title: A Phase I study with an anti-CD30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD30+ Hodgkin's and non-Hodgkin's lymphoma.
abstract: Ki-4.dgA is an anti-CD30 immunotoxin (IT) constructed by coupling the monoclonal antibody Ki-4 via a sterically hindered disulfide linker to deglycosylated ricin A-chain. This IT was efficacious in vitro and in SCID mice with disseminated human Hodgkin's lymphoma. Accordingly, a Phase I trial in patients (pts) with Hodgkin's lymphoma was designed. The objectives of this Phase I trial were to determine the maximum tolerated dose, the dose-limiting toxicities, pharmacokinetics, and antitumor activity. Seventeen pts with relapsed CD30+ lymphoma were treated with escalating doses (5, 7.5, or 10 mg/m(2)/cycle) of the IT as four bolus infusions on days 1, 3, 5, and 7 for one to three cycles. All of the pts had progressive disease and were heavily pretreated. Nine had primary progressive disease and 14 had advanced disease with massive tumor burdens. The mean age was 35 years (24-52 years). Peak serum concentrations of the intact IT varied from 0.23 to 1.1 microg/ml. Side effects and dose-limiting toxicities were related to vascular leak syndrome, i.e., decreases in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. The maximum tolerated dose was 5 mg/m(2). Seven of 17 (40%) pts made human antiricin antibodies (> or =1.0 microg/ml), and 1 pt developed human antimouse antibodies (> or =1.0 microg/ml). Clinical response in the 15 evaluable pts included 1 partial remission, 1 minor response, and 2 stable diseases. In conclusion, the IT was less well tolerated than other ITs of this type. This might be because of the low number of CD30+ peripheral blood mononuclear cells, and in part because of binding of the IT to soluble CD30 antigen and the resulting circulation of IT/sCD30 complexes.
authors.affiliation: Department of Internal Medicine I, University of Koeln, Joseph-Stelzmann-Strasse 9, D-50924 Koeln, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schnell
authors.forename: Oliver
authors.initials: O
authors.lastname: Staak
authors.forename: Peter
authors.initials: P
authors.lastname: Borchmann
authors.forename: Christine
authors.initials: C
authors.lastname: Schwartz
authors.forename: Bärbel
authors.initials: B
authors.lastname: Matthey
authors.forename: Hinrich
authors.initials: H
authors.lastname: Hansen
authors.forename: John
authors.initials: J
authors.lastname: Schindler
authors.forename: Victor
authors.initials: V
authors.lastname: Ghetie
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Vitetta
authors.forename: Volker
authors.initials: V
authors.lastname: Diehl
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
mesh_terms: D000328:Adult; D016026:Bone Marrow Transplantation; D005260:Female; D005434:Flow Cytometry; D006689:Hodgkin Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017730:Ki-1 Antigen / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000473:pathology / Q000628:therapy; D009367:Neoplasm Staging; D012276:Ricin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000922:Immunotoxins; D017730:Ki-1 Antigen; D012276:Ricin