Originally published as JCO Early Release 10.1200/JCO.2003.01.082 on July 1 2003

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Phase I/II Trial of Epratuzumab (Humanized Anti-CD22 Antibody) in Indolent Non-Hodgkin’s Lymphoma

John P. Leonard, Morton Coleman, Jamie C. Ketas, Amy Chadburn, Scott Ely, Richard R. Furman, William A. Wegener, Hans J. Hansen, Heather Ziccardi, Michael Eschenberg, Urte Gayko, Alessandra Cesano, David M. Goldenberg

From the Center for Lymphoma and Myeloma, Division of Hematology and Oncology, and Department of Pathology, Weill Medical College of Cornell University and New York Presbyterian Hospital; New York, NY; Immunomedics, Inc, Morris Plains; Center for Molecular Medicine and Immunology; Garden State Cancer Center; Belleville, NJ; and Amgen Inc, Thousand Oaks, CA.

Address reprint requests to John P. Leonard, MD, Center for Lymphoma and Myeloma and Division of Hematology and Oncology, Weill Medical College of Cornell University and New York Presbyterian Hospital, 520 East 70th Street, New York, NY 10021; email: jpleonar{at}med.cornell.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: This single-center, dose-escalation study examines the safety, efficacy, and pharmacokinetics of epratuzumab (anti-CD22 humanized monoclonal antibody) in patients with recurrent indolent non-Hodgkin’s lymphoma (NHL).

Patients and Methods: Patients had indolent NHL and recurrent disease after at least one chemotherapy regimen. Epratuzumab was administered intravenously at 120 to 1,000 mg/m² over 30 to 60 minutes weekly for four treatments.

Results: Fifty-five patients received epratuzumab and were assessable for safety; 51 patients were assessable for response. Patients were heavily pretreated (50% had at least four prior regimens) and 49% had bulky disease ( 5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. More than 95% of infusions were completed in approximately 1 hour. Mean serum half-life was 23 days. Across all dose levels and histologies, nine patients (18%; 95% confidence interval, 8% to 31%) achieved objective response, including three complete responses (CRs). All responses were in patients with follicular NHL: 24% of these patients responded, including 43% in the 360 mg/m² dose group and 27% in the 480 mg/m² dose group. No responses were observed in other indolent histologies. Median duration of objective response was 79.3 weeks (range, 11.1 to 143.3 weeks), with median time to progression for responders of 86.6 weeks by Kaplan-Meier estimate.

Conclusion: Epratuzumab was well tolerated at up to 1,000 mg/m²/wk (for 4 weeks) and had clinical activity. One third of responding patients achieved CR. A 43% objective response rate in follicular NHL patients treated at 360 mg/m²/wk indicates that this dose should be explored in additional studies.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE NON-HODGKIN’S lymphomas (NHL) are a heterogeneous group of lymphoid malignancies that vary in their histology, clinical course, and response to treatment. Indolent (or low-grade) B-cell lymphomas represent approximately 40% of NHLs. When patients are asymptomatic, a watchful waiting approach is usually indicated because it has not been demonstrated that early treatment affects survival.¹ Most patients with indolent NHL, however, have disseminated disease at the time of their diagnosis and ultimately require therapy. Effective treatments include radiotherapy; single-agent chemotherapy such as chlorambucil, cyclophosphamide, or fludarabine; or combination chemotherapy such as cyclophosphamide, vincristine, and prednisone, or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). As first-line therapy, response rates in the range of 60% to 80% have been reported with these regimens.² Despite the high rate of response of indolent NHL to initial therapy, subsequent courses are generally characterized by cycles of relapse, re-treatment, and remission, with responses generally becoming less likely and of shorter duration. Over time, the disease frequently becomes resistant to treatment or transforms to a more aggressive histology; either outcome generally portends a poor prognosis. Myeloablative therapy with autologous stem-cell transplant has not been clearly shown to improve survival in indolent NHL patients who experience relapse,³ and the addition of interferon alfa-2b to combination chemotherapy regimens has shown only inconsistent benefit.^4,5 Despite the development of new therapeutic agents, most patients with indolent NHL ultimately die from their disease and overall survival has not changed significantly in the last 20 years.

B-cell NHLs are characterized by expression of lineage-specific B-cell antigens, such as CD19, CD20, and CD22. Monoclonal antibodies against some of these antigens have been shown to be active in the treatment of NHL both preclinically and clinically. Potential mechanisms of action include mediation of antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and direct induction of apoptosis in tumor cells. Rituximab, a naked chimeric monoclonal antibody against the CD20 antigen, was approved in 1997 for the treatment of relapsed or refractory, low-grade or follicular, CD20⁺ B-cell NHL, and has now become a commonly employed therapy. In the phase I multiple-dose trial of rituximab by Maloney et al,⁵ six of 18 assessable patients (33%) had an objective response (OR), all partial responses (PR), with a median time to progression (TTP) of 6.4 months. In subsequent clinical studies of patients with relapsed or refractory indolent NHL, rituximab produced overall responses (complete response [CR] + PR) in the range of 45% to 60%, with response durations of a year or more.^6–8

The targeting of other B-cell antigens with monoclonal antibodies may also offer therapeutic potential for lymphoma. CD22 is a 135-kd B-cell–restricted sialoglycoprotein present in the cytoplasm of virtually all developing B cells, but detectable on the cell surface only at the mature stages of differentiation.⁹ In humans, most circulating immunoglobulin M–positive (IgM-positive), IgD-positive B cells express cell-surface CD22 while in lymphoid tissues. CD22 expression is strong in follicular, mantle, and marginal zone B cells, but weak in germinal center B cells.⁹ In B-cell malignancies, CD22 expression has been reported in at least 60% to 80% of tumor samples depending on the histologic type and the assay used (immunohistochemistry or flow cytometry).¹⁰ The function of CD22 is uncertain, although recent studies have implicated roles for the antigen both as a component of the B-cell activation complex¹¹ and as an adhesion molecule.¹² CD22-deficient mice have a reduced number of mature B cells in the bone marrow and in circulation.¹³ In these mice, the B cells have a shorter life span and enhanced apoptosis, thus indicating a key role of this antigen in B-cell development and survival.¹³ After binding with its natural ligand(s) or antibodies, CD22 is rapidly internalized, providing a potent costimulatory signal in primary B cells and proapoptotic signals in neoplastic B cells.¹⁴

The LL2 antibody (formerly called HPB-2) is an IgG_2a mouse monoclonal antibody directed against the CD22 antigen.¹⁵ In vitro immunohistologic evaluations demonstrated that the LL2 antibody was reactive with 50 of 51 B-cell NHL specimens tested, but not with other malignancies or normal nonlymphoid tissues.^16,17 The humanized IgG₁ version of LL2, epratuzumab, was developed to reduce the potential for immunogenicity, prolong half-life, and increase effector function.¹⁵

This article describes the safety, clinical activity, pharmacokinetics, and immunogenicity of epratuzumab as a naked (unlabeled) antibody in patients with recurrent indolent NHL. Effects on blood mononuclear cells, Ig levels, and other laboratory parameters also were assessed. Epratuzumab was administered as four once-weekly infusions across a wide range of doses to patients with various indolent NHL histologies. These data demonstrate that epratuzumab has an acceptable safety profile, exhibits clinical activity, and offers promise as a new agent with potential therapeutic utility for indolent NHL.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Population
Fifty-five patients with indolent NHL were enrolled in this phase I/II study between April 1998 and September 2001. Patients were men or women with a diagnosis of B-cell malignancy (including chronic lymphocytic leukemia or small lymphocytic lymphoma [CLL/SLL]) who had progressive disease after at least one regimen of standard chemotherapy. Patients were required to have CD22⁺ NHL, as shown by either immunohistochemistry or flow cytometry of malignant tissue obtained at any time point before enrollment. This analysis was not performed in a standardized fashion, with positivity determined either by the primary (outside) pathologist at the time of diagnosis or at the study site before study entry. International Working Formulation classification of lymphoma subtype was used at the time of study design and for this report. Patients were at least 4 weeks beyond prior chemotherapy, radiotherapy, or biologic therapy, and 2 weeks beyond corticosteroid use. Additional study eligibility criteria included the following: Karnofsky performance status of 60% or greater, serum creatinine of less than 1.5x the upper limits of normal, serum bilirubin of less than 1.5x the upper limits of normal, and absence of hepatitis B and C positivity. The protocol was approved by the Weill Medical College of Cornell University and New York Presbyterian Hospital (New York, NY) Institutional Review Board, and all patients provided informed consent.

Study Drug Administration
Epratuzumab (humanized IgG₁ anti-CD22 monoclonal antibody [hLL2]) was produced and quality was controlled at Immunomedics, Inc (Morris Plains, NJ); the drug was administered by intravenous infusion, delivered within approximately 1 hour, at doses of 120, 240, 360, 480, 600, or 1,000 mg/m²/wk for 4 consecutive weeks.

Dose escalation was sequential, with each sequential dose cohort initiated in the absence of any dose-limiting toxicities. After completion of dose escalation, additional patients were treated at the doses at which activity had been observed. Before each infusion, patients were premedicated with acetaminophen and diphenhydramine to minimize any potential infusion reactions.

Study Design
The study was an open-label, phase I/II trial designed to evaluate the safety and efficacy of a range of epratuzumab doses in patients with NHL. Epratuzumab infusions were given once weekly for 4 consecutive weeks, with restaging for treatment response performed 4 weeks after the last infusion. Patients were then evaluated every 3 to 4 months for the first 2 years and subsequently every 6 months until disease progression. Adverse events were recorded throughout the study and graded according to the National Cancer Institute common toxicity criteria (version 2, March 28, 1998). Laboratory assessments (including serum chemistry, complete blood count, immunophenotyping of blood mononuclear cells, urinalysis, and quantitative serum immunoglobulin) were performed at screening, 24 hours after the last infusion, and at restaging. Vital signs were monitored every 15 minutes during the infusions. Blood samples to evaluate for human antihuman antibodies (HAHA) were tested using an enzyme-linked immunosorbent assay developed by Immunomedics, Inc. Samples were obtained within 4 weeks before study entry, 24 hours after the last infusion, at restaging, and 3 to 4 months after restaging. Bone marrow aspirate and biopsy were performed at study entry, and to confirm CR after treatment in those patients with no radiographic or other evidence of disease.

Bidimensional computed tomography data for the neck and chest, and abdomen and pelvis were collected at screening, restaging, and follow-up for evaluation of disease response. Response was classified using Eastern Cooperative Oncology Group definitions for CR, PR, stable disease (SD), and progressive disease.¹⁸

Blood samples to determine serum concentrations of epratuzumab were collected from a subset of patients before each weekly infusion, 30 minutes after the end of each infusion, and periodically thereafter during the following 8 weeks.

Study End Points
Safety. Safety end points included the incidence of adverse events (including those during or within 7 days of the epratuzumab infusion, as well as any later events deemed possibly or probably related to drug administration), and change in HAHA status, laboratory values, and infusion-day vital signs. Epratuzumab serum concentration was also determined at various time intervals.

Efficacy. Efficacy was evaluated by calculating the OR rate at each dose level (the proportion of patients whose best response at any time during the study was either a CR or PR); duration of response, defined as the time from the date a response is determined to the date of first evidence of progression; and TTP, defined as the time from study day 1 to the date of first evidence of progression.

Statistical Analysis
Safety analyses were performed on all patients who received at least one dose of epratuzumab. The analyses of OR rate for a given dose and TTP were based on the evaluable patient subset (ie, all enrolled patients who received at least one dose of epratuzumab, had a diagnosis of recurrent indolent NHL, and had at least one posttreatment evaluation for response or had withdrawn from study before the first posttreatment evaluation of response because of disease progression). Duration of response was analyzed for the responder subset. The proportion of patients with OR was provided with its 95% confidence intervals (CIs). The Kaplan-Meier method was used to estimate median duration of response and TTP.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Fifty-five patients with indolent NHL received epratuzumab and were assessable for safety; 51 patients were assessable for response. Four patients were not assessable for efficacy for the following reasons: different histology (one patient with B-cell acute lymphocytic leukemia) and no available postbaseline evaluation for response (three patients).

Patient Characteristics
Demographic characteristics for patients receiving at least one dose of epratuzumab are shown in Table 1. Similar proportions of men and women were enrolled. The median age was 61 years (range, 26 to 81 years). Approximately half had lesions of 5 cm and 40% had elevated lactate dehydrogenase (LDH) levels. Patients had received multiple prior therapies (median of three to four prior radiotherapy, chemotherapy, and immunotherapy regimens [range, one to 10 regimens]) and 44% had previously received rituximab. Almost three fourths of patients had follicular NHL and approximately one fourth of patients had CLL/SLL. Fifteen follicular and nine CLL/SLL patients had received prior rituximab, whereas 25 follicular and four CLL/SLL patients were rituximab-naive.

Safety
Eighty-four percent of patients experienced one or more adverse events. The vast majority of patients who experienced treatment-related events (occurring within 7 days from an infusion) had grade 1 events (Fig 1). These events occurred less frequently with subsequent infusions. The most frequent toxicity was nausea (22%). Other common toxicities (including all events, whether or not they were related to infusion) included fatigue, back pain, anemia, and limb pain (Table 2). No correlation between the frequency of adverse events and administered dose was observed, and no dose-limiting toxicity occurred. No clinically significant changes in laboratory measures (including hematology values and immunoglobulin levels) or vital signs were noted, and no serious, treatment-related adverse events occurred. No patient developed HAHA antibodies.

View larger version (14K): [in this window] [in a new window]   Fig 1. Treatment-related adverse events by infusion and National Cancer Institute common toxicity criteria grade (N = 55).

Epratuzumab Half-Life and Effects on Peripheral Blood Lymphocytes
On the basis of measurements after the last infusion, epratuzumab had a mean serum half-life of 23 days (standard deviation, 9 days; n = 35), which is comparable to the half-life of a human IgG₁ (21 days).¹⁹ Epratuzumab treatment did not affect T-cell levels as measured by CD3⁺ cell count, but did decrease B-cell levels (approximately 75% decrease from baseline) for up to 9 months as measured by CD19⁺ cell counts (Fig 2). Because some patients had high levels of peripheral blood B cells because of their disease (eg, CLL/SLL) and others had below-normal levels as a consequence of previous treatment, and because the number of patients at each dose level was small, it is not possible to draw any meaningful conclusions regarding correlations between specific epratuzumab dose levels and peripheral blood B-cell counts.

View larger version (9K): [in this window] [in a new window]   Fig 2. Median B-cell counts (CD19+) by visit for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and non-CLL/SLL histology. Logarithms were taken before the analysis. Twenty-four hours (24HR) and 4 weeks (4WK) represent time from the last infusion date; all of the following visits (3-[3M], 6-[6M], and 9-month [9M] follow-up [FU]) represent time from the 4-week restaging visit. BL, baseline.

View larger version (12K): [in this window] [in a new window]   Fig 3. Objective response rates by dose for assessable patients with follicular non-Hodgkin’s lymphoma. The 95% confidence intervals were 11% to 40%, 18% to 71%, and 6% to 61% for the overall rates, the 360 mg/m2 group, and the 480 mg/m2 group, respectively.

View larger version (12K): [in this window] [in a new window]   Fig 4. Maximum percent change in sum of products of greatest diameter (SPD) for each assessable indolent non-Hodgkin’s lymphoma patient (n = 51). () Patients without SPD measurement but with evident disease progression; (*) patients with absolute value of maximum percent change 1.

View larger version (11K): [in this window] [in a new window]   Fig 5. Kaplan-Meier curves of time to progression for responders and for all assessable patients. C, censored observation; 95% confidence intervals are displayed for the cumulative percent of progression-free patients by month 8.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

This is the first report of the safety and activity of epratuzumab (humanized anti-CD22) over a wide range of doses and indolent NHL histologies. Although the function of CD22 is not completely understood, it appears to play an important role in both B-cell adhesion and activation. As a specific marker for most neoplastic and nonneoplastic B cells, which characterizes their cell lineage as well as stage of development, CD22 is a promising target for the treatment of NHL. In vitro, monoclonal antibodies against CD22 induce cell death in several Burkitt’s lymphoma cell lines,²⁵ and in animal models CD22-blocking antibodies mediate antitumor effects (R. Stein and D.M. Goldenberg, unpublished observation). Importantly, because epratuzumab is a humanized IgG₁ antibody, this results in a demonstrated lower immunogenicity than murine monoclonal antibodies²⁴ and a theoretically lower immunogenicity than chimeric antibodies.

We have demonstrated that epratuzumab is well tolerated when infused at doses of 120 to 1,000 mg/m²/wk for four doses each over 1 hour. Even with the rapid infusion time and with high protein doses, the safety profile of epratuzumab in this study compared favorably to what has been observed historically with rituximab⁷ and Campath-1H.^26,27 The excellent infusion tolerability may relate to the fact that epratuzumab does not activate complement and thus produces a less-dramatic depletion of B cells. In addition, these dosing regimens resulted in an extended serum half-life of 23 days (compared with approximately 10 days with rituximab⁷).

The significant number of objective tumor responses (including durable CRs) in this first clinical study of an unlabeled anti-CD22 antibody indicates that epratuzumab is a promising new therapy for NHL. A total of nine of 51 assessable patients (18%) achieved an OR after four once-weekly infusions of epratuzumab: three (6%) CRs and six (12%) PRs. All responses were observed in the follicular group at doses of 360 mg/m² (43%) and 480 mg/m² (27%). Of the 51 patients, 20 (39%) had SD as the best response. Seven patients have had sustained responses of greater than 8 months and one response is ongoing at 7 months after treatment. TTP for responding patients was a median of 86.6 weeks. As previously observed with rituximab, clinical activity was reduced in patients with CLL/SLL in this early-stage evaluation. Reasons for this are unclear, and could relate to lower levels of antigen expression (as with CD20) or relative resistance of this histology to antibody treatment in general. Additional exploration of alternative dosing regimens of epratuzumab is warranted in other indolent NHL subtypes.

This was a relatively small, phase I and II trial designed to test the safety and efficacy of epratuzumab over a wide range of doses and in various NHL histologies; as such, these preliminary findings will need to be confirmed in larger studies designed to determine efficacy in specific NHL patient populations. Nevertheless, the early results are encouraging because evidence of antitumor activity was seen in a number of patients and responses were durable. In comparison, tumor responses in the phase I trial of rituximab occurred in 33% of patients, all PRs, with a median TTP of 6.4 months.⁵ Another positive aspect of the current report is that the TTP and sum of products of greatest diameter data indicate stabilization of disease after administration of epratuzumab in additional patients, and approximately 50% demonstrated evidence of antilymphoma effects.

Baseline characteristics of the responders showed that patients with follicular morphology, lower tumor burden, and normal LDH tended to be more likely to respond to epratuzumab. This is not surprising; these characteristics are also associated with response to other antilymphoma agents. Pretherapy B-cell counts were similar in responders and nonresponders, although this information is confounded in some cases by prior rituximab therapy (and resultant low B-cell counts) as well as high numbers of circulating malignant B cells, as in patients with CLL/SLL (who were generally nonresponsive). Because CD22 expression was not assessed in a standardized fashion, we were unable to correlate expression levels with response. This is an important issue that is best addressed in a uniform study population treated with the same dosing regimen, with correlation of immunohistochemistry performed with a standard method. This approach is underway in follow-up studies of epratuzumab in NHL.

Two of the nine responders had previously been treated with rituximab, which indicates potential activity in patients with disease progression after rituximab therapy. Of importance is whether patients resistant to one B-cell–directed antibody are likely to respond to another, or whether cross-resistance occurs. Elucidation of this important issue was not the intent of this phase I and II study, and is the subject of additional evaluation.

Responses were seen in the 360 and 480 mg/m² dose groups, but not in the 600 or 1,000 mg/m² dose groups, likely because of the smaller numbers of patients enrolled in the higher dose groups and an unplanned patient selection: the baseline characteristics of patients in the higher dose groups were somewhat less favorable than those of the 360 and 480 mg/m² groups. For example, several patients with CLL/SLL (a histologic type associated with lack of response to epratuzumab in this study) received the higher doses. On the basis of these preliminary efficacy data, the dosages of 360 to 480 mg/m²/wk (for 4 weeks) are active for follicular lymphoma and will be evaluated in future clinical studies, as well as other regimens in other clinical settings. The extended half-life of epratuzumab also indicates that less frequent dosing schedules may be feasible.

Because naked monoclonal antibodies achieve their efficacy through different mechanisms of action than traditional cytotoxic chemotherapy drugs, their toxicities do not generally overlap and they may have additive or synergistic activity. Coadministration, therefore, represents an attractive possibility. Epratuzumab in combination with chemotherapy could potentially improve effectiveness versus standard regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone, as preliminarily shown with rituximab.²⁸ Combination regimens including chemotherapy plus epratuzumab and rituximab are currently under evaluation. Furthermore, potential non–cross-resistance between epratuzumab and rituximab could result in improved clinical activity when the combination is used to treat indolent NHL patients who are responsive to both agents, or could permit responses in rituximab-refractory patients. Preliminary findings in a murine model²⁹ and in patients^30,31 indicate that the combination of rituximab and epratuzumab is well tolerated and may result in improved clinical activity versus the single agents alone. Ongoing and future studies will continue to define the therapeutic role of epratuzumab, both as a single agent or in combination therapy, in patients with indolent NHL.

	ACKNOWLEDGMENTS

 
We thank the patients who participated in this clinical trial. Jennifer Fiore, Alan Dosik, Darlene Dreher, Manuel Vargas, Michelle Ashe, Ding Shieh, and Yan Xing assisted in study conduct. Christine Dale, Raquel Izumi, and Scott Z. Fields assisted in manuscript preparation. Heather Kapushoc and StatProbe, Inc, provided assistance with statistics.

	NOTES

 
Supported by Immunomedics, Inc, Morris Plains, NJ, and Amgen Inc, Thousand Oaks, CA. J.P.L. is supported in part by a K23 award from the National Institutes of Health (RR16814-02), and a pilot grant from the Cornell Center for Aging Research and Clinical Care. J.P.L. has served as a consultant to Amgen. M.C., W.A.W., H.J.H., H.Z., and D.M.G. are officers and/or employees of Immunomedics, Inc. M.E., U.G., and A.C. are employees of Amgen, Inc.

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Submitted January 14, 2003; accepted March 28, 2003.

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