Two Phase I Open-Label Studies of the Fully Human HLA-DR-Specific IgG 4 Monoclonal Antibody 1D09C3 in Patients with Relapsed and/or Refractory B-Cell Lymphoproliferative Neoplasias on a Weekly and Bi-Weekly Dosing Scheme.

Background: Lymphomas are increasing in frequency and represent the fifth most common cancer diagnosis in the United States. 1D09C3 is a fully human anti-HLA-DR monoclonal antibody (mAb) derived from a human combinatorial antibody library (HuCAL®) that has consistently demonstrated activity against various lymphoid tumors, both in vitro and in vivo (Nat Med2002;8:801–7). Therefore 1D09C3 may offer a novel therapy to patients with B-cell lymphoma who have failed therapy. Two phase I studies are ongoing to determine i) the maximum tolerated dose (MTD) and phase II recommended dose (RD), ii) the pharmacodynamic (pd)- and pharmacokinetic (pk)-profile and iii) the immunogenicity of 1D09C3 given within a bi-weekly and weekly schedule in this patient population. Material and methods: Patients with relapsed/refractory B-cell lymphoproliferative diseases are included in the two studies. 1D09C3 dose escalation is performed using modified Fibonacci increments with a minimum of 3 patients (pts) per dose level. It is administered once every week or every other week by a 2-hour intravenous (iv) infusion at escalating dose levels of 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 10 mg/kg/day for either 4 or 8 weeks. All toxicities are assessed according to the NCI CTC version 3.0. Blood samples are collected at different times in the study to determine pd- and pk- parameters and to assess immunogenicity of 1D09C3. Results: 19 pts have been enrolled into both protocols to date (13M/6F), median age 58 (range 30–76), pts with Hodgkin’s lymphoma (5), non-Hodgkin’s lymphoma (8) and chronic lymphocytic leukemia (6). The 4 th dose level (2.0mg/kg/day) has been completed within the bi-weekly dosing scheme and accrual is ongoing until the MTD and thus the phase II RD will be determined. The safety profile was positive, with only few and mild treatment-related side-effects such as fatigue noted, although one dose limiting toxicity (DLT) was seen at the bi-weekly dose level 0.5 mg/kg/day. Pk analysis of intravenous 1D09C3 indicated the drug to be cleared rapidly from blood circulation. 2 pts have been tested positive for human anti-1D09C3 antibodies (HAHA) at the 2 nd and 3 rd dose level, respectively; no allergic reactions were noticed. Clinical benefit was observed in 3 out of 14 evaluable pts who experienced partial response (PR), whereas 8 had no changes (NC) and 3 progressive disease (PD). After study completion an independent response evaluation team (RET) will review the information provided and determine individual treatment responses for the overall study. Conclusion: Two phase I dose escalation studies of the anti-HLA-DR mAb 1D09C3 are currently open in three sites for accrual of pts with relapsed/refractory B-cell lymphoproliferative diseases to determine the MTD and phase II RD for a weekly and bi-weekly schedule. Preliminary data suggest that 1D09C3 is well tolerated within this heavily pre-treated patient population. Pd- and pk-data, development of HAHA and clinical responses will continue to be evaluated.