Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non–Hodgkin's Lymphoma

Abstract

Purpose: B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeostasis and immunoglobulin production and are overexpressed in B-cell malignancies. Atacicept (TACI-Ig), a recombinant fusion protein that inhibits both B-lymphocyte stimulator and a proliferation-inducing ligand, may be a novel treatment for B-cell malignancies. Experimental Design: A phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was done. Atacicept was given s.c. weekly for 5 weeks to sequential patient cohorts at doses of 2, 4, 7, or 10 mg/kg. Patients responding or with stable disease were eligible for treatment on an extension study for up to 24 weeks or until disease progression. Results: All patients were heavily pretreated (median number of previous treatments, 5; range, 1-10), and four patients had previously received a stem cell transplant. Four patients were treated at the 2, 4, or 7 mg/kg dose levels, and three patients received 10 mg/kg of atacicept. Atacicept was well tolerated at all doses. Three adverse events with grade 3 severity were reported for one patient, including jaw pain, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Pharmacokinetic results were nonlinear, and treatment with atacicept resulted in dose-dependent decreases in immunoglobulin concentrations. Two patients had stable disease at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns. Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and showed biological activity by decreasing immunoglobulin concentrations, although tumor responses were not observed.

Atacicept in relapsed/refractory multiple myeloma or active Waldenström's macroglobulinemia: a phase I study

“…Similarly, no DLTs were observed using repeated doses of atacicept up to 10 mg kg À1 in a study in patients with advanced B-cell lymphomas in which, although atacicept showed biological activity, clinical responses were not observed (Ansell et al, 2008). In this study, it is encouraging that, as well as being generally well tolerated up to 10 mg kg À1 , both biological and clinical responses were observed.…”

Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase II, randomized, placebo-controlled trial

“…The reason for these differential responses is not clear. One possible explanation is selective mobilization of plasma cells into the circulation during treatment (i.e., weeks [16][17][18][19][20][21][22][23][24][25][26]. Another possibility is that this could result from rapid transition of mature B cells into plasma cells.…”

“…Phase I studies of atacicept in healthy volunteers and in patients with systemic lupus erythematosus (SLE), patients with RA, or patients with B cell lymphoma indicated that atacicept was well tolerated over a range of doses, with no unexpected safety concerns (6)(7)(8)18,19). In the study of patients with RA, atacicept was associated with treatment-related decreases in immunoglobulins, including total immunoglobulin, RF, and ACPAs (6).…”

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

“…Several phase I studies of subcutaneous and intravenous atacicept have been completed, including a safety study in healthy volunteers and dose-escalating studies in patients with SLE, RA, or B cell malignancies (22)(23)(24)(25)(26). In all 5 phase I studies reported to date, atacicept raised no unexpected safety concerns over a range of doses.…”