A PHASE-I STUDY OF BOLUS VERSUS CONTINUOUS-INFUSION OF THE ANTI-CD19 IMMUNOTOXIN, IGG-HD37-DGA, IN PATIENTS WITH B-CELL LYMPHOMA

IgG-HD37-SMPT-dgA is a deglycosylated ricin A chain (dgA)containing im munotoxin (IT) prepared by conjugating the monoclonal murine (MoAb) an ti-CD19 antibody, HD37, to dgA using the heterobifunctional hindered d isulfide linker, l-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio) to luene (SMPT). In this report, we have used two regimens for the admini stration of IgG-HD37-SMPT-dgA to patients with non-Hodgkin's lymphoma (NHL) in two concomitant phase I trials. One trial examined four inter mittent bolus infusions administered at 48-hour intervals. The other s tudied a continuous infusion (CI) administered over the same 8-day per iod. In the intermittent bofus regimen, the maximum tolerated dose (MT D) was 16 mg/m(2)/8 d and the dose limiting toxicity (DLT) consisted o f vascular leak syndrome (VLS), aphasia, and evidence of rhabdomyolysi s encountered at 24 mg/m(2)/8 d. Using the Cl regimen, the MTD was def ined by VLS at 19.2 mg/m(2)/8 d. At the MTD of both regimens, a novel toxicity, consisting of acrocyanosis with reversible superficial dista l digital skin necrosis in the absence of overt evidence of systemic v asculitis, occurred in 3 patients. Of 23 evaluable patients on the bol us schedule, there was 1 persisting complete response (OR; >40 months) and 1 partial response (PR). Of 9 evaluable patients on the continuou s infusion regimen, there was 1 PR. Pharmacokinetic parameters for the bolus regimen at the MTD showed a mean maximum serum concentration (C -max) of 1,209 +/- 430 ng/mL, with a median T(1/2)beta for all courses of 18.2 hours (range, 10.0 to 80.0 hours), a volume of distribution ( Vd) of 10.9 L (range, 3.1 to 34.5 L), and a clearance (CL) of 0.45 L/h (range, 0.13 to 2.3 L/h). For the Ci regimen at MTD, the mean C-max w as 953 +/- 473 ng/mL, with a median T(1/2)beta for all courses of 22.8 hours (range, 24.1 to 30.6 hours), a Vd of 9.4 L (range, 4.4 to 19.5 L), and a CL of 0.32 L/h (range, 0.12 to 0.55 L/h). Twenty-five percen t of the patients on the bolus infusion regimen and 30% on the CI regi men made antibody against mouse Ig (HAMA) and/or ricin A chain antibod y (HARA). We conclude that this IT can be administered safely and that both regimens achieve comparable peak serum concentrations at the MTD ; these concentrations are similar to those achieved previously using other regimens with IgG-dgA ITs at their respective MTDs. Thus, toxici ty is related to tile serum level of the IT and does not differ with d ifferent targeting MoAbs. (C) 1996 by The American Society of Hematolo gy.