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Atacicept in Relapsed&Sol;Refractory Multiple Myeloma Or Active British Journal of Cancer (2009) 101, 1051 – 1058 & 2009 Cancer Research UK All rights reserved 0007 – 0920/09 $32.00 www.bjcancer.com Atacicept in relapsed/refractory multiple myeloma or active Waldenstro¨m’s macroglobulinemia: a phase I study *,1,2,4,5 1,2 3 2 5 5 6 7 J-F Rossi , J Moreaux , D Hose , G Requirand , M Rose , V Rouille´ , I Nestorov , G Mordenti , 3 7 1,2,4 H Goldschmidt , A Ythier and B Klein 1CIC-Biothe´rapie BT 509, CHU Montpellier, Montpellier, France; 2INSERM, U847, Montpellier, France; 3Medizinische Klinik und Poliklinik V, 4 5 Universita¨tsklinikum Heidelberg, INF410, Germany; Universite´ Montpellier1, France; Department of Haematology and Clinical Oncology, CHU 6 7 Montpellier, France; Clinical Development, ZymoGenetics Inc., Seattle, WA, USA; Clinical Development, Merck Serono S.A. (an affiliate of Merck KGaA, Darmstadt, Germany), Geneva, Switzerland Clinical Studies BACKGROUND: Advanced multiple myeloma (MM) and Waldenstro¨m’s macroglobulinemia (WM) are incurable B-cell malignancies. This is the first full clinical report of atacicept, a fusion protein that binds to and neutralises the B-cell survival factors, B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL), in MM and WM. METHODS: In this open-label phase-I study, 16 patients with advanced disease (12 MM, 4 WM) received one cycle of five once-weekly À1 subcutaneous injections of atacicept (2, 4, 7 or 10 mg kg ). Patients with stable disease after cycle 1 entered an extension study À1 À1 (either two additional cycles (2, 4 and 7 mg kg cohorts) or 15 consecutive weekly injections of atacicept 10 mg kg ). RESULTS: Atacicept was well tolerated, systemically and locally; the maximum tolerated dose was not identified. Of 11 patients with MM who completed initial treatment, five patients were progression-free after cycle 1 and four patients were progression-free after extended therapy. Of four patients with WM, three patients were progression-free after cycle 1. Consistent with atacicept’s mechanism of action, polyclonal immunoglobulin isotypes and total B cells were reduced. Bone-marrow density, myeloma cell numbers and plasma concentrations of soluble CD138 also decreased. CONCLUSION: Atacicept is well tolerated in patients with MM and WM, and shows clinical and biological activity consistent with its mechanism of action. British Journal of Cancer (2009) 101, 1051 – 1058. doi:10.1038/sj.bjc.6605241 www.bjcancer.com & 2009 Cancer Research UK Keywords: atacicept; multiple myeloma; Waldenstro¨m’s macroglobulinemia; BLyS; APRIL Multiple myeloma (MM) is the second most prevalent blood et al, 2000). The Fourth International Workshop on WM reviewed cancer, accounting for 10% of haematological malignancies. The treatment guidelines for patients with WM who require systemic median age at diagnosis is 68 years and the incidence increases therapy; current primary treatments include alkylating agents, with advancing age (Ferlay et al, 2004). Among patients treated nucleoside analogues and immunotherapies, as single agents and with conventional chemotherapy, the median survival is about 42 in combination regimens (Dimopoulos et al, 2009). The need for months (Blade´ et al, 1994). In patients younger than 65 years, high- and development of new therapies for patients with WM was dose chemotherapy supported by autologous stem cell transplan- further discussed at the recent Fifth International Workshop on tation increases the median survival to 60 months (Harousseau WM (Treon et al, 2009). and Moreau, 2007). Despite recent innovations in approaches to B-lymphocyte stimulator (BLyS, CD257, also known as B-cell therapy, options remain limited for the majority of patients. activating factor (BAFF)) (Schneider et al, 1999) and A prolifera- Waldenstro¨m’s macroglobulinemia (WM) is a B-cell malig- tion-inducing ligand (APRIL, CD256) stimulate the growth of nancy, which results from a clonal proliferation of lymphocytes primary myeloma cells (Moreaux et al, 2004; Novak et al, 2004). and plasma cells that produce monoclonal immunoglobulin (Ig) M, BLyS and APRIL share two receptors, trans-membrane activator and our understanding of this clinico-pathological entity has and CAML interactor (TACI, CD267) (Von Bulow and Bram, 1997) improved in recent years (Vitolo et al, 2008; Dimopoulos et al, and B-cell maturation antigen (BCMA, CD269) (Gras et al, 1995); 2009). The median age at presentation is 63 years (Dimopoulos BLyS also binds to a third receptor, BAFF-R (also known as BR3, CD268) (Thompson et al, 2001). Most myeloma cell lines and primary myeloma cells express one or more of these receptors for *Correspondence: Professor J-F Rossi or Professor B Klein, Service BLyS (Novak et al, 2004; Moreaux et al, 2007, 2009) and also d’He´matologie Clinique, CIC-Biothe´rapie; CHU Montpellier, Hoˆpital aberrantly express BLyS and APRIL mRNA (Moreaux et al, 2004). Lapeyronie, 371, avenue du Doyen Giraud, Montpellier 34295, cedex 5, BLyS and APRIL are also produced in large amounts in the tumour France. bone marrow environment, primarily by myeloid cells, monocytes E-mail: [email protected] or [email protected] and osteoclasts (Moreaux et al, 2005; Abe et al, 2006; Tai et al, Received 3 March 2009; revised 30 June 2009; accepted 16 July 2009 2006; Yaccoby et al, 2008). Exogenous BLyS and APRIL act as Atacicept in MM and WM J-F Rossi et al 1052 potent survival factors for primary myeloma cells cultured within Excluded: n = 2 the bone marrow microenvironment (Moreaux et al, 2004, 2009). Screened: n = 18 (MM) because of Similar patterns of BLyS expression and tumourigenic activity (14 MM, 4 WM) SAE before have been observed in patients with WM (Elsawa et al, 2006). treatment Atacicept is a fusion protein composed of the human IgG Fc portion and the extracellular, ligand-binding portion of the TACI Enrolled: n = 16 (12 MM, 4 WM) receptor, which neutralises both BLyS and APRIL (Gross et al, Withdrawn because of 2000, 2001). The addition of atacicept to primary myeloma cells disease progression Initial with SAE after abrogates proliferative effects and induces apoptosis (Moreaux Treated: n = 16 treatment two injections: et al, 2004; Abe et al, 2006). (12 MM, 4 WM) (cycle 1) n = 1 (MM); The purpose of this investigation was to assess the overall safety assessed Clinical Studies and tolerability of atacicept in patients with refractory or relapsed for safety MM or progressive WM, and to evaluate the overall clinical-benefit Assessed: n = 15 rate, pharmacokinetics, pharmacodynamics and immmuno- (11 MM, 4 WM) genicity of atacicept in this population. Stable disease 2 months’ No after treatment? follow-up: n = 7 (6 MM, 1 WM) MATERIALS AND METHODS Yes Study design and interventions We report the results of two studies conducted in one centre in Extension Enrolled: n = 8 France. The protocols were developed in collaboration with, and study (5 MM, 3 WM) approved by, an independent ethics committee, and the studies were carried out in accordance with the Declaration of Helsinki, the standards of the International Conference on Harmonization, Assessed at the end of treatment extension: Guideline for Good Clinical Practice and local regulations. Patients n = 8 (5 MM, 3 WM) gave written informed consent for participation in each study. This study was initiated in November 2004 and at that time was not registered in a clinical trial registry. n = 6 with stable disease n = 2 with Adults (X18 years of age) with confirmed relapsed and/or (4 MM, 1 WM) or minimal progressive disease refractory MM or progressive WM were recruited into an response (1 WM) (1 MM, 1 WM) exploratory single-arm, open-label, dose escalating, repeat-dose Figure 1 Study design and patient disposition. Abbreviations: MM, study (defined as cycle 1). Eligible patients were enrolled in multiple myeloma; SAE, serious adverse event; WM, Waldenstro¨m’s sequential cohorts to receive one cycle of five weekly subcutaneous macroglobulinemia. injections of atacicept (Merck Serono S.A. – Geneva, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany) and ZymoGenetics À1 Inc., Seattle, WA, USA) at doses of 2 mg kg (cohort 1, 3 patients), and the willingness to use acceptable methods of contra- 4mgkgÀ1 (cohort 2, 3 patients), 7 mg kgÀ1 (cohort 3, 3 patients) or À1 ception during the study and until 3 months after the last dose 10 mg kg (cohort 4, 7 patients). Escalation to the next dose of atacicept. The main exclusion criteria included: non-secretory cohort and identification of the maximum tolerated dose (MTD) myeloma, amyloidosis, active infection, stem cell transplantation for atacicept depended on the frequency of dose-limiting toxicities in the previous 6 months, receipt of any investigational product, (DLTs) in the preceding cohort and approval by the safety radiation, chemotherapy, biological therapy, immunotherapy or committee. corticosteroids (410 mg dayÀ1) in the previous month, dialysis Patients who completed cycle 1, demonstrated at least stable concurrent to study treatment, previous history of congestive heart disease after a 4-week follow-up period and had not experienced failure, significant cardiac ejection fraction abnormalities and any DLTs were eligible to enter the extension study. During the presence or history of other types of cancer. extension study, patients received either two additional cycles of atacicept subcutaneously (five weekly injections), at the same dose as cycle 1, separated each by a 4-week wash-out period (cohorts Safety 1–3) or one continuous cycle of 15 weekly injections of À1 Throughout both studies, safety was assessed by adverse event atacicept 10 mg kg (cohort 4). After the extension treatment (AE) reports, occurrence of DLTs, direct physical examination and cycles, patients entered a 4-week post-treatment period and a clinical laboratory tests. subsequent 2-month follow-up period. Figure 1 summarises the Owing to the mechanism of action of atacicept, AEs in the study design and patient disposition. system organ class (SOC) of ‘Infections and infestations’ were closely monitored.
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