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: Gautam Borthakur, Michael G Rosenblum, Moshe Talpaz, Naval Daver, Farhad Ravandi, Stefan Faderl, Emil J Freireich, Tapan Kadia, Guillermo Garcia-Manero, Hagop Kantarjian, Jorge E Cortes
• Journal: Haematologica (Haematologica) Vol. 98 Issue 2 Pg. 217-21 (Feb 2013) ISSN: 1592-8721 [Electronic] Italy
• PMID: 22875630 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Immunoglobulin G
• Immunotoxins
• Ribosome Inactivating Proteins, Type 1
• monoclonal antibody M195
• GEL protein, Gelonium multiflorum

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (immunology, pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Female
• Humans
• Immunoglobulin G (blood, immunology)
• Immunotoxins (immunology, pharmacology, therapeutic use)
• Leukemia, Myeloid (drug therapy, immunology, pathology)
• Male
• Middle Aged
• Ribosome Inactivating Proteins, Type 1 (immunology, pharmacology, therapeutic use)
• Treatment Outcome