weekly oral swainsonine at escalating dose levels (50-600 microgram/kg) in 16 patients with advanced malignancies and 2 HIV-positive patients unsuitable for conventional therapy. Eastern Cooperative Oncology Group performance status was </=2. The maximum tolerated dose was defined as 300 microgram/kg/day due primarily to serum AST abnormalities and dyspnea. Other adverse events present in >20% of patients included increase in serum AST (all patients), fatigue (n = 9), anorexia (n = 6), dyspnea (n = 6), and abdominal pain (n = 4). Inhibition of Golgi alpha-mannosidase II occurred in a dose-dependent manner. Examination of immunological parameters revealed a transient decrease in CD25(+) peripheral blood lymphocytes and, in seven of eight patients, an increase in CD4(+):CD8(+) ratios at 2 weeks. Serum drug levels peaked 3-4 h following a single oral dose in most patients and were proportional to dose at levels >/=150 microgram/kg. We conclude that oral swainsonine is tolerated by chronic intermittent administration at doses up to 150 microgram/kg/day. Adverse events considered drug related were similar to those observed in the infusional study but with fatigue and neurological effects also noted. Investigations of alternative dosing schedules with low starting doses are suggested for further clinical testing.
Goss
P E
PE
The Toronto Hospital, Department of Medical Oncology, MLW2-022, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4 Canada.
Reid
C L
CL
Bailey
D
D
Dennis
J W
JW
D000328:Adult; D000368:Aged; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D001219:Aspartate Aminotransferases / Q000097:blood; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D008297:Male; D008361:Mannosidases / Q000037:antagonists & inhibitors; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D017026:Swainsonine / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D043323:alpha-Mannosidase
D000972:Antineoplastic Agents, Phytogenic; D009844:Oligosaccharides; D001219:Aspartate Aminotransferases; D008361:Mannosidases; D043323:alpha-Mannosidase; D017026:Swainsonine