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. Ó2015 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 Ó2015 American Association for Cancer Research. test the efficacy and safety of siltuximab in MCD (11). The www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst January 19, 2015; DOI: 10.1158/1078-0432.CCR-14-1678 Deisseroth et al. 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-