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Phase I Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Non–Hodgkin's Lymphoma

Authors' Affiliations: ¹ Division of Hematology, Mayo Clinic, Rochester, Minnesota; ² Merck-Serono International SA, Geneva, Switzerland; and ³ ZymoGenetics, Inc., Seattle, Washington

Requests for reprints: Stephen M. Ansell, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: 507-284-0923; Fax: 507-266-4972; E-mail: ansell.stephen{at}mayo.edu.

	Abstract

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Purpose: B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeostasis 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, or 10 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.

In previous work, we have shown that malignant B cells can produce BLyS and that cells from patients with chronic lymphocytic leukemia and lymphoma commonly express TACI and BAFF-R (9, 10). We have found that BLyS protects malignant B cells from apoptosis and that serum BLyS levels in lymphoma patients correlate with response to therapy and overall survival. We have also found that patients with a family history of B-cell malignancies have a higher incidence of elevated serum BLyS levels, and this is associated with a polymorphism in the BLyS promoter region (11). It is therefore anticipated that molecules that inhibit the effects of BLyS will provide novel strategies to treat patients with B-cell malignancies.

Atacicept (formerly known as TACI-Ig) is a recombinant fusion protein containing the extracellular, ligand-binding portion of the receptor TACI and the Fc portion of human IgG1 modified to eliminate effector function. Atacicept acts as an antagonist to BLyS and APRIL by working as a decoy receptor that binds these ligands and thereby potentially decreases the prosurvival signals they deliver to malignant B cells. Atacicept decreases the survival of lymphoma cells in vitro and decreases serum immunoglobulin levels in vivo. In vitro studies with immunoglobulin-fusion proteins of all three receptors (BCMA, TACI, and BAFF-R) showed that only atacicept (TACI-Ig) was able to block the biological activity of the heterotrimeric complexes. (8) To date, human data obtained in healthy male volunteers have shown atacicept to be safe and well tolerated by subjects at doses up to 630 mg (12) The nature, incidence, and severity of adverse events were comparable between atacicept treatment groups and placebo. Local tolerability at the site of administration was good. Approximately, 200 patients have received atacicept in phase I trials for rheumatoid arthritis, systemic lupus, and systemic lupus nephritis. These trials have also shown atacicept to be safe and well tolerated at single doses up to 18 mg/kg and multiple dose schedules of 6 mg/kg every other week for 3 months (data on file; Merck-Serono, S/A). Based on its effects on B cells, atacicept may offer a novel treatment for B-cell malignancies.

The primary objectives of the study were therefore to determine the tolerability of weekly administration of atacicept in the phase I study and subsequent extension study for up to 6 months in subjects with advanced B-cell neoplasms and to identify the optimal dose of atacicept. The secondary objectives were to evaluate antitumor responses, pharmacokinetics, pharmacodynamics, and immunogenicity of atacicept given weekly for up to 6 months.

	Patients and Methods

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Patient eligibility. In this single center study, patients were required to be 18 years of age or older with confirmed relapsed and/or refractory B-cell lymphoma. Patients with multiple myeloma were enrolled in a separate study. Intermediate or high-grade lymphoma subjects were required to have received a prior anthracycline-containing regimen. Patients were required to have measurable disease, an Eastern Cooperative Oncology Group performance status of 0 to 2, a life expectancy of at least 6 months, and adequate hepatic, renal, and hematologic function.

Exclusion criteria included active infection (including VZV, HBV, HCV, or HIV); autograft or allograft in the previous 6 months; investigational agents, corticosteroids, chemotherapy, immunotherapy, biological therapy, and/or radiation therapy in the previous 1 month; rituximab in the previous 6 weeks; alemtuzumab in the previous 8 weeks; failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment; or previous atacicept therapy. Pregnant and nursing women were not eligible for the study. All patients were required to give informed consent, and the Institutional Review Board of the Mayo Clinic approved the study.

Study design. In this phase I dose escalation study, subjects received five consecutive weekly doses of atacicept s.c. Atacicept was given in single weekly doses of 2, 4, 7, or 10 mg/kg to sequential patient cohorts. An intermediate dose level could be defined if necessary should dose-limiting toxicity be encountered. 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 study used a standard "cohort of three" phase I trial design with three to six patients enrolled at each dose level. Rather than closing the study while observing patients for toxicity, patients who were eligible for the study during this period could be enrolled at the previous dose level to provide additional safety and biological information at that dose.

If none of the three subjects in a given cohort experienced dose-limiting toxicity (DLT), dose escalation was advanced to the next sequential cohort. If one of three patients in a given cohort experienced DLT, an additional three subjects would be enrolled in that dose cohort. If two or fewer subjects of six experienced DLT, dose escalation would be advanced to the next sequential cohort. If more than one of three subjects in a given cohort experienced DLT, dose deescalation would occur and three subjects would be treated at an intermediate dose between the dose that elicited DLT and the next lower dose. If none of the three subjects experienced DLT at the intermediate dose, then enrollment would be halted and the intermediate dose would be the maximum tolerated dose (MTD). If one of three subjects experienced DLT at the intermediate dose, then an additional three subjects would be enrolled in that cohort. If one of six subjects experienced DLT, then the intermediate dose would be the MTD; if two or more of six subjects experienced DLT, then enrollment would stop and the dose level below would be the MTD.

Patients treated on the phase I study who tolerated all five doses of atacicept and whose disease was stable or responding could be enrolled in a subsequent extension study, in which the safety and tolerability of longer-term administration of atacicept was evaluated. The primary objective of this extension study was to determine tolerability of weekly administration of atacicept for up to 6 months in subjects with advanced B-cell neoplasms. Secondary objectives included evaluation of antitumor response, pharmacokinetics, pharmacodynamics, and immunogenicity of atacicept given weekly for up to 6 months. Patients received up to 6 months of weekly atacicept at the dose the subject previously received and tolerated without experiencing DLT in the dose escalation study. Eligibility for this study was the same as the phase 1 study except for the fact that only patients treated in the phase 1 trial 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 the Common Terminology Criteria for Adverse Events version 3 as any of the following as assessed either by the investigator or the medical reviewer: any serious adverse event unless unrelated to study agent, any grade 3 adverse event suspected to be related to the study agent except adverse events related to lymphopenia, as lymphopenia was an expected effect of BLyS and APRIL inhibition. Hypersensitivity reactions of grade 2 or greater were considered dose limiting for an individual subject. Grade 3 or grade 4 hypersensitivity reaction reported in multiple subjects in the same dose level were considered DLT for the study. Safety review was conducted before accrual to successive dose cohorts. A safety monitoring committee reviewed all adverse events and safety laboratories through 2 weeks after receipt of fifth dose for all subjects enrolled in a cohort and all available cumulative safety data for all subjects enrolled at time of cohort review. The decision to dose escalate was taken upon the recommendation of the safety monitoring committee. Treatment responses or stable disease after participation in the study, as well as disease progression, was determined using the "International Workshop to Standardize Response Criteria for NHL" (13) and the "Working Group Guidelines for Chronic Lymphocytic Leukemia" (14).

Pharmacokinetic evaluations. Plasma concentrations of atacicept were assessed before and weekly after the s.c. injection in all patients participating in the study. Plasma concentrations of atacicept were measured using an ELISA developed by Merck-Serono, S/A. Serum levels of BLyS or APRIL could only be measured before treatment, as the presence of atacicept in the serum interfered with the assay. The atacicept-BLyS complex was therefore quantified as a measure of BLyS binding. The atacicept-BLyS complex was also measured using an ELISA.

Statistical methods. The primary objectives of this phase I study were to characterize the safety and tolerability of atacicept and to determine the MTD and DLT of atacicept when given on a weekly dosing schedule. The safety variables included adverse events, vital sign measurements, clinical laboratory tests, physical examinations, and diagnostic tests (including chest X-rays and computed tomography scans). All safety variables were summarized using descriptive statistics. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia were assessed using the continuous variables as the outcome measures (primarily nadir and percentage change from baseline values), as well as categorization via CTC version 3 standard toxicity grading. Nonhematologic toxicities were evaluated via the ordinal CTC version 3 standard toxicity grading only. Frequency distributions and other descriptive measures formed the basis of the analysis of these variables. The secondary objective was to characterize the pharmacokinetic profile of atacicept. The pharmacokinetic variables were summarized using descriptive statistics. Clinical responses were summarized by simple descriptive summary statistics delineating complete and partial responses, as well as stable and progressive disease.

	Results

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Patient characteristics. Between October 2005 and July 2006, 15 patients with relapsed or refractory B-cell lymphoma were enrolled in this study. Six patients had diffuse large B-cell lymphoma, five had follicular grade 2 lymphoma, two had small lymphocytic lymphoma, and two had mantle-cell lymphoma. An inclusion criterion for the study was relapsed or refractory disease; therefore, all the patients had progressed on prior therapy before receiving atacicept. Twelve subjects (80%) were Eastern Cooperative Oncology Group status 1; the remaining three subjects were Eastern Cooperative Oncology Group status 0. All patients were heavily pretreated (median number of previous treatments, 5; range, 1-10), and four patients had previously received an autologous stem cell transplant. Patients received atacicept at doses of 2, 4, or 7 mg/kg (four patients per dose cohort) or 10 mg/kg atacicept (three patients). Patient characteristics are shown in Table 1 .

The adverse event profile and clinical laboratory findings observed in this trial showed that atacicept was well tolerated. All subjects experienced treatment-emergent adverse events; however, events reported in all but one of these subjects were of grade 1 or grade 2 severity, and no subjects experienced DLT. The adverse events are shown in Table 2 . The most commonly reported adverse events were fatigue, injection site bruising, dyspnoea, anorexia, diarrhea, and nausea. Sixteen events in eight subjects were felt to be possibly, probably, or definitely related to study drug. Only fatigue (reported in four subjects) was considered to be treatment-related in more than two subjects overall. Four serious adverse events considered unrelated to study drug were reported for two subjects. One 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.

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 total atacicept compared with free atacicept, yielding a median accumulation ratio of around 2 or more for the five successive weekly doses of the first dosing cycle. The BLyS/atacicept complex concentration-time profiles continued to increase beyond the last dose, reaching maximum levels at the end of the observation period (1,344 h).

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   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.

Lymphocyte cell counts by flow cytometry. Flow cytometric analyses produced varying results between individual subjects, and the analysis was limited by the low total lymphocyte counts present at baseline and throughout the study. No consistent findings were observed across treatment groups or among subjects with the same clinical diagnosis. Modest increases in total, helper, and cytotoxic T-cell concentrations were observed in several subjects during dosing, with T-cell concentrations appearing to generally resolve toward baseline during follow up. Transient increases in total B cells were observed after the first dose of atacicept on day 7 in subjects from the 2 and 4 mg/kg cohorts and a modest reduction in total B-cell concentrations was seen over the course of the study in three subjects from the 2 and 4 mg/kg cohorts. It was unclear whether these modest changes were related to drug treatment. Three subjects in the 7 mg/kg cohort doubled their total B-cell and chronic lymphocytic leukemia cell concentrations during dosing, but because cell concentrations continued to increase after dosing ended, it was unclear whether these changes were associated with atacicept treatment.

Immunoglobulin subset levels (IgA, IgM, and IgG). Levels of IgA, IgG, and IgM in subjects in the lowest dose cohort did not notably decrease from baseline; however, immunoglobulin levels decreased with repeated dosing at the 4, 7, and 10 mg/kg dose levels (Fig. 2 ). In certain cases, this decrease seemed to be dose-dependent. Nadirs were generally attained within 2 weeks after the last dose of atacicept, after which some immunoglobulin levels started to return toward baseline, whereas others were still decreasing at day 56. The maximum median decrease from baseline was 40% for IgA and IgM, and for IgG, it was <30%. Using a one-way ANOVA model testing for differences in immunoglobulin levels among the treatment groups, there was a significant difference in IgA levels at day 28 (P = 0.048) and in IgG levels at day 42 (P = 0.022). There was no statistically significant difference in serum IgM levels between the treatment groups. These results indicate that atacicept is biologically active in this subject population.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   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, and 7 mg/kg dose level and three patients at the 10 mg/kg dose level are included.

	Discussion

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B-cell neoplasms constitute a heterogeneous group of lymphoproliferative cancers with varied patterns of clinical behavior and responses to therapy. The overall prognosis can be predicted with reasonable accuracy by histologic type of tumor, stage of disease, and treatment previously received (15). They occupy a spectrum of diseases ranging from indolent lymphomas that, although ultimately incurable, tend to be associated with a relatively good prognosis, with median survival in the range of 10 years. More aggressive types of B-cell neoplasms can be cured with intensive combination chemotherapy regimens, and approximately half of subjects survive for at least 5 years. Although addition of rituximab to therapeutic regimens has generally improved clinical outcomes, B-cell neoplasms frequently recur after initial treatment and new therapeutic agents are clearly needed.

Atacicept is a recombinant fusion protein containing the extracellular, ligand-binding portion of the receptor TACI and the modified Fc portion of human IgG1. Atacicept acts as an antagonist to BLyS and APRIL by binding these ligands and preventing them from sending prosurvival signals via their cognate receptors, TACI, BCMA, and BAFF-R to malignant B cells. In support of this mechanism, atacicept has been shown to inhibit BLyS and APRIL activation of B-cell proliferation and/or survival in vitro. Furthermore, treatment of mice with atacicept or murine TACI-Ig results in a partial block in B-cell development at the transitional B-cell stage, whereas having minimal effects on B-cell precursors in the bone marrow and on other cell lineages, including peripheral blood T cells, monocytes, and neutrophils. Also, transgenic mice engineered to overexpress TACI-Ig produce fewer mature B cells and show reduced levels of circulating antibody (4).

These data suggest that atacicept would potentially be effective in depleting malignant B cells. Some preliminary clinical results have been obtained in patients with refractory or relapsed multiple myeloma or previously treated Waldenstrom's macroglobulinemia treated with atacicept (16). In this open-label, dose-escalation phase Ib study, 16 patients received one cycle of five weekly s.c. injections of atacicept at 2, 4, 7, or 10 mg/kg. Similar to the current study, treatment with atacicept was well tolerated, and no dose-limiting toxicity was observed. In this study, there were decreases seen in the patient's monoclonal protein, and disease stabilization was observed in several patients.

In the current study, atacicept at doses of up to 10 mg/kg was well tolerated and showed biological activity by decreasing immunoglobulin levels in this heavily pretreated population of subjects with refractory B-cell lymphoma. No DLT was observed, and the MTD was not reached. The majority of subjects had low total baseline lymphocyte counts; therefore, the effect of atacicept on lymphocyte counts could not be fully assessed. The pharmacokinetics of free atacicept, total atacicept, and BLyS/atacicept complex behaved consistently across the doses studied. Whereas no tumor responses were observed in this trial, 4 of 15 subjects (26.7%) had stable disease.

Based on the observed safety profile and evidence of biological activity in this phase I trial, further study of atacicept is warranted in subjects with B-cell malignancies. However, the lack of clinical benefit seen in this heavily pretreated and heterogeneous subject population suggests that further evaluation of potential atacicept antitumor activity may best be conducted in a less refractory and more homogeneous subject population.

	Footnotes

 
Grant support: NIH grant CA121569 and Leukemia and Lymphoma Society translational research grant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Presented in part at the American Society of Hematology 48th annual meeting, December 2006.

Received 9/24/07; revised 11/27/07; accepted 11/27/07.

	References

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