Originally published as JCO Early Release 10.1200/JCO.2006.07.8972 on May 21 2007

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Phase I/II Study of an Anti-CD30 Monoclonal Antibody (MDX-060) in Hodgkin's Lymphoma and Anaplastic Large-Cell Lymphoma

Stephen M. Ansell, Steven M. Horwitz, Andreas Engert, Khuda Dad Khan, Thomas Lin, Roger Strair, Tibor Keler, Robert Graziano, Diann Blanset, Michael Yellin, Steven Fischkoff, Albert Assad, Peter Borchmann

From the Mayo Clinic School of Medicine, Rochester, MN; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Cologne, Cologne, Germany; American Health Network Oncology, Indianapolis, IN; Ohio State University, Columbus, OH; University of Medicine and Dentistry of New Jersey, Newark; and Medarex Inc, Princeton, NJ

Address reprint requests to Stephen M. Ansell, MD, PhD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: ansell.stephen{at}mayo.edu

	ABSTRACT

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Purpose: MDX-060 is a human anti-CD30 immunoglobulin (Ig) G1 monoclonal antibody that inhibits growth of CD30-expressing tumor cells in preclinical models. To determine the safety, maximum-tolerated dose (MTD), and efficacy of MDX-060 in patients with relapsed or refractory CD30+ lymphomas, sequential phase I and II studies were performed.

Patients and Methods: In the phase I portion, MDX-060 was administered intravenously at doses of 0.1, 1, 5, or 10 mg/kg weekly for 4 weeks to cohorts of three to six patients. Twenty-one patients—16 with Hodgkin's lymphoma (HL), three with anaplastic large-cell lymphoma (ALCL), and two with CD30+ T-cell lymphoma—were enrolled. Because of the lack of a defined MTD or dose-response correlation, the phase II portion was amended to include several dose levels. In the phase II portion, an additional 51 patients, 47 with HL and four with ALCL, were treated at doses of 1, 5, 10, and 15 mg/kg.

Results: MDX-060 was well tolerated, and an MTD has not been identified. Only 7% of patients experienced grade 3 or 4 treatment-related adverse events. Among the 72 patients treated, clinical responses were observed in six. Twenty-five patients had stable disease, including five who remained free from progression 1 year after treatment.

Conclusion: MDX-060 was well tolerated at doses up to 15 mg/kg. MDX-060 has limited activity as a single agent, but the minimal toxicity observed and the significant proportion of patients with stable disease suggests that further study of MDX-060 in combination with other therapies is warranted.

	INTRODUCTION

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CD30 is a 120-kD transmembrane protein from the tumor necrosis factor receptor family. CD30 expression is restricted in normal tissues to activated B and T cells,^1,2 and to cells infected with Epstein-Barr virus.³ Cells from various lymphocytic malignancies have also been noted to express CD30.^3,4 These include Ki-1–positive cells in anaplastic large-cell lymphoma (ALCL) and Reed-Sternberg cells in Hodgkin's lymphoma (HL).⁵ Also, 30% of T-cell lymphomas and 20% of B-cell lymphomas express CD30. Furthermore, soluble CD30 has been recognized as a negative prognostic sign in HL.⁵

The CD30 ligand (CD153) is a type II membrane glycoprotein expressed on activated T cells, macrophages, B cells, neutrophils, eosinophils, and mast cells, and ligand binding induces activation, proliferation, differentiation, and apoptosis in different cell types.^4,6 It is speculated that CD153 expressed on nonmalignant intratumoral cells⁷ recruited by the Reed-Sternberg cells,⁸ regulates the growth and activation of the malignant cells.^9,10 Interruption of this interaction may potentially lead to inhibition of malignant cell growth.

MDX-060 is a fully human anti-CD30 immunoglobulin G1 monoclonal antibody that binds to CD30 with nanomolar affinity. It was generated in human monoclonal antibody mice that are transgenic for human immunoglobulin genes and therefore generate fully human antibodies when exposed to nonmurine antigens. MDX-060 showed specific and dose-dependent binding to recombinant CD30 by enzyme-linked immunosorbent assay. As demonstrated by flow cytometry, it also binds to CD30+ lymphoma cell lines.¹¹ MDX-060 has shown preclinical evidence that it modulates signaling to inhibit cell proliferation and induces antibody-dependent cytotoxicity.¹¹ Furthermore, it has been shown to kill HL cell lines in vitro and in xenograft tumor models.¹¹ MDX-060 does cross-react with activated T cells from cynomolgus monkeys; however, weekly doses of 5 and 50 mg/kg for 13 weeks were well tolerated in these animals, and no drug-related clinical or pathologic findings were noted (data on file at Medarex Inc, Princeton, NJ).

Because HL and ALCL cells express CD30, we conducted a phase I/II study to characterize the safety and tolerability of MDX-060 as a single-agent therapy for patients with CD30-positive lymphoma, and to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of MDX-060 when administered for 4 weeks. Additional objectives included characterization of the pharmacokinetic profile of MDX-060 and assessment of efficacy in patients with CD30-expressing lymphomas.

	PATIENTS AND METHODS

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Patient Eligibility
To be eligible for participation in this study, patients were 12 years of age with histologic proof of CD30-positive lymphoma. CD30 positivity was defined as the expression of CD30 on at least 50% of malignant cells, specifically the Reed-Sternberg cells in HL, as detected histologically on a biopsy obtained at any time in the disease course, by immunohistochemistry or flow cytometry using any commercially available anti-CD30 antibody. Patients were required to be refractory to prior therapy or have relapsed after chemotherapy or radiation therapy, or after an autologous or allogeneic bone marrow transplant.

The following laboratory values, completed 28 or fewer days before treatment, were required: a total WBC count of at least 1,500/µL, an absolute neutrophil count (ANC) of at least 1,000/µL, a platelet count of at least 75,000/µL, hemoglobin of at least 8 g/dL, total bilirubin no more than 2 mg/dL, serum creatinine of at least 2x the upper limit of the institution normal range (ULN), AST less than 2x ULN, and ALT less than 3x ULN. All patients were required to have a life expectancy of at least 12 weeks and an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2. Patients previously treated with an anti-CD30 antibody were not eligible. Known HIV-positive patients and patients requiring concurrent steroid therapy were not eligible. Patients recently treated with chemotherapy or radiation therapy were eligible only after 4 weeks had elapsed since the most recent treatment. Other exclusion criteria included active infection, purified protein derivative recently converted to positive, and CNS involvement by lymphoma. Pregnant and nursing women were not eligible for the study. All patients were required to give informed consent, and the institutional review boards of the participating institutions approved the study.

Study Design: Phase I
This portion of the trial was a multicenter dose-escalation study with three to six patients at each dose level. Cohorts of patients received MDX-060 at escalating dose levels of 0.1, 1.0, 5.0, and 10.0 mg/kg, administered weekly for 4 weeks as an intravenous infusion. MDX-060 was administered as an intravenous infusion using a volumetric pump over a period of 90 minutes, and not as an intravenous bolus injection. Dosing of patient cohorts at the next higher dose level was not initiated until 3 weeks after the last dose in the preceding patient cohort. The duration of treatment for all patients was 4 weeks, and patients were treated at each escalating dose level until DLT or MTD was achieved.

If no DLT was observed in a cohort of three patients treated at dose levels 0.1 and 1.0 mg/kg during the treatment period (4 weeks), the next cohort of three new patients would be treated at the next higher dose level. At dose levels 5.0 and 10.0 mg/kg, six patients were to be enrolled at each level to obtain additional safety and pharmacokinetic information. If DLT was encountered in one of the first three patients at any dose level, then a maximum of three additional patients would be treated at that same level. Subsequently, if the total incidence of DLT among those six patients was one in six, then the next three-patient cohort would be treated at the next higher dose level. If two or more patients at a given dose level experienced DLT, this dose level would exceed the MTD level, no additional patients would be enrolled at that level, and dose escalation would stop.

Study Design: Phase II
The phase II portion of the study was originally designed to enroll additional patients at the MTD. Because of the minimal toxicity observed in the phase I portion, no MTD was identified and no dose-response correlation was seen. The phase II portion of the protocol was amended to treat additional patients at a range of doses including the previously studied doses of 1, 5, and 10 mg/kg and a higher dose level of 15 mg/kg.

Toxicity and Response Evaluation
Patients treated at each dose level were evaluated weekly during therapy and 4 and 8 weeks afterward to assess toxicity. Doses were not escalated in any individual patient. DLT was defined as an adverse event or a new laboratory abnormality that occurred during or after the 28-day MDX-060 infusion period (up to 5 months post-treatment), judged to be related to MDX-060 and meeting any of the following criteria: grade 4 or higher toxicity, grade 3 or higher toxicity excluding tumor-associated toxicity (defined as local pain, irritation, or rash, localized at sites of known or suspected tumor), grade 4 or higher infusion toxicity (occurring 24 hours or sooner after the start of the infusion of MDX-060), or grade 3 infusion toxicity that persisted for greater than 6 hours.

Should a patient have stable disease or be responding to treatment at the time of the evaluation at 8 weeks, patients were followed monthly for a further 3 months and then every three months thereafter. Patients having objective progression of disease or clinical deterioration were taken off study. Patient responses to therapy were assessed using the International Working Group recommendations for response criteria for non-Hodgkin's lymphoma.¹²

Pharmacokinetic Evaluations
Plasma concentrations of MDX-060 were assessed before, during, and after the infusion in all patients participating in the phase I portion of the study. Specimens were obtained after the first and fourth infusions of MDX-060. Plasma concentrations of MDX-060 were measured using an enzyme-linked immunosorbent assay developed by Medarex Inc.

Statistical Methods
The primary objectives of the phase I portion of the study were to characterize the safety and tolerability of MDX-060 as a single-agent therapy and to determine the MTD and DLT of MDX-060 when administered on a weekly dosing schedule for 4 weeks. The primary objectives of the phase II portion of the study were to determine the clinical efficacy as well as the toxicity of MDX-060 in patients with relapsed or refractory CD30 positive lymphoma. The safety parameters included adverse events, vital sign measurements, clinical laboratory tests, physical examinations, and diagnostic tests (including ECG, chest x-ray, and computed tomography scans). All safety parameters 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 percent change from baseline values) as well as categorization via National Cancer Institute Common Toxicity Criteria (CTC) standard toxicity grading. Nonhematologic toxicities were evaluated via the ordinal CTC 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 MDX-060. The pharmacokinetic parameters were summarized using descriptive statistics. The estimated response rate was determined by evaluation of MDX-060–treated patients in both phase I and II studies. The clinical responses were summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. Additional efficacy parameters included duration of tumor response and time to tumor progression.

	RESULTS

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Patient Characteristics
Seventy-two patients with CD30-positive lymphoma were enrolled. Twenty-one patients were treated on the phase I portion of the study and 51 patients on the phase II portion. All patients received at least one dose of MDX-060. Patient characteristics by study phase are shown in Table 1.

Adverse Events in All Patients Treated With MDX-060
MDX-060 was well tolerated at the doses at administered in this trial. All grade 3 and 4 adverse events both suspected and not suspected to be due to MDX-060 are shown in Table 2. Serious adverse events that were felt to be possibly drug related occurred in five patients and included grade 3 elevations in liver transaminases in one patient, grade 3 epistaxis and grade 3 anemia in one patient, grade 3 dyspnea in one patient, and grade 4 dyspnea in one patient. One patient developed grade 4 acute respiratory distress syndrome felt to be possibly related to MDX-060, and one patient developed cardiac tamponade. All other serious adverse events were felt to be unrelated to MDX-060. No significant infusion-related toxicity was seen, and no patient required premedication. No detectable human antihuman antibody responses were detected.

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Plasma levels of MDX-060 by patient cohort treated in the phase I portion of the study. (A) Plasma levels of MDX-060 over a 48-hour period after the first infusion of MDX-060. (B) Plasma levels of MDX-060 over 48 hours after the fourth and final infusion of MDX-060.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Percentage change in tumor size for all patients enrolled onto the study.

Four of the responding patients received concomitant corticosteroids with the administration of MDX-060 as ongoing management of constitutional symptoms. One patient who had a complete response was receiving steroids for disease symptoms when enrolled and remained on the same dose throughout the study. A second patient who had a complete response received topical steroids for psoriasis. A third patient who had a partial response received 4 days of oral steroids followed by 20 days of inhaled steroids for pulmonary symptoms felt to be secondary to lymphoma. A fourth patient who had a partial response received intermittent doses of oral steroids for constitutional symptoms related to the underlying disease persistently while on study. Although it could be argued that the use of steroids may have contributed to the clinical response seen in this fourth patient, all of the patients were felt to be refractory to previous corticosteroid therapy, and we feel that it is unlikely that steroids contributed to the responses seen in these patients.

	DISCUSSION

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HL is a curable disease for the majority of patients when treated with combination chemotherapy, and in many cases adjuvant radiation therapy.¹³ The prognosis for other CD30-expressing lymphomas, particularly ALCL, is more variable and depends on features such as expression of the ALK-1 protein.¹⁴ Some patients who relapse, particularly those with HL, can be cured with second-line treatment, such as high-dose therapy with stem-cell transplantation.^15,16 However, patients who relapse after these procedures, or who are ineligible for second-line approaches, have a very poor prognosis.

Several anti-CD30 antibodies have been used in clinical trials to treat patients with relapsed and refractory CD30-expressing lymphomas.^17-22 These trials have evaluated chimeric or murine antihuman CD30 bispecific antibodies or antibodies conjugated to immunotoxins or radiolabeled with iodine-131. The chimeric anti-CD30 antibody SGN-30 has shown activity in early-phase clinical trials.^22,23 Preliminary results using SGN-30 showed that the drug was well tolerated, and responses were seen predominantly in patients with ALCL.²³ Furthermore, anti-CD30 antibodies have shown enhanced antitumor activity in vitro when administered as radioimmunoconjugates or when combined with chemotherapy.^21,24,25

In this study using MDX-060, doses up to 15 mg/kg were administered, and the MTD was not reached. Although clinical responses were seen in both patients with HL and ALCL and at most dose levels 1 mg/kg and higher, the overall response rate was only 8%. Stabilization of disease, at times durable, was observed in 35% of patients. Of the six responding patients, four patients received corticosteroids while on the study. However, it is important to note that in this cohort of heavily pretreated patients, 27 other patients were enrolled while receiving corticosteroids or received corticosteroids while on study. In the majority of these patients, corticosteroids were administered for symptoms secondary to the underlying malignancy, and the majority of these patients did not have a response to therapy. Although preclinical data do exist to suggest a possible synergistic effect between MDX-060 and dexamethasone in HL cell lines,²⁴ our assessment is that the patients in this study were refractory to corticosteroids, and the use of corticosteroids did not appear to potentiate the effect of MDX-060.

Although the number of patients was small, there was a suggestion that patients with ALCL may be more likely to respond to therapy with MDX-060. Of the seven patients with ALCL, two (28%) had a response to MDX-060, compared with 6% of patients (four of 63) with HL. An explanation for this difference in response rate may be the pattern of expression of CD30 in ALCL compared with HL. CD30 is highly expressed on most cells in ALCL, whereas in HL, CD30 is only expressed on the Reed-Sternberg cells, which commonly form a minority of the intratumoral cells. Based on the responses seen in this study, a further phase II study of MDX-060 as a single agent is being performed in ACLC, whereas in HL, MDX-060 is being combined with chemotherapy.

The results of this study show that MDX-060 administered to patients with relapsed or refractory CD30 expressing lymphomas is well tolerated. The safety of MDX-060 and the suggestion of antitumor activity make the use of this agent in combination with other therapies an attractive option for future studies.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Tibor Keler, Medarex; Robert Graziano, Medarex; Diann Blanset, Medarex; Michael Yellin, Medarex; Steven Fischkoff, Medarex; Albert Assad, Medarex Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Stephen M. Ansell, Medarex; Steven M. Horwitz, Medarex; Andreas Engert, Medarex; Khuda Dad Khan, Medarex; Thomas Lin, Medarex; Roger Strair, Medarex; Peter Borchmann, Medarex Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Stephen M. Ansell, Steven M. Horwitz, Michael Yellin, Steven Fischkoff

Financial support: Steven Fischkoff

Provision of study materials or patients: Stephen M. Ansell, Steven M. Horwitz, Andreas Engert, Khuda Dad Khan, Thomas Lin, Roger Strair, Peter Borchmann

Collection and assembly of data: Tibor Keler, Robert Graziano, Diann Blanset, Albert Assad

Data analysis and interpretation: Stephen M. Ansell, Steven M. Horwitz, Tibor Keler, Robert Graziano, Diann Blanset, Michael Yellin, Steven Fischkoff, Albert Assad

Manuscript writing: Stephen M. Ansell, Steven M. Horwitz

Final approval of manuscript: Stephen M. Ansell, Steven M. Horwitz, Andreas Engert, Khuda Dad Khan, Thomas Lin, Roger Strair, Tibor Keler, Robert Graziano, Diann Blanset, Michael Yellin, Steven Fischkoff, Albert Assad, Peter Borchmann

	NOTES

 
published online ahead of print at www.jco.org on May 21, 2007.

S.M.A. and S.M.H. contributed equally to this work.

Presented in part at the 45th Annual Meeting of the American Society of Hematology, December 6-9, 2003, San Diego, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted June 15, 2006; accepted April 10, 2007.

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