title: Phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with advanced myeloid malignancies.
abstract: We conducted a phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with relapsed, refractory myeloid leukemias. Twenty-eight patients received the construct intravenously at four dose levels (12, 18, 28 and 40 mg/m(2) per course) in a "3+3" study design. The dose-limiting toxicity was infusion-related allergic reaction including hypoxia and hypotension. The 28 mg/m(2) total dose was considered the maximally tolerated dose. Four patients developed a reduction in peripheral blood blasts of at least 50%. Three patients treated with the 10, 12 and 28 mg/m(2) doses showed a 38-50% reduction in bone marrow blasts. There was normalization of platelets in one patient treated with 40 mg/m(2). Pharmacokinetic analysis demonstrated that the highest blood levels achieved were 200-300 ng/mL which cleared with a half-life of ∼20 hours. Antigenicity was low with one patient at the 12 mg/m(2) dose and one patient at the 18 mg/m(2) dose (2/23, <10%) developing antibodies to the recombinant gelonin component after 28 days. We concluded that HUM-195/rGel can be safely administered in a multi-dose cycle to patients with advanced myeloid malignancies and warrants further investigation.
authors.affiliation: Departments of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenblum
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Naval
authors.initials: N
authors.lastname: Daver
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Emil J
authors.initials: EJ
authors.lastname: Freireich
authors.forename: Tapan
authors.initials: T
authors.lastname: Kadia
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D054789:Ribosome Inactivating Proteins, Type 1 / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; C101579:monoclonal antibody M195; C025674:GEL protein, Gelonium multiflorum