Final Results of a Phase Ib Trial of Atacicept to Neutralize APRIL and BLyS in Patients with Refractory or Relapsed Chronic Lymphocytic Leukemia (CLL).

CLL cells are not highly proliferative, but are resistant to apoptosis and thus exhibit prolonged survival and accumulation in vivo. Exogenous soluble BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand) bind to the TACI receptor and have been shown to protect CLL cells from apoptosis in vitro. Nurse-like cells derived in vitro from CLL patients express high levels of APRIL and BLyS and thereby support CLL cell survival. Inhibition of both APRIL and BLyS (but not BLyS alone) significantly reduces CLL viability in vitro, indicating an important role for APRIL in this setting. Atacicept is a soluble receptor fusion protein comprised of the extracellular domain of TACI and the Fc (modified) portion of a human IgG. It binds and neutralizes both APRIL and BLyS. We present the final results of a phase I study of atacicept.

This is an open-label, dose-escalation trial to assess the safety, pharmacokinetics and biological effects of atacicept dosed intravenously once weekly for 5 weeks to patients with refractory or relapsed CLL. Eligible patients have been enrolled in sequential cohorts of 3 to receive atacicept at doses of 1, 4, 10, 15, 20 or 27 mg/kg (max. dose proposed due to high protein load). Patients who demonstrated at least stable disease after the first cycle (5 weeks treatment, 3 weeks follow-up) were allowed to receive up to 4 additional treatment cycles depending on response. PK was assessed after the 1st, 2nd, 3rd, and 5th dose in cycle 1. The biological activity assessment comprised peripheral leukocyte counts, lymphocyte subpopulation counts (by flow cytometric analysis) and lymph node size (assessed by CT scan). Response has been assessed using NCI-WG criteria at the end of cycle 1 and at regular intervals thereafter.

Twenty-one CLL patients with an average number of 7 prior treatments have been treated with atacicept for at least one cycle. Before starting Atacicept treatment, most patients had rapidly increasing leukocyte counts. No dose-limiting toxicity has been reported and no SAE related to study drug has been observed. One case of mild nausea is the only drug-related toxicity reported to date. Five of nine patients treated with 10, 15 or 20 mg/kg experienced a stabilization of their disease during the treatment period. At the dose of 27 mg/kg, one of six patients experienced a partial response (PR), which has lasted for 12 months. Five of six patients treated with 27 mg/kg experienced a stabilization of their disease during the treatment period. At lower dose levels (1 and 4 mg/kg) all patients demonstrated progressive disease.

Treatment with atacicept was well tolerated. The multiple cases of disease stabilization and one PR seen at higher dose levels in this heavily pre-treated patient population suggest that atacicept might interfere with CLL cell proliferation and survival in vivo.

Off Label Use: Atacicept is a soluble receptor fusion protein comprised of the extracellular domain of TACI and the Fc (modified) portion of a human IgG. It binds and neutralizes the proteins APRIL and BLyS which are suspected to drive disease progression in CLL patients. Gianella-Borradori:Merck Serono: Employment.