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Developmental Therapeutics Program, Clinical Trials Unit, Medicine Branch [R. A. M., A. M. S., E. A. S.], Biostatistics and Data Management Section [S. M. S.], Pharmacy Department [D. K.], Medicine Branch [D. H., W. D. F., H. C.], Biologic Resources Branch [S. C.], and Laboratory of Pathology [E. S. J., M. S-S.], National Cancer Institute, Bethesda, Maryland 20892-1906; Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, Texas 75235 [E. S. V., J. S., V. G.]; and Science Applications International Corporation-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, NIH, Frederick, Maryland 21702-1201 [D. F. M.]
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 
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.
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