A phase I study of combination therapy with immunotoxins IgG-HD37-deglycosylated ricin A chain (dgA) and IgG-RFB4-dgA (Combotox) in patients with refractory CD19(+), CD22(+) B cell lymphoma.
This study used an 8-day continuous infusion regimen of a 1:1 mixture of two immunotoxins (ITs) prepared from deglycosylated ricin A chain (dgA) conjugated to monoclonal antibodies directed against CD22 (RFB4-dgA) and CD19 (HD37-dgA; Combotox) in a Phase I trial involving 22 patients with refractory B cell lymphoma to determine the maximum tolerated dose, clinical pharmacology, and toxicity profile and to characterize any clinical responses. Adult patients received a continuous infusion of Combotox at 10, 20, or 30 mg/m2/192 h. No intrapatient dose escalation was permitted. Patients with > or =50 circulating tumor cells (CTCs)/mm3 in peripheral blood tolerated all doses without major toxicity. The maximum level of serum IT (Cmax) achieved in this group was 345 ng/ml of RFB4-dgA and 660 ng/ml of HD37-dgA (1005 ng/ml of Combotox). In contrast, patients without CTCs (<50/mm3) had unpredictable clinical courses that included two deaths probably related to the IT. Additionally, patients exhibited a significant potential for association between mortality and a history of either autologous bone marrow or peripheral blood stem cell transplants (P2 = 0.003) and between mortality and a history of radiation therapy (P2 = 0.036). In patients with CTCs, prior therapies appeared to have little impact on toxicity. Subsequent evaluation of the ITs revealed biochemical heterogeneity between two lots of HD37-dgA. In addition, HD37-dgA thawed at the study site tended to contain significant particulates, which were not apparent in matched controls stored at the originating site. This suggests that a tendency to aggregate may have resulted from shipping, storage, and handling of the IT that occurred prior to preparation for administration. It is not clear to what extent, if any, the aggregation of HD37-dgA IT was related to the encountered clinical toxicities; however, the potential to aggregate does suggest one possible basis for problems in our clinical experience with HD37-dgA and leads us to the conclusion that non-aggregate-forming formulations for these ITs should be pursued prior to future clinical trials.
Messmann
R A
RA
Developmental Therapeutics Program, Clinical Trials Unit, Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892-1906, USA. messmann@pop.nci.nih.gov
Vitetta
E S
ES
Headlee
D
D
Senderowicz
A M
AM
Figg
W D
WD
Schindler
J
J
Michiel
D F
DF
Creekmore
S
S
Steinberg
S M
SM
Kohler
D
D
Jaffe
E S
ES
Stetler-Stevenson
M
M
Chen
H
H
Ghetie
V
V
Sausville
E A
EA
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood / Q000187:drug effects; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D018941:Antigens, CD19 / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D019540:Area Under Curve; D002199:Capillary Permeability / Q000187:drug effects; D015815:Cell Adhesion Molecules; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D037102:Lectins; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000473:pathology; D012276:Ricin / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D051918:Sialic Acid Binding Ig-like Lectin 2; D016896:Treatment Outcome
D000906:Antibodies; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; C497867:CD22 protein, human; D015815:Cell Adhesion Molecules; D004338:Drug Combinations; D000922:Immunotoxins; D037102:Lectins; D051918:Sialic Acid Binding Ig-like Lectin 2; C577568:combotox; D012276:Ricin