FDA Approval: Siltuximab for the Treatment of Patients with Multicentric Castleman Disease Albert Deisseroth1, Chia-Wen Ko2, Lei Nie2, Jeanne F

Published OnlineFirst January 19, 2015; DOI: 10.1158/1078-0432.CCR-14-1678

CCR Perspectives in Drug Approval Clinical Cancer Research FDA Approval: Siltuximab for the Treatment of Patients with Multicentric Castleman Disease Albert Deisseroth1, Chia-Wen Ko2, Lei Nie2, Jeanne F. Zirkelbach3, Liang Zhao3, Julie Bullock3, Nitin Mehrotra3, Pedro Del Valle1, Haleh Saber1, Christopher Sheth1, Brenda Gehrke1, Robert Justice1, Ann Farrell1, and Richard Pazdur1

Abstract

On April 22, 2014, the FDA granted full approval to siltuximab Tumor response was based on independent review of CT scans (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human- using the revised Response Criteria for Malignant Lymphoma, mouse monoclonal antibody to IL6, for the treatment of patients and symptomatic response was defined as complete resolution or with multicentric Castleman disease (MCD) who are human stabilization of 34 MCD-related signs and symptoms as reported immunodeficiency virus (HIV) negative and human herpesvi- by the investigator. Thirty-four percent of patients in the siltux- rus-8 (HHV-8) negative. The approval was primarily based on imab arm and no patients in the placebo arm met the primary the results of a randomized, double-blind trial in which 79 endpoint (P ¼ 0.0012). The most common adverse reactions symptomatic patients with MCD were allocated (2:1) to siltux- (>10% compared with placebo) during treatment with siltuximab imab plus best supportive care (BSC) or to placebo plus BSC. The were pruritus, increased weight, rash, hyperuricemia, and upper primary efficacy endpoint was the proportion of patients in each respiratory tract infection. Clin Cancer Res; 21(5); 1–5. 2015 arm achieving a durable tumor and symptomatic response that AACR. persisted for a minimum of 18 weeks without treatment failure.

Introduction refs. 6, 7), the disease is driven more by the viral (HHV-8) IL6, rather than by endogenous IL6 secreted by the germinal center Castleman disease is a rare disorder characterized by hyperpla- cells and is essentially a different disease which has a different sia of lymphoid tissue, resulting in lymphadenopathy, which may pattern of response to therapy. This is especially true of antibodies be unicentric Castleman disease (UCD) or multicentric Castle- to endogenous IL6, which do not bind to viral (HHV-8) IL6. man disease (MCD). UCD may be approached by local therapy, There are three different histopathologic variants: the plasma- whereas MCD requires a systemic approach. When the lymph- cytic variant, the hyaline vascular variant, and the mixed subtype adenopathy of Castleman disease is multicentric, it is also (8). In the plasmacytic variant, there is abundant infiltration of the associated with signs and symptoms of excess IL6 secretion by germinal centers with plasma cells and the IL6 levels are high. In germinal center B-cell lymphocytes (1–4). Patients with MCD the hyaline vascular variant, there is less of the plasma cell may have symptoms of fatigue, fever, weakness, day or night infiltration and lower levels of IL6. In patients with the hyaline sweats, anorexia, pruritus, pain, and/or dyspnea (5). The physical vascular variant, clonal proliferation of lymphocytes may occur. signs of the disease include fever, weight loss, fluid retention, In a fraction of patients with the hyaline vascular subtype, this edema, effusions, ascites, neuropathy, skin rashes, skin nodules, may evolve into non–Hodgkin lymphoma. lymphadenopathy, splenomegaly, and hepatomegaly. Laborato- Until the present time, there was no approved therapy in the ry abnormalities may include anemia, thrombocytopenia, elevat- United States for MCD. The following treatments have been tried: ed C-reactive protein (CRP), and hypoalbuminemia. chemotherapy with steroids and/or rituximab, bortezomib, tha- When MCD is associated with viral infections such as human lidomide, and autologous bone marrow transplantation follow- immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8; ing high-dose therapy. Initial responses may occur but are fol- lowed by relapse and progression of disease. A humanized mAb to the human IL6 receptor (tociluzumab) was administered to 28 1 Office of Hematology and Oncology Drug Products, Center for Drug patients with MCD (9). Although the authors did not report Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. 2Office of Biostatistics, Center for Drug Evaluation evidence of reduction of lymphadenopathy by CT scans, the dose and Research, U.S. Food and Drug Administration, Silver Spring, of corticosteroids required to manage symptoms was reduced 3 Maryland. Office of Clinical Pharmacology, Center for Drug Evalua- during therapy. tion and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. A phase I study of siltuximab, an anti-IL6 mAb administered by i.v. infusion, enrolled 37 patients with Castleman disease Note: This is a U.S. Government work. There are no restrictions on its use. (10). Siltuximab, which binds to IL6, is different from tocilu- Corresponding Author: Albert Deisseroth, U.S. FDA CDER, 10903 New Hamp- zumab, an antibody that binds to the IL6 receptor. According to shire Avenue, WO22-2334, Silver Spring, MD 20993-0002. Phone: 301-796- central radiologic review, there was one complete response 4864; Fax: 301-796-9845; E-mail: [email protected] (CR) and 11 partial responses (PR). This experience led to a doi: 10.1158/1078-0432.CCR-14-1678 phase II, randomized, placebo-controlled, double-blind trial to 2015 American Association for Cancer Research. test the efficacy and safety of siltuximab in MCD (11). The

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results of these trials were submitted in support of a Biologics downregulated by IL6. This may result in increased metabolism of License Application (BLA) for siltuximab for the treatment of CYP450 substrates compared with metabolism before treatment patients with MCD that was not associated with HHV-8 infec- with siltuximab. If siltuximab is coadministered with CYP450 tion. The BLA was received on August 30, 2013, and was substrate drugs with a narrow therapeutic range, the dose of the approved on April 23, 2014. The FDA review of the BLA is concomitant medication may need to be adjusted. On the basis of summarized below. the population pharmacokinetic analysis, no initial dosage adjustment is necessary for patients with baseline mild to severe Chemistry renal impairment (CLCr 15 mL/minute) or for patients with Siltuximab is a glycosylated human-mouse chimeric IgG1 k baseline mild to moderate hepatic impairment (Child-Pugh Class mAb that is produced in Chinese hamster ovary cells. The product A and B). Patients with baseline severe hepatic impairment is supplied as 100-and 400-mg single-use vials containing a (Child-Pugh Class C) were not included in clinical trials. sterile, white, preservative-free, lyophilized powder. Within the serum siltuximab exposure range observed following administration of 11 mg/kg i.v. every 3 weeks, no exposure–response relationships between serum CRP and siltux- Nonclinical pharmacology and toxicology imab exposure or between durable tumor and symptomatic Siltuximab binds to soluble human IL6 with high selectivity response rate and siltuximab exposure were identified. Following fi ¼ and af nity (KD 34 pmol/L). Upon binding to IL6, siltuximab siltuximab dosing, 0.2% (1/411) of patients tested positive for inhibits IL6-related signaling pathways in cell culture, including anti-siltuximab antibodies. Further immunogenicity analyses of IL6-mediated proliferation of cell lines, IL6-stimulated produc- the single positive sample revealed a low titer of anti-siltuximab tion of acute phase proteins (serum amyloid A), and the secretion antibodies with nonneutralizing capabilities. of IgM antibodies. Siltuximab binds human and cynomolgus monkey IL6 with similar affinity; hence, toxicology studies were conducted mainly in cynomolgus monkeys. Toxicities observed in Clinical Trial the 6-month repeat-dose studies in cynomolgus monkeys using Design the intravenous route of administration were consistent with the Seventy-nine patients with symptomatic MCD associated with pharmacology of siltuximab. measurable disease who did not have infections with HIV or Findings included a trend for reduction in the size of the splenic HHV-8 were randomly allocated (2:1) to siltuximab with best germinal centers following KLH immunization, lower anti-KLH supportive care (BSC) or to placebo with BSC. Patients with HIV IgM and IgG levels in the T-dependent antigen response assay, and or HHV-8 infections were excluded from the trial because in a lower globulin levels. These effects suggest the potential for nonclinical study, siltuximab did not bind to virally produced IL6. infection secondary to immune modulation. Other findings Patients received siltuximab 11 mg/kg or placebo i.v. every 3 included sporadic episodes of low heart rate and blood pressure, weeks until treatment failure, discontinuation of treatment, with- first-dose infusion reaction in one out of 52 animals, and skin drawal from the study, or until 48 weeks after the last subject erythema with corresponding hyperkeratosis or acanthosis of started study treatment. Patients who met the criteria for treat- minimal severity. Toxicokinetic results indicated that anti-siltux- ment failure were allowed to cross-over from the placebo arm to imab antibodies did not interfere with exposure or study results. the siltuximab arm. Reproductive toxicology studies consisted of a fertility study The primary endpoint was the proportion of patients achieving conducted in mice with an anti-mouse IL6 mAb, an embryofetal a tumor and symptomatic response (CR and PR) which is durable developmental study in cynomolgus monkeys with siltuximab, (that persisted for a minimum of 18 weeks) without treatment and an enhanced pre- and postnatal developmental (ePPND) failure. Treatment failure is defined as: study with a human IL6 mAb. The fertility study did not indicate a. A sustained increase from baseline in disease-related symp- any adverse fertility findings in mice. Administration of siltux- toms grade 2 persisting for at least 3 weeks despite BSC; imab or a human version of the antibody to pregnant monkeys b. Onset of any new disease-related (grade 3 or higher) symptom did not result in maternal or fetal toxicities; however, there were despite BSC; significant decreases in globulin concentration in dams and c. Sustained (at least 3 weeks) deterioration if performance infants. This may be secondary to reduction in the immunoglob- status (PS) by more than 1 point (ECOG PS) despite BSC; ulin level. The parturition, postnatal survival, or the growth and d. Radiologic progression; and development of infants were not affected in the ePPND study. On e. Initiation of any other therapy. the basis of the pharmacology of the drug and findings in animals, children born to a pregnant woman treated with siltuximab A complete response for this combined endpoint was defined may be at increased risk of infection; hence, a pregnancy Category as complete disappearance of all measurable and evaluable dis- C has been assigned to this drug. ease using the revised criteria for malignant lymphoma (12), and resolution of 34 clinicians reported baseline physical signs and Clinical pharmacology symptoms attributed to MCD as defined by the MCD-related A population pharmacokinetic analysis indicated that the overall symptom score (11), which is sustained for at least 18 clearance of siltuximab in patients is 0.23 L/day (51% CV), and weeks. The overall symptom score was calculated with each cycle body weight is the only significant covariate identified for siltux- of therapy as the sum of the investigator-determined severity imab clearance. The mean serum terminal half-life (t1/2) for grades (NCI-Common Terminology Criteria for Adverse Events siltuximab in patients after the first i.v. infusion of 11 mg/kg is v 4.0) of MCD-related signs and symptoms. PR for this combined 21 days (range: 14–30 days). Binding of bioactive IL6 by siltux- endpoint was defined as a 50% decrease in the sum of the imab may normalize CYP450 enzyme activity that was previously product of the diameters of index lesion(s), with at least stable

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disease in all other evaluable disease in the absence of treatment Table 1. Baseline demographics failure, which is sustained for at least 18 weeks. Siltuximab Placebo with BSC with BSC If the primary endpoint achieved a statistically significant dif- (n ¼ 53) (n ¼ 26) ference in the proportion of patients achieving a durable tumor and Mean time from diagnosis (y) 1.8 2.8 symptomatic response, the following secondary endpoints were Median time from diagnosis (y) 0.6 1.1 analyzed in a fixed order at a two-sided 5% level of significance: (i) Pathologic subtypes Plasmacytic (%) 25% 19% tumor response by central review; (ii) median time to treatment Hyaline vascular (%) 34% 31% failure on each arm; (iii) percentage of patients on each arm who Mixed (%) 42% 50% were anemic within 2 weeks before study treatment on each arm Number of Castleman disease who showed an increase in hemoglobin level at week 13 of 1.5 g/dL baseline symptoms or more over baseline; (iv) median time to improvement in the 1–5 58% 27% – MCD symptom scale as reported by patients; (v) median time to 6 10 30% 58% >10 11% 15% improvement in the Functional Assessment of Chronic Illness Physical signs of MCD Therapy Fatigue score (FACIT-F); and (vi) the proportion of patients Splenomegaly 13% 12% on each arm who were corticosteroid free for at least 9 consecutive Hepatomegaly 9% 19% weeks during the blinded treatment period. Edema (any) 28% 62% Ascites 4% 8% Pericardial effusion 0% 8% Demographics Pleural effusion 9% 12% Edema and/or effusion 32% 65% The median age was 48 years. Sixty-six percent of patients were Weight loss 30% 31% male, 48% Asian, 39% white, and 4% black. Thirty-three percent Symptoms of MCD had the hyaline vascular subtype, 23% the plasmacytic subtype, Fatigue 89% 81% and 44% the mixed subtype. Of the 79 patients on the protocol, Malaise 62% 58% 78.5% (62/79) had 4 symptoms of MCD before initiation of Night and day sweats 55% 65% therapy, and 58% had received at least one prior treatment. The Anorexia 42% 23% Pruritis 32% 45% baseline features of the patients entered onto the siltuximab and Dyspnea 32% 42% placebo arms are summarized in Table 1. Tumor pain 23% 27% Fever 17% 15% Efficacy Eighteen patients (34.0%; 95% confidence intervals, 11.1%– Safety 54.8%) on the siltuximab arm had a durable tumor and symp- In the randomized trial, the median duration of treatment was tomatic response (1 CR and 17 PRs) compared with no patients 375 days in the siltuximab arm and 152 days in the placebo arm. on the placebo arm (P ¼ 0.0012; calculated with an exact The median number of completed infusions was more than Cochran–Mantel–Haenszel test adjusted for baseline corticoste- double in the siltuximab group (19 infusions) compared with roid use). There were eight responses in 13 patients with the the placebo group (8 infusions). To control for the disparate plasmacytic subtype, 10 responses in 12 patients with the mixed number of infusions, the per patient incidence of adverse reac- subtype, and no responses in 18 patients with the hyaline vascular tions occurring during the first eight infusions is shown in Table 3. subtype. The median duration of tumor and symptomatic Only adverse reactions that occurred in >3% of patients on the response could not be reliably estimated because only one of the siltuximab arm are presented. The most common adverse reac- 18 responders had lost the response at the time of the data cutoff. tions (>10% compared with placebo) during treatment with The results for each of the secondary endpoints are shown siltuximab were pruritus, increased weight, rash, hyperuricemia, in Table 2. The results of three of the six secondary endpoints were and upper respiratory tract infection. There were no adverse events statistically significant. The percentage of patients on the siltux- leading to death, and the percentage of patients who discontinued imab and placebo arms with a partial tumor response or better because of adverse events was 23% on the siltuximab arm and was 38% and 4%, respectively. With 422 days of follow-up, the 39% on the placebo arm. time to treatment failure was not reached on the siltuximab arm Over 750 patients have been treated with siltuximab. One and was 134 days on the placebo arm. The percentage of patients patient had an anaphylactic reaction. In the randomized trial, who were anemic at baseline with an increase in hemoglobin infusion reactions were seen in 8% of patients on the siltuximab 1.5g/dL at 13 weeks was 61% on the siltuximab arm compared arm (one grade 3 and the rest grade 1 or 2) and in no patients on with 0% on the placebo arm. the placebo arm.

Table 2. Efﬁcacy results for secondary endpoints Endpoint Siltuximab Placebo P Tumor response (CR þ PR) 37.7% 3.8% 0.0022 Median time to treatment failure (median 422 days follow-up) NR 124 days 0.0084 Increase in hemoglobin by 1.5 g/dL at 13 weeks 61% 0% 0.00002 Time to improvement by MCDSS 85 days 262 days >0.05 Time to improvement by FACIT-F 22 days 15 days >0.05 Discontinuation of steroids for 9 consecutive weeks 31% 11% >0.05 Abbreviations: MCDSS, Multicentric Castleman Disease Symptom Scale; NR, not reached.

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Table 3. Per-patient incidence (expressed as a percentage of total entered on arm) of common adverse reactions during initial eight infusions Siltuximab, Siltuximab, Placebo, Placebo, all grades grades 3–4 all grades grades 3–4 (n ¼ 53) (n ¼ 53) (n ¼ 26) (n ¼ 23) Skin disorders Rash 28% 2% 12% 0% Pruritis 28% 0% 8% 0% Skin: increase in pigmentation 4% 0% 0% 0% Eczema 4% 0% 0% 0% Psoriasis 4% 0% 0% 0% Dry skin 4% 0% 0% 0% Lower respiratory tract infections 8% 4% 4% 4% Upper respiratory tract infections 26% 2% 15% 4% Thrombocytopenia 9% 4% 27% 0% Edema 25% 8% 27% 0% Constipation 8% 0% 4% 0% Hypertriglyceridemia 8% 0% 0% 0% Hypercholesterolemia 4% 0% 4% 0% Hyperuricemia 11% 2% 0% 0% Oropharyngeal pain 8% 0% 4% 0% Renal impairment 8% 0% 0% 0% Headache 8% 0% 4% 0% Weight gain 19% 2% 0% 0% Hypotension 4% 2% 0% 0%

The safety of long-term administration of siltuximab was vided challenges in terms of the real-time review of the histopa- addressed in an extension study derived from the initial phase thology as part of eligibility assessment. There were challenges as I dose-finding study in patients with MCD who were benefitting well as for the real-time review of the responses or progression of from chronic therapy and receiving siltuximab 11 mg/kg every 3 to the lymphadenopathy, symptoms and signs following adminis- 6 weeks. At the time of the last analysis, 19 patients had been tration of the siltuximab. This required seven medical monitors enrolled, and the median duration of treatment was 5.1 years with responsibilities around the world. Special measures were (range, 3.4–7.2 years). The most common adverse reactions required for obtaining histopathologic material from countries in (>20%) were upper respiratory tract infection (63%), diarrhea which the export of such samples is tightly regulated. These (32%), pain in extremities (21%), arthralgia (21%), and fatigue measures allowed the entry onto a pivotal trial of 79 patients (21%). No cumulative toxicities or deaths were reported. who were randomized 2:1; siltuximab plus standard of care was compared with placebo plus standard of care. The review was complicated by the composite primary end- Discussion point that was used to capture the effect of siltuximab on the The approval of siltuximab was notable for several reasons: (i) it cardinal features of the disease: the signs and symptoms arising is the first FDA approval of a treatment for MCD and first approval from increased IL6 levels, as well as lymphadenopathy, effusions, of an anti-IL6 antibody; (ii) the treatment targets the pathophys- and enlargement of the spleen and liver. The response of the signs iological mechanism of the disease; (iii) the company succeeded and symptoms of MCD was measured by investigator assessment. in enrolling sufficient numbers of patients in a randomized trial The major finding of the trial was a durable tumor and symp- despite the rarity of the disease; and (iv) the trial met its pre- tomatic response rate of 34% in the siltuximab arm versus 0% in specified primary endpoint as well as three secondary endpoints. the placebo arm. Durable tumor and symptomatic responses were MCD is a disease of lymphadenopathy accompanied by signs seen consistently across all histopathologic subgroups except for and symptoms associated with elevated levels of IL6. One of the the hyaline vascular subgroup. Although the analysis of secondary most interesting aspects of the randomized trial design was the endpoints in this subgroup must be considered exploratory, some composite primary endpoint composed of tumor response by CT of the results suggest that siltuximab may reduce the severity of scan combined with changes in signs and symptoms of the the anemia in MCD in the hyaline vascular subgroup as well. disease. This endpoint was designed to capture all of the major Similarly, the median time to treatment failure in the hyaline defining hallmarks of the disease: lymphadenopathy and clini- vascular subgroup was 206 days on the siltuximab arm and 70 cian-reported signs and symptoms of excessive IL6 exposure. days on the placebo arm. The fact that the disease is defined by dramatic symptomatol- The most common adverse reactions with siltuximab in the ogy as well as equally notable physical findings which arise from randomized trial were pruritis, increased weight, rash, hyperuri- increased levels of IL6, as well as the extreme rarity of the disease, cemia, and upper respiratory tract infection. Although infusion provided challenges for the design of the trial as well as the reactions were reported in 4.8% of patients receiving monother- analysis of the results by the FDA. apy, the median number of completed infusions and the duration The trial was supported by 38 hospitals in the following of treatment in the siltuximab arm was more than double the countries: Canada, United States, Brazil, Finland, Norway, United placebo arm. There were no adverse events leading to death, and Kingdom, France, Spain, the Netherlands, Germany, Belgium, more patients on the placebo arm discontinued treatment due to Hungary, Irael, Egypt, Jordan, Russia, Korea, China, India, Hong adverse events. In addition, patients on the phase 1 extension Kong, Taiwan, Malaysia, Australia, and New Zealand. This pro- study continued siltuximab infusions for a median of 5.1 years.

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This result not only suggests that patients with MCD receiving Analysis and interpretation of data (e.g., statistical analysis, biostatistics, siltuximab are deriving benefit, but also that the toxicity profile is computational analysis): A. Deisseroth, C.-W. Ko, L. Nie, J.F. Zirkelbach, acceptable for this patient population. L. Zhao, N. Mehrotra, A. Farrell, R. Pazdur Writing, review, and/or revision of the manuscript: A. Deisseroth, C.-W. Ko, Infusions of siltuximab are well tolerated and many patients L. Nie, J.F. Zirkelbach, L. Zhao, J. Bullock, N. Mehrotra, P.D. Valle, H. Saber, remain on therapy for years. Siltuximab provides symptomatic B. Gehrke, R. Justice, A. Farrell, R. Pazdur relief to a substantial number of patients with MCD for whom Administrative, technical, or material support (i.e., reporting or organizing there is no other approved therapy. data, constructing databases): A. Farrell, R. Pazdur Other (wrote the first draft of the article from scratch): A. Deisseroth Disclosure of Potential Conflicts of Interest Other (reviewed drafts of sections pertaining to nonclinical pharmacology and toxicology of siltuximab): C. Sheth No potential conflicts of interest were disclosed.

Received September 11, 2014; revised November 14, 2014; accepted Novem- Authors' Contributions ber 15, 2014; published OnlineFirst January 19, 2015. Conception and design: A. Farrell, R. Pazdur Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): L. Zhao

References 1. Castleman B, Towne VW. Case records of the Massachusetts general sequences in multicentric Castleman's disease. Blood 1995;86: hospital; weekly clinicopathological exercises; founded by Richard C. 1276–80. Cabot. N Engl J Med 1954;251:396–400. 8. Frizzera G, Banks PM, Massarelli G, Rossai J. A systemic lymphoprolifera- 2. Dispenzieri A, Armitage JO, Loe MJ, Geyer SM, Allred J, Camoriano JK, et al. tive disorder with morphologic features of Castleman's disease. Patholog- The clinical spectrum of Castleman's disease. Am J of Hematol 2012;87: ical findings in 15 patients. Am J Surg Pathol 1983;7:211–31. 997–1002. 9. Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, 3. van Rhee F, Stone K, Szmania S, Barlogie B, Singh Z. Castleman disease in et al. Humanized anti-interleukin-6 receptor antibody treatment of multi- the 21st century: an update on diagnosis, assessment and therapy. Clin Adv centric Castleman disease. Blood 2005;106:2627–32. Hematol Oncol 2010;8:486–98. 10. Kurzrock R, Voorhees PM, Casper C, Furman RR, Fayad L, Lonial S, 4. Waterston A, Bower M. Fifty years of multicentric Castleman's disease. Acta et al. A phase I, open-label study of siltuximab, an anti-IL-6 mono- Oncol 2004;43:698–704. clonal antibody, in patients with B-cell non–Hodgkin lymphoma, 5. Herrada J, Cabanillas F, Rice L, Manning J, Pugh W. The clinical behavior of multiple myeloma, or Castleman disease. Clin Cancer Res 2013;19: localized and multicentric Castleman disease. Ann Intern Med 1998;128: 3659–70. 657–62. 11. van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fossa A, et al. Siltuximab 6. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. for multicentric Castleman's disease: a randomised, double-blind, place- Identification of herpesvirus-like DNA sequences in AIDS-associated Kapo- bo-controlled trial. Lancet Oncol 2014;15:966–74. si's sarcoma. Science 1994;266:1865–9. 12. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, 7. Soulier J, Groller L, Oksenhendler E, Cacoub P, Cazals-Hatem D, et al. Revised response criteria for malignant lymphoma. J Clin Oncol Bibinet P, et al. Kaposi's sarcoma-associated herpesvirus-like DNA 2007;25:579–86.

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FDA Approval: Siltuximab for the Treatment of Patients with Multicentric Castleman Disease

Albert Deisseroth, Chia-Wen Ko, Lei Nie, et al.

Clin Cancer Res Published OnlineFirst January 19, 2015.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-14-1678

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