Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non ^ Hodgkin’S Lymphoma Stephen M

$Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non ^ Hodgkin’S Lymphoma Stephen M$

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 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, 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. were eligible to be treated in the extension study. Toxicity and response evaluation. Stopping rules were in place to halt enrollment in the event that DLT was observed. DLT was defined using Patients and Methods the Common Terminology Criteria for Adverse Events version 3 as any of the following as assessed either by the investigator or the medical Patient eligibility. In this single center study, patients were required reviewer: any serious adverse event unless unrelated to study agent, any to be 18 years of age or older with confirmed relapsed and/or refractory grade 3 adverse event suspected to be related to the study agent except B-cell lymphoma. Patients with multiple myeloma were enrolled in a adverse events related to lymphopenia, as lymphopenia was an separate study. Intermediate or high-grade lymphoma subjects were expected effect of BLyS and APRIL inhibition. Hypersensitivity reactions required to have received a prior anthracycline-containing regimen. of grade 2 or greater were considered dose limiting for an individual Patients were required to have measurable disease, an Eastern subject. Grade 3 or grade 4 hypersensitivity reaction reported in Cooperative Oncology Group performance status of 0 to 2, a life multiple subjects in the same dose level were considered DLT for the expectancy of at least 6 months, and adequate hepatic, renal, and study. Safety review was conducted before accrual to successive dose hematologic function. cohorts. A safety monitoring committee reviewed all adverse events and Exclusion criteria included active infection (including VZV, HBV, safety laboratories through 2 weeks after receipt of fifth dose for all HCV, or HIV); autograft or allograft in the previous 6 months; subjects enrolled in a cohort and all available cumulative safety data for investigational agents, corticosteroids, chemotherapy, immunotherapy, all subjects enrolled at time of cohort review. The decision to dose biological therapy, and/or radiation therapy in the previous 1 month; escalate was taken upon the recommendation of the safety monitoring rituximab in the previous 6 weeks; alemtuzumab in the previous committee. Treatment responses or stable disease after participation in 8 weeks; failure to fully recover from acute, reversible effects of prior the study, as well as disease progression, was determined using the chemotherapy regardless of interval since last treatment; or previous ‘‘International Workshop to Standardize Response Criteria for NHL’’ atacicept therapy. Pregnant and nursing women were not eligible for (13) and the ‘‘Working Group Guidelines for Chronic Lymphocytic the study. All patients were required to give informed consent, and the Leukemia’’ (14). Institutional Review Board of the Mayo Clinic approved the study. Pharmacokinetic evaluations. Plasma concentrations of atacicept Study design. In this phase I dose escalation study, subjects received were assessed before and weekly after the s.c. injection in all patients five consecutive weekly doses of atacicept s.c. Atacicept was given in participating in the study. Plasma concentrations of atacicept were single weekly doses of 2, 4, 7, or 10 mg/kg to sequential patient cohorts. measured using an ELISA developed by Merck-Serono, S/A. Serum An intermediate dose level could be defined if necessary should levels of BLyS or APRIL could only be measured before treatment, as the

Clin Cancer Res 2008;14(4) February 15, 2008 1106 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. Phase I Trial of Atacicept in Lymphoma

complete and partial responses, as well as stable and progressive Table 1. Patient characteristics (n = 15) disease.

Gender Results Male 13 Female 2 PS Patient characteristics. Between October 2005 and July 032006, 15 patients with relapsed or refractory B-cell lymphoma 112were enrolled in this study. Six patients had diffuse large B-cell Age (y), median (range) 75 (49-82) lymphoma, five had follicular grade 2 lymphoma, two had Disease histology at study entry B-CLL/SLL 2 small lymphocytic lymphoma, and two had mantle-cell Diffuse large cell lymphoma 6 lymphoma. An inclusion criterion for the study was relapsed Follicular lymphoma 5 or refractory disease; therefore, all the patients had progressed Mantle cell lymphoma 2 on prior therapy before receiving atacicept. Twelve subjects Disease duration (y), median (range) 6 (2-14) (80%) were Eastern Cooperative Oncology Group status 1; the No. prior treatments, median (range) 5 (1-10) Prior rituximab 14 remaining three subjects were Eastern Cooperative Oncology Prior radiation therapy 4 Group status 0. All patients were heavily pretreated (median Prior autologous stem cell transplant 4 number of previous treatments, 5; range, 1-10), and four Pretreatment serum IgG level (mg/dL), 616 (185-1,030) patients had previously received an autologous stem cell median (range) Pretreatment serum IgA level (mg/dL), 59 (3-297) transplant. Patients received atacicept at doses of 2, 4, or median (range) 7 mg/kg (four patients per dose cohort) or 10 mg/kg atacicept Pretreatment serum IgM level (mg/dL), 25 (5-294) (three patients). Patient characteristics are shown in Table 1. median (range) Dose escalation and adverse events. All patients completed study treatment (five doses) except for two patients who Abbreviations: PS, performance status; B-CLL, B-cell chronic withdrew due to disease progression. One subject in the 7 mg/ lymphocytic leukemia; SLL, small lymphocytic lymphoma. kg group received four of the five scheduled doses, and one subject in the 7 mg/kg group received only two of the five scheduled doses. Atacicept was well tolerated at all four dose levels with no DLTs observed at any dose. The dose of atacicept presence of atacicept in the serum interfered with the assay. The was escalated to 10 mg/kg, and a MTD was not reached. atacicept-BLyS complex was therefore quantified as a measure of BLyS Atacicept was given s.c. in this study, and the 10 mg/kg dose binding. The atacicept-BLyS complex was also measured using an level required a minimum of four injections to administer each ELISA. dose. Further escalation of the dose required a prohibitive Statistical methods. The primary objectives of this phase I study number of injections, and hence, a higher dose was not were to characterize the safety and tolerability of atacicept and to determine the MTD and DLT of atacicept when given on a weekly explored. Further dose escalation is being explored in a dosing schedule. The safety variables included adverse events, vital sign different study using an i.v. formulation of atacicept. measurements, clinical laboratory tests, physical examinations, and The adverse event profile and clinical laboratory findings diagnostic tests (including chest X-rays and computed tomography observed in this trial showed that atacicept was well tolerated. scans). All safety variables were summarized using descriptive statistics. All subjects experienced treatment-emergent adverse events; Hematologic toxicity measures of thrombocytopenia, neutropenia, and however, events reported in all but one of these subjects were of leukopenia were assessed using the continuous variables as the grade 1 or grade 2 severity, and no subjects experienced DLT. outcome measures (primarily nadir and percentage change from The adverse events are shown in Table 2. The most commonly baseline values), as well as categorization via CTC version 3 standard reported adverse events were fatigue, injection site bruising, toxicity grading. Nonhematologic toxicities were evaluated via the dyspnoea, anorexia, diarrhea, and nausea. Sixteen events in ordinal CTC version 3 standard toxicity grading only. Frequency distributions and other descriptive measures formed the basis of the eight subjects were felt to be possibly, probably, or definitely analysis of these variables. The secondary objective was to characterize related to study drug. Only fatigue (reported in four subjects) the pharmacokinetic profile of atacicept. The pharmacokinetic variables was considered to be treatment-related in more than two were summarized using descriptive statistics. Clinical responses were subjects overall. Four serious adverse events considered summarized by simple descriptive summary statistics delineating unrelated to study drug were reported for two subjects. One

Table 2. Adverse events occurring in two or more subjects

Event 2 mg/kg 4 mg/kg 7 mg/kg 10 mg/kg Total n =4 n =4 n =4 n =3 N =15(%) Fatigue 1 3 3 0 7 (47) Injection site bruising 1 1 0 1 3 (20) Anorexia 0 1 1 0 2 (13) Diarrhea 0 0 0 2 2 (13) Dyspnea 0 1 1 0 2 (13) Nausea 0 1 0 1 2 (13)

www.aacrjournals.org 1107 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

Pharmacokinetics. Pharmacokinetic results were nonlinear and consistent with observations in other indications. The pharmacokinetics of free atacicept, total atacicept, and BLyS/ atacicept complex behaved consistently across the doses studied (Fig. 1). The mild nonlinearities in the pharmacokinetic variables (greater than dose proportional increase in free and total atacicept and less than dose proportional increase in BLyS/ atacicept complex) were due to receptor mediation of the drug kinetics by its ligands. The multiple dosing profiles revealed a slightly higher accumulation of BLyS/atacicept complex and

Fig. 1. Median of free atacicept (A), total atacicept (B), and BLyS/atacicept complex (C) concentrations by dose cohort. Data from four patients at the 2, 4, and 7 mg/kg dose level and three patients at the 10 mg/kg dose level are included. subject experienced serious adverse events of gastrointestinal hemorrhage and sepsis and died on study day 41. The other subject experienced fever and had a pulmonary embolism. Treatment-emergent changes from baseline in hematologic and clinical chemistry variables were minimal and with the exception of one subject who had grade 2 low platelet counts, all were grade 1 in severity. The majority of these changes were transient fluctuations, and values generally returned to baseline values at the last visit. None of these changes seemed to be temporally associated with atacicept dosing. No clinically significant changes in coagulation variables or urinalysis were observed. None of the eight subjects who underwent immu- Fig. 2. Mean relative change from baseline in serum IgM (A), IgA (B), and IgG (C). Points, mean; bars, SE at each time point. Data from four patients at the 2, 4, nogenicity testing tested positive for antiatacicept-binding and 7 mg/kg dose level and three patients at the 10 mg/kg dose level are antibodies. included.

Clin Cancer Res 2008;14(4) February 15, 2008 1108 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. Phase I Trial of Atacicept in Lymphoma total atacicept compared with free atacicept, yielding a median subjects (11 of 15; 73.3%) had progressive disease. Fourteen accumulation ratio of around 2 or more for the five successive of 15 subjects (93.3%) had previously received rituximab. Of weekly doses of the first dosing cycle. The BLyS/atacicept these, four patients had received rituximab within 6 months complex concentration-time profiles continued to increase of the first dose of atacicept treatment. Of the four patients beyond the last dose, reaching maximum levels at the end of who had received prior rituximab within 6 months, one the observation period (1,344 h). patient had stable disease after receiving atacicept, and the All subjects participating in this trial were evaluated for serum remaining three patients had disease progression after levels of free BLyS and APRIL at baseline. Because assays to detect receiving atacicept. Two of the four subjects with stable free BLyS and free APRIL are not considered reliable in the disease at 8 weeks entered the extension study and received presence of atacicept, levels of free BLyS and APRIL were not additional doses of atacicept before later discontinuing evaluated in serum samples taken after study drug administra- treatment due to disease progression. The remaining two tion. Eleven subjects (73.3%) had measurable BLyS levels at subjects experienced tumor growth, which, although not baseline and four subjects (26.7%) had baseline levels that were consistent with the definition of progressive disease, was below the lower level of quantification (1.56 ng/mL). The average determined to preclude entry onto the extension study. serum BLyS concentration in the 11 subjects who had measurable BLyS at baseline was 11.7 ng/mL (SD, 10.4 ng/mL). All subjects Discussion had measurable levels of APRIL at baseline. The average serum APRIL concentration was 84.2 ng/mL (SD, 36.3 ng/mL). B-cell neoplasms constitute a heterogeneous group of Lymphocyte cell counts by flow cytometry. Flow cytometric lymphoproliferative cancers with varied patterns of clinical analyses produced varying results between individual subjects, behavior and responses to therapy. The overall prognosis can and the analysis was limited by the low total lymphocyte be predicted with reasonable accuracy by histologic type of counts present at baseline and throughout the study. No tumor, stage of disease, and treatment previously received consistent findings were observed across treatment groups or (15). They occupy a spectrum of diseases ranging from among subjects with the same clinical diagnosis. Modest indolent lymphomas that, although ultimately incurable, increases in total, helper, and cytotoxic T-cell concentrations tend to be associated with a relatively good prognosis, with were observed in several subjects during dosing, with T-cell median survival in the range of 10 years. More aggressive concentrations appearing to generally resolve toward baseline types of B-cell neoplasms can be cured with intensive during follow up. Transient increases in total B cells were combination chemotherapy regimens, and approximately half observed after the first dose of atacicept on day 7 in subjects of subjects survive for at least 5 years. Although addition of from the 2 and 4 mg/kg cohorts and a modest reduction in total rituximab to therapeutic regimens has generally improved B-cell concentrations was seen over the course of the study in clinical outcomes, B-cell neoplasms frequently recur after three subjects from the 2 and 4 mg/kg cohorts. It was unclear initial treatment and new therapeutic agents are clearly whether these modest changes were related to drug treatment. needed. Three subjects in the 7 mg/kg cohort doubled their total B-cell Atacicept is a recombinant fusion protein containing the and chronic lymphocytic leukemia cell concentrations during extracellular, ligand-binding portion of the receptor TACI and dosing, but because cell concentrations continued to increase the modified Fc portion of human IgG1. Atacicept acts as an after dosing ended, it was unclear whether these changes were antagonist to BLyS and APRIL by binding these ligands and associated with atacicept treatment. preventing them from sending prosurvival signals via their Immunoglobulin subset levels (IgA, IgM, and IgG). Levels of cognate receptors, TACI, BCMA, and BAFF-R to malignant B IgA, IgG, and IgM in subjects in the lowest dose cohort did not cells. In support of this mechanism, atacicept has been shown notably decrease from baseline; however, immunoglobulin to inhibit BLyS and APRIL activation of B-cell proliferation and/ levels decreased with repeated dosing at the 4, 7, and 10 mg/kg or survival in vitro. Furthermore, treatment of mice with dose levels (Fig. 2). In certain cases, this decrease seemed to be atacicept or murine TACI-Ig results in a partial block in B-cell dose-dependent. Nadirs were generally attained within 2 weeks development at the transitional B-cell stage, whereas having after the last dose of atacicept, after which some immunoglob- minimal effects on B-cell precursors in the bone marrow and ulin levels started to return toward baseline, whereas others on other cell lineages, including peripheral blood T cells, were still decreasing at day 56. The maximum median decrease monocytes, and neutrophils. Also, transgenic mice engineered from baseline was 40% for IgA and IgM, and for IgG, it was to overexpress TACI-Ig produce fewer mature B cells and show <30%. Using a one-way ANOVA model testing for differences reduced levels of circulating antibody (4). in immunoglobulin levels among the treatment groups, there These data suggest that atacicept would potentially be was a significant difference in IgA levels at day 28 (P = 0.048) effective in depleting malignant B cells. Some preliminary and in IgG levels at day 42 (P = 0.022). There was no clinical results have been obtained in patients with refractory or statistically significant difference in serum IgM levels between relapsed multiple myeloma or previously treated Walden- the treatment groups. These results indicate that atacicept is strom’s macroglobulinemia treated with atacicept (16). In this biologically active in this subject population. open-label, dose-escalation phase Ib study, 16 patients received Clinical responses. None of the subjects in this trial one cycle of five weekly s.c. injections of atacicept at 2, 4, 7, or achieved a complete or partial response. Four of 15 subjects 10 mg/kg. Similar to the current study, treatment with atacicept (26.7%) had stable disease at day 56, including one subject was well tolerated, and no dose-limiting toxicity was observed. with mantle cell lymphoma (treated at 2 mg/kg atacicept) and In this study, there were decreases seen in the patient’s three subjects with follicular lymphoma (one subject each monoclonal protein, and disease stabilization was observed treated at 2, 4, and 10 mg/kg atacicept). The remainder of the in several patients.

www.aacrjournals.org 110 9 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

In the current study, atacicept at doses of up to 10 mg/kg tumor responses were observed in this trial, 4 of 15 subjects was well tolerated and showed biological activity by (26.7%) had stable disease. decreasing immunoglobulin levels in this heavily pretreated Based on the observed safety profile and evidence of population of subjects with refractory B-cell lymphoma. No biological activity in this phase I trial, further study of atacicept DLT was observed, and the MTD was not reached. The is warranted in subjects with B-cell malignancies. However, the majority of subjects had low total baseline lymphocyte lack of clinical benefit seen in this heavily pretreated and counts; therefore, the effect of atacicept on lymphocyte heterogeneous subject population suggests that further evalu- counts could not be fully assessed. The pharmacokinetics of ation of potential atacicept antitumor activity may best be free atacicept, total atacicept, and BLyS/atacicept complex conducted in a less refractory and more homogeneous subject behaved consistently across the doses studied. Whereas no population.

References 1. Mackay F, Browning JL. BAFF: a fundamental survival newly identified TNF receptor that specifically inter- atacicept in healthy volunteers. Eur J Clin Pharmacol factor for B cells. Nat Rev Immunol 2002;2:465 ^ 75. acts with BAFF. Science 2001;293:2108 ^ 11. 2007;63:647^56. 2. Marsters SA, Yan M, Pitti RM, Haas PE, Dixit VM, 8. RoschkeV, Sosnovtseva S,Ward CD, et al. BLyS and 13 . Cheson BD, Horning SJ, Coiffier B, et al.; NCI Spon- Ashkenazi A. Interaction of theTNF homologues BLyS APRIL form biologically active heterotrimers that are sored InternationalWorking Group. Report of an inter- and APRIL with theTNF receptor homologues BCMA expressed in patients with systemic immune-based national workshop to standardize response criteria for andTACI.CurrBiol2000;10:785^8. rheumatic diseases. J Immunol 2002;169:4314^ 21. non-Hodgkin’s lymphomas. J Clin Oncol 1999;17: 3. GrossJA,JohnstonJ,MudriS,etal.TACIandBCMA 9. Novak AJ, Bram RJ, Kay NE, Jelinek DF. Aberrant ex- 124 4 ^ 5 3. are receptors for aTNF homologue implicated in B-cell pression of B-lymphocyte stimulator by B chronic 14. Cheson BD, Bennett JM, Grever M, et al. National autoimmune disease. Nature 2000;404:995 ^ 9. lymphocytic leukemia cells: a mechanism for survival. Cancer Institute-sponsored working group guide- 4. GrossJA,DillonSR,MudriS,etal.TACI-Igneutral- Blood 2002;100:2973 ^ 9. lines for chronic lymphocytic leukemia: revised izes molecules critical for B cell development and 10. Novak AJ, Grote DM, Stenson M, et al. Expression guidelines for diagnosis and treatment. Blood 1996; autoimmune disease: impaired B cell maturation in of BLyS and its receptors in B-cell non-Hodgkin lym- 87:4990 ^ 7. mice lacking BLyS. Immunity 2001;15:289 ^302. phoma: correlation with disease activity and patient 15. Ansell SM, ArmitageJ. Non-Hodgkin lymphoma: di- 5. Schneider P, Mackay F, Steiner V, et al. BAFF, a novel outcome. Blood 2004;104:2247 ^ 53. agnosis and treatment. Mayo Clin Proc 2005;80: ligand of the tumor necrosis factor family, stimulates B 11. Novak AJ, Grote DM, Ziesmer SC, et al. Elevated se- 10 87 ^ 97. cell growth. J Exp Med 1999;189:1747 ^ 56. rum B-lymphocyte stimulator levels in patients with 16. RossiJ, Borghini-Fuhrer I, MoreauxJ, et al. A Phase 6. Dillon SR, Gross JA, Ansell SM, Novak AJ. An APRIL familial lymphoproliferative disorders. J Clin Oncol I/II study ofTACI-Ig to neutralizeAPRIL and BLyS(R) in to remember: novelTNF ligands as therapeutic targets. 2006;24:983^7. patients with refractory or relapsed multiple myeloma Nat Rev Drug Discov 2006;5:235 ^ 46. 12. MunafoA, PriestleyA, Nestorov I,VisichJ, Rogge M. or active previously-treated Waldenstrom’s macro- 7. Thompson JS, Bixler SA, Qian F, et al. BAFF-R, a Safety, pharmacokinetics and pharmacodynamics of globulinemia [abstract#2566].Blood 2005;106:721a.

Clin Cancer Res 2008;14(4) February 15, 2008 1110 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2008 American Association for Cancer Research. Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non −Hodgkin's Lymphoma

Stephen M. Ansell, Thomas E. Witzig, David J. Inwards, et al.

Clin Cancer Res 2008;14:1105-1110.

Updated version Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/14/4/1105

Cited articles This article cites 16 articles, 8 of which you can access for free at: http://clincancerres.aacrjournals.org/content/14/4/1105.full#ref-list-1

Citing articles This article has been cited by 2 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/14/4/1105.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/14/4/1105. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.