Curr Oncol Rep (2015) 17:29 DOI 10.1007/s11912-015-0453-1

EVOLVING THERAPIES (R BUKOWSKI, SECTION EDITOR)

Clinical Development of Siltuximab Christine C. Davis 1 & Katherine S. Shah 1 & Mary Jo Lechowicz 2,3

# Springer Science+Business Media New York 2015

Abstract Siltuximab is a chimeric monoclonal antibody targeting interleukin-6 (IL-6), which in the fall of 2014 became the first FDA-approved treatment of the rare disease idiopathic multicentric Castleman’s disease (MCD). MCD is a non-clonal lymphoproliferative disorder in which common symptoms include fever, night sweats, weight loss, and fatigue. Symptoms are driven by an overall hypercytokinemia, predominantly IL-6. While under clinical development, siltuximab was studied in several other disease states including multiple myeloma, non-Hodgkin lymphomas, and several solid tumors in which it did not demonstrate significant benefit. The efficacy of siltuximab in MCD is mainly confined to systemic symptomatic response and quality of life benefits with minimal complete responses and approximately 30 % partial responses, by radiographic criteria. Siltuximab treatment therefore is important in the overall treatment of this rare disease state. This review focuses on the clinical development and pharmaceutical approval of siltuximab.

This article is part of the Topical Collection on Evolving Therapies * Mary Jo Lechowicz [email protected] Christine C. Davis [email protected] Katherine S. Shah [email protected] 1

Department of Pharmaceutical Services, Emory Healthcare, Atlanta, GA, USA

2

Department of Hematology and Medical Oncology Emory University, Atlanta, GA, USA

3

Emory University Healthcare and Winship Cancer Institute of Emory University, 1365 C Clifton Rd. Rm 2054, Atlanta, GA 30322, USA

Keywords Siltuximab . Multicentric Castleman’s disease . Monoclonal antibody . Interleukin-6 . Myeloma

Introduction In June 2014, the Food and Drug Administration (FDA) approved the first agent, siltuximab (Sylvant), for multicentric Castleman’s disease (MCD) in patients who are not infected with either human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8). Previously known as CNTO 328, siltuximab is a chimeric, humanmurine, immunoglobulin (Ig) Gκ monoclonal antibody that binds human interleukin-6 (IL-6). IL-6 is multifunctional T cell-derived B cell differentiation factor with roles including the regulation of the immune response, inflammation, hepatic acute phase reactions, and hematopoiesis [1]. IL-6 signaling occurs through two possible pathways (Fig. 1) [2]. In the classic pathway, IL-6 binds to the plasma membrane-bound IL-6 receptor, activating signal transduction by gp130 which turns on the pathways of JAK1/JAK2-STAT3 and MAPK [2]. Alternatively, the trans-activating pathway consists of IL-6 binding to the soluble IL-6 receptor forming a complex, which binds to membrane-bound gp130 with similar results [2]. The trans-activating pathway activates a broader range of cell types as gp130 is expressed ubiquitously compared to the classic pathways where membrane-bound IL-6 receptor is exclusively found in lymphoid cells [2]. Siltuximab prevents IL-6 from binding to both soluble and membrane bound IL-6 receptors with high affinity and specificity and results in deactivation of IL-6 and an overall clinical response in patients with idiopathic MCD (iMCD) [3].

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Fig. 1 Siltuximab mechanism of action. IL-6 Interleukin-6, JAK Janus kinase, STAT signal transducers and activators of transcription, MAPK mitogenactivated protein kinase

Siltuximab in Castleman’s Disease Castleman’s disease (CD) is a rare lymph node hyperplasia characterized by germinal-center formation and marked capillary proliferation with unknown pathogenesis [4]. Histological subtypes include hyaline-vascular (HV), plasma cell (PC), and occasionally a mixed hyaline-vascular plasma cell subtype (HVPC) [5, 6]. Further review of CD can be found in the 2014 expert review by Liu [7]. CD presents as two major subtypes, either unicentric or multicentric. Unicentric Castleman’s disease (UCD) is a localized disease, commonly in a more central lymph node. Alternatively, a disseminated lymphadenopathy was first described in 1978 and designated multicentric Castleman’s disease (MCD) [8]. MCD is further sub-classified by association with or without HHV-8, also named Kaposi’s sarcoma-associated herpesvirus, and HIV [9]. MCD occurs in a significant subset of patients with HHV-8 positive status. Patients negative for both viruses fall into the category of MCD-not otherwise specified (NOS), also termed idiopathic MCD (iMCD), which is a diagnosis of exclusion [9]. While the overall pathogenesis of all CD is still unknown, the affected lymph nodes in CD have been found to produce IL-6 [10]. Overproduction of the cytokine IL-6 in mice resulted in anemia, transient granulocytosis, hypoalbuminemia, and polyclonal hypergammaglobulinemia, with marked splenomegaly and peripheral lymphadenopathy [11]. The strong association of IL-6 overproduction and MCD is now well known with evidence of serum levels of IL-6 correlating with the clinical features of MCD [11]. In HHV-8-associated MCD,

the HHV-8 genome produces a homologue to IL-6, viral IL-6 (vIL-6) which is approximately 25 % identical to human IL-6 which has shown proliferative activity on human cells [12]. Similar to the experiments with human IL-6, vIL-6 induces a clinical condition reminiscent of MCD [13]. The clinical presentation varies greatly with the subtypes of CD. UCD often remains either asymptomatic or with nonspecific lymphadenopathy and may only be detected incidentally with imaging for an unrelated reason. UCD is most common in the third or fourth decade of life [14]. The more aggressive MCD is more common in the sixth decade of life, or younger in the HIV(+) population [15]. MCD presents with fever, night sweats, weight loss, malaise, weakness, fatigue, widespread systemic lymphadenopathy, and multi-organ involvement suggestive of a chronic inflammatory syndrome [5, 16]. A recent systematic literature review in iMCD described similar clinical features as well [17••]. The natural history of MCD can range from HIV(+) patients experiencing fatal progression, an indolent progressive course with persistent moderate symptoms, or a more episodic disease with frequent exacerbations and spontaneous remissions [18]. In general, MCD symptoms can wax and wane however if left untreated, it is often fatal as a result of complications including development of lymphoma, organ failure, or infections [5, 16]. The most common causes of death in the iMCD population include septic shock, multi-organ failure, including renal and cardiac, pulmonary complications, and malignancy [17••]. Surgical resection, unlike in UCD, has no role in MCD compared to other modes of treatment [14]. In MCD, there

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is no known cure, and treatment has historically been mainly supportive. The CD treatment literature consists mostly of case series. Until 2014, there were no FDA-approved treatment options for CD and in general, no consensus guidelines on definitions of responses or treatment recommendations [18]. In MCD patients with HIV(+) disease, Highly Active Antiretroviral Therapy (HAART) is recommended to reduce the risk the transformation to non-Hodgkin lymphoma (NHL) or development of Kaposi’s sarcoma, although it is unclear whether HAART has any impact on relative risk of developing MCD [19]. Use of antiviral therapy such as ganciclovir or valganciclovir has evidence for use in HHV-8 positive MCD [20]. Other treatments available in the US, which have evidence of efficacy, include corticosteroids, anti-CD20 monoclonal antibodies, chemotherapy regimens similar to those used in lymphoma, immunomodulatory agents, and bone marrow transplantation [21–24]. Overall, these responses are incomplete and not indefinite, which highlights the need for novel therapies [18].

Preclinical Preclinical development of an IL-6 monoclonal antibody originated in studies of IL-6 proliferation of myeloma cells in vivo and increased serum IL-6 levels in patients with terminally ill plasma cell leukemia [25]. A major role of IL-6 in multiple myeloma (MM) has been suggested due to observation of serum IL-6 elevation in patients, especially with late-stage disease [26]. Initially, murine monoclonal antibodies IL-6 (BE-4 and BE-8) were prepared by immunizing mice with recombinant IL-6 followed by purification and analysis. In vitro, the anti-IL-6 monoclonal antibodies inhibited proliferation of MM cells, which were subsequently reinduced by an excess of IL-6 [25]. Subsequently, human antibodies to the BE-8 or the BE-4 monoclonal antibody were identified in HIV-1(+) patients, and the production of IL-6 levels of >18 μg/day are not effectively antagonized by BE-8 [27]. Due to the short half-life of BE-4 of 3–4 days, multiple doses would be required for repression of delayed IL-6 production. It was determined that murine monoclonal antibodies would likely be neutralized by the human anti-mouse response with approximately 2 weeks of treatment [27]. Alternatively, a chimeric human-mouse IL-6 antibody was developed for a phase 1 dose escalation study in advanced MM. This antibody contains the variable antigen-binding region of the murine anti-IL-6 monocolonal antibody and the constant region of the human immunoglobulin G1k [26]. While this antibody did not show evidence of efficacy in the MM population, it did show low toxicity, low immunogenicity, and a long half-life [26]. Based on the report of response of the murine IL-6 antibody in a plasma cell leukemia patient, similar treatment was subsequently used in a case report of

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treating MCD [28]. A humanized chimeric IL-6 receptor monoclonal antibody, tocilizumab, was then examined in a case series of seven patients with PC or mixed MCD. The combination of these reports indicated clinical activity by blocking either IL-6 or the IL-6 receptor in MCD [29]. Further studies with the antibody targeting the IL-6 receptor signaling showed response in MCD patients with PC histology led to the approval for use of tocilizumab for MCD in Japan in 2005; however, it remains approved only for rheumatoid arthritis in the USA [29, 30]. A report from a 5-year analysis in 30 patients who remained on tocilizumab demonstrated clinical improvements were sustained, as well as an overall steroidsparing effect [31]. With growing evidence of IL-6 as a driving factor of pathogenesis in idiopathic MCD, phase 1 studies for clinical development of siltuximab included a subset of these patients.

Clinical Efficacy: Phase I An open-label, dose-finding, phase I study included patients with NHL, MM, or CD. Thirty-seven patients with symptomatic, unresectable UCD or MCD, all HIV and HHV-8 negative except for one HHV-8 positive patient received siltuximab at 3, 6, 9, or 12 mg/kg weekly every 2 or 3 weeks. This was the largest data set of MCD patients studied prospectively at that time [32]. While there are no validated methods recognized for measuring response in CD, clinical benefit response (CBR) for CD was defined as improvement from baseline in one or more symptoms and no worsening in the remaining of the following: ≥2 g/dL increase in hemoglobin without transfusions; ≥1 grade decrease in fatigue; ≥1 grade decrease in anorexia; ≥2° Celsius (C) decrease in fever or return to 37° C or improvement in night sweats; ≥5 % increase in weight; or ≥25 % decrease bidimensionally in the size of the largest lymph node [32]. Radiographic response was measured previously defined using Cheson criteria modified to include measurable cutaneous lesions [33]. Interim analysis of 23 CD patients demonstrated a median age of 49 years; histologic variants were HV (44 %), PC (52 %), and mixed cellularity (4 %), with median disease duration of 5 m and 12 patients (32 %) newly diagnosed [32]. In the results, CBR was seen in 18 patients (78%; 95 % CI 56 to 93 %) in all doses. All 11 patients in the 12 mg/kg cohort achieved CBR demonstrating dose-related response. Radiographically, in the 12-mg/kg cohort, eight patients (73 %) achieved an objective response. Overall, outcomes achieved included both symptom control and normalization of laboratory measures [32]. Final results of the total 37 evaluable CD patients demonstrated the following: 1 patient (3 %) had a CR, 11 patients (31 %) had a PR, 3 patients (8 %) had unconfirmed PR, 20 patients (55 %) had stable disease (SD), and 3 patients (8 %)

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had progressive disease (PD). After a median follow-up of almost 30 months, time to progression (TTP) was not reached for responding patients with CD. The majority of CD patients experienced improvements in fatigue (78 %), size of the largest lymph node (65 %), weight (60 %), and fever/night sweats (51 %) with siltuximab treatment. Median overall survival (OS) was not reached with a follow-up of approximately 2.5 years with only three deaths. This trial supported a safe and efficacious dose of 12 mg/kg given over 1 h every 3 weeks [34••]. In this same study, 17 patients were included with MM with median disease duration of 3.0 (range 1.4–9.5) years; however, only 13 patients were evaluable [34••]. Responses included two patients (15 %) obtaining a confirmed CR with response duration lasting 11.7 and 16.7 months. Eight patients (61 %) experienced SD (range 0.5–18.0 months), and three patients (23 %) had PD. With a small population of MM patients, it is difficult to determine the clinical response of siltuximab. In addition to MM, elevation in IL-6 levels is predominant in several other cancer types, including prostate cancer and renal cell carcinoma, and correlates with poor prognosis [35, 36]. Due to this common clinical finding, phase I studies have been designed with siltuximab including renal cancer, hormone-refractory prostate cancer, myelodysplastic syndrome, and additional solid tumors. Due to a lack of a signal for activity, clinical development has been discontinued in most other cancers.

Clinical Efficacy: Phase II Based on the promising responses seen in phase I investigations, a randomized, double-blind, placebo-controlled phase 2 study was initiated in MCD. The study included 79 patients with HIV and HHV-8 negative MCD who were either newly diagnosed or pre-treated on stable, low-dose corticosteroids defined as 1 mg/kg prednisone or lower for at least 4 weeks. Patients were randomized in a 2:1 ratio where 53 patients were treated with siltuximab 11 mg/kg IV every 3 weeks and best supportive care (BSC), and 26 patients received placebo and BSC and were stratified by baseline corticosteroid use [37••]. Because of a 9 % difference in the absorptivity constant used for calculating the dose of study drug administered in the published phase I study, 11 mg/kg dose was administered as this was the true maximum dose used [38]. The patient population was predominately Asian or Caucasian male patients with a median age of 48 years from 38 hospitals in 19 countries worldwide. Prior systemic therapy used in 46 patients (58 %) and 22 patients (28 %) were on corticosteroids. All histological subtypes were included. Disease-related symptom score was calculated by adding together the NCI-CTCAE, v4.0 grade number of 34 symptoms

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in categories of general MCD-related symptoms, autoimmune phenomena, fluid retention, neuropathy, and skin disorders. Patients had a disease-related overall symptom median score of 6 (range 2–31) in the siltuximab group or 10 (range 1–30) in the placebo group which was not statistically significantly different [37••]. Median duration of treatment was 375 days (range 1–1031) with siltuximab and 152 days (range 55–666) with placebo with 31 patients (59 %) still receiving siltuximab and 6 (23 %) continuing to receive placebo at the time of analysis. The primary end point of durable tumor and symptomatic response by independent review in the intent-to-treat population occurred in 18 patients (34 %) in the siltuximab group and none of the patients in the placebo group (p=0.0012). A large majority of the tumor and symptomatic responses were considered partial responses (PR) in 17 patients (32 %) and lasted a median duration of 383 days. Tumor response by independent review alone was seen in 20 of siltuximab patients (38 %) and 1 (4 %) placebo patient (p=0.0022). This study led to the currently approved dose of 11 mg/kg over 1 h every 3 weeks until disease progression or intolerable toxicity. A steroid-sparing effect was seen with the use of siltuximab with four patients (31 %) on siltuximab able to discontinue use and one (11 %) receiving placebo (p = 0.3602). In the siltuximab group, 19 out of 21 patients with baseline anemia had an increase of 1.5 g/dL in hemoglobin compared with no increases observed in patients receiving placebo. Overall, abnormal laboratory values return to normal quickly; however, resolution of lymphadenopathy occurred over a median time of 155 days. Overall survival was shown to have no difference between the two groups. However, this was only evaluated at 1 year, and 13 out of 26 patients who started out in the placebo group crossed over to receive siltuximab, which may have confounded the survival analysis [37••]. A phase 2 extension study of 19 patients who responded in the phase 1 study is ongoing to determine long-term effects of siltuximab. In an interim analysis, MCD patients who were HIV and HHV-8 negative were mostly males with median age 44 years and 7 patients (37 %) were newly diagnosed. At initiation of the extension study, by independent radiographic review, 1 patient had CR, 11 had PR, and 7 had SD. All 19 patients demonstrated SD or better by investigator assessment, including 8 patients on an extended interval of every 6 weeks after established prolonged response. Upon analysis, patients had a median duration of 5 years of treatment, and all 19 patients were alive and continuing to receive siltuximab [39]. To date, three phase 2 studies of siltuximab in MM patients have been completed without showing beneficial outcomes [40, 41•, 42•]. The first phase 2 study in relapsed/refractory MM showed that in combination with dexamethasone, siltuximab 6 mg/kg on days 1 and 15 of a 28-day cycle showed suppression of serum C-reactive protein (CRP) with only PR in eight patients (17 %) and minimal response rate in

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three patients (6 %) and no patients responding with siltuximab alone [40]. In a subsequent phase 2 study, transplant-ineligible patients with newly diagnosed MM were treated with bortezomib, melphalan, and prednisone (VMP) alone or VMP with siltuximab 11 mg/kg every 3 weeks [41•]. Overall response (CR+PR) with VMP alone was seen in 39 patients (80 %; range 66–90) and 43 patients (88 %; 75–95) with VMP plus siltuximab [41•]. Overall, adding siltuximab to VMP did not improve CR, PFS, or OS but improved very good partial response in MM [41•]. Most recently, siltuximab was added to bortezomib in a placebo-controlled trial in relapsed/refractory MM patients [42•]. Outcomes were not statistically different between the two groups with a median PFS with bortezomib and siltuximab of 8.0 months and bortezomib alone 7.6 months, and overall response rate was 72 patients (55 %) vs. 60 patients (47 %; p=0.213), respectively [42•]. Data from select studies are summarized in Table 1.

Toxicity No dose-related toxicities were found in phase 1 dose-finding studies, which included patients with NHL or MM in addition to MCD. All-grade adverse events considered possibly related to siltuximab were thrombocytopenia in 17 patients (25 %), neutropenia in 13 patients (19 %), hypertriglyceridemia in 13 patients (19 %), leukopenia 12 patients (18 %), hypercholesterolemia in 10 patients (15 %), and anemia in 7 patients (10 %). The only grades 3 to 4 toxicities regardless of relationship to siltuximab included neutropenia in 14 patients (21 %) and grade 3 hypertension in 6 patients (9 %). Only two patients experienced a dose delay or discontinuation, and this was due to either neutropenia or thrombocytopenia. Infections regardless of relationship to siltuximab occurred in 44 patients (66 %), with the most common including upper respiratory infection (URI) in 17 patients (39 %), urinary tract infection in 7 patients (16 %), sinusitis in 5 patients (12 %), cellulitis in 4 patients (9 %), nasopharyngitis in 3 patients (7 %), and ear infection 3 patients (6 %); among these, 1 case of URI and 4 cases of cellulitis occurred at grade ≥3. No deaths were considered related to siltuximab. Prolonged exposure showed decreased grade ≥3 adverse events each year. Out of 31 patients, none developed antibodies to siltuximab [34••]. Nearly all patients had at least one adverse event in the phase 2 study, with approximately 50 % of the adverse events being ≥grade 3 in both the siltuximab and placebo groups. Grade 3 fatigue and night sweats occurred in 5 patients (9 %) and 4 patients (8 %), respectively, in the siltuximab arm. While dose reductions were not permitted, at least one dose was delayed in 21 patients (40 %) receiving siltuximab due to neutropenia, defined as absolute neutrophil count ≤1.0×109/L, as the most common reason. All grade adverse

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events, which occurred commonly in the siltuximab arm (≥25 % of patients), included pruritis in 22 patients (42 %), URI in 19 patients (36 %), fatigue in 18 patients (34 %), maculopapular rash in 18 patients (34 %), peripheral edema in 17 patients (32 %), and malaise in 15 patients (28 %). This side effect profile differs from that seen in the phase 1 investigation. In the phase 2 study, while neutropenia and thrombocytopenia occurred in 7 patients (13 %) and 8 patients (15 %) of siltuximab patients, respectively, no lipid abnormalities were reported. Of patients receiving siltuximab, 3 patients (6 %) had a serious adverse event reasonably related to siltuximab, including lower respiratory tract infection, anaphylactic reaction, or sepsis. No deaths were determined related to the study drug, and only one patient developed antibodies neutralizing siltuximab [37••]. Long-term safety has been reported from an interim analysis of the phase 2 extension trial. Overall, siltuximab is well tolerated with a low rate of serious adverse events and no evidence of treatment discontinuations or cumulative toxicity. Adverse events were similar or lower in the longer-term subgroups (duration of therapy of 2–4 years or more than 4 years) compared with the 0–2 years. The most common all grade adverse events included gastrointestinal in 6 patients (32 %); infections in 5 patients (26 %) with grade ≥3 hypertension reported in 3 patients (16 %); grade ≥3 nausea, cellulitis, and fatigue in 2 patients (11 %) each [39]. Notably, no patients have experienced infusion-related reactions with this monoclonal antibody in this study [39]. Safety data from studies with siltuximab is also available from the non-MCD population. See Table 2 for the summary of the toxicities of siltuximab in select studies.

Pharmacokinetics While under clinical development, a three-part pharmacokinetic (PK) and pharmacodynamic (PD) study of multiple doses of siltuximab in metastatic renal cell carcinoma (RCC) patients was conducted [43]. Patient characteristics included a median age range of 57–62 years, 9 male patients (82 %), with median body weight range of 77–86 kg. The recommended PK model of siltuximab IV infusion was a two-compartment model with first-order elimination. The first part of the study consisted of administration of siltuximab infused intravenously over 2 h in a phase I, open-label dose-escalation design. Based on a non-compartmental analysis, siltuximab was found to have a dose-related exposure, did not reach steady state after four doses, and had a volume of distribution and clearance independent of dose. The half-life was found to be approximately 17 days [43]. In the phase 1 study of siltuximab in MCD, mean terminal-phase half-life following the first dose range 18 to 21 days, the mean clearance range 4.03 to 4.59 mL/day/kg and no evidence of time-dependent changes

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Table 1

Selected efficacy data

Cancer type, n

Treatment

Response endpoint

Results

MM, [40] n=53 NHL, MM, CD, [34••] n=67

Siltuximab 6 mg/kg and dexamethasone

ORR

8 % (95 % CI 2–21)

Dose escalation

CBR

NHL: 14 % had PR, 50 % with SD MM: 15 % CR, 62 % SD CD: 3 % had CR, 39 % had PR, 56 % had SD

Siltuximab 11 mg/kg IV q3 weeks vs. placebo

Durable tumor and symptomatic response CR rate

Siltuximab 34 vs 0 % placebo, p=0.0012

PFS

Median PFS 8.0 months in S+B vs. 7.6 months in placebo+B, p=0.345

CD, [37••] n=79 MM, [41•] n=98

Siltuximab 11 mg/kg q3 weeks+bortezomibmelphalan-prednisone (VMP) vs. placebo with VMP Siltuximab 6 mg/kg IV q2 weeks+bortezomib vs. placebo+bortezomib

MM, [42•] n=286

Table 2

S-VMP 27 vs. 22 % VMP (did not meet prespecified increase of at least 10 %)

Selected toxicity data

Cancer type, n

Treatment

Toxicities

MM [40], n=53

Siltuximab 6 mg/kg+dexamethasone

Neutropenia (29 %), anemia (35 %), Neutropenia (18 %), thrombocytopenia (49 %) Fatigue thrombocytopenia (26 %), (43 %), abnormal hepatic function infections (18 %), fatigue (31 %), diarrhea (29 %), peripheral (8 %), abnormal hepatic edema (29 %), dyspnea (27 %), function (8 %) dizziness (25 %), nausea (22 %), insomnia (22 %), constipation (20 %), weight increase (20 %), myalgia (16 %) enzyme abnormality (16 %), hypertriglyceridemia (14 %) Thrombocytopenia (25 %), Neutropenia (16 %), neutropenia (19 %), thrombocytopenia (4 %), hypertriglyceridemia (19 %), sepsis (1.5 %), and leukopenia (18 %), hyperlipidemia (1.5 %) hypercholesterolemia (15 %), anemia (10 %) Pruritis (42 %), URI (36 %), fatigue Fatigue (9 %), night sweats (34 %), rash (34 %), peripheral (8 %), localized edema (4 %), edema (32 %), malaise (28 %), weight gain (4 %), dyspnea (25 %), peripheral hyperhidrosis (4 %), neuropathy (25 %), diarrhea thrombocytopenia (4 %), (23 %), localized edema (21 %), hyperuricemia (4 %), weight gain (21 %) neutropenia (4 %), hypertension (4 %), hyperkalemia (4 %) Not reported Neutropenia (62 %), thrombocytopenia (44 %), infections (23 %), pneumonia (17 %)

NHL, MM, CD [34••], Dose escalation n=67

CD [37••], n=53

Siltuximab 11 mg/kg IV q3 weeks

MM [41•], n=52

Siltuximab 11 mg/kg q3 weeks+bortezomibmelphalan-prednisone (VMP) vs. placebo with VMP Siltuximab 6 mg/kg IV q2 weeks+bortezomib

MM [42•], n=142

Neutropenia (59 %), thrombocytopenia (57 %), neuropathy (49 %), diarrhea (36 %), anemia (31 %), fatigue (27 %), nausea (27 %), leukopenia (25 %), decreased appetite (23 %), neuralgia (22 %)

Grade 3/4 toxicities

Any AE: 27 %

Discontinuation due to AEs 23 %

12 %

2%

0 % in maintenance phase of siltuximab 24 %

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in pharmacokinetics [34••]. Overall, the PK parameters resulted were similar to the values reported in the RCC trial. Mean terminal half-life as described by the drug manufacturer ranges from 14.2 to 29.7 days with the approved 11 mg/kg dose. At steady state, the mean Cmax for siltuximab is 332 μg/mL and the predose trough is 84 μg/mL when dosed every 3 weeks. Steady state is achieved by the sixth infusion. Volume of distribution in a 70-kg male is 4.5 L based on population pharmacokinetics. Body weight is the only covariate for siltuximab clearance, making weight-based dosing appropriate, and based on population PK, clearance is 0.23 L/day. In patients with renal impairment (creatinine clearance ≥15 ml/min) and mild or moderate hepatic impairment (Child-Pugh A or B), clearance of siltuximab is unchanged. There is not sufficient data in patients with end-stage renal disease or severe hepatic impairment [44].

Pharmacodynamics While many medications are dosed by determining maximum-tolerated dose based on dose-limiting toxicity, dosing of monoclonal antibodies requires more of an understanding and consideration of the pharmacodynamic effects, as these agents are generally well-tolerated treatments [43]. Clinical investigations have shown that serum IL-6 is the primary inducer of hepatocyte synthesis of CRP [45]. As a result, CRP levels are directly correlated with IL-6 levels and can be used as a surrogate marker for IL-6 activity, indicating disease severity and progression. This is helpful as presence of siltuximab interferes with the IL-6 assay [46]. In part one of the pharmacokinetic/pharmacodynamic study in RCC patients, serum CRP was not suppressed by siltuximab at a dose of 1 mg/kg, whereas dosing at 3 or 6 mg/kg showed complete CRP suppression to the lower limit of quantification when a patient’s siltuximab serum concentration was ≥10 μg/mL at baseline [43]. Specifically in CD patients treated with 12 mg/kg every 3 weeks, a 25 % greater CRP decrease (77 % median reduction) was demonstrated over the 9 mg/kg every 3 weeks (52 % median reduction) cohort after 2 cycles [34••]. The phase 2 study also demonstrated a correlation with CRP and IL-6 levels with an r2 =0.7. Median CRP decreased rapidly with siltuximab 11 mg/kg; however, CRP decrease was not associated with durable tumor and symptomatic response [37••]. Cardiac safety and drug interactions are additional pharmacodynamic effects where siltuximab has been examined. A study of patients with baseline QTc of ≤500 ms and no underlying heart disease showed no evidence of QT prolongation with up to four doses of siltuximab 15 mg/kg [47]. While in vitro or in vivo drug-drug interactions studies have not been

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conducted with siltuximab, cytokines such as IL-6 are known to downregulate cytochrome P450s in the liver. Inhibition of IL-6 would therefore upregulate many drug-metabolizing enzymes for weeks after siltuximab dosing, resulting in decreased exposure to other P450 substrates medications (i.e., oral contraceptives, atorvastatin, etc.). Special attention of the pharmacodynamic effects of drug metabolism should be analyzed when siltuximab is co-administered with drugs with a narrow therapeutic index such as warfarin [44]. Additional pharmacodynamic effects include gain in muscle mass of 0.6 kg (median 0.9 kg, range −5.5 to 4.4 kg) with siltuximab 11 mg/kg IV every 3 weeks dosing for a median duration of approximately 700 days demonstrating an overall reduction in muscle wasting [48]. A study examining quality of life including symptoms, functioning, and well-being using the general patient reported outcome questionnaire (Short Form-36) in patients with MCD receiving either siltuximab or placebo was completed. A return to health norms (a validated health-related quality-of-life outcome) in vitality, roleemotional, and social functioning were statistically superior in patients treated with siltuximab over those on placebo [49•].

Conclusions Siltuximab has overall shown efficacy in the symptomatic management of iMCD by blocking the manifestations of increased IL-6 levels. This is of great significance as it expands treatment options in this subset of patients where no other treatments have been studied in randomized controlled trials. Additionally, there are ongoing clinical trials investigating siltuximab in high-risk smoldering MM as well as in MCD. Siltuximab requires infusions every 3 weeks until disease relapse. Even considering cost and the inconvenience of frequent treatments, evidence has demonstrated overall improvement in symptom control and an increase in patients’ quality of life. Additional research is needed to investigate novel treatment combinations and other therapeutic approaches for patients with MCD.

Compliance with Ethics Guidelines

Conflict of Interest Christine C. Davis declares that she has no conflict of interest. Katherine S. Shah declares that she has no conflict of interest. Mary Jo Lechowicz has served as a consultant for Janssen Pharmaceuticals. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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