Phase I study of the antineovascularization drug CM101.
CM101 is a bacterial polysaccharide that induces neovascular inflammation in malignant tumors. Fifteen patients with refractory malignancies received CM101 i.v. by a 15-min infusion every other day, three times in 1 week, at doses ranging from 1 unit (7.5 microgram)/kg to 5 units/kg. Serum was analyzed for anti-CM101 IgG and IgM weekly. Plasma levels of inflammatory cytokines, including tumor necrosis factor alpha, interleukin 8, interleukin 10, MIP-1alpha, and soluble E-selectin, were analyzed from -15 min to 12 h during each treatment. Dose-limiting toxicities, including grade IV dyspnea and arrhythmia, were encountered at the 5-unit/kg level. Toxicities occurred primarily within the first 12 h after therapy and included mild-to-moderate fever and chills, nausea, cough, headache, facial flushing, dyspnea, myalgias, and acute tumor-related pain. No patient developed detectable antibodies to CM101. All patients experienced marked time- and dose-dependent elevations in all cytokines studied. Three patients experienced tumor shrinkage. The results show that CM101 can be safely administered at doses that produce evidence for severe, and possibly tumor-specific, inflammation. Further study is necessary to better characterize the mechanism of action and determine the optimal dose and schedule of this new agent.
DeVore
R F
RF
Departments of Medicine, Biochemistry, Pediatrics, and Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.
Hellerqvist
C G
CG
Wakefield
G B
GB
Wamil
B D
BD
Thurman
G B
GB
Minton
P A
PA
Sundell
H W
HW
Yan
H P
HP
Carter
C E
CE
Wang
Y F
YF
York
G E
GE
Zhang
M H
MH
Johnson
D H
DH
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000009:adverse effects*; D012882:Skin Tests
D000970:Antineoplastic Agents; D016207:Cytokines; D011135:Polysaccharides, Bacterial; C032263:streptococcal polysaccharide type III group B