Cancer Therapy: Clinical Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non ^ Hodgkin’s Lymphoma Stephen M. Ansell,1Thomas E.Witzig,1David J. Inwards,1Luis F. Porrata,1Arnaud Ythier,2 Lee Ferrande,2 Ivan Nestorov,3 Todd DeVries,3 Stacey R. Dillon,3 Diana Hausman,3 and Anne J. Novak1 Abstract Purpose: B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeosta- sis 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 prolifer- ation-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, or10 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. B-lymphocyte stimulator (BLyS; also known as BAFF, TALL-1, identification of a second growth factor, a proliferation- THANK, and zTNF4) is a tumor necrosis factor family molecule inducing ligand (APRIL), which is most closely related to BLyS that promotes B-cell survival and is a key regulator of peripheral and shares some of its biological activities (3–5). The role of B-cell populations. It binds to three receptors: B-cell maturation APRIL in B-cell biology in vivo is not entirely understood, but antigen, (BCMA) transmembrane activator and CAML inter- growing evidence suggests that it is a critical survival factor for actor (TACI), and B-cell activating factor of the tumor necrosis immunoglobulin-secreting cells and for various malignant factor family receptor (BAFF-R; refs. 1, 2). BLyS plays a crucial B cells (1, 6). TACI and BCMA bind both BLyS and APRIL, role in B-cell survival and maintenance and is overexpressed in whereas BAFF-R binds BLyS with high affinity (2, 7). As a result, B-cell malignancies. The tumor necrosis factor subfamily, to BLyS is able to signal through all three receptors, whereas APRIL which BLyS belongs, has grown in complexity, as a result of the signals just through TACI and BCMA. In addition, circulating heterotrimeric complexes of BLyS and APRIL (groupings of three subunits containing one or two copies each of BLyS and APRIL) have been identified in serum samples taken from subjects with systemic immune-based rheumatic diseases (8). Authors’ Affiliations: 1Division of Hematology, Mayo Clinic, Rochester, 2 Heterotrimer complexes of BLyS and APRIL have also been Minnesota; Merck-Serono International SA, Geneva, Switzerland; and in vitro 3ZymoGenetics, Inc., Seattle,Washington shown to induce B-cell proliferation (8). Received 9/24/07; revised 11/27/07; accepted 11/27/07. In previous work, we have shown that malignant B cells can Grant support: NIH grant CA121569 and Leukemia and Lymphoma Society produce BLyS and that cells from patients with chronic translational research grant. lymphocytic leukemia and lymphoma commonly express The costs of publication of this article were defrayed in part by the payment of page TACI and BAFF-R (9, 10). We have found that BLyS protects charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. malignant B cells from apoptosis and that serum BLyS levels Note: Presented in part at the American Society of Hematology 48th annual in lymphoma patients correlate with response to therapy and meeting, December 2006. overall survival. We have also found that patients with a Requests for reprints: Stephen M. Ansell, Division of Hematology, Mayo Clinic, family history of B-cell malignancies have a higher incidence 200 First Street SW, Rochester, MN 55905. Phone: 507-284-0923; Fax: 507- 266-4972; E-mail: [email protected]. of elevated serum BLyS levels, and this is associated with a F 2008 American Association for Cancer Research. polymorphism in the BLyS promoter region (11). It is doi:10.1158/1078-0432.CCR-07-4435 therefore anticipated that molecules that inhibit the effects www.aacrjournals.org 110 5 Clin Cancer Res 2008;14(4) February 15, 2008 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. Cancer Therapy: Clinical of BLyS will provide novel strategies to treat patients with dose-limiting toxicity be encountered. After 8 weeks, patients with B-cell malignancies. responding or stable disease were eligible for treatment on an extension Atacicept (formerly known as TACI-Ig) is a recombinant study at the dose previously received for up to 24 weeks or until disease fusion protein containing the extracellular, ligand-binding progression. The study used a standard ‘‘cohort of three’’ phase I trial design with three to six patients enrolled at each dose level. Rather than portion of the receptor TACI and the Fc portion of human closing the study while observing patients for toxicity, patients who IgG1 modified to eliminate effector function. Atacicept acts as were eligible for the study during this period could be enrolled at the an antagonist to BLyS and APRIL by working as a decoy previous dose level to provide additional safety and biological receptor that binds these ligands and thereby potentially information at that dose. decreases the prosurvival signals they deliver to malignant B If none of the three subjects in a given cohort experienced dose- cells. Atacicept decreases the survival of lymphoma cells in vitro limiting toxicity (DLT), dose escalation was advanced to the next and decreases serum immunoglobulin levels in vivo. In vitro sequential cohort. If one of three patients in a given cohort experienced studies with immunoglobulin-fusion proteins of all three DLT, an additional three subjects would be enrolled in that dose cohort. receptors (BCMA, TACI, and BAFF-R) showed that only If two or fewer subjects of six experienced DLT, dose escalation would atacicept (TACI-Ig) was able to block the biological activity of be advanced to the next sequential cohort. If more than one of three subjects in a given cohort experienced DLT, dose deescalation would the heterotrimeric complexes. (8) To date, human data occur and three subjects would be treated at an intermediate dose obtained in healthy male volunteers have shown atacicept to between the dose that elicited DLT and the next lower dose. If none of be safe and well tolerated by subjects at doses up to 630 mg the three subjects experienced DLT at the intermediate dose, then (12) The nature, incidence, and severity of adverse events were enrollment would be halted and the intermediate dose would be the comparable between atacicept treatment groups and placebo. maximum tolerated dose (MTD). If one of three subjects experienced Local tolerability at the site of administration was good. DLT at the intermediate dose, then an additional three subjects would Approximately, 200 patients have received atacicept in phase I be enrolled in that cohort. If one of six subjects experienced DLT, then trials for rheumatoid arthritis, systemic lupus, and systemic the intermediate dose would be the MTD; if two or more of six subjects lupus nephritis. These trials have also shown atacicept to be experienced DLT, then enrollment would stop and the dose level below safe and well tolerated at single doses up to 18 mg/kg and would be the MTD. Patients treated on the phase I study who tolerated all five doses of multiple dose schedules of 6 mg/kg every other week for atacicept and whose disease was stable or responding could be enrolled 3 months (data on file; Merck-Serono, S/A). Based on its effects in a subsequent extension study, in which the safety and tolerability of on B cells, atacicept may offer a novel treatment for B-cell longer-term administration of atacicept was evaluated. The primary malignancies. objective of this extension study was to determine tolerability of weekly The primary objectives of the study were therefore to administration of atacicept for up to 6 months in subjects with determine the tolerability of weekly administration of atacicept advanced B-cell neoplasms. Secondary objectives included evaluation of in the phase I study and subsequent extension study for up to antitumor response, pharmacokinetics, pharmacodynamics, and im- 6 months in subjects with advanced B-cell neoplasms and to munogenicity of atacicept given weekly for up to 6 months. Patients identify the optimal dose of atacicept. The secondary objectives received up to 6 months of weekly atacicept at the dose the subject were to evaluate antitumor responses, pharmacokinetics, previously received and tolerated without experiencing DLT in the dose escalation study. Eligibility for this study was the same as the phase 1 pharmacodynamics, and immunogenicity of atacicept given study except for the fact that only patients treated in the phase 1 trial weekly for up to 6 months.