Annals of Oncology Advance Access originally published online on April 29, 2007
Annals of Oncology 2007 18(7):1216-1223; doi:10.1093/annonc/mdm114
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© 2007 European Society for Medical Oncology
hematologic malignancies |
A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma
1 Division of Hematology/Oncology, Weill Medical College of Cornell University and NewYork-Presbyterian Hospital, New York, NY
2 Lymphoma Clinical Research, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY
3 Division of Cancer Medicine Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston, TX
4 Department of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, MA
5 Division of Hematology/Oncology, Northwestern University, Chicago, IL
6 Division of Hematology—Oncology, Duke University, Durham, NC
7 Departments of Hematologic Oncology and Bone Marrow Transplantation, Roswell Park Cancer Institute, Buffalo, NY
8 Section of Hematology/Oncology, University of Arizona, Tucson, AZ
9 Division of Hematology/Oncology, Loyola University Medical Center, Chicago, IL
10 Department of Hematology, Georgetown University Hospital, Washington, DC
11 Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL
12 Department of Hematology/Oncology - Medical Research
13 Department of Biostatistics
14 Department of Medical Writing, Biogen Idec Inc., San Diego, CA, USA
* Correspondence to: Dr J. P. Leonard, Weill Medical College of Cornell University and NewYork-Presbyterian Hospital, Starr Building, Room 340, 520 East 70th Street, New York, NY 10021 USA. Tel: +1 212-746-2932; Fax: +1 212-746-3844; E-mail: jpleonar{at}med.cornell.edu
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Abstract |
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Background: Galiximab is a monoclonal antibody that targets CD80, a costimulatory molecule constitutively expressed on follicular and other lymphomas. Modest single-agent clinical activity and tolerability were demonstrated in a phase I study in relapsed or refractory, follicular non-Hodgkin's lymphoma (NHL). A phase I/II study was conducted to evaluate galiximab in combination with a standard course of rituximab. Safety, pharmacokinetics, and efficacy were evaluated.
Patients and methods: Patients with follicular NHL who had relapsed or failed primary therapy were enrolled. Rituximab-refractory patients (no response or a response with time to progression <6 months) were excluded. Patients received 4 weekly i.v. infusions of galiximab (125, 250, 375, or 500 mg/m2) and rituximab (375 mg/m2). International Workshop Response Criteria (IWRC) were used to evaluate response.
Results: Seventy-three patients received treatment. All had received at least one prior lymphoma therapy; 40% were rituximab naive. Infusions were delivered in an outpatient setting and were well tolerated. The most common study-related adverse events (AE) were lymphopenia, leukopenia, neutropenia, fatigue, and chills. The overall response rate at the recommended phase II dose of galiximab (500 mg/m2) was 66%: 19% complete response, 14% unconfirmed complete response, and 33% partial response. The median progression free survival was 12.1 months. Combination therapy did not appear to alter pharmacokinetics.
Conclusion: These results indicate that galiximab can be safely combined with a standard course of rituximab. This doublet biologic approach offers the potential to avoid or delay chemotherapy or to integrate with other lymphoma therapies. A phase III, randomized study evaluating clinical benefit of rituximab versus the combination has been initiated.
Key words: galiximab, lymphoma, monoclonal antibody, rituximab, CD80
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Treatment of follicular non-Hodgkin's lymphoma (NHL) is characteristically associated with a high rate of initial response, followed by relapse. Subsequent remissions occur, but at a progressively lower rate and with progressively shorter durations [1]. Despite improvements in response rates with more aggressive combination regimens, the increased toxicity and/or logistics of administration with these regimens limit their use in a significant number of patients [2–5]. The introduction nearly a decade ago of therapeutic monoclonal antibodies provided patients with an alternative. Single-agent rituximab (anti-CD20 antibody) has demonstrated response rates of
50% with a favorable safety profile in relapsed or refractory, low-grade or follicular B-cell NHL [6]. Studies investigating maintenance/extended treatment with rituximab have shown prolonged progressive free survival (PFS) and event free survival (EFS) in indolent NHL [7, 8]. Antibody combination therapies are also under development to improve clinical response and/or to extend remission without increasing toxicity. Galiximab, an anti-CD80 antibody, is one such therapy. Galiximab was developed as a macaque–human chimera (human constant regions and primate variable regions) to minimize immunogenicity and is structurally indistinguishable from human antibodies [9]. It binds specifically to CD80, which is transiently expressed on the surface of activated B cells and antigen-presenting cells including dendritic cells, but is constitutively expressed on a variety of NHLs, including follicular lymphoma; thus, CD80 is an attractive target for lymphoma therapy [10–14]. Preclinical studies indicate that targeting this antigen has antitumor effects. In vitro, cross-linking CD80 with anti-CD80 antibodies on lymphoma cells has been shown to inhibit cell proliferation, up-regulate proapoptotic molecules, and induce antibody-dependent cell-mediated cytotoxicity (ADCC) [15]. In vivo, galiximab delays progression and prolongs survival in a human lymphoma xenograft/severe combined immunodeficiency (SCID) mouse model [16]. Previous clinical studies with galiximab have shown promising results. A phase I/II, single-agent, dose escalation, multiple-dose study demonstrated that 4 weekly infusions of galiximab (125, 250, 375, or 500 mg/m2) were well tolerated. Modest single-agent activity was observed [11% overall response rate (ORR)] and nearly half of all patients had a decrease in tumor burden [17].
Galiximab in combination with the anti-CD20 monoclonal antibody rituximab has also been evaluated. In vitro, combination therapy increased ADCC over that observed with either agent alone. Treatment with galiximab or rituximab in SCID mice with human SKW NHL xenografts, which express both CD80 and CD20, increased survival over untreated controls, and the combination of the two antibodies appeared more effective than either agent alone [16]. These observations provided the rationale for developing galiximab in combination with rituximab as a targeted therapy for the treatment of patients with relapsed or refractory, follicular NHL.
Herein, we report results from a multicenter, phase I/II clinical study evaluating galiximab in combination with a standard course of rituximab in patients with relapsed or refractory, follicular NHL.
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patients and methods |
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study objectives
The primary objective of the study was to characterize the safety profile and define the recommended phase II dose of galiximab in combination with rituximab in patients with relapsed or refractory, follicular NHL. Secondary objectives included the evaluation of pharmacokinetics (PK), efficacy, and immunogenicity.
eligibility criteria
Adult patients (
18 years) with histologically confirmed, follicular NHL who had relapsed or failed primary therapy were eligible for this study. Patients were required to have progressive disease after at least one prior standard therapy. Patients who were rituximab-refractory [defined as no response to prior rituximab or prior rituximab-containing regimen or a response with a time to progression (TtP) of <6 months] were not eligible for this study. Previously published studies have demonstrated that CD80 is universally expressed on lymphoma cells; therefore, CD80 expression was not a requirement for study eligibility. Patients were not permitted to have had radiotherapy, biological therapy, chemotherapy, prednisone, or other immunosuppressive therapy within 3 weeks before the first scheduled treatment. Inclusion criteria also required patients to have a World Health Organization performance status of two or less; bidimensionally measurable disease with at least one lesion 2.0 cm in a single dimension; and adequate hematological, renal, and hepatic function. Patients were excluded if they had central nervous system lymphoma, chronic lymphocytic leukemia, a prior diagnosis of aggressive NHL or mantle-cell lymphoma, active opportunistic infection, serious nonmalignant disease, or were human immunodeficiency virus positive. Concomitant treatment with additional lymphoma treatments or other investigational drugs was not permitted during the study.
The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients, and each participating clinical site received approval from its Institutional Review Board.
study design
This was an open-label, multicenter, dose escalation, phase I/II study. In phase I, patients were enrolled into four treatment groups using a standard 3 + 3 dose escalation design for galiximab (125, 250, 375, or 500 mg/m2). Subjects received 4 weekly i.v. infusions of rituximab (375 mg/m2) and galiximab (Figure 1). For safety reasons, the first infusions of rituximab and galiximab were given on separate days. The first infusion of rituximab was given on day 1, and subjects were monitored for infusion-related events known to occur. The first infusion of galiximab was given on day 3. Thereafter, rituximab and galiximab were given on the same infusion day (days 8, 15, and 22). Enrollment into a higher dose cohort was not permitted until three patients in the previous treatment group were at least 12 days beyond their first infusion of galiximab with no dose-limiting toxic effects (DLTs) reported. If one of three patients experienced DLT, an additional three patients were to be enrolled in the treatment group and no further DLT (i.e. one of six patients) were observed before dose escalation could proceed. If two of three patients experienced DLT, additional patients were not to be enrolled in that treatment group and the preceding dose of galiximab in combination with rituximab was to be the recommended phase II dose. DLT was defined as grade 3 toxicity not associated with an infusion, grade 4 toxicity, or adverse reactions that prevented completion of an infusion within 48 h. In phase II, enrollment was expanded to treat 60 patients at the dose recommended from phase I.
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Following the administration of study treatment, patients entered a follow-up period (through month 48). All patients who withdrew from the study early or were alive at the end of the 48-month study period were followed, at 6-month intervals, for continuation of response (if applicable), initiation of a subsequent lymphoma therapy, and survival.
study treatment
Study treatment was administered as i.v. infusions in an outpatient setting. Rituximab was given according the package insert directions. The median infusion duration for galiximab was 1 h. Doses were individually formulated according to assigned treatment group and the patient's body surface area. In calculating the dose, there was no downward adjustment to ‘ideal’ body weight.
study end points
safety.
Safety evaluations included physical examinations, clinical adverse events (AEs), hematology, blood chemistry, immunology, vital sign measurements, and urinalysis. AEs were encoded using MedDRA (version 8.0) and graded using the National Cancer Institute Common Toxicity Criteria (version 2.0). Immunology evaluations included immunoglobulin concentrations (immunoglobulin G, immunoglobulin M, and immunoglobulin A), T- and B-lymphocyte subsets (CD3+, CD3+CD4+, CD3+CD8+, CD19+), antigaliximab antibody formation, and antihuman chimeric antibody (HACA) formation. Antigaliximab and HACA formation were evaluated at baseline and months 3, 6, 9, and 12 post-treatment using an enzyme-linked immunosorbent assay method.
pharmacokinetics.
Serum samples to evaluate galiximab and rituximab concentrations were obtained before and after the completion of each infusion and posttreatment up to month 12. Data were analyzed using noncompartmental methods. PK parameters evaluated included maximum observed concentration (Cmax), elimination half-life (t1/2), and area under the concentration–time curve (AUC).
efficacy.
Disease assessments were carried out by comprehensive scans (computed tomography or magnetic resonance imaging) and physical examination at study entry, 1 month after completion of galiximab treatment (day 50), every 3 months thereafter for years 1 and 2, and every 6 months for years 3 and 4. Response to treatment was analyzed using the IWRC for NHL [18]. The primary efficacy end point was ORR at the recommended phase II dose of galiximab. Secondary efficacy end points included complete response (CR) rate, unconfirmed complete response (CRu) rate, partial response (PR) rate, duration of response, TtP, time to next anticancer therapy, overall survival (OS), EFS, and PFS.
statistical methods
Phase I was to include three to six subjects at up to four dose levels for a total of 12–24 subjects. In phase II, additional subjects were to be enrolled for a total of 60 per protocol subjects treated at the recommended phase II dose. With a sample size of 60 per protocol subjects, the precision of the objective ORR estimate, reflected by the width of the 95% confidence interval (CI), would range from 20% to 26%.
Patients were considered assessable for safety and efficacy if they received any part of an infusion of study treatment. Patients were considered assessable for PK analyses if they received four infusions of galiximab and had sufficient data available for calculation of PK parameters.
Summary descriptive statistics were used for all continuous variables (n, mean, standard deviation, median, minimum, maximum) and categorical variables (n, %). All CIs for proportions were calculated using the methodology for inference about a single proportion. For Kaplan–Meier median estimates, a 95% CI was calculated on the basis of the sign test proposed by Brookmeyer and Crowley [19].
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patient characteristics
From 27 November 2002 to 05 March 2004, 75 patients with relapsed or refractory, follicular lymphoma were enrolled at 18 clinical sites in the United States. Of the 75 patients enrolled, 72 received all scheduled infusions of study treatment (three at 125 mg/m2, three at 250 mg/m2, three at 375 mg/m2, and 63 at 500 mg/m2), one patient discontinued treatment after three infusions due to disease progression (500 mg/m2 group), and two patients withdrew from the study before treatment.
A summary of baseline characteristics for all treated patients is presented in Table 1. The median age of patients was 59 years. All had progressed after a median of two prior treatment regimens; 29 (40%) were rituximab naive. The majority of patients had disease stage III/IV (88%). Distribution by Follicular Lymphoma International Prognostic Index (FLIPI) risk group was good (23%), intermediate (41%), and poor (36%). The median time from diagnosis to study entry was 4.4 years.
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Seventy-three patients were evaluated for safety and efficacy. Efficacy is also reported for the 64 patients treated at the recommended phase II dose of galiximab (500 mg/m2). Fifteen patients remain on study in long-term follow-up; the median follow-up is 25 months (1–34.8 months) as of 17 May 2006.
clinical adverse events
Antibody infusions were well tolerated. No DLTs were reported at any dose, and no patient withdrew from the study due to toxicity.
AEs of possible, probable, or unknown relationship to study treatment are presented in Table 2. Seventy (96%) patients experienced at least one study-related AE; the most common were lymphopenia (48%), leukopenia (36%), fatigue (36%), chills (27%), and neutropenia (22%). Eighteen (25%) patients experienced grade 3 study-related AEs. One (1%) patient experienced a grade 4 study-related AE (neutropenia), which was classified as ‘possibly’ related to study treatment. The patient was treated with filgrastim and the event resolved.
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Thirteen serious adverse events (SAEs) were reported in six patients. One patient experienced SAEs considered possibly related to the first administration of rituximab (grade 1 hypotension and nausea and grade 3 vomiting). The rituximab infusion was interrupted until the events resolved. All other SAEs were considered by investigators to be unrelated to study treatment.
infections
Twenty-six (36%) patients experienced an infection during the study. The most common infections were upper respiratory tract infections (7%), nasopharyngitis (6%), pneumonia (6%), and urinary tract infections (6%). The majority of infections were grade 1 or 2. Four grade 3 infections were experienced by three patients: pneumonia, bronchitis, sinusitis, and central line infection. None were considered by the investigator to be related to study treatment, and all resolved with medication. No patient experienced a grade 4 infection.
immunological parameters and lymphocyte subsets
Detailed analyses of changes in immunological parameters and lymphocyte subsets were carried out. Median serum immunoglobulin concentrations and T- and B-lymphocyte subset counts fluctuated throughout the study, but remained within the normal range with the exception of CD19+ B-cell counts. Median CD19+ cell counts decreased below the normal range by study day 8 (median of 0 cell counts). CD19+ counts returned to normal in the majority of patients with measurements at study month 12. No patient developed detectable antigaliximab antibody or HACA titers post-treatment.
pharmacokinetics
For galiximab, Cmax and AUC values were proportional to the administered dose. Concentrations were measurable in most patients up to 6 months after dosing at 500 mg/m2, but seldom thereafter. Figure 2 shows the mean serum concentrations of galiximab and rituximab over time for the 500 mg/m2 galiximab treatment group. The mean half-life for 500 mg/m2 galiximab was 25.8 days, and the mean half-life for rituximab was 27.3 days.
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efficacy
The primary efficacy end point was ORR at the recommended phase II dose of galiximab. The ORR in the 500-mg/m2 galiximab treatment group was 66% (42 of 64 treated patients; 95% CI, 52.6–76.8%) with a 19% CR rate, 14% CRu rate, and 33% PR rate. An additional 28% (18 of 64) had stable disease [The appendix of the protocol defined stable disease as
50% decrease in the sum of the products of the greatest diameters (SPD) of the 6 largest dominant nodes or nodal masses, but 50% increase from nadir in the SPD] as their best response. The median PFS was 12.1 months. The ORR for patients who were rituximab naive was 70% (19 of 27) with a median PFS of 15.4 months. The ORR for all treatment groups was 63% (46 of 73) with a median PFS of 11.7 months. In some patients, response improved over time between the 1- and 4-month scans. A summary of efficacy end points for the 500-mg/m2 galiximab treatment group and for overall is presented in Table 3.
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The median OS has not been reached to date. Of the 73 patients treated, 63 (86%) patients remain alive and 10 have died. Nine deaths occurred off study; six were attributed to disease progression and two were from unknown causes. One death occurred on study. The subject had a history of dyspnea, dry cough, sleep apnea, obesity, hypertension, and diabetes. He received all infusions of study treatment and experienced respiratory failure and died 9 days after his last infusion. The investigator classified the event as unrelated to study treatment. The cause of death was reported as respiratory failure due to chronic obstructive pulmonary disease, most likely related to obesity; however, a potential relationship to study treatment cannot be definitively ruled out.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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A therapeutic goal in the management of follicular NHL is to extend remission without increasing toxicity. Many standard of care therapies are limited by their toxicity profiles and/or logistics of administration. The benefit of targeted therapies, such as monoclonal antibodies, is a potential for lower toxicity of treatment. Galiximab is an investigational monoclonal antibody that targets CD80, a costimulatory molecule universally expressed on NHL and Hodgkin's cells [10–14, 20–22]. Because galiximab's safety profile and mechanism of action differ from chemotherapeutic agents and other monoclonal antibodies, galiximab offers the potential for integration with other lymphoma therapies. This clinical study employs a doublet of two biologic agents (antibodies against CD20 and CD80) in follicular lymphoma, an approach that offers the potential to avoid or delay chemotherapy (and its associated toxic effects) or to integrate it with other lymphoma therapies. The current approved schedule for rituximab is weekly times four; therefore, a weekly dosing schedule with combination therapy was chosen based on the ease of administration for patients and clinicians.
The favorable safety profile of galiximab is notable, particularly, with respect to the lack of myelosuppression typical with standard chemotherapies, radiotherapy, and other antibody therapies [2, 3, 23–25]. The ease of galiximab administration was also favorable; galiximab infusions were delivered in an outpatient setting and were well tolerated. The toxicity profile of rituximab is well known, and the addition of galiximab to rituximab in this current study did not appear to increase the overall incidence of AEs or alter the AE profile. Additionally, the median serum half-life of rituximab when administered in this combination is similar to that observed in several recent studies of rituximab monotherapy [26–28]. Laboratory correlative studies showed no evidence of T-cell depletion following galiximab monotherapy [17] or galiximab in combination with rituximab. Transient B-cell depletion was observed in this current study, but not in the galiximab monotherapy study and was attributed to the use of rituximab in the combination regimen. The pattern of transient B-cell depletion is similar to that seen with rituximab monotherapy. A reasonable concern would be that targeting the CD80 antigen could impair antigen-presenting function. However, we could find no evidence of this. Since galiximab is a primatized antibody, the risk of immunogenicity is low compared with murine and some chimeric antibodies, which can potentially restrict repeated administration. To confirm this, no patient developed HACA or antigaliximab antibodies, no secondary malignancies or lymphoproliferative disorders have been reported, and there was no significant increase in infections compared with rituximab monotherapy.
Galiximab monotherapy produced modest clinical activity (11% ORR) [17]. Combination therapy with rituximab produced an ORR of 66% with a median PFS of 12.1 months. There appeared to be a trend for patients in lower FLIPI risk groups and rituximab-naive patients to have better clinical outcome as measured by ORR and PFS. Three historical rituximab monotherapy studies using a standard course of rituximab monotherapy in follicular NHL showed an ORR of 58%, with a median PFS of 9.4 months [29–31]. A phase III, randomized, double-blind study comparing galiximab in combination with rituximab with rituximab and placebo for the treatment of relapsed and refractory, follicular NHL has been initiated. In addition, accrual has recently been completed in an investigator-sponsored Cancer and Leukemia Group B study evaluating efficacy after up-front galiximab plus rituximab therapy (weekly for 4 weeks) followed by extended dosing with rituximab and galiximab (every 2 months times four) in previously untreated follicular NHL patients.
Defining an optimal phase II dose with biologic therapy is challenging. The maximum tolerated dose was not reached in this study, and dose escalation with galiximab was feasible up to 500 mg/m2. This dose was demonstrated to be safe and active in the single-agent, phase 1 study, and we did not observe additional efficacy or an increase in toxicity in the combination study when the galiximab dose was escalated from 375 to 500 mg/m2. Patients did not appear to be underdosed, as evident by the PK profile. Therefore, the 500 mg/m2 dose was considered to be a reasonable dose to evaluate in phase II. However, we recognize that higher or lower doses may also be effective. Additional studies are planned to explore alternative dosing schedules. Potential future directions also include evaluating maintenance therapy with this combination regimen in follicular NHL and galiximab, rituximab, plus chemotherapy for follicular and diffuse aggressive NHL.
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Acknowledgements |
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We would like to acknowledge Margaret Whiteley and the Biogen Idec 114-21 study management team and the investigational site coordinators. This study was supported by Biogen Idec Inc. This work was presented in part at the 9th International Conference on Malignant Lymphoma (June 2005) and the Annual Meeting of the American Society of Hematology (December 2005). The following authors have indicated a financial interest. JPL, JWF acted as a consultant or advisor for Biogen Idec within the last 2 years. JPL, DF, LIG, and JM received honoraria from Biogen Idec. LIG, TM, AF-T, and MC received research funding from Biogen Idec. NC, BM, DF, and AM are employees of Biogen Idec and own stock.
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Footnotes |
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These authors contributed equally to this work and share first authorship. 
Received for publication November 7, 2006. Revision received February 21, 2007. Accepted for publication February 22, 2007.
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