Phase 1 Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Lymphoma.

Background: Atacicept (TACI-Ig) is a recombinant fusion protein that inhibits BLyS (B lymphocyte stimulator) and APRIL (a proliferation-inducing ligand), cytokines that are involved in B-cell homeostasis and immunoglobulin (Ig) expression and are overexpressed in B-cell malignancies. In vitro, atacicept decreases the survival of lymphoma cells and in vivo, atacicept decreases serum immunoglobulin levels. Based on its effects on B cells, atacicept may offer a novel treatment for B-cell malignancies.

Methods: A Phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was performed. Atacicept was administered subcutaneously for 5 weeks in single weekly doses of 2, 4, 7, or 10 mg/kg to sequential patient cohorts. After 8 weeks, patients with responding or stable disease were eligible for treatment on an extension study at the dose previously received for up to 24 weeks or until disease progression. The primary study objective was evaluation of overall safety and the maximum tolerated dose. Pharmacokinetics and biomarkers were also investigated.

Results: As of July 2006, 15 patients with relapsed and refractory diffuse large B-cell lymphoma (7), follicular lymphoma (4), small lymphocytic lymphoma/chronic lymphocytic leukemia (2), and mantle-cell lymphoma (2) received 2, 4, or 7 mg/kg atacicept (4 patients per dose cohort) or 10 mg/kg atacicept (3 patients). All patients were heavily pretreated (median number of previous treatments was 5, range 1–10) and 4 patients had previously received a stem cell transplant. All patients completed study treatment (5 doses), except 2 who withdrew due to disease progression after receiving 2 and 4 doses. Atacicept was well tolerated at all doses. The most common adverse events (AEs) that occurred in ≥20% of patients were fatigue (47%) and injection site bruising (20%). Three AEs with ≥ grade 3 severity were reported for 1 patient including pain in jaw, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Four SAEs considered unrelated to atacicept were reported for 2 patients who withdrew due to disease progression. Pharmacokinetic results were nonlinear and consistent with observations in other indications. Five weekly doses produced low to moderate accumulation of free total atacicept and atacicept/BLyS complex in serum. IgA, IgG, and IgM concentrations decreased in a dose-related pattern with a mean decrease of 15–40% from baseline after 4 weeks of atacicept. Peripheral B-cell numbers were variable and were difficult to evaluate due to low B-cell values at baseline in the majority of patients. At the 8-week evaluation, no objective responses were observed. Two patients had stable disease (1 with mantle cell lymphoma and 1 with follicular lymphoma) at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns. Both patients however later discontinued treatment due to disease progression.

Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and demonstrated biological activity by decreasing Ig concentrations in this heavily pretreated cohort of patients with refractory B-cell lymphoma, although tumor responses were not observed.